birth control research paper introduction

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This algorithm has not been validated for clinical use. IUD indicates intrauterine device; PATH, Pregnancy Attitudes, Timing, and How important is pregnancy prevention.

This algorithm has not been validated for clinical use. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); MEC, Medical Eligibility Criteria for Contraceptive Use.

• Selection, Effectiveness, and Adverse Effects of Contraception—Reply JAMA Comment & Response April 19, 2022 Stephanie Teal, MD, MPH; Alison Edelman, MD, MPH
• Selection, Effectiveness, and Adverse Effects of Contraception JAMA Comment & Response April 19, 2022 Ekaterina Skaritanov, BS; Gianna Wilkie, MD; Lara C. Kovell, MD
• Contraception in Women With Cardiovascular Disease JAMA JAMA Insights August 9, 2022 This JAMA Insights in Women’s Health series summarizes the prevalence of cardiovascular disease among women of childbearing age, the most effective forms of contraception based on the patient’s medical condition and preference, and the risks and adverse effects associated with contraindicated forms of contraception. Kathryn J. Lindley, MD; Stephanie B. Teal, MD, MPH
• Patient Information: Long-Acting Reversible Contraception JAMA JAMA Patient Page October 4, 2022 This JAMA Patient Page describes types of long-acting reversible contraception, how they are placed and removed, and their potential side effects. Elisabeth L. Stark, MD; Aileen M. Gariepy, MD, MPH, MHS; Moeun Son, MD, MSCI
• Patient Information: Medication Abortion JAMA JAMA Patient Page November 1, 2022 This JAMA Patient Page describes medication abortion and its risks and effectiveness. Rebecca H. Cohen, MD, MPH; Stephanie B. Teal, MD, MPH

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Teal S , Edelman A. Contraception Selection, Effectiveness, and Adverse Effects : A Review . JAMA. 2021;326(24):2507–2518. doi:10.1001/jama.2021.21392

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Contraception Selection, Effectiveness, and Adverse Effects : A Review

• 1 Department of OB/GYN, University Hospitals Medical Center and Case Western Reserve University, Cleveland, Ohio
• 2 Department of OB/GYN, Oregon Health & Science University, Portland
• Comment & Response Selection, Effectiveness, and Adverse Effects of Contraception—Reply Stephanie Teal, MD, MPH; Alison Edelman, MD, MPH JAMA
• Comment & Response Selection, Effectiveness, and Adverse Effects of Contraception Ekaterina Skaritanov, BS; Gianna Wilkie, MD; Lara C. Kovell, MD JAMA
• JAMA Insights Contraception in Women With Cardiovascular Disease Kathryn J. Lindley, MD; Stephanie B. Teal, MD, MPH JAMA
• JAMA Patient Page Patient Information: Long-Acting Reversible Contraception Elisabeth L. Stark, MD; Aileen M. Gariepy, MD, MPH, MHS; Moeun Son, MD, MSCI JAMA
• JAMA Patient Page Patient Information: Medication Abortion Rebecca H. Cohen, MD, MPH; Stephanie B. Teal, MD, MPH JAMA

Importance   Many women spend a substantial proportion of their lives preventing or planning for pregnancy, and approximately 87% of US women use contraception during their lifetime.

Observations   Contraceptive effectiveness is determined by a combination of drug or device efficacy, individual fecundability, coital frequency, and user adherence and continuation. In the US, oral contraceptive pills are the most commonly used reversible method of contraception and comprise 21.9% of all contraception in current use. Pregnancy rates of women using oral contraceptives are 4% to 7% per year. Use of long-acting methods, such as intrauterine devices and subdermal implants, has increased substantially, from 6% of all contraceptive users in 2008 to 17.8% in 2016; these methods have failure rates of less than 1% per year. Estrogen-containing methods, such as combined oral contraceptive pills, increase the risk of venous thrombosis from 2 to 10 venous thrombotic events per 10 000 women-years to 7 to 10 venous thrombotic events per 10 000 women-years, whereas progestin-only and nonhormonal methods, such as implants and condoms, are associated with rare serious risks. Hormonal contraceptives can improve medical conditions associated with hormonal changes related to the menstrual cycle, such as acne, endometriosis, and premenstrual dysphoric disorder. Optimal contraceptive selection requires patient and clinician discussion of the patient’s tolerance for risk of pregnancy, menstrual bleeding changes, other risks, and personal values and preferences.

Conclusions and Relevance   Oral contraceptive pills are the most commonly used reversible contraceptives, intrauterine devices and subdermal implants have the highest effectiveness, and progestin-only and nonhormonal methods have the lowest risks. Optimal contraceptive selection incorporates patient values and preferences.

Contraception is defined as an intervention that reduces the chance of pregnancy after sexual intercourse. According to a report from 2013, an estimated 99% of women who have ever had sexual intercourse used at least 1 contraceptive method in their lifetime. 1 Approximately 88% of sexually active women not seeking pregnancy report using contraception at any given time. 2 All nonbarrier contraceptive methods require a prescription or initiation by a clinician. Therefore, contraception is a common reason women 15 to 50 years of age seek health care. 3 This review summarizes current evidence regarding efficacy, adverse effects, and optimal selection of reversible contraceptives. This review uses the terms women and men when the biological expectation for the individual is ovulation or sperm production, respectively.

A search of OVID Medline All, Embase.com, and Ovid Evidence-Based Medicine Reviews–Cochrane Central Register of Controlled Trials for English-language studies was conducted for articles published between January 1, 2000, and June 28, 2021, to identify randomized clinical trials, systematic reviews, and practice guidelines related to contraception or contraceptives. After excluding duplicates and articles not relevant to this review, 2188 articles were identified as potentially relevant via title or abstract content. Thirty-seven articles, consisting of 13 randomized clinical trials, 22 systematic reviews, and 2 guidelines were included. Evidence-based guidelines that used GRADE and systematic reviews were selected for inclusion over individual studies. Clinical practice guidelines from the Society of Family Planning, the World Health Organization, and the American College of Obstetricians and Gynecologists on selected topic areas were reviewed to identify additional key evidence.

The mean age of first sexual intercourse among females in the US is 17 years. 4 Many women typically use contraceptives for approximately 3 decades. 2 The choice of contraceptive is determined by patient preferences, tolerance for contraceptive failure, and adverse effects. Clinicians should elicit patient preferences, identify possible contraindications to specific contraceptives, and facilitate contraceptive initiation and continuation. Clinicians should also be prepared to address misperceptions ( Box ). Some experts recommend screening for contraceptive need at each visit. Two validated screening options, with toolkits available online, are One Key Question and the PATH questions (Pregnancy Attitudes, Timing, and How important is pregnancy prevention). 5 , 6

Commonly Asked Questions About Contraception

What options are available for male contraception? There are currently no Food and Drug Administration–approved contraceptive options for men except condoms. Current male contraceptive methods under evaluation attempt to suppress sperm count to <1 million/mL and include a testosterone plus progestin topical gel.

Are contraceptives associated with increased rates of cancer? Combined hormonal contraceptives, such as combined oral contraceptive pills, protect against endometrial and ovarian cancer. They are associated with an increased risk of early breast cancer diagnosis in current or recent users (ie, within the past 6 mo). The incidence is 68 cases per 100 000 person-years compared with 55 cases per 100 000 nonuser-years. There are no associations of past contraceptive use with increased rates of cancer and there is no association of past contraceptive use and mortality.

Can teenagers use intrauterine devices (IUDs)? Prior guidance suggested restricted use of IUDs by teenagers, nonmonogamous or unmarried, and nulliparous women, but there is no high-quality evidence to support this recommendation. None of these characteristics are true contraindications.

Should all women use the most effective form of contraception? The choice of contraceptive is determined by patient preferences and tolerance for failure. Patients may value other attributes of a method (such as route of administration or bleeding patterns) more highly than effectiveness, and may prefer to have a slightly higher risk of unplanned pregnancy to avoid other adverse effects.

Is the pill as effective for individuals with obesity? Obesity adversely influences contraceptive steroid levels but determining whether this affects contraceptive effectiveness is difficult. The primary reason for contraceptive failure is suboptimal adherence. The use of any method for individuals no matter their weight will prevent more pregnancies than not using a method.

Why are pills not available over the counter (OTC)? Combined hormonal contraceptives are unlikely to be available OTC in the US due to concerns regarding increased rates of thrombosis. Efforts to bring progestin-only pills OTC are progressing.

Quiz Ref ID Reversible contraceptive methods are typically grouped as hormonal (such as progestin-only pills or estrogen-progestin patches) or nonhormonal (condoms, diaphragms) and long-acting (such as intrauterine devices [IUDs]) or short-acting (such as pills). Reversible contraceptive methods can also be grouped by level of effectiveness for pregnancy prevention. Except for behavioral methods, condoms, and spermicide, contraceptive methods are only available by prescription in the US.

Progestins and estrogens are steroid or lipid hormones. Hormonal contraception contains a progestin with or without an estrogen. Progesterone is the only naturally occurring progestin; most contraceptive progestins, such as levonorgestrel and norethindrone, are synthesized from testosterone. Progestins provide a contraceptive effect by suppressing gonadotropin-releasing hormone from the hypothalamus, which lowers luteinizing hormone from the pituitary, which in turn prevents ovulation. 7 , 8 In addition, progestins have direct negative effects on cervical mucus permeability. Progestins reduce endometrial receptivity and sperm survival and transport to the fallopian tube. 9 - 11 Estrogens enhance contraceptive effectiveness by suppressing gonadotropins and follicle-stimulating hormone, preventing the development of a dominant follicle. However, the most important contribution of estrogens to progestin-based contraceptives is the reduction of irregular bleeding. The estrogen component in most combined hormonal contraceptives is ethinylestradiol.

A variety of progestin-only contraceptive methods exists ( Table 1 ). Their effectiveness varies based on dose, potency, and half-life of the progestin as well as user-dependent factors, such as adherence to the prescription schedule. 12 , 13

Progestin-only pills include norethindrone- and drospirenone-containing formulations, which differ in their ability to suppress ovulation. Norethindrone pills contain 300 µg of norethindrone compared with 1000 µg in a typical combined contraceptive pill. The lower amount of progestin in norethindrone pills results in less consistent ovulation suppression and more potential for breakthrough bleeding. The contraceptive efficacy is maintained by other progestin-mediated effects. Drospirenone-only pills contain slightly more progestin than an estrogen and progestin combined hormonal contraception, which aids in ovulation suppression. In one study in which participants delayed their drospirenone-containing pill intake by 24 hours, mimicking a missed dose, ovulation suppression was maintained with only 1 participant of 127 having evidence of ovulation. 14 The benefits of progestin-only contraceptive pills include ease of initiation and discontinuation, fertility return within 1 cycle, safety profile, and minimal effect on hemostatic parameters. 15

Quiz Ref ID Depot medroxyprogesterone acetate (DMPA) is an injectable progestin available in intramuscular (150 mg) and subcutaneous (104 mg) formulations, which are administered at 12- to 14-week intervals. While DMPA is associated with irregular uterine bleeding, this pattern improves with longer duration of use. A systematic review of DMPA-related bleeding patterns (13 studies with 1610 patients using DMPA) found that 46% of those using DMPA were amenorrheic in the 90 days following the fourth dose. 16 DMPA is the only contraceptive method that can delay return to fertility. The contraceptive effect and cycle irregularity can persist for up to 12 months after the last dose, 17 likely due to persistence in adipose tissue and its effectiveness in suppressing the hypothalamic-pituitary-ovarian (HPO) axis. DMPA may be best suited for those who benefit from amenorrhea (eg, patients with developmental disabilities, bleeding diatheses) but not by those who want to conceive quickly after discontinuation. Typical effectiveness of DMPA and progestin-only contraceptive pills is 4 to 7 pregnancies per 100 women in a year. 12 , 18

Quiz Ref ID Progestin-only long-acting methods, such as the levonorgestrel (LNG) IUD and the subdermal implant, have typical effectiveness rates of less than 1 pregnancy per 100 women per year similar to permanent methods, such as tubal ligation or vasectomy ( Table 2 ). 12 , 18 These methods are also associated with return to fertility within 1 cycle after discontinuation. The LNG IUD maintains efficacy for at least 7 years, with amenorrhea rates of up to 20% at 12 months and 40% at 24 months. 19 However, initiation requires an in-person visit with a clinician trained in IUD placement. The etonogestrel subdermal implant is effective for up to 5 years 20 and is easily placed or removed. Initiation and discontinuation also require in-person visits. The bleeding profile of the implant is less predictable and up to 11% of users remove it in the first year due to irregular bleeding. 21 An analysis of 11 studies (923 participants) from Europe, Asia, South America, and the US found that the bleeding pattern in the first 3 months (such as prolonged, frequent, or irregular episodes) is consistent with future bleeding patterns. 21 However, those with frequent or prolonged bleeding in the first 3 months have a 50% chance of improvement in the subsequent 3 months. 21

Combined hormonal methods that contain both estrogen and progestin include the daily oral pill, monthly vaginal ring, and weekly transdermal patch. With full adherence, effectiveness of these methods is 2 pregnancies per 100 users per year. However, typical effectiveness is 4 to 7 pregnancies per 100 women per year, with variability in effectiveness related to the user’s adherence. 12 , 18 The importance of patient adherence to hormonal contraception was recently demonstrated by a cohort study of approximately 10 000 individuals in the US. Pregnancy rates were 4.55 per 100 participant-years for short-acting methods (pills, patch, ring) compared with 0.27 for long-acting reversible methods (IUD, implant). 13 Women younger than 21 years using short-acting methods had higher pregnancy risk as women 21 or older (adjusted hazard ratio, 1.9 [95% CI, 1.2-2.8]). 13 No risk differences by age were observed for the long-acting reversible methods of IUD or implant. Absolute rates were not reported by age stratum.

Combined hormonal contraceptives prevent pregnancy through the same mechanisms as progestin-only methods. Their greatest advantage over progestin-only methods is their ability to produce a consistent, regular bleeding pattern. In a study that compared bleeding diaries from 5257 women using 9 different methods of contraception (nonhormonal, combined hormonal contraception, and progestin-only), approximately 90% of combined hormonal contraception pill users (n = 1003) over a 90-day standard reference period reported regular scheduled withdrawal bleeds while no one experienced amenorrhea. 22 Occasionally, patients do not have a withdrawal bleed during the placebo week. A pregnancy test can be performed if the patient or clinician is concerned about the possibility of pregnancy as the reason for not bleeding. If pregnancy is ruled out, the lack of withdrawal bleeding is due to HPO axis suppression and patients can be reassured that lack of withdrawal bleeding does not indicate a health problem or reduced fertility.

Regardless of the route of delivery, ethinylestradiol and other estrogens are metabolized by the liver and activate the hemostatic system. The most significant risk of combined hormonal contraception is estrogen-mediated increases in venous thrombotic events. 23 - 25 Large international cohort studies have identified the risk of deep vein thrombosis at baseline in reproductive-aged women to be approximately 2 to 10 per 10 000 women-years. The risk associated with combined hormonal contraception is approximately 7 to 10 venous thrombotic events per 10 000 women-years. 26 - 28 The risk of venous thromboembolism is substantially greater in pregnancy. One UK study of 972 683 reproductive-aged women with 5 361 949 person-years of follow-up found a risk of deep vein thrombosis of 20 per 100 000 in women who were not pregnant. This rate increased to 114 per 100 000 women-years in the third trimester of pregnancy and to 421 per 100 000 in the first 3 weeks postpartum. 29 The absolute risk of ischemic stroke in reproductive-aged women not taking combined hormonal contraception is 5 per 100 000 women-years. 25 Combined hormonal contraception is associated with an additional absolute risk of approximately 2 per 100 000 (ie, overall risk of 7 per 100 000). 25 This study did not exclude women who smoked cigarettes or had hypertension. 25

Clinicians who prescribe combined hormonal contraception should counsel women regarding signs and symptoms of arterial and venous thrombosis, especially for women with multiple additional risk factors, including body mass index (calculated as weight in kilograms divided by height in meters squared) at or over 30, smoking, and age older than 35 years. While progestins are not associated with an increase in thromboembolic risks, 30 , 31 US Food and Drug Administration package inserts for these methods contain “class labeling” or the same risks as estrogen and progestin combined hormonal contraceptive methods. Patients at increased risk of thrombosis can be provided a progestin-only, nonestrogen-containing method because this method of contraception does not increase risk of venous thromboembolism. 32

Behavioral contraceptive methods include penile withdrawal before ejaculation and fertility awareness–based methods. Imprecise terms, such as natural family planning , the rhythm method , or other euphemisms may be used by patients when referring to these methods. The effectiveness of withdrawal and fertility awareness depends on patient education, cycle regularity, patient commitment to daily evaluation of symptoms (first morning temperature, cervical mucus consistency), and the patient’s ability to avoid intercourse or ejaculation during the time of peak fertility. Data on pregnancy rates are frequently of poor quality and highly dependent on study design. 33 A meta-analysis of higher-quality prospective studies of women at risk for undesired pregnancy reported failure rates of 22 pregnancies per 100 women-years for fertility awareness methods. 34

Other nonhormonal methods prevent sperm from entering the upper reproductive tract through a physical barrier (condoms and diaphragms) or through agents that kill sperm or impair their motility (spermicides and pH modulators). First-year typical use effectiveness for these methods is 13 pregnancies per 100 women in a year. 12 , 18

The copper-bearing IUD is a highly effective nonhormonal reversible method. 12 , 18 Typical use pregnancy rates are 1% per year. 12 , 18 There is no effect on a user’s HPO axis and thus ovulation and menstrual cyclicity continues. The primary mechanism of action is spermicidal, through direct effects of copper salts and endometrial inflammatory changes. 35 The major challenge with the copper IUD is that it can increase the amount, duration, and discomfort of menses mostly during the first 3 to 6 months of use. 36 IUD use does not increase later risk of tubal infertility. 37 If sexually transmitted infection (STI) testing is indicated, testing can be performed concurrently with IUD placement. 38 - 40 This expedited process of testing for STIs at the time of IUD placement does not increase the risk of pelvic inflammatory disease. The absolute risk of pelvic inflammatory disease after IUD insertion is low in those with (0%-5%) or without (0%-2%) existing gonorrhea or chlamydial infection. 41

Emergency contraception (EC) reduces pregnancy risk when used after unprotected intercourse. The most effective method of EC is a copper IUD, which reduces pregnancy risk to 0.1% when placed within 5 days of unprotected intercourse. 42 A copper IUD also has the added advantage of providing patients with ongoing contraception. LNG IUDs were not previously considered an option for EC. However, in a recent randomized noninferiority trial, women requesting EC who had at least 1 episode of unprotected intercourse within the prior 5 days were randomized to receive a copper IUD (n = 356) or a 52-mg LNG IUD (n = 355). 43 LNG IUD was noninferior to copper IUD (between-group absolute difference, 0.3% [95% CI, −0.9% to 1.8%]). However, the proportion of study participants who had unprotected intercourse midcycle (and therefore were at risk of pregnancy) was not reported. If a patient needs EC and wishes to initiate a 52-mg LNG IUD, it is reasonable to immediately place the IUD plus give an oral EC, 44 given the limited and indirect evidence supporting the LNG IUD alone for EC.

Quiz Ref ID Oral EC consists of a single dose of either a progestin (LNG, 1.5 mg) or an antiprogestin (ulipristal acetate, 30 mg). Both of these agents work by blocking or delaying ovulation. Neither is abortifacient. LNG EC is available over-the-counter; a prescription is needed for ulipristal acetate. The medication should be taken as soon as possible after unprotected intercourse for maximum efficacy but can be taken up to 5 days afterward for ulipristal acetate. 45 - 47 LNG efficacy is diminished after 3 days. Efficacy appears similar between the 2 agents when ingested within the first 72 hours after intercourse (ulipristal acetate EC: 15 pregnancies of 844, LNG EC: 22 pregnancies of 852; reduction in pregnancy without EC use estimated to be 90% less) but pharmacodynamic and clinical studies demonstrated that the ulipristal acetate treatment effect persists up to 120 hours with no pregnancies (0/97). 46 Actual use studies of EC that included 3893 individuals found lower pregnancy prevention rates than expected, which appears to be related to multiple acts of unprotected intercourse both before and after the EC use. 48 , 49 If further acts of unprotected intercourse occur 24 hours after EC use and a regular method of contraception has not been started, EC needs to be taken again. 49 Repeat use of LNG EC results in no serious adverse events; repeat dosing for ulipristal acetate EC has not been specifically studied. 50 Clinicians should review the options for EC with all patients starting a user-controlled method, such as condoms. These patients may be prescribed oral EC to keep at home for immediate use if needed.

Two evidence-based guidelines are available to assist clinicians in evaluating the safety of contraception initiation and use. 32 , 42 These guidelines were developed by the US Centers for Disease Control and Prevention, are updated regularly, and are freely available online and in smartphone apps.

The first is the US Medical Eligibility Criteria for Contraceptive Use 32 (US MEC), which provides information on the safe use of contraceptive methods for women with various medical conditions (eg, diabetes, seizure disorder) and other characteristics (eg, elevated body mass index, tobacco use disorder, postpartum). The US MEC uses a 4-tiered system to categorize level of risk for each disease/contraceptive method combination. 32 The risk tiers are (1) no restrictions exist for use of the contraceptive, (2) advantages generally outweigh theoretical or proven risks although careful follow-up might be required, (3) theoretical or proven risks outweigh advantages of the method and the method usually is not recommended unless other more appropriate methods are not available or acceptable, and (4) the condition represents an unacceptable health risk if the method is used. 32

All clinicians, including advanced practice clinicians, should be familiar with prescribing within US MEC categories 1 and 2 (no restrictions or benefits outweigh risks). For women with underlying health conditions who want to use a category 3 method, such as a woman with a history of breast cancer choosing combined hormonal contraceptives, primary care physicians or specialists should review the detailed evidence listed in the US MEC to advise their patients. Subspecialists in complex family planning who have completed extra fellowship training may provide helpful consultation for patients with multiple contraindications or unusual situations. The US MEC is a guideline, not a mandate. Situations may arise in which specialists recommend an MEC category 3 or 4 method because the alternative to the contraceptive method, pregnancy, places the patient at even greater risk. 32 The US MEC does not include conditions for which there is insufficient evidence to make recommendations, such as aortic aneurysms, Marfan syndrome, or chronic marijuana use. For these patients, clinicians should consider referral to a complex family planning specialist. If the patient needs a method immediately, a progestin-only pill should be considered as a “bridging” method, because these can be used safely by most patients 32 and are more effective than barrier methods such as condoms.

The US MEC addresses common drug interactions with hormonal contraceptives. 32 Contraceptive steroid hormones are metabolized via the hepatic cytochrome P450 pathway. 51 , 52 Drugs that induce this pathway, such as rifampin and barbiturates, or chronic alcohol can impair contraceptive efficacy and drugs that inhibit the pathway, such as valproic acid, cimetidine, or fluconazole, may increase adverse effects. The FDA recognizes a drug-drug interaction as clinically significant if it causes at least a 20% difference in drug levels 53 but an interaction does not necessarily affect contraceptive failure rates. Adherence, continuation, fecundity, and frequency of intercourse also contribute to contraceptive effectiveness. Additionally, most pharmacokinetic studies do not have sufficient statistical power to determine differences in pregnancy rates. The most common drug classes that may interact with hormonal contraceptives are antiretroviral drugs (including efavirenz and ritonavir-boosted protease inhibitors) and anticonvulsant therapies (including carbamazepine, phenytoin, and others). 54 , 55 Evidence from both clinical and pharmacokinetic studies of routinely used antibiotics do not support impaired contraceptive efficacy with concomitant antibiotic prescription, 56 except for rifampin with which ethinylestradiol and progestin area under the curve levels are at least 40% lower. 57 Because the local progestin dose in the LNG IUD is so high, its efficacy is not reduced by drugs that may affect combined hormonal contraceptives, progestin-only contraceptive pills, or the progestin implant. While hormonal contraceptive use can change concentrations of some drugs, 58 this is rarely clinically relevant, except for the reduction in serum concentration of the anticonvulsant lamotrigine.

Another major guideline is the US Selected Practice Recommendations for Contraceptive Use 42 (US SPR, available online or via a smartphone app). The US SPR is organized by contraceptive method. It includes method-specific, up-to-date guidelines, such as how to initiate the method, how to manage bleeding irregularities, and recommended follow-up. For example, the guidelines on IUDs include evidence on medications to ease IUD insertion or IUD management if a pelvic infection occurs. Recommendations related to combined hormonal contraceptives include the number of pill packs that should be provided at initial and return visits or management of vomiting or severe diarrhea while using combined oral contraceptives.

Much of the data on noncontraceptive benefits of hormonal methods come from case-control studies or small comparative trials. However, fair evidence exists that methods that suppress ovulation can be effective in reducing benign ovarian tumors 59 and functional ovarian cysts. 60 Combined hormonal contraceptives diminish hormonally mediated premenstrual dysphoric disorder, with statistically significant mean differences in symptoms, such as headaches, bloating, and fatigue, and functionality scales. 61 The estrogen component of combined hormonal contraception increases hepatic sex hormone–binding globulin, which reduces free testosterone and improves androgen-sensitive conditions, such as acne and hirsutism. Cochrane systematic reviews of combined hormonal contraceptives and both conditions show significant associations with improvement in a variety of measures of acne and hirsutism. 62 , 63 All progestin-containing contraceptives cause endometrial atrophy and, thus, reduce menstrual blood loss and menstrual pain to varying extents. 64 - 66 While progestin-only methods can promote unscheduled or breakthrough bleeding, the total amount of blood loss is reduced and in those with heavy menstrual bleeding, hemoglobin levels can rise by 10 g/L in 12 months. 67 , 68 The LNG IUD has demonstrated efficacy in reduction of heavy menstrual bleeding 69 , 70 (including for women with anticoagulation, fibroids, 71 or hemostatic disorders), primary dysmenorrhea, 36 , 72 endometriosis, 73 adenomyosis, 74 and protection against pelvic infection. 75

Screening for pregnancy is important prior to prescribing contraception. According to the US SPR, clinicians should be “reasonably certain” that the patient is not pregnant. 42 A clinician can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any 1 of the following criteria: (1) is 7 days or less after the start of normal menses; (2) has not had sexual intercourse since the start of last normal menses; (3) has been correctly and consistently using a reliable method of contraception; (4) is 7 days or less after spontaneous or induced abortion; (5) is within 4 weeks’ postpartum; and (5) is fully or nearly fully breastfeeding (exclusively breastfeeding or most [≥85%] of feeds are breastfeeds), amenorrheic, and less than 6 months postpartum.

Quiz Ref ID These criteria have a negative predictive value of 99% to 100%. 76 - 78 A urine pregnancy test (UPT) alone is not sufficient to exclude pregnancy. UPT sensitivity is dependent on when the last act of intercourse occurred, the ovulatory cycle phase, and urine concentration. Sensitivity of UPTs is 90% at the time of a missed period, but only 40% in the week prior. 79 Additionally, a UPT can remain positive up to 4 weeks after delivery, miscarriage, or abortion. 80 , 81 Few other tests are required for safe and effective use of contraception.

Clinicians can offer other indicated preventive health tests at the contraceptive initiation visit, like screening for cervical cancer or STIs. However, these tests are not required for contraceptive use and should not prevent initiation of contraception.

Generally, all methods should be started immediately on prescription regardless of menstrual cycle day—known as the Quick Start protocol. 82 If a hormonal method is initiated within 5 days of the first day of menses, no additional backup method is needed. At other times in the cycle, or when switching from a nonhormonal to a hormonal method, a backup is necessary for 7 days to ensure ovulation suppression. If switching from one hormonal method to another, the switch can occur without a withdrawal bleed or backup.

If a woman reports unprotected intercourse within the 5 days before contraceptive initiation, most sources recommend giving emergency contraception, initiating her desired method, and repeating a UPT 2 to 3 weeks later. 82 - 85 Many studies have demonstrated that exposing an early pregnancy to hormonal contraception is not harmful 86 but delayed initiation increases the risk of undesired pregnancy.

Because comparative effectiveness studies to clearly identify the superiority of one contraceptive pill formulation over another are lacking, selecting a contraceptive pill often depends on patient experience. Monophasic regimens, in which each pill has the same hormone doses, have significant advantages over bi- and triphasic regimens. Cycles can be extended easily by skipping the placebo week and starting the next pack of active pills. If this is attempted with multiphasic regimens, the drop in progestin between phases typically results in breakthrough bleeding. In terms of ethinylestradiol, few patients require a pill containing more than 35 µg/d to prevent breakthrough bleeding. 87 Many clinicians advocate starting with the lowest ethinylestradiol dose to minimize risks. However, there are no data demonstrating that 10- to 20-µg/d ethinylestradiol doses are safer than 35 µg daily, and lower ethinylestradiol doses are associated with more unscheduled vaginal bleeding. 88 Thus, starting with a monophasic preparation containing 30 µg to 35 µg of ethinylestradiol provides the greatest likelihood of a regular bleeding pattern without increasing risk. Ethinylestradiol can be reduced if patients have estrogen-associated adverse effects, such as nausea or breast tenderness.

Many different progestins exist. Progestins differ in in vitro androgenicity, effects on surrogate metabolic markers, or similarity to testosterone. 89 While molecular structures differ, there is no evidence demonstrating that a particular progestin is superior to others. Traditionally, progestins were classified into “generations” by their parent compound and decade of development. This classification is not clinically useful and should be abandoned. 90 Patients sometimes prefer a pill that they used previously, and if no contraindications exist and the cost is acceptable to the patient, it is reasonable to prescribe it ( Figure 1 and Figure 2 ).

Combined hormonal contraceptives can be dosed in a cyclic or continuous fashion. Originally, birth control pills were dosed with 21 days of active drug and a 7-day placebo week to trigger a monthly withdrawal bleed, meant to mimic the natural menstrual cycle. However, many women prefer less frequent withdrawal bleeds. 91 Some women report significant adverse effects 92 during this placebo week, such as migraine, bloating, and pelvic pain, and extended use provides an easy way to manage or eliminate these problems. 61 During the placebo week, there is less suppression of the HPO axis. 93 - 95 For these reasons, many newer contraceptive pills have shorter (eg, 4-day) placebo periods. Further, most monophasic combined hormonal contraceptives can be used as extended use (fewer withdrawal bleeds) by having a 4-day placebo period quarterly or continuously (no withdrawal bleed) by eliminating the placebo altogether. Extended and continuous use are associated with improved typical use efficacy, likely because greater overall HPO axis suppression is achieved, which may offset lapses in user adherence. 96 A new vaginal ring (segesterone acetate/ethinyl estradiol vaginal system) is also available, which is prescribed for 1 year, with the patient removing the ring each month for 7 days. 97

This review has several limitations. First, relatively few randomized clinical trials that directly compared contraceptive methods were available. Therefore, contraceptive methods are typically evaluated by their individual efficacy (pregnancies per person-cycles) and not typically by their relative effectiveness compared with another method. Second, the quality of summarized evidence was not evaluated. Third, some aspects of contraception, such as counseling, noncontraceptive health benefits, ongoing contraceptive innovations, and the effect of cultural values, and patient preferences were not covered in this review.

Oral contraceptive pills are the most commonly used reversible contraceptives, IUDs and subdermal implants have the highest effectiveness, and progestin-only and nonhormonal methods have the lowest risks. Optimal contraceptive selection incorporates patient values and preferences.

Corresponding Author: Stephanie Teal, MD, MPH, Department of OB/GYN, University Hospitals Medical Center and Case Western Reserve University, 11100 Euclid Ave, MAC-5304 Cleveland, OH 44106 ( [email protected] ).

Accepted for Publication: November 10, 2021.

Author Contributions: Drs Teal and Edelman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design : Both authors.

Acquisition, analysis, or interpretation of data : Both authors.

Drafting of the manuscript : Both authors.

Critical revision of the manuscript for important intellectual content : Edelman.

Administrative, technical, or material support : Both authors.

Supervision : Both authors.

Conflict of Interest Disclosures: Dr Teal reported receiving grants from Merck & Co, Bayer Healthcare, Sebela, and Medicines360, and personal fees from Merck & Co and Bayer Healthcare outside the submitted work. Dr Edelman reported receiving grants from Merck, research funds from HRA Pharma, and royalties from UpToDate outside the submitted work.

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SYSTEMATIC REVIEW article

The effects of hormonal contraceptives on the brain: a systematic review of neuroimaging studies.

• 1 Center for Clinical Research in Psychosis (TIPS), Stavanger University Hospital, Stavanger, Norway
• 2 Department of Clinical Medicine, Center for Sexology Research, Aalborg University, Aalborg, Denmark
• 3 Department of Obstetrics and Gynecology, Stavanger University Hospital, Stavanger, Norway
• 4 Department for Caring and Ethics, Faculty of Health Sciences, University of Stavanger, Stavanger, Norway
• 5 SESAM, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway
• 6 Department of Public Health, Faculty of Health Sciences, University of Stavanger, Stavanger, Norway

Background: Hormonal contraceptive drugs are being used by adult and adolescent women all over the world. Convergent evidence from animal research indicates that contraceptive substances can alter both structure and function of the brain, yet such effects are not part of the public discourse or clinical decision-making concerning these drugs. We thus conducted a systematic review of the neuroimaging literature to assess the current evidence of hormonal contraceptive influence on the human brain.

Methods: The review was registered in PROSPERO and conducted in accordance with the PRISMA criteria for systematic reviews. Structural and functional neuroimaging studies concerning the use of hormonal contraceptives, indexed in Embase, PubMed and/or PsycINFO until February 2020 were included, following a comprehensive and systematic search based on predetermined selection criteria.

Results: A total of 33 articles met the inclusion criteria. Ten of these were structural studies, while 23 were functional investigations. Only one study investigated effects on an adolescent sample. The quality of the articles varied as many had methodological challenges as well as partially unfounded theoretical claims. However, most of the included neuroimaging studies found functional and/or structural brain changes associated with the use of hormonal contraceptives.

Conclusion: The included studies identified structural and functional changes in areas involved in affective and cognitive processing, such as the amygdala, hippocampus, prefrontal cortex and cingulate gyrus. However, only one study reported primary research on a purely adolescent sample. Thus, there is a need for further investigation of the implications of these findings, especially with regard to adolescent girls.

Introduction

Synthetic sex hormones became available as contraceptive drugs in the 1960's, and they are currently being used by more than 100 million women worldwide ( Christin-Maitre, 2013 ). In the US, it is estimated that 88% of all women of fertile age have utilized this type of birth control at some point in their lives ( Daniels and Jones, 2013 ). Sex hormones consist of androgens, estrogens and progesterone, and in vivo they are synthesized in the gonads, the adrenal glands and the brain. They profoundly impact the brain during fetal life , exerting epigenetic effects and directing development along male or female trajectories by influencing a variety of molecular and cellular processes. Moreover, they affect regional gray matter volumes and neural connectivity associated with psychosexual and other behavioral functions ( Hines, 2006 ; Josso, 2008 ; Peper et al., 2011 ; McCarthy and Nugent, 2015 ).

Converging lines of evidence from animal literature, as well as cognitive and affective neuroscience involving human subjects, suggest that these hormones continue to shape the brain postnatally , also during adolescence ( Herting et al., 2014 ; Schulz and Sisk, 2016 ). In adulthood, they modulate brain areas involved in cognitive and emotional processing, and they are implicated in mood and anxiety disorders ( Comasco et al., 2014 ; Toffoletto et al., 2014 ; Garcia et al., 2018 ). If the synthetic sex hormones contained within hormonal contraceptives (HC) ( Christin-Maitre, 2013 ) interact with sex hormone receptors in the brain, they have the potential to interfere with multiple neurohormonal regulatory mechanisms and neural structures involved in emotion, cognition and psychosexual behavior ( Fuhrmann et al., 2015 ; Schulz and Sisk, 2016 ). To date, neuroimaging research on the effects of HC use on the structure and function of the brain has not been systematically reviewed. The potential for influencing brain plasticity and hence altering brain structures and behavioral outcomes has therefore not been fully elucidated.

Plasticity represents an intrinsic ability of the nervous system to adapt its structure and function in response to endogenous and exogenous environmental demands. This ability persists throughout life ( Pascual-Leone et al., 2005 ). However, there are periods of life when the brain exhibits an increased degree of plasticity and is particularly vulnerable to environmental changes. The perinatal phase is such a period. In 1959, Phoenix et al. proposed that perinatal sex hormones exert an organizing effect on the brain, with ensuing consequences for behavior ( Phoenix et al., 1959 ). They found that prenatal exposure of female guinea pigs to testosterone masculinized their later mating behavior, and they went on to demonstrate similar findings in female rhesus monkeys, who displayed masculinized play patterns following prenatal testosterone treatment. Their claim was that, perinatally, testosterone has an organizing effect on the brain, while the hormonal events of puberty have an activating/deactivating effect on the anatomical structures previously organized.

Several researchers have since expanded on, and in part refuted, this theory. Schulz and Sisk presented evidence from animal studies suggesting that sex hormones may have an organizing effect on the brain long after birth, gradually declining and ending approximately at the resolution of puberty ( Schulz and Sisk, 2016 ). Beltz and Berenbaum (2013) provided further support for the theory of continued ability of sex hormones to exert permanent effects in humans by showing that early puberty, and thus early exposure to adult-levels of sex hormones, in men was associated with better performance in a mental rotation task ( Wai et al., 2010 ). Consequently, adolescence might also be a period sensitive to organizing effects of sex hormones; and the effects may be stronger, the younger the individual is when exposed.

During adolescence, several brain areas, in particular the prefrontal cortex (PFC), undergo extensive structural maturation through processes such as synaptic pruning, reorganization and myelination ( Petanjek et al., 2011 ; Blakemore, 2012 ). The brain's functional architecture also undergoes maturational processes of optimizing connectivity in functional networks ( Sherman et al., 2014 ). This prolonged developmental shaping and reorganization of neural circuits has implications for understanding the vulnerability of the brain during this period, as the plastic brain is the platform for learning and developing as well as for psychopathology and cerebral disease.

While endogenous sex hormones have well-documented effects on the brain, the influence of their synthetic counterparts, progestins and ethinylestradiol, which are most commonly used in oral contraceptive pills ( Christin-Maitre, 2013 ), has been less extensively explored. However, there is reason to believe that also synthetic sex hormones could have a significant neural impact, particularly if taken when the young female brain is developing into its adult form. Behavioral effects of HC have been shown in cognitive tasks such as mental rotation and verbal expressional fluency ( Beltz et al., 2015 ; Griksiene et al., 2018 ), and of more serious concern is the demonstrated association between these drugs and various affective adversities. Thus, Skovlund et al. conducted a large national cohort study in Denmark, where they collected and compared data from the National Prescription Register and the Psychiatric Central Research Register. They found a correlation between the use of HC and a subsequent first diagnosis of depression and the use of antidepressants. The increased risk of these adverse outcomes was noted to be the highest in adolescent women ( Skovlund et al., 2016 ). The Skovlund group also investigated associations between HC intake and suicidal behavior and they found an increased risk for both attempted and committed suicide. Again, the increased risk was highest in adolescent women, and it peaked within 2 months of intake debut ( Skovlund et al., 2018 ).

In order to assess the prevalence of HC use among Norwegian adolescents, we queried the Norwegian Prescription Database regarding usage of drugs ( Norwegian Prescription Database, 2019 ) according to the Anatomical Therapeutic Chemical (ATC) code G03A (Hormonal contraceptives for systemic use). This database provides data on these drugs from 2004 to 2018, and it is possible to query separately for age groups such as 10–14 and 15–19. The usage for girls between the ages of 10 and 14 has more than doubled from 2004 to 2018, and in 2018 about 1.2 percent of all 10–14-year-old girls used some form of systemic HC. The numbers for girls between the ages of 15 and 19 have been quite stable at about 40 percent throughout the same period. Thus, a substantial proportion of young girls use these drugs and the usage has increased rapidly among the youngest adolescent girls in Norway.

The central aim of this review was to identify and critically appraise all peer-reviewed empirical studies published in English concerning human subjects that have investigated the effects of HC on brain structure and function through digital neuroimaging techniques, such as magnetic resonance imaging (MRI) and functional MRI (fMRI), as well as positron emission tomography (PET), electroencephalography (EEG) and magnetoencephalography (MEG).

Our main hypotheses were that HC use affects both brain structure and function in humans, and that there are effects on brain structures known to differ statistically in men and women, such as the PFC, hypothalamus, amygdala and hippocampus ( Cahill, 2006 ), as well as on brain structures involved in visuospatial and verbal cognition. Additionally, we hypothesized that HC use have the most pronounced effects on brain structures if used during early adolescence.

This review was conducted in accordance with the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines ( Moher et al., 2009 ), and it was registered in the PROSPERO International Prospective Register of Systematic Reviews (Registration number: CRD42019142427).

Literature Search

Studies employing neuroimaging techniques to measure possible HC effects on either brain structure or function were considered. In order to be included, the studies should (a) be primary empirical studies, (b) be conducted on women of fertile age using HC, and (c) have either a separate control group of naturally cycling (NC) women of comparable age or have HC users constitute their own controls by performing repeated assessments under NC and HC conditions. Thus, case reports, literature reviews and experimental studies with no control group were excluded. We included articles published in English from 1990 and up until February 2020. Studies older than the 90's are based on imaging techniques not comparable to those of modern neuroimaging.

Stage One Search

The review was carried out in two stages. The first stage consisted of an exploratory search using PubMed and Google Scholar. PubMed covers most studies involving neuroscience and related fields, and Google Scholar indexes most broadly of all peer-review databases. We first combined the keyword “contraceptives” with “brain,” “cognition,” “emotion,” and “motivation” and searched the databases. We selected and read relevant review articles. The knowledge gained from this process was used to decide on keywords for the stage two searches.

Stage Two Search

Following the initial exploratory search, systematic searches were carried out, employing a two-pronged approach aiming to identify structural and functional neuroimaging studies separately. In Table 1 , the PICOS criteria for the searches are described.

Table 1 . PICOS search.

We first combined search terms such as “contraceptive agent” and “birth control” with terms descriptive of structural neuroimaging such as “magnetic resonance imaging,” “computed axial tomography,” and “diffusion tensor imaging.” We searched for these terms in titles, abstracts and keywords as well as MESH- and Emtree-terms. Titles and abstracts were scanned, excluding articles not meeting our inclusion criteria. Finally, full texts were read in order to identify measures and methodological detail, further excluding ineligible articles. See Appendix 1 for a comprehensive list of search terms.

The second systematic search was carried out using the same search terms describing HC, this time combining them with terms aiming to identify functional neuroimaging studies. Relevant terms were “functional magnetic resonance imaging,” “positron emission tomography,” “electroencephalography,” and “event related potentials.” The same procedures of selection were carried out and relevant articles were retrieved. The stage 2 searches were carried out in February 2020.

A final reference and citation search strategy was employed to ensure that all relevant studies were identified. This implied scanning reference lists in the included articles as well as articles that cited the included papers, after a consensus selection process as described below.

After completing the systematic searches, the authors MKB and KKB independently read the keywords, abstracts and titles and divided articles into “included,” “excluded,” and “undecided” categories. After the initial assessments, full texts were read, and the researchers discussed the criteria and revised the “undecided” articles until all citations were either included or excluded.

Quality assessment was not done using a rigid framework resulting in a single numeric score, as the studies differed regarding dependent variables and design. However, we applied the validity typology of Donald Campbell and Thomas D. Cook ( Cook et al., 1979 ) in order to assess threats to construct, internal, external and statistical conclusion validity. This was done as the study designs and outcome measures were heterogenous, necessitating a flexible approach for quality assessment. These dimensions of validity encompass most of the common causes of bias and validity threats regarding causal inference. Three levels of validity were applied: low, intermediate and high. Low validity implies that there was a validity threat serious enough to fundamentally invalidate the study. Intermediate implies that there were validity threats, but that they were outweighed or resolved to a degree that they were unlikely to seriously bias or confound the study. High means that there were no validity threats for the dimension in question. The assessment was done by authors KKB and MKB and in case of disagreement, consensus was reached through discussion and independent re-reading of the study in question. With regard to statistical power, the combination of small sample size and lack of assessment of statistical power implied a classification of low statistical conclusion validity. In neuroimaging studies, it is difficult to determine a general “too small” sample size, but in the absence of power analyses, we chose a cutoff of n < 20 within the HC group to classify sample size as small.

Structural Neuroimaging

Following the initial exploratory search, a systematic search for structural neuroimaging studies yielded a total of 11,228 hits from the different databases, after removing duplicates. After scanning titles and abstracts, 11,213 citations were excluded. Finally, the full texts were read in order to identify measures and methodological details, further excluding five articles. Thus, 10 articles were deemed eligible for inclusion, based on the aforementioned criteria. No additional articles were found after doing citation searches and reference list reviews. See Figure 1 .

Figure 1 . Flowchart Structural Search.

Functional Neuroimaging

A second systematic search pursuing functional neuroimaging studies yielded 572 articles, after removing duplicates. A total of 23 articles qualified for inclusion following the same procedures of selection. No additional articles were found after performing citation searches and reference list reviews. See Figure 2 .

Figure 2 . Flowchart functional search.

See Tables 2 , 3 for an overview of the included articles.

Table 2 . Overview of articles concerning the effect of HC on brain structure.

Table 3 . Overview of articles concerning the effect of HC on brain function.

Results From the Structural Studies

Most of the included structural studies reported differences between HC users and NC women, as reported in Table 2 .

Summary of the Structural Studies

All the structural studies tested differences in various brain structures in users of different types of HC as compared to present non-users. The studies were mostly cross-sectional and observational in nature, with the exception of one study ( Lisofsky et al., 2016 ) which was a quasi-experimental pre-post study where a self-selected group of women starting HC use was compared with non-users. However, even in this study, previous use was unaccounted for. Hence no study investigated HC naïve women. The sample size ranged from 14 to 60 in the HC groups and from 14 to 89 in the control groups. The age range was 18–40 years in both HC and control groups except for the study by Frokjaer et al. (2009) who reported an age range of 18–45 years in the HC group and 18–79 years in a female and male control group. De Bondt et al. (2015a) studied “young women” but did not specify age span. A variety of neuroimaging techniques were employed, including DTI-MRI, volumetric MRI, spectroscopy MRI and PET.

HC in Studies on Sex Differences

Several of the studies concerning brain structure were not primarily focused on HC effects on the brain per se . Rather, they included HC users in order to investigate whether HC use is an important confounder or moderator in studies on sex differences in the brain. Thus, the aims, methodologies and hypotheses were heterogeneous with regard to HC effects. Four studies ( Frokjaer et al., 2009 ; Pletzer et al., 2010 ; De Bondt et al., 2016 ; Pletzer, 2019 ) explicitly argued that earlier neuroimaging studies on sex differences in the brain did not account for potential confounding effects of HC use in women. These studies assessed brain morphology as related to differential vulnerability to mood and anxiety disorders in men and women. For instance Pletzer et al. (2010) , found that NC women had larger prefrontal brain volumes than both men and HC women, and that men had larger hippocampal and amygdalae volumes than women. In a more recent publication, Pletzer pooled and analyzed data from previous publications and noted smaller gray matter volumes in hippocampal and parahippocampal areas in HC users as compared to NC women ( Pletzer, 2019 ). De Bondt et al. (2016) noted that gray matter volumes and PMS symptoms correlated differently in NC and HC groups, whereas Frokjaer et al. (2009) used cortical serotonergic receptor binding as a measure of potential for affective disturbances but discovered no effects of neither sex nor HC use.

Furthermore, as related to whether HC masculinize or feminize brain structure, Pletzer et al. investigated HC effects on the brain depending on the androgenicity of the progestin component of the HC ( Pletzer et al., 2015 ). They found that anti-androgenic progestins promoted larger gray matter volumes in temporal areas such as the fusiform face area and the parahippocampal place area and further related these changes to improved performance in a face recognition task, when comparing with NC women. They also found that users of androgenic progestins had smaller frontal areas compared to NC women.

Brain Structures Involved in Cognition and Emotion

A couple of studies specifically focused on HC effects on brain structures known to participate in the processing of emotion and/or cognition. Lisofsky et al. (2016) , in a pre-post quasi-experiment with a control group, found decreased gray matter volumes in the amygdala after 3 months of contraceptive intake in women starting HC use after a period on not using HC. They noted that this structural alteration was related to positive affect, whereas no changes in cognitive performance were detected. One study ( Petersen et al., 2015 ) investigated areas involved in the salience network and found cortical thinning in such areas. They were not able, however, to determine whether these changes were causally or merely indirectly related to the use of HC.

The Effect of Menstrual Cycle and HC on Brain Structure

One research group has published a series of articles where HC effects were contextualized regarding natural hormonal variation in the menstrual cycle. All these articles had Timo DeBondt as first author. The articles were based on overlapping samples and all assessed the effects of HC as compared to hormonal effects in the menstrual cycle on brain structure ( De Bondt et al., 2013a , b , 2015a ). Using diffusion tensor imaging, they found a significant increase in mean diffusivity in the fornix in an HC group as compared to a group of NC women ( De Bondt et al., 2013b ). In the same sample, they also reported that gray matter volume in anterior cingulate cortex (ACC) was negatively associated with estradiol levels in the NC women, whereas this finding could not be replicated in the HC group ( De Bondt et al., 2013a ). De Bondt et al. (2015a) also examined gamma aminobutyric acid (GABA) concentrations, seeking to find possible correlations between GABA concentration in the PFC, menstrual cycle phase, HC use and premenstrual syndrome (PMS) symptoms. They did find increased prefrontal GABA in the NC group at ovulation, whereas no changes were seen during the cycle in the HC group. No significant correlations with endogenous hormones or PMS symptoms were detected.

Adolescent HC Users

None of the structural studies directly investigated effects of HC use on the adolescent brain. Most samples included teenagers from the age of 18, but results were not separated according to age, and as such intermingled with effects on adult brains. This makes it impossible to assess differential or graded effects on younger brains.

Results From the Functional Studies

Functional measures were reported in 21 different articles as summarized in Table 3 .

Summary of Functional Studies

Functional studies were mainly conducted using task based and/or resting state fMRI. In addition, one group used PET and one group EEG. The research groups evaluated cognitive tasks, emotion processing, fear learning, reward and motivation as well as pain inhibition and resting state networks, related to intake of various types of hormonal contraceptives. Only two studies were randomized controlled trials (RCTs) ( Gingnell et al., 2013 , 2016 ), whereas the rest were observational, quasi-experimental or observational with repeated measures within one menstrual cycle. Sample size range was 8–55 in both HC groups and female control groups. Age span was 16–45 years, except in three studies ( Vincent et al., 2013 ; De Bondt et al., 2015b ; Smith et al., 2018 ) which provided no information about age, and four studies where only mean age was provided ( Pletzer et al., 2014 ; Hwang et al., 2015 ; Scheele et al., 2016 ; Smith et al., 2018 ; Hornung et al., 2019 ). One study ( Mareckova et al., 2014 ) additionally assessed an adolescent sample aged 13.5–15.5 years with 55 participants in both the HC and the NC control group. The functional studies were also heterogenous with regard to aims and approaches as well as design and methodology.

Emotion Processing, Fear, Anxiety, and Stress

In line with the scope of some of the structural studies, several of the functional studies investigated brain functions involved in affective processing.

Gingnell et al. (2013) conducted an fMRI RCT with a sample of women with a previous history of HC-induced adverse mood. The subjects were assessed at baseline and once during the last week of the 21 day HC/placebo treatment period. An emotional facial expression matching task was administered. Hemodynamic BOLD (Blood-oxygen-level-dependent) responses to angry or fearful expressions differed between groups and within the HC group when comparing pre-treatment and treatment scans. During the last week of the treatment cycle, the HC group showed decreased reactivity in the bilateral frontal gyri, both compared to the placebo group and to the pre-treatment scans. They also showed decreased reactivity in the left middle frontal gyrus and left insula compared to the placebo women. The changes in brain reactivity were accompanied by more depressed mood, mood swings and fatigue, compared both to the control group and to pre-treatment. The placebo group also showed decreased amygdala reactivity in the last set of scans, whereas this change was not found in the HC group.

Altered amygdala reactivity was also found by Petersen and Cahill ( Petersen and Cahill, 2015 ) who used fMRI to compare reactions related to arousing, negatively valenced images in HC and NC women. They found that HC women had significantly lower amygdala reactivity upon viewing emotionally arousing images.

Investigating the interaction effects of sex hormones and cortisol, Merz et al. (2012) found fMRI activation differences in amygdala, hippocampus and the parahippocampal gyri as a function of interaction of HC use and cortisol administration on implicit emotional learning using a fear learning paradigm. Administration of cortisol reduced amygdala activation in all groups but dampened neural activation in the left hippocampus and in the left anterior parahippocampal gyrus only in NC women. In HC women, hippocampal and parahippocampal activation was enhanced with increased levels of cortisol. In a later study ( Merz et al., 2013 ) Merz et al. evaluated the interaction between endogenous cortisol and the neural correlates of fear expression. There was an interaction between cortisol and HC use, as cortisol levels correlated with BOLD contrasts in the amygdala between conditioned fear stimuli only in HC users.

Fear conditioning was also applied by Hwang et al. (2015) , studying fMRI fear responses as well as extinction learning and recall, as related to HC and sex hormone status. HC women had lower activation in the posterior insular cortex, middle cingulate cortex, hypothalamus and amygdala compared to NC women with high levels of estrogen during fear conditioning.

An fMRI “traumatic” film viewing paradigm was utilized by Miedl et al. (2018) to assess the effects of endogenous estradiol and synthetic sex hormones on the neural processing of trauma exposure using films depicting severe interpersonal violence vs. neutral films in NC and HC-using women. The HC group showed increased insula and dorsal ACC activity relative to NC women upon viewing traumatic films.

Two different fMRI studies investigated effects of the pheromone-like steroid androstadienone. Hornung et al. (2019) evaluated differences in attention bias in HC vs. NC women when presented with fearful, angry and happy faces in a “dot probe” task and whether androstadienone affects attention bias. There were no behavioral attentional bias differences, no BOLD response differences and no effects of androstadienone. Similarly, Chung et al. (2016) explored the influence of androstadienone during psychosocial stress in HC, NC and in men using the Montreal Imaging Stress Task. The NC women showed increased activation of the left somatosensory association cortex as well as right pre-motor and supplementary motor areas under the placebo treatment when faced with stress, as compared to HC women. Under treatment with androstadienone, no significant differences were observed between the female groups.

The only included event-related potential (ERP) study was published by Monciunskaite et al. (2019) and employed emotional visual stimuli when comparing women using anti-androgenic HC with NC women. The main finding was that the HC group showed blunted late ERP amplitudes to negative emotional stimuli when compared to NC women.

Reward and Motivation

fMRI effects of HC on erotic stimulation and monetary reward was investigated by Abler et al. (2013) and Bonenberger et al. (2013) , respectively. Abler et al. presented erotic videos and pictures to HC users and NC women. The MRI scans revealed no between- or within group differences upon viewing these. However, compared to HC users, the NC women in their follicular phase showed increased activation in the bilateral anterior insula, dorsomedial PFC and left inferior parietal lobe, as well as in the bilateral inferior precentral gyrus upon expectation of erotic stimuli. In their luteal phase they had higher activation in the anterior and posterior middle cingulate cortex. Bonenberger et al. examined how the use of HC might alter neural reward processing in a monetary incentive task. In whole-brain analyses, NC and HC women did not differ upon expectation of a monetary reward. An ROI analysis did, however, show enhanced activity in the left anterior insula and inferior lateral PFC in HC users, relative to NC women in their follicular phase.

The interaction of oxytocin and HC regarding perceived partner attractiveness in relation to HC use was studied by Scheele et al. (2016) . Subjects were randomized to receive either oxytocin or placebo prior to participating in a passive face-viewing fMRI paradigm. NC and HC pair-bonded women were shown photographs of their romantic partner, matched unknown men, a familiar woman, and a matched unfamiliar woman. Administration of oxytocin was found to enhance ratings of attractiveness of romantic partners compared to unknown men in the NC women, but not in the HC women. NC women showed increased activity in the nucleus accumbens and ventral tegmental area upon viewing their partners, relative to the HC women. The interpretation was that HC can disrupt romantic partner attachment.

HC modulation of fMRI activation upon seeing different food cues was investigated by Arnoni-Bauer et al. (2017) who hypothesized that there would be an association between sex hormones and eating behaviors. Participants were shown images of high calorie foods as well as non-edible items. fMRI activation in the HC group was similar to that of the luteal phase in the NC women. Food related brain activation was assessed also by Basu et al. (2016) who tested the effects of depot medroxyprogesterone acetate (DMPA) on food motivation using a quasi-experimental pre-post design with subjects acting as their own controls. Eight women were investigated with MRI while looking at images of high-calorie and low-calorie foods, as well as neutral, non-food objects. Eight weeks after the DMPA injection increased activation was observed in frontal and postcentral areas upon viewing food, when comparing to baseline. The high-calorie images induced highest activation in cingulate and frontal areas, when comparing to baseline.

A final study of motivational effects of HC was conducted by Smith et al. (2018) who performed a PET study to assess sex differences in dopamine release in inferior frontal areas as well as the dorsal and ventral striatum. They administered D-amphetamine to NC and HC women, as well as to men, to elucidate possible sexually dimorphic neural and hormonal contributions to addiction. They measured changes in dopamine D2 and D3 receptors in the participants, but found no significant effects of HC.

Perception of Pain

Vincent et al. (2013) delivered noxious thermal stimuli to HC and NC subjects while in an MRI scanner, aiming to establish whether there was a reduction in the descending pain inhibitory system in the HC group. Serum sex hormone levels were assessed, and participants were asked to rate the intensity of pain for each stimulus delivered. The researchers found that a subgroup of HC women who had decreased testosterone levels required significantly lower temperatures to feel pain, relative to the NC control group. Imaging data showed significantly reduced activity in the rostral ventromedial medulla in response to the noxious stimuli in the low testosterone women, suggesting that failure to engage pain inhibition at this level might be involved in the increased sensitivity to pain in this group. NC women showed higher amygdala activation when compared to high testosterone HC women, but this was not seen when comparing with the low testosterone HC women.

Cognitive Tasks

Gingnell et al. (2016) published an fMRI RCT on the effects of HC on brain reactivity during response inhibition, where participants were asked to complete a go/no-go inhibition task. All participants were scanned at baseline and again during the last week of a 21-day treatment cycle. Only the women in the HC group improved performance significantly. HC women showed decreased reactivity in the right orbitofrontal cortex during correct response inhibition. Based on these findings the authors suggest that the use of HC does not necessarily have a negative impact on cognitive control and that, if anything, it might lead to a slight improvement.

Pletzer et al. (2014) assessed fMRI activations during two different numerical tasks which in previous studies had shown systematic sex differences in behavioral performance. HC users were compared to NC women in the follicular and luteal phases of their menstrual cycles, as well as to a group of men. They tested the assumption that brain effects of the synthetic form of progesterone in HC could be induced either by androgenic influences of these progestins (HC group should resemble men), by progestogenic influences (HC group should resemble the luteal group) or through an attenuation of endogenous steroids (HC groups should resemble the follicular group). The HC women resembled the follicular women the most regarding behavioral performance, but their BOLD response resembled that of the men in both cognitive tasks. The main conclusion drawn by the authors was that brain activation patterns in the HC users resembled that of men, but that no behavioral resemblance could be established.

Also employing cognitive tasks in which sex differences have previously been shown, Rumberg et al. (2010) employed fMRi scanning during a verb generation task which consisted of thinking about verbs corresponding to nouns being presented. They found increased activation in the right superior temporal lobe in HC women compared with NC women in their menstrual phase, and in the right inferior frontal cortex comparing with NC women in their mid-cycle phase.

Social cognition was evaluated by Mareckova et al. (2014) in a study on the influence of hormones on face perception. They recruited women using HC as well as NC women and performed fMRI scans while the women were shown ambiguous and angry faces. Both groups underwent fMRI scanning twice, once during the mid-cycle phase and once in the menstrual phase in both groups. Scans revealed stronger BOLD activation in the right fusiform face area in response to both ambiguous and angry faces in the HC groups as compared to the NC group.

Resting State and Functional Connectivity

Two of the research groups employed resting state fMRI to study the brain in the absence of tasks. Petersen et al. (2014) measured salivary hormone levels and compared brain activity in the anterior default mode network (DMN) and executive control network (ECN) in early follicular NC women, luteal NC women, HC users in active and inactive pill phases. They found that both endogenous hormone fluctuations and administration of synthetic sex hormones were associated with changes in these networks. De Bondt et al. (2015b) assessed hormone levels as well as symptoms of PMS in NC and HC women in addition to conducting fMRI analyses, but found no significant alterations in the DMN or ECN as a result of neither menstrual cycle phase nor the use of HC. They did, however, observe a positive correlation between PMS-like symptoms in women using HC and functional connectivity in the posterior part of the DMN.

Only one functional study ( Mareckova et al., 2014 ) investigated HC effects on a purely adolescent sample. This sample included teenagers from the age of 13.5–15.5 years. In this study, ROI findings from experiments done on adult participants ( Mareckova et al., 2014 ) were replicated. The teenagers using HC showed increased activity in the left fusiform face area of the temporal lobe upon viewing video clips of faces with ambiguous facial expressions.

In summary, most of the identified neuroimaging studies found effects of HC usage on the female brain, mainly in areas involved in emotional and cognitive processing. However, methodological challenges in almost all the included studies limit our ability to accurately interpret their results and render our main hypotheses to some extent unresolved. The studies by Gingnell et al. (2013 , 2016) were the only RCTs concerning the effects of HC. The sample consisted of women with previously reported HC-induced adverse mood, and the articles demonstrated that in women with adverse mood effects, HC may influence negative emotional reactivity and neural networks involved in cognitive inhibition.

Most of the other studies also found effects of HC use on brain structure or function, but these studies had major methodological problems with regard to internal validity or statistical conclusion validity resulting from using familywise uncorrected analyses of MRI-images or small sample sizes. Thus, although we discuss the possible implications of the findings, the reader should keep in mind that these studies are potentially biased. An overview of bias can be found in Supplementary Table 1 and methodological limitations are described in detail in a concluding section. Further, there was only one study with a sample of women in early adolescence, and this was a self-selected convenience sample and hence it may be biased. Thus, our hypothesis regarding effects in adolescence remains unresolved.

Implications of Structural and Functional Alterations

Most of the included studies indicate that several brain alterations are associated with the use of HC substances. We will discuss the most robust and convergent findings.

Several studies showed effects in areas of the brain known to be implicated in affective processing. Brain mechanisms involving affective changes caused by using of HC are crucial, due to their direct implications for mental health. This point is made convincingly by the register studies by Skovlund et al. showing that HC usage increases depression and suicide risk and that the effects are larger for the youngest women ( Skovlund et al., 2016 , 2018 ). According to Gingnell et al. (2013) the use of a combined HC has the potential to negatively affect mood and to induce changes in brain reactivity in structures involved in the processing of fear and other forms of negative affect. In the present review, their studies ( Gingnell et al., 2013 , 2016 ) were the strongest in terms of design, and are the only neuroimaging RCTs ever to be performed on functional brain effects of HC. The studies' risk of bias were small, but the researchers only included women with previously reported negative affect in response to the use of HC. Consequently, their sample is not representative for the general female population and external validity is hence limited. However, the study does contribute explanatory findings that are valid for women who experience adverse mood as a side effect of HC use. The women randomized to receive HC showed depressed mood after 1 month of use. This was linked to lower activity in frontal and insular brain areas upon viewing images of angry and fearful facial expressions, as compared to women randomized to receive placebo drugs. In the latter group, less amygdala reactivity was seen in response to images of emotional facial expressions upon a second exposure to these stimuli, whereas a difference upon re-exposure was not seen in women randomized to receive HC drugs. The researchers hypothesized that this might be indicative of decreased amygdala habituation in HC women, and as such attributed the deteriorated mood to an increased vigilance to emotional stimuli.

Further, several other studies in this review, shown in Tables 2 , 3 , indicate that HC use may affect structures in fear detecting and fear learning circuits in the brain, such as the amygdala. Amygdala functioning is strongly related to fear and learning of fear responses. This is clinically relevant, as fear learning is involved in phobias and other anxiety disorders ( Phelps and LeDoux, 2005 ; Adhikari et al., 2015 ; Hu et al., 2017 ). However, the findings are inconsistent, and the studies are heterogenous and confounded by lack of control regarding the androgenic and anti-androgenic effects of the progestins involved. Thus, a balanced interpretation would be that HC use likely affects fear circuits, but that the underlying mechanisms of such effects are not yet understood.

Several studies focused on cognition. The inferior and middle frontal gyri, in particular on the right side of the brain, are associated with inhibition and attentional control ( Booth et al., 2005 ; Aron et al., 2014 ). In a 2016 RCT, Gingnell et al. (2016) found decreased activity in the right middle frontal gyrus in HC women during a repeated go/no-go inhibition task, both comparing to the pre-treatment cycle and to the NC women. No difference in performance was detected at baseline, but the behavioral performance of the HC women improved more than that of the NC women in the retest session. The authors speculated that this might mean reduced effort in maintaining inhibitory control in the HC women leading to an enhanced inhibitory control in women taking these drugs. Thus, the reduced BOLD activations may be interpreted as increased efficiency and not as an expression of behavioral disinhibition.

Many of the included studies showed effects on the parahippocampal gyrus, both structurally ( Pletzer et al., 2010 , 2015 ; Lisofsky et al., 2016 ) and functionally ( Merz et al., 2012 ; Lisofsky et al., 2016 ). The parahippocampal gyrus is highly interesting in the context of sex hormones, as it is involved in encoding spatial layout of three-dimensional “scenes” ( Furuya et al., 2014 ). Spatial cognitive ability is one of the cognitive functions where the largest sex differences have been shown ( Voyer et al., 1995 ). However, none of the included studies focused on visuospatial cognition, where functional effects of the identified structural findings would be expected. The structural findings are inconsistent, as Lisofsky et al. (2016) found decreased parahippocampal volume in HC users, whereas Pletzer et al. (2010) found increased volume. Pletzer et al. suggest that an explanation may be that some progestins in HC are androgenic while others are anti-androgenic. They found larger gray matter volumes in the parahippocampal gyri in users of anti-androgenic progestins, but not in users of androgenic progestins, both compared to NC women. The Lisofsky article did not report the specific type of progestin, leaving this inconsistency unresolved.

Facial perception is a process considered to be important for social cognition which is a cognitive function where sex-differences have been found. The fusiform face area plays a role in facial recognition ( Axelrod and Yovel, 2015 ) and effects in this area was reported in the structural studies by Pletzer et al. (2010 , 2015) as well as the functional Marečková studies ( Mareckova et al., 2014 ) conducted with adult and adolescent samples. These studies found increased BOLD response in the fusiform face area upon viewing ambiguous and angry faces. The Marečková findings also provide a link between duration of HC use and extent of impact on the brain, as the activity in this area was increased as a function of length of use. The authors suggest a long-term plastic adaptation of the brain related to the use of HC. Thus, HC may influence social cognition, although the functional implications are unresolved.

Several research groups found functional effects of HC use in areas involved in the regulation of reward and motivation. The researchers used food-related, romantic, and sexual as well as monetary stimuli as a means of measuring such effects. The most important areas in the brain regarding reward, involve the dopaminergic mesolimbic structures such as nucleus accumbens in the striatum as well as the ventral tegmental area (VTA) ( Arias-Carrion et al., 2010 ). Oxytocin-releasing neurons terminate on these areas and oxytocin is thought to mediate reward ( Peris et al., 2017 ). Changes in these systems may affect all forms of motivated behaviors, thus having important effects in all areas of life. For instance, the study by Scheele et al. (2016) which assessed perceived partner attractiveness, found that upon viewing the partner's face, treatment with oxytocin increased the behavioral evaluation of partner attractiveness as well as BOLD responses in the nucleus accumbens and the VTA, in the NC group. This was not found in the HC group. The possible implication is that HC may attenuate partner-bonding. This remains speculative but should be explored further due to the seriousness of the potential consequences. The studies on sexual, monetary and food-related rewards ( Abler et al., 2013 ; Bonenberger et al., 2013 ; Basu et al., 2016 ) suffer from possible retest effects in only some of the subjects, post-hoc finding present only in an ROI based analysis and a small sample, respectively, thus presenting with reduced validity.

Lack of Pure Adolescent Samples

In addition to hypothesizing about the ability of HC to affect structural and functional aspects of the brain, we expected effects to be larger in adolescent subjects than in adult subjects. However, as we identified only one neuroimaging study ever to be performed on a purely adolescent sample, this hypothesis remains unresolved and the effects of such drugs on developing brains remain undetermined. The studies included many older subjects, making it impossible to disentangle potential differences between effects on the adolescent brain and effects on the adult brain. None of the studies investigated structural changes related to the use of HC in drug-naïve teenagers, but rather included convenience samples with mostly adult subjects. Only one functional study ( Mareckova et al., 2014 ) included a strictly adolescent sample, but there was no direct comparison with older subjects, nor any statistical test of age-covariates.

Given the evidence from the animal literature, as well as clinical registry studies such as that by Skovlund et al. (2016 , 2018) , which strongly indicate an increased vulnerability of the brain during adolescence, combined with the fact that girls are using these substances from an early adolescent age, we argue that there is a strong need for future studies to be carried out on adolescent use of HC.

Methodological Limitations in the Included Studies

We applied the validity typology of Donald Campbell and Thomas D. Cook ( Cook et al., 1979 ) which encompasses 4 types of validity threats with regard to our ability to make causal inferences: Internal validity, external validity, statistical conclusion validity and construct validity. While all types are important, low internal validity is paramount as is concerns whether an intervention was the likely cause of an effect. Thus, internal validity mainly encompasses confounders. See Supplementary Table 1 for a summary of the quality evaluation.

With the exception of Gingnell et al. (2013 , 2016) , none of the studies randomized participants to receive either HC or placebo, and most of the studies were observational with no inclusion of HC-naïve women. Hence, only the Gingnell studies reached high internal validity. The combined structural and functional MRI study by Lisofsky et al. (2016) achieved intermediate internal validity as they employed a pre-post quasi-experiment with control group, because even though the subjects self-selected to use HC, risk of bias was lowered due to the longitudinal design, enabling comparisons of within and between group effects. Yet, this design cannot control for effects of previous use. While this is true also for Gingnell, they explicitly aimed to generalize to a population of previous users. Thus, as stated previously, the Gingnell study cannot be generalized to the population of all women.

The conclusion regarding internal validity is that all studies, except the ones by Gingnell et al. were susceptible to bias and confounding due to selection phenomena and unobserved variables. Convenience sampling without disclosed detail concerning recruitment, as well as lack of randomization and control groups in almost all of the included studies, makes it impossible to ascertain causality.

Furthermore, most studies had poor control regarding type of substance currently or previously used, and no control for age at start of previous use, leading to low external validity. This critique also pertain to the Gingnell RCTs, as it is only possible to generalize to women with previous negative mood effects while using HC.

Most studies had low statistical conclusion validity, with small samples, resulting in low statistical power, making negative findings difficult to interpret, but also to an increased risk of false positive results ( Button et al., 2013 ). Many of the findings were also based on ROI analyses without familywise error (FWE) corrected whole brain analyses. ROI areas can be chosen based on post-hoc considerations, and so there should be a strong theoretical and/or empirical basis for choice of ROI areas. Several studies also employed whole brain analyses without correction for FWE. This may have led to type 1 errors.

Thus, while most studies found effects of HC on brain function or structure, confounding cannot be ruled out. While different studies had different methodological problems, the main source of low validity was self-selection in all of these studies, with the exception of the Gingnell studies. Thus, we discuss the effects of self-selection in the next paragraph.

The Impact of Sampling Bias and Self-Selection

Self-selection is a major internal validity threat in all of the non-randomized studies and is highly problematic in the present context. Choosing or not choosing to use HC may be influenced by various psychological factors that are associated with differences in brain structure and function. Mental and behavioral functions are, to a large extent, determined by brain function which ultimately is determined by brain structure. Thus, in the absence of randomization, self-selection by choosing or not choosing to use contraceptive drugs could be caused by psychological factors that are at least partly determined by brain function or structure. This could lead to serious confounding that could threaten internal validity.

Delayed sexual debut or sexual abstinence are examples of behaviors that may in part be determined by differences in brain function or structure when contrasted with being sexually active. Personality factors such as extraversion are central in this regard. In a large Dutch study, extraversion was found to affect friendships which again affected sexual debut and behavior ( van Leeuwen and Mace, 2016 ). A meta-analysis including altogether 420,595 subjects showed that extraversion was clearly positively associated with sexual activity ( Allen and Walter, 2018 ). Extraversion is further associated with distinct resting state fMRI patterns, such as increased long-range functional connectivity ( Pang et al., 2017 ). Structurally, it is associated with smaller gray matter volumes in the bilateral basal ganglia and increased dopamine receptor density in the striatum ( Baik et al., 2012 ). Also, negative associations with right PFC volumes have been found ( Forsman et al., 2012 ). This exemplifies how closely sexual activity is related to personality, which is further associated with differences both in brain function and structure. It thus illustrates how self-selection may have seriously confounded the included studies.

Another important source of possible bias is discontinued use of HC due to negative side effects. Different women may experience different side effects, and if such effects are not independent from brain function or structure, this will bias the finding. Thus, women who have chosen not to continue using HC will not be included in studies on effects of such drugs, unless the design of the study is a randomized design, and not based on self-selection.

As almost all the included studies were non-randomized case control-studies they might have ignored factors like these, and this might have introduced a strong sampling or selection bias. If the researchers had used only drug-naïve subjects for both controls and HC users, one could eliminate possible confounding effects of earlier use on their brains. By also employing longitudinal designs with drug-naïve subjects and pre-usage measures of brain-behavior relationships, validity could be further increased.

Contraceptive Content and Routes of Administration

There is a wide variety of HC drugs available, and these might affect the female brain in different ways. The orally administered drugs can be combination pills that commonly consist of ethinylestradiol and a progestin, or progestin-only formulations. They may have different cycle regimens, such as mono-, bi-, tri-, and quadriphasic as well as flexible regimens. Both the estrogen and the progestin contents of these pills have been gradually lowered over the years in an effort to reduce side effects ( Christin-Maitre, 2013 ).

Different types of formulation may also be associated with different side effects. Some progestins are considered to have androgenic properties, while others may have anti-androgenic effects on brain and behavior ( Pletzer and Kerschbaum, 2014 ; Giatti et al., 2016 ). Progesterone may lead to reduced testosterone action due to affinity for the enzyme 5α-reductase, and this may reduce conversion of testosterone into the more potent dihydrotestosterone ( Pletzer and Kerschbaum, 2014 ). Combined oral contraceptives with a progestin content considered to be anti-androgenic, such as drospirenone and desogestrel, have been postulated to be favorable in terms of mood symptoms in comparison with progestins displaying an androgenic profile ( Poromaa and Segebladh, 2012 ).

Alternative administration routes have also been developed over the years, such as vaginal or transdermal. Long-acting reversible contraception (LARC) such as progestogen-releasing intrauterine devices as well as injectable substances and implantable devices are effective contraceptive options that have become increasingly popular in the past decades ( Kavanaugh et al., 2015 ). Several of the included studies have recruited participants not using the same drug and/or using different routes of administration, and other studies do not provide information about these variables. This introduces the chance of committing type II errors and hence neglecting to uncover effects of the given drugs, since other drugs studied simultaneously, but having a different profile, may have counteracted or canceled out the effects on a group level.

Conclusions

This review found evidence that the use of HC can alter both structure and function of the brain. Furthermore, it contributed to accentuating the need for future research on HC and the ways in which they may affect the brain. There is a need for systematic research that considers the differences in formulation and administration of the various contraceptive drugs, employing a longitudinal, within-subject design with matched and randomized control groups consisting of HC-naïve subjects.

The impact of structural changes in the brain on functional outcomes such as motivational factors, affective phenomena and cognitive abilities should indeed be further investigated. Given the well-known sex hormone-dependent brain plasticity ( Schulz and Sisk, 2016 ), adolescence may be seen as a window of both increased opportunity and increased vulnerability, where implications of interference with endogenous processes could be far-reaching and affect emotional, relational, educational and vocational aspects of life. As a substantial number of women start using HC at a young age ( Martinez et al., 2020 ), these are issues that need to be scientifically addressed in order to provide female adolescents with individualized and informed contraceptive choices.

Author Contributions

MB: initial draft. MB and KB: conception/design and acquisition. All authors: analysis, interpretation of data, revision, final approval, and agreement to be accountable for all aspects of the work.

This project was partially funded by a research grant provided to author MB by Stavanger University Hospital, Psychiatric Division.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyg.2020.556577/full#supplementary-material

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Keywords: hormonal contraceptives, brain, neuroimaging, MRI, PET, EEG

Citation: Brønnick MK, Økland I, Graugaard C and Brønnick KK (2020) The Effects of Hormonal Contraceptives on the Brain: A Systematic Review of Neuroimaging Studies. Front. Psychol. 11:556577. doi: 10.3389/fpsyg.2020.556577

Received: 28 April 2020; Accepted: 25 September 2020; Published: 27 October 2020.

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Copyright © 2020 Brønnick, Økland, Graugaard and Brønnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Marita Kallesten Brønnick, mk.bronnick@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Contraception and Birth Control Research Activities and Advances

NICHD relies on several organizational units to study different aspects of contraception, from the biological mechanisms of different methods to the relevant decisions and behaviors of individuals and couples. The information below describes a few of these activities.

Institute Activities and Advances

NICHD has long been a source of funding for and expertise on contraception research. Extramurally, this expertise and support is led by what is now the Contraception Research Branch (CRB) , although it has had slightly different names over the years. For some time, the CRB has focused on supporting and conducting research in contraceptive discovery and development, including dual-use methods that prevent both pregnancy and sexually transmitted diseases (STDs) . The Branch is the largest source of support for research on contraceptive development within the federal government. It has responsibility for discovery, development, and evaluation of contraceptive agents.

The CRB uses a combination of grants and contracts to support and/or conduct activities including (but not limited to):

• Phase I, II, III, or IV clinical trials to evaluate the safety and efficacy of new contraceptive methods for women and men
• Research to develop methods for male contraception, including hormonal and nonhormonal control of sperm production and/or sperm function
• Basic and translational contraceptive research and development that may lead to new hormonal or nonhormonal methods for inhibiting ovulation or fertilization
• Experimental studies in animals to determine the safety and efficacy of novel potential contraceptive agents
• Research to define optimal formulations and dosages of contraceptive agents, spermicidal microbicides, and therapies (in animals and humans)
• Projects, as appropriate, on health effects related to contraceptive use and its relationship with other health issues, such as cancer
• Expertise about contraception and contraceptives that contributes to discussions, reports, and evidence-based recommendations, including those of the Cochrane Collaboration and the World Health Organization

The CRB addresses many of these research topics through cooperative agreements with research centers and research networks. These collaborative approaches are described in the Other Activities and Advances section.

Other extramural Branches—such as the Population Dynamics Branch (PDB) , the Fertility and Infertility (FI) Branch , and the Gynecologic Health and Disease Branch (GHDB) —study different aspects of contraception, but not development or testing of contraceptive agents. For example:

• PDB funds research on demographic, social, and behavioral aspects of sexual behaviors and their relationship to contraceptive use and non-use in both domestic and international populations. These efforts include studies of the determinants and consequences of contraceptive use in men and women, and basic and interventional research on the sexual transmission of HIV and other STDs. A particular focus of Branch-funded research is the interrelationships among pregnancy, pregnancy prevention, and prevention of STDs.
• The FI Branch supports research to alleviate human infertility, uncover new possible pathways to control fertility, and expand fundamental knowledge of processes that underlie human reproduction. Within this context, the FI Branch studies molecular and basic mechanisms of reproductive processes as a way to regulate fertility.
• GHDB supports basic, translational, and clinical research programs related to gynecologic health throughout the reproductive lifespan, starting at puberty and extending through the early menopause. Branch projects include studies to understand and treat gynecological problems, such as endometriosis, uterine fibroids, and heavy menstrual bleeding, including using contraceptive agents in these treatments.

In 2014 to 2015, NICHD convened an expert panel, comprising experts in basic, clinical, and behavioral research and representatives of industry and non-governmental organizations. The panel was charged with assessing the past accomplishments and impact of NICHD's contraceptive research initiatives, the current status of contraception research at and funded by NICHD, and suggestions for future activities and directions in contraception research. Activities of the CRB, PDB, and FI Branch were the focus of the panel's efforts.

The panel presented its findings to the NICHD advisory council in January 2015, and NICHD is in the process of implementing some of the panel's findings and ideas. You can read more about the panel and its findings at Assessment of the Contraceptive Research Activities of the NICHD: Executive Summary (PDF - 138 KB).

The Cell Regulation and Development Affinity Group , part of the Institute's  Division of Intramural Research (DIR) , investigates the molecular basis of peptide hormone control of gonadal function and is working on research to support the development of a male contraceptive.

As NICHD continues shifting the priorities of its various components, its commitment to supporting and conducting contraception research—including development of new contractive compounds—remains.

Other Activities and Advances

• The ability of progestin- and testosterone-based topical gels to inhibit sperm production to provide hormonal contraception for men
• A progesterone receptor modulator, CDB-2914, as an emergency oral contraceptive for women when taken within 72 hours of unprotected intercourse
• The effectiveness of a new female condom to prevent both pregnancy and STDs
• Progestin-based compounds that can prevent pregnancy without increasing the risk of blood clots and other venous thromboembolism-type conditions, especially in obese women
• A progestin- and estradiol-releasing vaginal ring that would be an effective contraceptive without increasing the risk of blood clots and other venous thromboembolism-type conditions, especially in obese women
• Developing a male contraceptive that inhibits an enzyme needed to produce sperm
• Developing a vaginal ring that acts as a contraceptive and also promotes brain health
• Understanding how egg cells develop and mature and how they are released to be fertilized
• Developing new delivery methods for contraceptive agents
• Developing dual-use compounds that protect against sexually transmitted infections and pregnancy
• Conducting translational research to identify or optimize male contraceptive products
• Developing nonhormonal contraception methods that inhibit ovulation
• How mechanisms regulating sperm maturation might be targeted by novel male contraceptives
• How sperm development could be inhibited using l targets, such as by disrupting the tight junctions between Sertoli cells and germ cells
• Testing of injectable form of acyline, a male hormonal contraceptive, to assess safety and ability to suppress spermatogenesis
• Development of an oral contraceptive for men, H2-gamendazole

Birth Control

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• Should Health Insurance Companies Provide Complete Coverage for Birth Control?
• Does learning about birth control in school help prevent teen pregnancy?
• Should pharmacists be allowed to refuse to fill emergency contraception prescriptions?
• Should Americans have easier access to contraception?
• What are some of the current birth control options?
• How are federal reproductive health rights legislation or denied by state and local government?
• Laws about RU-486 or "morning after pill"?
• What myths about health risks associated with contraceptive devices?
• Should birth control be taught in school as a way of preventing teen pregnancy?
• Should schools distribute birth control?
• What are some of the religious/ethical issues arising from the usage of birth control?
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Home — Essay Samples — Nursing & Health — Public Health Issues — Birth Control

Birth Control Essay Examples

Birth control essay topics and outline examples, essay title 1: birth control methods and their impact on reproductive health and family planning.

Thesis Statement: This essay explores various birth control methods, their effectiveness, and their impact on reproductive health and the ability to make informed family planning decisions.

• Introduction
• Overview of Birth Control Methods: Contraception Options and Their Mechanisms
• Effectiveness and Safety: Evaluating the Reliability and Risks of Different Methods
• Reproductive Health: Discussing the Positive and Negative Effects of Birth Control
• Family Planning: Examining the Role of Birth Control in Decision-Making
• Access and Education: Addressing Barriers and Promoting Awareness
• Conclusion: Empowering Individuals to Make Informed Choices

Essay Title 2: The Societal Impact of Birth Control: Shaping Gender Equality, Family Dynamics, and Healthcare Policies

Thesis Statement: This essay delves into the societal consequences of birth control, including its role in promoting gender equality, influencing family structures, and shaping healthcare policies.

• Gender Equality: Analyzing How Birth Control Empowers Women and Promotes Equal Opportunities
• Family Dynamics: Exploring Changes in Family Size, Planning, and Roles
• Healthcare Policies: Investigating the Accessibility and Regulation of Birth Control
• Ethical Considerations: Discussing Moral and Religious Perspectives
• Global Impact: Examining Birth Control in the Context of Population Control and Development
• Conclusion: Reflecting on Birth Control's Evolving Role in Society

Essay Title 3: Birth Control Education: Promoting Comprehensive Sexual Health Programs for Informed Choices and Safer Practices

Thesis Statement: This essay advocates for comprehensive sexual health education programs that equip individuals with knowledge about birth control options, safe practices, and informed decision-making.

• Sexual Health Education: The Importance of Providing Comprehensive and Accurate Information
• Birth Control Methods: Teaching About Options, Effectiveness, and Risks
• Safe Practices: Promoting Responsible and Consensual Sexual Behavior
• Addressing Myths and Misconceptions: Dispelling Common Misinformation
• Role of Schools and Parents: Collaborative Approaches to Sexual Health Education
• Conclusion: Fostering a Knowledgeable and Empowered Youth

The Importance of Birth Control in Preventing Unwanted Pregnancy

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The in vitro fertilization, teenage pregnancy: health concerns and the ways to prevent, analysis of low fertility rate and its outcomes, get a personalized essay in under 3 hours.

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Exploring The Association Between Oral Contraceptive Pills and Glaucoma

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Research on velocity feedforward control and precise damping technology of a hydraulic support face guard system based on displacement feedback.

1. Introduction

2. establishing the mechanical–hydraulic coupling analysis model for the hydraulic support face guard system, 2.1. modelling the mechanical sub-model, 2.2. modelling the hydraulic sub-model, 2.3. static operation testing of the hydraulic support face guard system, 3. designing the face guard structure controller, 3.1. design of adaptive fuzzy pid controller, 3.2. introduction of feedforward compensation, 4. simulation results and analysis, 4.1. unified simulation model, 4.2. controller tracking performance testing, 4.3. controller disturbance rejection performance test, 4.4. influence of pressure loss on the performance of the controller, 4.5. analysis of the coal wall’s response to impact, 5. conclusions, author contributions, data availability statement, conflicts of interest.

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Zeng, Q.; Hu, Y.; Meng, Z.; Wan, L. Research on Velocity Feedforward Control and Precise Damping Technology of a Hydraulic Support Face Guard System Based on Displacement Feedback. Machines 2024 , 12 , 676. https://doi.org/10.3390/machines12100676

Zeng Q, Hu Y, Meng Z, Wan L. Research on Velocity Feedforward Control and Precise Damping Technology of a Hydraulic Support Face Guard System Based on Displacement Feedback. Machines . 2024; 12(10):676. https://doi.org/10.3390/machines12100676

Zeng, Qingliang, Yulong Hu, Zhaosheng Meng, and Lirong Wan. 2024. "Research on Velocity Feedforward Control and Precise Damping Technology of a Hydraulic Support Face Guard System Based on Displacement Feedback" Machines 12, no. 10: 676. https://doi.org/10.3390/machines12100676

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• Published: 28 September 2024

Efficient DC motor speed control using a novel multi-stage FOPD(1 + PI) controller optimized by the Pelican optimization algorithm

• Mostafa Jabari 1 ,
• Serdar Ekinci 2 ,
• Davut Izci 2 , 3 , 4 ,
• Mohit Bajaj 5 , 6 , 7 &
• Ievgen Zaitsev 8 , 9  

Scientific Reports volume  14 , Article number:  22442 ( 2024 ) Cite this article

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• Electrical and electronic engineering
• Energy science and technology
• Engineering
• Mathematics and computing

This paper introduces a novel multi-stage FOPD(1 + PI) controller for DC motor speed control, optimized using the Pelican Optimization Algorithm (POA). Traditional PID controllers often fall short in handling the complex dynamics of DC motors, leading to suboptimal performance. Our proposed controller integrates fractional-order proportional-derivative (FOPD) and proportional-integral (PI) control actions, optimized via POA to achieve superior control performance. The effectiveness of the proposed controller is validated through rigorous simulations and experimental evaluations. Comparative analysis is conducted against conventional PID and fractional-order PID (FOPID) controllers, fine-tuned using metaheuristic algorithms such as atom search optimization (ASO), stochastic fractal search (SFS), grey wolf optimization (GWO), and sine-cosine algorithm (SCA). Quantitative results demonstrate that the FOPD(1 + PI) controller optimized by POA significantly enhances the dynamic response and stability of the DC motor. Key performance metrics show a reduction in rise time by 28%, settling time by 35%, and overshoot by 22%, while the steady-state error is minimized to 0.3%. The comparative analysis highlights the superior performance, faster response time, high accuracy, and robustness of the proposed controller in various operating conditions, consistently outperforming the PID and FOPID controllers optimized by other metaheuristic algorithms. In conclusion, the POA-optimized multi-stage FOPD(1 + PI) controller presents a significant advancement in DC motor speed control, offering a robust and efficient solution with substantial improvements in performance metrics. This innovative approach has the potential to enhance the efficiency and reliability of DC motor applications in industrial and automotive sectors.

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Introduction.

The application of DC motors is of significant importance within the engineering domain, primarily attributed to their manageability, longevity, and cost-efficiency according to Deng, et al. 1 and Varatharajan, et al. 2 . Nevertheless, the management of speed poses a formidable challenge owing to intricate surroundings and nonlinear dynamics, resulting in potential instability 3 , 4 . Furthermore, DC motors exhibit high sensitivity towards disturbances in load, consequently leading to notable speed deviations. These disturbances may stem from alterations in load torque, fluctuations in power supply, or external environmental influences 2 , 5 . Moreover, fluctuations in motor characteristics such as variations in resistance, inductance, or back electromotive force (EMF) constant, attributed to factors like aging, temperature fluctuations, or inconsistencies in manufacturing, can introduce challenges in upholding consistent motor performance. This aspect becomes particularly critical in domains such as robotics, industrial automation, and electric vehicles, where even slight deviations in speed can trigger substantial performance issues or operational breakdowns 3 , 6 , 7 .

Several control methodologies have been developed in order to tackle these obstacles. The PID controllers are frequently employed in industrial settings because of their straightforwardness and efficiency in improving the transient and steady-state behaviors of systems 8 . These controllers modulate the control input by monitoring the error signal, offering a well-rounded approach to error rectification. Nonetheless, conventional PID controllers may encounter difficulties in handling the nonlinear and variable characteristics of DC motor dynamics, particularly in the presence of significant disturbances or parameter variations 9 . To enhance performance, advanced control approaches have been explored, with FOPID controllers emerging as a viable solution 10 . FOPID controllers exhibit superior performance and resilience compared to the traditional PID controllers in scenarios involving complex systems like DC motors that manifest nonlinearities and uncertainties 11 , 12 . By incorporating fractional calculus, FOPID controllers extend the capabilities of conventional PID controllers, enabling more adaptable tuning of control actions 13 . This enhanced flexibility equips FOPID controllers to manage the intricacies of DC motor control more effectively, leading to improved robustness and stability 11 , 14 .

In the realm of DC motor speed control, various control strategies beyond PID and FOPID controllers have been developed to enhance precision and robustness. Neural network controllers (NNCs), as discussed in 15 , can effectively learn and adapt to the intricate dynamics of the motor system. Fuzzy logic controllers (FLCs), as highlighted in 16 and 17 , utilize a rule-based approach to manage uncertainties and imprecise data, offering a flexible solution. Adaptive controllers, as mentioned in 18 , dynamically adjust their parameters to accommodate evolving system dynamics, ensuring real-time optimization. Additionally, sliding mode controllers, as detailed in 19 , maintain stability by employing high-frequency switching, providing a robust mechanism to counter disturbances and parameter variations in DC motor speed control systems.

To optimize controller parameters, various metaheuristic optimization algorithms are utilized, mimicking natural processes for efficient solutions in complex spaces. Particle swarm optimization (PSO) and differential evolution (DE) excel in exploring global optima 20 . GWO and enhanced version of SCA leverage wolf social behavior and mathematical functions, respectively, for successful parameter fine-tuning 21 , 22 . The hybrid SFS (HSFS) algorithm, combining SFS and pattern search optimization, has shown remarkable advancements in balancing exploration and exploitation phases for optimization tasks 23 .

Hekimoğlu 11 presents a promising approach to optimally tune FOPID controllers for DC motor speed control using a novel chaotic optimization algorithm, addressing a significant challenge in the field of motor control and automation. The paper proposes the use of the chaotic atom search optimization (ChASO) algorithm to optimally tune the five parameters \(\:({K}_{P},{K}_{I},{K}_{D},\lambda\:,\mu\:)\) of the FOPID controller for a DC motor speed control system. Eker, et al. 24 utilizes a novel hybrid optimization algorithm that combines the ASO algorithm with the simulated annealing (SA) algorithm. This hybrid algorithm is applied to two challenging optimization problems: training a multilayer perceptron (MLP) neural network and tuning a controller for DC motor speed control.

Ekinci, et al. 25 presents a promising approach to optimally tune PID controllers for DC motor speed control using a novel physics-inspired optimization algorithm, the opposition-based Henry gas solubility optimization (OBL/HGSO), addressing a significant challenge in the field of motor control and automation. The proposed OBL/HGSO algorithm combines the HGSO algorithm with the OBL strategy, which aims to improve the exploration and exploitation capabilities of the optimization process. In Idir, et al. 26 presents a novel approach for enhancing the performance of DC motor speed control systems. The study leverages the henry gas solubility optimization (HGSO) algorithm to fine-tune a fractionalized PID controller, resulting in improved precision and efficiency. Ekinci, et al. 27 presents a novel hybrid optimization algorithm (OBL-MRFO-SA) for optimally tuning a FOPID controller for precise speed control of DC motors, addressing the challenges posed by nonlinearities and complex optimization problems. Izci 28 by using a novel hybrid optimization algorithm combining the Lévy flight distribution and the Nelder–Mead simplex method for optimally tuning a PID controller to achieve precise speed regulation of DC motors, addressing a significant challenge in the field of motor control and automation. Ekinci, et al. 29 present a new method called the gazelle simplex optimizer (GSO), aimed at improving PID controllers to precisely control the speed of DC motors. Results demonstrate the superior performance of the GSO-PID controller in terms of faster response, better disturbance rejection, and reduced steady-state error compared to other tuning approaches. The advancements and comparative performances of various optimization algorithms for tuning PID and FOPID controllers in DC motor speed control, are summarized in Table  1 .

In the domain of DC motor speed control, considerable progress has been made in refining control strategies and optimization algorithms. However, inherent challenges persist, necessitating further advancements. Traditional proportional-integral-derivative (PID) controllers are simple and widely used, but they cannot struggle with complex systems and large disturbances. Fractional-order PID (FOPID) controllers address these issues by using fractional calculus. This means that instead of just having integer values for the derivative and integral parts, FOPID controllers can use fractional values. This extra flexibility allows for more precise tuning of the control response, making them better suited for systems that are hard to model accurately with regular PID controllers. FOPID controllers also adapt better to changes in system conditions and disturbances. This makes them more robust and reliable across a range of situations. In terms of performance, FOPID controllers often offer better stability and responsiveness. They provide improved phase and gain margins, which helps in maintaining control stability 30 .

Additionally, FOPID controllers lead to smoother control actions. This reduces problems like overshoot and long settling times, which are common with traditional PID controllers. Overall, FOPID controllers provide better control, stability, and adaptability, making them useful in applications where precise and stable operation is crucial 31 . Optimization algorithms, including metaheuristic and hybrid methodologies, encounter challenges in striking a balance between exploration and exploitation, with their computational demands posing constraints on real-time applications. While promising techniques have emerged, concerns persist regarding their robustness across diverse operational conditions. Moreover, the lack of comprehensive validation in practical environments characterized by varying loads and dynamic parameter changes undermines the broader applicability of existing approaches. Addressing these challenges requires the development of robust and adaptive control strategies capable of seamlessly adjusting to dynamic environments. This necessitates innovative algorithmic designs and comprehensive validation methodologies to bridge the gap between theoretical advancements and practical implementation. By overcoming these obstacles, significant enhancements in DC motor speed control can be achieved, enhancing reliability and effectiveness across a range of application scenarios.

This study introduces a novel controller, the fractional-order proportional-derivative (FOPD)(1 + PI), specifically designed to enhance the speed regulation of DC motors. The key contributions of this work are as follows:

Novel controller design: The FOPD(1 + PI) controller represents a significant advancement over traditional PID and Fractional-Order PID (FOPID) controllers by combining fractional-order and proportional-integral components. This unique design enables the controller to effectively address the nonlinearities and uncertainties inherent in DC motor control, offering a more robust and adaptable solution.

Advanced optimization using the pelican optimization algorithm (POA) 33 : The parameters of the FOPD(1 + PI) controller are meticulously tuned using the POA to minimize the integral of time multiplied by absolute error (ITAE), ensuring optimal performance. The POA’s ability to balance exploration and exploitation phases leads to superior tuning results compared to 13 other metaheuristic algorithms.

Performance superiority: Simulation and comparative assessments demonstrate the superior performance of the proposed POA-FOPD(1 + PI) controller in terms of response time, accuracy, and robustness. It consistently outperforms controllers tuned with other metaheuristic algorithms, particularly under varying operating conditions and disturbances.

Resilience and practical application: The POA/FOPD(1 + PI) controller exhibits high performance even in the presence of system uncertainties and load disturbances, highlighting its potential for real-world applications in robotics, industrial automation, and electric vehicles, where consistent motor performance is critical.

Significance and advancement of the field: By addressing these challenges, this research significantly advances the field of DC motor speed control, providing a robust, adaptable, and high-performance solution that bridges the gap between theoretical advancements and practical implementation.

The paper is structured as follows: “ Mathematical model of the DC motor ” section presents the mathematical model of the DC motor. “ Proposed multi-stage controller FOPD(1+PI) ” section introduces the proposed multi-stage controller, FOPD(1 + PI). “ Optimization method ” section outlines the optimization method. “ Simulation and analysis ” section presents the simulation and analysis. Finally, “ Conclusions and future research directions ” section concludes the paper, summarizing the key findings and suggesting directions for future research.

Mathematical model of the DC motor

This paper investigates the use of an externally excited DC motor for speed control achieved through armature voltage adjustments. By analyzing this electrical schematic, a mathematical model can be formulated to achieve a comprehensive understanding of the motor’s performance and its electrical pathways, as outlined in Fig.  1 .

Equivalent circuit of a DC Motor.

When the flux remains constant, the induced voltage \(\:{e}_{b}\) ​ varies in direct proportion to the angular velocity \(\:{\omega\:}_{m}\) , which is the rate of change of rotation \(\:\frac{d\theta\:}{dt}\) 11 .

The armature voltage \(\:{e}_{a}\) ​, regulates the speed of an armature-controlled DC motor 34 , 35 . Finally, in accordance with the mathematical representation of the DC motor, the circuit can be described as follows:

where \(\:{i}_{a}\) , \(\:{R}_{a}\) , and \(\:{L}_{a}\) shown the armature current, armature resistance, and armature inductance of the DC motor, respectively.

The torque generated by the armature current is the combined effect of inertia and friction torques.

where \(\:{\omega\:}_{m}\:\) refers to the angular speed of motor shaft, \(\:J\:\) represents the moment of inertia, \(\:B\) motor friction constant, and \(\:K\) denotes the motor torque constant 36 .

Assuming all initial conditions of the system are zero, applying the Laplace transform to Eqs. ( 1 ) -( 3 ) will result in the following Eq. 

where \(\:{K}_{b}\) is electromotive force constant.

Finally, the open loop equation of the system for \(\:{T}_{L}=0\) is defined as follows:

Additionally, when the input voltage \(\:\left({E}_{a}\right)\) is zero, the relationship between the motor speed \(\:{(\omega\:}_{m})\:\) and the torque applied by the load \(\:\left({T}_{L}\right)\) can also be given as:

The block diagram of the closed loop DC motor speed control system using the proposed controller is shown in Fig.  2 . In this diagram, \(\:R\left(s\right)\) represents the reference speed, \(\:E\left(s\right)\) denotes the difference between the reference speed and the actual output speed, \(\:U\left(s\right)\) indicates the armature voltage, \(\:T\left(s\right)\) is the motor torque, \(\:{T}_{L}\left(s\right)\) indicates the load torque and \(\:Y\left(s\right)\) denotes the output speed.

Block diagram of closed-loop DC motor with proposed controller.

The modeling of the DC motor was conducted in the MATLAB/Simulink environment, employing mathematical modeling techniques. The parameters utilized for the DC motor modeling in this research are outlined in Table  2 11 .

Proposed multi-stage controller FOPD(1 + PI)

This controller combination increases system dynamics and enables it to respond quickly to load changes and disturbances, surpassing the capabilities of traditional PI and FOPID controllers. Through strategic manipulation of motor loads, the FOPD(1 + PI) controller achieves significant speed tracking accuracy in shorter time intervals and effectively reduces steady-state errors and damping instabilities for smoother control performance.

In addition, the FOPD(1 + PI) controller significantly increases stability and performance, especially in ultra-fast tracking of reference speeds under various DC motor conditions. This capability is necessary to maintain stability in highly dynamic environments. Its skill in controlling instability and optimizing control mechanisms not only enhances control accuracy, but also optimizes motor efficiency by reducing unnecessary operational changes. By simplifying control responses and optimizing energy consumption, the FOPD(1 + PI) controller emerges as a powerful tool to achieve reliable and efficient performance in process control applications, which represents a significant advance in control technology. The block diagram illustrating the proposed controller is depicted in Fig.  3 .

Proposed FOPD(1 + PI) controller structure.

During first stage, the inclusion of FOPD leads to an enhanced system response. The fractional order operators introduced by the FOPD component accelerate the system’s response to changes and increase its performance in various situations.

The open-loop transfer function of the first stage controller is shown as Eq. ( 9 ):

Second stage provide stability and fine-tuned control for DC motor. The open-loop transfer function of the second stage controller is shown as Eq. ( 10 ):

The open-loop representation of the proposed controller can be depicted by Eq. ( 11 ).

According to the Eq. ( 7 ) and Eq. ( 11 ) for closed-loop system we have:

Finally, by substituting the parameter values, the closed-loop system’s transfer function is given by Eq. ( 13 ).

Moreover, an overview of the DC motor and the proposed controller studied in this research is depicted in Fig.  4 .

General scheme of the under-examination model.

Optimization method

Pelican optimization.

The suggested plan imitates the actions and tactics of pelicans in pursuing and capturing prey to refine potential solutions. This hunting approach is replicated through two phases 33 :

Advancing towards prey (exploratory phase).

Skimming the water surface with wings (exploitative phase).

In this stage POA consists of the initial movement towards the prey, which is referred to as the exploration phase. At this stage, the pelicans determine the hunting site and move towards it. Pelicans’ strategy involves scanning the search space and exploring different areas to find prey. The key aspect of POA is that the location of the bait is randomly generated in the search space, increasing the exportability of the algorithm. The movement of pelicans towards the prey by considering factors such as random numbers, the location of the prey and the value of the cost function, is shown mathematically in Eq. ( 14 ).

In Phase 1, the updated status of each pelican in a specific dimension, denoted as \(\:{X}_{i,j}^{{P}_{1}}\) , is determined. Here, the parameter I , a random number either one or two, is introduced. Additionally, \(\:{P}_{j}\) represents the prey’s location in the same dimension, \(\:{F}_{P}\) signifies the cost function value, and \(\:{F}_{i}\) is fitness value of the \(\:ith\) pelican. The parameter I varies randomly in each iteration and for every member. Its value of two prompts more significant displacement for a member, potentially leading them to explore new regions within the search space. Finally, the parameter I directly influences the POA exploration capability, allowing for a thorough scanning of the search space.

In the POA method, a pelican’s new position is only accepted if it results in an improvement in the cost function value. This selective updating mechanism, termed effective updating, prevents the algorithm from shifting towards non-optimal regions. This updating process is mathematically represented by Eq. ( 15 ).

where \(\:{X}_{i}^{P1}\) denotes the updated condition of the \(\:ith\) pelican, and \(\:{F}_{i}^{P1}\) ​​ signifies its cost function value derived from phase 1.

In next phase, when the pelicans reach the surface, they extend their wings across the water to push the fish up and subsequently collect the prey in their throat pouch. This tactic causes more fish to be captured by the pelicans in the target area. Simulating this pelican behavior increases the convergence of the proposed POA towards more favorable positions in the hunting area. This process enhances local exploration capabilities and exploitation potential. The effectiveness of POA stems from its systematic mathematical approach, where the algorithm methodically evaluates the nearest points relative to the pelican’s position, facilitating convergence towards a state-of-the-art solution. This mathematical representation corresponds to the hunting behavior of pelicans, as shown in Eq. ( 16 ).

In Eq. ( 16 ), the symbol \(\:{\:\:X}_{i,j}^{{P}_{2}}\) ​ denotes the updated status of the \(\:ith\) pelican in the \(\:jth\) dimension during phase 2. Here, R is a constant, fixed at 0.2. It is worth noting that the latter parameter is only adjustable parameter of the POA. The expression \(\:R.\left(1-\frac{t}{T}\right)\) represents the neighborhood radius of \(\:\:{X}_{i,j}\) ​, where t is the iteration counter and T is the maximum number of iterations. The coefficient \(\:R.\left(1-\frac{t}{T}\right)\:\) indicates the range of the neighborhood surrounding each member of the population, facilitating local search operations around each member aimed at converging towards an optimal solution. Initially, when t is small, this coefficient is large, leading to a wider exploration around each member. As the iterations progress, this coefficient decreases, thereby reducing the search radius around each member. Consequently, the algorithm systematically explores regions around population members with smaller and more precise steps, aiding in the convergence towards solutions closer to the global optimum. Equation ( 17 ) outlines the protocol for efficiently updating and determining the acceptance or rejection of the new position of the pelican during this phase.

where \(\:{X}_{i}^{P2}\) denotes the updated condition of the \(\:ith\) pelican, and \(\:{F}_{i}^{P2}\) ​​ signifies its cost function value derived from phase 2. Table  3 illustrates the optimization process steps using POA method.

Cost function definition

The cost function (CF) is a measure used by the designer to evaluate the dynamic response of the system. It is designed to ensure that the output of the desired control mechanism provides the most effective solution under various operating conditions with the specific cost of eliminating the steady state error of the system. This paper adopts the cost function as ITAE. The ITAE cost is defined as Eq. ( 18 ) 11 :

Here, \(\:\:{\Delta\:}S\) and \(\:{t}_{sim}\:\) are speed error between reference and actual angular speeds, and simulation time, respectively. The CF is restricted by the range of controller coefficients, defining the search space for the optimization problem as presented in Table  4 .

The POA optimization algorithm has been executed separately in twenty-five rounds, with Table  5 presenting the best, worst, and average CF values obtained with different controllers. Figure  5 illustrates the comprehensive flowchart of the proposed controller and the POA algorithm, which are implemented to enhance the performance of the DC motor speed control system. Figure  6 shows a comparative analysis using boxplots for three distinct algorithms: POA, WOA, and GWO, according to their effectiveness in minimizing the objective function. The boxplot displayed in Fig.  6 shows that the worst result obtained by the POA algorithm is significantly superior to the best results obtained by the other two algorithms, namely GWO and WOA. This emphasizes the obvious superiority of the proposed POA algorithm in terms of statistical performance.

Sufficient iterations of the POA algorithm have been conducted to ensure it converges to the optimal point. We utilize the POA technique to evaluate the effectiveness of the proposed controller. Figure  7 illustrates the results of this optimized approach, which achieves the lowest CF values after 50 iterations, thus highlighting the superior performance of the controller.

The schematic of the proposed controller utilizing the POA optimization method for regulating the speed of a DC motor.

Finally, Table  6 presents the optimal controller parameter values derived from the best results obtained through the POA algorithm.

Boxplots of POA, WOA and GWO algorithms using FOPD(1 + PI) controller.

Convergence profiles of POA, WOA and GWO algorithms using FOPD(1 + PI) controller.

To enable a comprehensive numerical comparison, calculations and reporting on time domain evaluation metrics have been conducted across various scenarios. These metrics include the integral of square error (ISE), integral of time-weighted square error (ITSE), integral of absolute error (IAE), and integral of time-weighted absolute error (ITAE). The corresponding equations for these metrics are outlined in Eq. (19) through (22) where, \(\:x\) is simulation time in \(\:s\) , and \(\:e\left(t\right)\) is an error signal between reference speed and actual speed in DC motor. Table  7 represents value of different cost function.

Simulation and analysis

In this section, the proposed FOPD (1 + PI) controller is operationalized and integrated into the DC motor control mechanism as discussed earlier. Moreover, these findings show a strong correlation between the results obtained from classical controllers 40 , 41 , 42 . Subsequently, the closed-loop system is implemented using MATLAB 2023a with Simulink. Using 50 iterations and participation of 20 particles, the POA algorithm effectively identifies the optimal controller coefficient values. The duration of the simulation is 2 s. The modeling of FO operators is facilitated through the use of the FOMCON plugin in this process, the frequency range for the operators is defined as [0.001, 1000] Hz, with an approximation order set to 5. Although we experimented with higher order approximations, they didn’t significantly alter the results when evaluated.in MATLAB 43 .

Frequency response analysis

The frequency response of a control system provides critical insights into its stability and performance. Key parameters such as gain margin, phase margin, and bandwidth are evaluated to assess the robustness of the system. The bode plot of the DC motor system employing the controller developed through the suggested method is depicted in Figs.  8 and 9 . Table  8 outlines the performance metrics of various approaches in terms of gain and phase margins, as well as bandwidth.

The gain margin of the proposed POA-FOPD(1 + PI) controller is infinite, indicating that the system is highly robust to gain variations. This robustness is superior compared to controllers such as GWO-FOPID, which exhibit lower phase margins. A higher gain margin typically correlates with increased stability, allowing the system to tolerate greater disturbances without compromising performance. The phase margin for the proposed controller is 179.5780°, which is close to 180°, suggesting excellent phase stability. This high phase margin ensures that the system remains stable even in the presence of phase variations due to changes in the motor’s operating conditions. The bandwidth of the POA-FOPD(1 + PI) controller is 950.3757 Hz, which is significantly higher than that of other controllers. This indicates that the proposed controller can effectively manage high-frequency components, resulting in a faster response to transient conditions and better overall performance.

Frequency response in proposed and FOPID controllers.

Frequency response in proposed and PID controllers.

Analyzed DC motor in different operation

Time response characteristics such as rise time, settling time, overshoot, and peak time are critical indicators of a control system’s performance. These parameters provide insights into how quickly and effectively the system can respond to changes in input or disturbances. In this section, we delve into the analysis of a DC motor operating under five distinct modes characterized by varying armature resistance \(\:{R}_{a}\) and motor constant \(\:K\) . Table  9 shows the different \(\:{R}_{a}\:\) and \(\:K\) values in various operation modes.

Mode 1: R a  = 0.30 and K  = 0.012

In this mode, the DC motor exhibits specific characteristics dictated by a relatively low armature resistance and motor constant. Lower armature resistance implies reduced power losses and improved efficiency. However, the lower motor constant may result in comparatively lower torque production and speed capabilities. This mode might be suitable for applications prioritizing energy efficiency over high torque output. Figures  10 and 11 illustrate step response of DC motor for proposed and other controller in mode 1. Also, Table  10 shows transient response of proposed controller.

In Mode 1, the proposed POA-FOPD(1 + PI) controller achieves a rise time of 0.0031 s, significantly faster than the ASO-FOPID and other traditional controllers. This rapid response is critical in applications requiring quick adjustments, ensuring that the motor reaches the desired speed swiftly. The settling time is reduced to 0.0054 s, showcasing the controller’s ability to stabilize the system quickly after a disturbance. This reduction in settling time minimizes the duration of transient states, leading to improved operational efficiency. The overshoot in Mode 1 is effectively minimized to 0.0016%, which is substantially lower than the overshoot observed with GWO-FOPID and other controllers. By limiting overshoot, the proposed controller prevents excessive deviations from the desired speed, thus enhancing system stability. The peak time is also optimized at 0.4498 s, indicating that the motor quickly reaches its maximum response without prolonged delays. This is beneficial in maintaining a responsive and agile system.

Step response of proposed and PID controllers in DC motor with \(\:{R}_{a}=0.30\) and \(\:K=0.012\)

Step response of proposed and FOPID controllers in DC motor with \(\:{R}_{a}=0.30\) and \(\:K=0.012\)

Mode 2: R a  = 0.30 and K  = 0.018

Transitioning to mode 2, we maintain the same armature resistance as mode 1 but introduce a higher motor constant. This adjustment enhances the motor’s torque capabilities and speed performance while still benefiting from the lower armature resistance’s efficiency gains. Mode 2 may find application in scenarios requiring moderate torque with improved speed dynamics. Figures  12 and 13 illustrate step response of DC motor for proposed and other controller in mode 2. Also, Table  11 shows transient response of proposed controller.

For Mode 2, the POA-FOPD(1 + PI) controller achieves an exceptional rise time of 0.0021 s. This rapid rise time is indicative of the controller’s capability to respond almost instantaneously to input changes, which is crucial in scenarios where fast speed adjustments are necessary. The controller’s settling time is reduced to 0.0037 s, demonstrating its effectiveness in quickly bringing the system to a steady state. This rapid stabilization is essential in maintaining consistent performance even with varying load conditions. The proposed controller limits the overshoot to 0.0026%, a significant improvement over traditional controller. This minimal overshoot ensures that the motor’s speed remains within a tight range around the desired setpoint, preventing potential instability. With a peak time of 0.0127 s, the motor reaches its maximum response quickly, ensuring that the system is both responsive and efficient. This is particularly beneficial in high-performance applications where speed and precision are critical.

Step response of proposed and PID controllers in DC motor with \(\:{R}_{a}=0.30\) and \(\:K=0.018\)

Step response of proposed and FOPID controllers in DC motor with \(\:{R}_{a}=0.30\) and \(\:K=0.018\)

Mode 3: R a  = 0.40 and K  = 0.015

In mode 3, the armature resistance is higher, and the motor constant is lower than mode 2. This causes more power loss and less efficiency. The lower motor constant also means the motor has less torque and speed. This mode could be used for applications where efficiency is not as important and moderate torque is enough. Figures  14 and 15 show the step response of the DC motor for the proposed and other controllers in mode 3. Table  12 shows the transient response results for the proposed controller.

In Mode 3, the proposed controller achieves a rise time of 0.0025 s, significantly improving the system’s ability to adapt rapidly to changes. This faster rise time is critical in applications where maintaining a precise speed is essential. The settling time is effectively minimized to 0.0044 s, highlighting the controller’s superior performance in bringing the system to stability quickly after a disturbance. The overshoot is reduced to a remarkable 0.0040%, which is considerably lower than what is achieved with GWO-FOPID and other controllers. This reduction in overshoot is crucial for maintaining stability and avoiding excessive speed deviations. The peak time is optimized at 0.0148 s, indicating that the motor quickly reaches its peak response. This rapid peak response is advantageous in ensuring that the motor operates efficiently and effectively, particularly in dynamic environments.

Step response of proposed and PID controllers in DC motor with \(\:{R}_{a}=0.40\) and \(\:K=0.015\)

Step response of proposed and FOPID controllers in DC motor with \(\:{R}_{a}=0.40\) and \(\:K=0.015\)

Mode 4: R a  = 0.50 and K  = 0.012

In mode 4, the armature resistance is increased while maintaining a lower motor constant. The higher armature resistance leads to increased power losses and reduced efficiency compared to modes 1 and 2. However, the lower motor constant limits the torque output and speed capabilities. This mode might be suitable for applications where efficiency is less critical, and moderate torque is acceptable. Figures  16 and 17 illustrate step response of DC motor for proposed and other controller in mode 4. Also, Table  13 shows transient response of proposed controller.

In Mode 4, the POA-FOPD(1 + PI) controller achieves a rise time of 0.0031 s. This quick response time is crucial in applications where rapid speed changes are required, ensuring that the motor can adapt swiftly to varying conditions. The controller reduces the settling time to 0.0054 s, significantly improving the system’s ability to reach a steady state quickly. This faster settling time reduces the period of transient response, enhancing the overall efficiency of the motor. The overshoot is effectively controlled at 0.0059%, which is much lower than that of other controllers. By minimizing overshoot, the proposed controller enhances the stability and reliability of the motor’s operation. With a peak time of 0.0181 s, the motor reaches its maximum speed promptly, ensuring that the system remains responsive. This optimized peak time is beneficial in maintaining high performance in environments where speed and precision are paramount.

Step response of proposed and PID controllers in DC motor with \(\:{R}_{a}=0.50\) and \(\:K=0.012\)

Step response of proposed and FOPID controllers in DC motor with \(\:{R}_{a}=0.50\) and \(\:K=0.012\)

Mode 5: R a  = 0.50 and K  = 0.018

Lastly, mode 5 combines a higher armature resistance with an increased motor constant. This configuration results in enhanced torque production and speed capabilities compared to mode 4. However, the higher armature resistance leads to greater power losses and reduced efficiency. Mode 5 could be applicable in scenarios demanding high torque output and dynamic speed control. Figures  18 and 19 illustrate step response of DC motor for proposed and other controller in mode 5. Also, Table  14 shows the transient response of the proposed controller.

For Mode 5, the proposed controller achieves an exceptionally fast rise time of 0.0021 s. This rapid rise time is essential for applications where immediate speed adjustments are necessary to maintain performance. The controller reduces the settling time to 0.0037 s, ensuring that the system stabilizes quickly after a disturbance. This quick stabilization is critical in maintaining consistent and reliable performance under varying operational conditions. The overshoot is controlled to a minimal 0.0074%, significantly reducing the risk of instability and ensuring that the motor’s speed remains close to the desired setpoint. The peak time of 0.0124 s reflects the controller’s ability to quickly bring the motor to its peak performance. This rapid peak response is vital for applications requiring fast and precise motor control.

Step response of proposed and PID controllers in DC motor with \(\:{R}_{a}=0.50\) and \(\:K=0.018\)

Step response of proposed and FOPID controllers in DC motor with \(\:{R}_{a}=0.50\) and \(\:K=0.018\)

General observations in terms of performance improvements for different modes

The performance improvements were evaluated across different modes of the DC motor. The following averages were observed:

1. Rise Time Reduction: The proposed controller consistently shows a reduction in rise time. Across all modes, the average reduction in rise time was found to be approximately 28%. For instance, in Mode 3, the rise time was reduced from 0.0379 s (ASO-FOPID) to 0.0025 s (POA-FOPD(1 + PI)), a reduction of approximately 93.40%. When considering various modes, the average reduction aligns with the 28%.

2. Settling Time Reduction: The settling time also saw substantial improvements, with an average reduction of around 35% across all modes. For example, in Mode 2, the settling time decreased from 0.0516 s (ASO-FOPID) to 0.0037 s (POA-FOPD(1 + PI)), a reduction of approximately 92.83%. This significant reduction, averaged across different conditions, supports the abstract’s claim.

3. Overshoot Reduction: The proposed controller effectively reduces overshoot, averaging a reduction of 22% across all tested modes. For instance, in Mode 3, the overshoot decreased from 0.3116% (GWO-FOPID) to 0.0040% (POA-FOPD(1 + PI)), a reduction of around 98.72%. The average reduction across multiple tests was approximately 22%, consistent with the abstract.

4. Steady-State Error Minimization: The proposed controller achieves excellent steady-state performance, minimizing the steady-state error to 0.3%. This was consistently observed across various simulations, demonstrating the controller’s precision in maintaining the desired output without significant error.

Load disturbance response

This section illustrates the effectiveness of the closed-loop DC motor speed control system in mitigating disturbances, particularly focusing on the proposed controllers and comparing them with alternative ones tested under step load disturbance. In the context of the DC motor speed control system, when there’s a change in load torque, it’s crucial for the system’s output speed response to quickly stabilize back to zero. Figures  20 and 21 depict the dynamic response of the DC motor speed control to a step load disturbance. It’s evident from the graph that the proposed FOPD(1 + PI) controller exhibits superior response to load disturbances, characterized by minimal undershoot and shorter settling time compared to other controllers. Consequently, the proposed controller effectively suppresses load disturbances.

Step load disturbance response of DC motor in proposed and PID controllers.

Step load disturbance response of DC motor in proposed and FOPID controllers.

Conclusions and future research directions

The proposed FOPD(1 + PI) controller, optimally tuned using the pelican optimization algorithm (POA), presents a robust and high-performance solution for precise speed regulation of DC motors. Through extensive simulations and comparative evaluations, the superiority of the POA-FOPD(1 + PI) controller has been demonstrated, outperforming traditional PID, FOPID, and other advanced controllers tuned by metaheuristic algorithms like ASO, SFS, GWO, and SCA. The novel controller design, combining fractional-order and proportional-integral components, effectively addresses the nonlinearities and uncertainties inherent in DC motor dynamics. The POA’s ability to balance exploration and exploitation phases during the optimization process ensures optimal tuning of the controller parameters, minimizing the ITAE as the objective function.

The POA-FOPD(1 + PI) controller exhibits remarkable performance in terms of response time, accuracy, and robustness across diverse operating conditions and disturbances. Its resilience to system uncertainties and load variations underscores its potential for practical applications in robotics, industrial automation, electric vehicles, and other domains where consistent motor performance is critical. While traditional PID controllers struggle with nonlinear dynamics and large disturbances, and advanced FOPID controllers are complex to implement, the proposed FOPD(1 + PI) controller offers a balanced solution, combining simplicity with enhanced adaptability and robustness. Furthermore, the POA’s computational efficiency makes it suitable for real-time implementation, addressing the limitations of computationally intensive optimization algorithms. This research contributes significantly to the field of DC motor speed control by introducing a novel controller design and leveraging an advanced optimization algorithm. The promising results pave the way for further exploration and practical implementation of the POA-FOPD(1 + PI) controller in various industrial and research applications, ultimately enhancing the precision, reliability, and efficiency of DC motor-driven systems.

Future research directions should focus on further enhancing the proposed controller’s performance and applicability. This includes investigating adaptive control strategies that can dynamically adjust controller parameters based on real-time system behavior, as well as exploring hybrid control approaches that combine the proposed controller with machine learning algorithms for improved adaptability and robustness. Hardware implementation of the controller should be explored to evaluate its performance in real-world applications, considering factors like computational efficiency and hardware constraints. Additionally, experimental validation of the controller on a variety of DC motor setups is essential to validate its effectiveness and robustness in practical applications. Other areas of research could include fault-tolerant control strategies, energy efficiency optimization, and multi-motor coordination using the proposed controller.

Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

Direct current

Pelican optimization algorithm

Integral of time-weighted absolute error

Proportional–integral

Fuzzy logic controller

Proportional–integral–derivative

Fractional order PID

Atom search optimization

Stochastic fractal search

Gray wolf optimization

Sine–cosine algorithm

Back electromotive force

Differential evolution

Opposition- based learning

Lévy flight distribution

Speed error between reference and actual angular speeds

Chaotic atom search optimization

Simulated annealing

Multilayer perceptron

Henry gas solubility optimization

Gazelle optimization algorithm

Gazelle simplex optimizer

Harris Hawks optimization

Opposition-based Henry gas solubility optimization

Whale optimization algorithm

Hybrid atom search optimization with simulated annealing

Hybrid Lévy flight distribution and Nelder–Mead

Opposition-based hybrid manta ray foraging optimization and simulated annealing algorithm

Particle swarm optimization

Proportional gains of multi-stage controller

Derivative gain of multi-stage controller

Error signal between reference speed and actual speed

Neural network controller

Armature voltage

Armature resistance

Armature inductance

Input voltage

Field current

Armature current

Induced voltage

Electromotive force constant

Angular speed of motor shaft

Inertia torque of motor

Motor friction constant

Motor torque

Motor load torque

Motor torque constant

Cost function

Integral of absolute error

Integral of time-weighted square error

Integral of square error

Speed reference motor

Integral gains of multi-stage controller

Integral and derivative order

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Jabari, M., Ekinci, S., Izci, D. et al. Efficient DC motor speed control using a novel multi-stage FOPD(1 + PI) controller optimized by the Pelican optimization algorithm. Sci Rep 14 , 22442 (2024). https://doi.org/10.1038/s41598-024-73409-5

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Language: English | French

Male contraception: narrative review of ongoing research

Eli j. louwagie.

1 University of South Dakota Sanford School of Medicine, 1400 W 22nd St, Sioux Falls, SD 57105 USA

Garrett F.L. Quinn

Kristi l. pond, keith a. hansen.

2 Chair and Professor, Dept. of Obstetrics and Gynecology, University of South Dakota Sanford School of Medicine; Reproductive Endocrinologist, Sanford Fertility and Reproductive Medicine, 1500 W 22nd St Suite 102, Sioux Falls, SD 57105 USA

Associated Data

Not applicable.

Since the release of the combined oral contraceptive pill in 1960, women have shouldered the burden of contraception and family planning. Over 60 years later, this is still the case as the only practical, effective contraceptive options available to men are condoms and vasectomy. However, there are now a variety of promising hormonal and non-hormonal male contraceptive options being studied. The purpose of this narrative review is to provide clinicians and laypeople with focused, up-to-date descriptions of novel strategies and targets for male contraception. We include a cautiously optimistic discussion of benefits and potential drawbacks, highlighting several methods in preclinical and clinical stages of development.

As of June 2023, two hormonal male contraceptive methods are undergoing phase II clinical trials for safety and efficacy. A large-scale, international phase IIb trial investigating efficacy of transdermal segesterone acetate (Nestorone) plus testosterone gel has enrolled over 460 couples with completion estimated for late 2024. A second hormonal method, dimethandrolone undecanoate, is in two clinical trials focusing on safety, pharmacodynamics, suppression of spermatogenesis and hormones; the first of these two is estimated for completion in December 2024. There are also several non-hormonal methods with strong potential in preclinical stages of development.

Conclusions

There exist several hurdles to novel male contraception. Therapeutic development takes decades of time, meticulous work, and financial investment, but with so many strong candidates it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.

Résumé

Depuis la sortie de la pilule contraceptive orale combinée en 1960, les femmes ont assumé le fardeau de la contraception et de la planification familiale. Plus de 60 ans plus tard, c’est toujours le cas, car les seules options contraceptives pratiques et efficaces disponibles pour les hommes sont les préservatifs et la vasectomie. Cependant, il existe maintenant une variété d’options contraceptives masculines hormonales et non hormonales prometteuses qui sont à l’étude. Le but de cette revue narrative est de fournir aux cliniciens et aux profanes des descriptions ciblées et à jour de nouvelles stratégies et cibles pour la contraception masculine. Nous incluons une discussion prudemment optimiste sur les avantages et les inconvénients potentiels, en soulignant plusieurs méthodes aux stades précliniques et cliniques du développement.

Résultats

En juin 2023, deux méthodes contraceptives masculines hormonales faisaient l’objet d’essais cliniques de phase II pour leur innocuité et leur efficacité. Un essai international de phase IIb à grande échelle, portant sur l’efficacité de l’acétate de ségestérone transdermique (Nestorone) et du gel de testostérone, a recruté plus de 460 couples et devrait être achevé pour la fin de 2024. Une seconde méthode hormonale, l’undécanoate de diméthandrolone, fait l’objet de deux essais cliniques axés sur l’innocuité, la pharmacodynamique, la suppression de la spermatogenèse et des hormones; le premier de ces deux essais devrait être achevé en décembre 2024. Il existe également plusieurs méthodes non hormonales à fort potentiel aux stades précliniques de développement.

Il existe plusieurs obstacles à la nouvelle contraception masculine. Le développement thérapeutique nécessite des décennies de temps, un travail méticuleux et un investissement financier ; mais avec autant de candidats solides, nous espérons qu’il y aura bientôt plusieurs options contraceptives sûres, efficaces et réversibles, disponibles pour les hommes.

Introduction

In the wake of the Dobbs v. Jackson Women’s Health Organization 2022 decision, the resultant “trigger laws” in 13 U.S. states, and the lingering retraction of reproductive rights in many more [ 1 , 2 ], the need for novel contraceptive options has gained urgency across the United States. Unfortunately, due to a complex combination of medical challenges and societal beliefs [ 3 – 6 ], the burden of contraception has fallen almost entirely on women, and the only practical effective options available to males are condoms and vasectomy. Even with ‘perfect use’, the failure rate of condoms is still over 10% [ 7 ], and vasectomy is largely irreversible. Further, many of the contraceptive options currently available have high discontinuation rates [ 8 ], contributing to high rates of unintended pregnancy in the United States [ 9 , 10 ]. With that in mind, there is a growing demand for safe, effective, and reversible male contraception that would allow men to share the burden of family planning [ 11 , 12 ].

Male fertility is dependent on production of an adequate number of viable, motile sperm capable of moving through the female reproductive tract and fertilizing oocytes. Fertile males generally have seminal sperm concentrations greater than 15 million sperm/mL [ 13 ], and adequate sperm suppression for contraception requires sperm levels ≤ 1 million/mL [ 14 ]. The process of sperm production is termed spermatogenesis and is controlled by the hypothalamic-pituitary-testicular (HPT) axis (Fig. ​ (Fig.1) 1 ) [ 15 ]. Briefly, the hypothalamus produces gonadotropin-releasing hormone (GnRH) in a pulsatile fashion, which stimulates the anterior pituitary to secrete the gonadotrophic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates androgen production by testicular Leydig cells, and FSH, along with high levels of intratesticular T, enables spermatogenesis within the seminiferous tubules [ 16 ]. T exerts negative feedback on GnRH release and therefore suppresses LH and FSH secretion; the same effect is seen with exogenous androgens. Similarly, natural and synthetic progesterone, the latter termed progestins, exert negative feedback on the HPT axis to suppress LH and FSH release [ 16 ]. These concepts underlie the mechanisms of hormonal contraceptives discussed in this review, which generally target spermatogenesis, sperm motility, or transport through the vas deferens (Fig. ​ (Fig.1 1 ).

Overview of the hypothalamic-pituitary-testicular (HPT) axis and targets of male contraception. The HPT axis consists of the hypothalamus, pituitary gland, and testes. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in a pulsatile fashion which signals for release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH drive testosterone (T) production and spermatogenesis in the testes. T and the hormonal contraceptives exert negative feedback on the hypothalamus to inhibit GnRH, LH, and FSH release, therefore suppressing spermatogenesis. Non-hormonal methods focus on distinct targets to inhibit spermatogenesis, sperm motility, or transit through the vas deferens. Pointed arrows indicate activation; red broad-tipped arrows indicate inhibition. NES/T, Nestorone/testosterone; DMAU, dimethandrolone undecanoate; 11β-MNTDC, 11β-methyl-19-nortestosterone dodecylcarbonate; RARA, retinoic acid receptor alpha; BRDT, bromodomain testis-specific protein; TSSK, testis-specific serine/threonine kinase; sAC, soluble adenylyl cyclase; CatSper, cation channel of sperm; SLO3, slowpoke homolog 3; RISUG, reversible inhibition of sperm under guidance. Figure created by EJL using BioRender.com

There are several promising male contraceptive options in development, and they can be broadly categorized as either hormonal or non-hormonal. The purpose of this review is to provide an overview of the most promising male contraceptive methods under study, including how they work, their current state in research and development, and potential side effects or barriers to marketability. We will also briefly discuss some methods in preclinical stages of development to demonstrate that men may soon have access to a variety of safe, effective, and reversible contraceptive options.

Materials and methods

For this narrative review, authors searched the online databases MEDLINE (via PubMed.gov), Cochrane Reviews, CENTRAL (via CochraneLibrary.com), ClinicalTrials.gov, and the World Health Organization’s International Clinical Trials Registry Platform for publications and ongoing clinical trials through 20 June 2023. Search terms included “contraception”, “male contraception”, “hormonal contraception”, “spermatogenesis inhibition”, “vas deferens occlusion”, and terms related to methods discussed below. Authors considered all identified ongoing studies related to male contraception, but we excluded from discussion those evaluating 7α-Methyl-19-nortestosterone (MENT) [ 17 – 19 ] or T combined with GnRH antagonists [ 20 , 21 ], estradiol [ 22 ], or progestins (medroxyprogesterone acetate [ 23 , 24 ] or norethisterone enanthate [ 25 – 28 ]) as these treatments ultimately failed to progress in clinical trials. Several past trials evaluating T injection alone [ 29 – 35 ] were also excluded as ongoing trials use T as a supplemental rather than primary compound. Authors EJL, GFLQ, and KLP completed literature search and assessed methodology of ongoing trials with particular focus on sample size ( n ), primary and secondary outcomes, and inclusion and exclusion criteria; none of the studies were excluded due to grossly unsound methodology.

Hormonal methods

Three hormonal methods show great promise in male contraception: segesterone acetate (Nestorone; NES), dimethandrolone undecanoate (DMAU), and 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC). NES and DMAU are currently in phase II clinical trials, and 11β-MNTDC has completed one phase II trial. Each method will be discussed separately below, and the clinical trials investigating these three compounds are summarized in Table ​ Table1 1 .

Summary of clinical trials investigating NES/T, DMAU, and 11β-MNTDC

Trial summaries are listed by method in reverse chronological order

NES/T  Nestorone/testosterone; RCT  Randomized controlled trial; DMAU  Dimethandrolone undecanoate; LNG  Levonorgestrel; IM  Intramuscular; SC  Subcutaneous; E2  Estradiol; SHBG  Sex hormone binding globulin; 11β-MNTDC  11β-methyl-19-nortestosterone dodecylcarbonate

Segesterone acetate + testosterone (NES/T)

Segesterone acetate, most often identified by its trade name Nestorone (NES), is a potent progestin with virtually no affinity for androgen receptors (AR) or estrogen receptors (ER) and minimal glucocorticoid activity [ 49 – 51 ]. NES shows low bioavailability when taken orally but is readily absorbed by transdermal application [ 52 ]; it has been available with ethinyl estradiol in the ANNOVERA vaginal ring (Mayne Pharma, Raleigh, NC) since 2018 and is a well-tolerated female contraceptive with > 97% efficacy [ 53 – 55 ]. NES is now compounded with T in a transdermal gel (NES/T) in a phase II clinical trial evaluating efficacy [ 36 , 37 ]. T is added to improve suppression of spermatogenesis and minimize potential symptoms of androgen deficiency [ 56 ].

Phase I trials of NES/T daily gel (approximately 8.3 mg/62.5 mg) have demonstrated gonadotropin suppression adequate to suppress spermatogenesis in nearly 90% of participants [ 38 , 39 ], suggesting that NES/T will be an effective form of male birth control [ 57 ]. Importantly, in these same studies there were no severe side effects with treatment. The main adverse effects were similar to the combined estrogen-progestin contraceptive pills used by women [ 58 ] and included minor mood symptoms, acne, and likely transient gastrointestinal symptoms [ 38 – 40 ]. From the most recent Phase I trial and a survey on attitudes towards NES/T, the majority of participants (79% and 56%, respectively) were satisfied or very satisfied with the treatments, and 50–51% reported that they would use NES/T daily gel as a sole form of contraception [ 38 , 59 ].

A phase IIb trial investigating NES/T efficacy is currently underway at 17 medical centers across 8 U.S. states and 7 other countries [ 36 , 37 ]; it is sponsored by the Population Council and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Participants are self-administering the transdermal gel with one of two T doses (both compounded as NES/T; 8 mg/62 mg or 8 mg/74 mg), and participants showing low serum T with symptoms of hypogonadism will be offered additional T [ 37 ]. The trial is broken down into phases. There is an initial screening phase, after which participants begin daily NES/T. Within 20 weeks of beginning treatment, participants must show sperm suppression to levels ≤ 1 million sperm/mL before entering the 52-week efficacy phase. The recovery phase is intended to assess sperm production after ceasing NES/T application and continue symptom surveillance of both males and their female partners [ 37 ]. Enrollment was completed in November 2022 with 462 couples having started treatment. Completion of the primary endpoint, contraceptive efficacy, is estimated for late 2024, with full study results likely available in early 2025 [ 36 , 37 ].

Dimethandrolone undecanoate (DMAU)

DMAU is a testosterone-derived pro-drug, metabolized to active form dimethandrolone (DMA), with high affinity for AR and, to a lesser degree, progesterone receptors (PR) [ 60 ]. DMAU and DMA are not aromatized and therefore lack estrogenic effects [ 61 ], but DMAU is highly lipophilic and experiences first-pass metabolism by the liver [ 62 ], requiring study of a variety of formulations to determine the optimal delivery method. In preclinical animal studies including non-human primates, DMAU was shown to effectively, reversibly suppress gonadotropins and spermatogenesis while maintaining physiologic androgenic effects without serious side effects [ 63 – 65 ]; importantly, there were no signs of liver toxicity, a well-characterized side effect of many exogenous androgens [ 66 ]. DMAU has been studied in several clinical trials for safety, pharmacodynamics, and gonadotropin suppression to evaluate its potential in male contraception, and phase I and phase II clinical trials are currently underway.

Early human trials of DMAU evaluated safety and absorption with doses up to 800 mg. In 2014, the first clinical trial orally dosed DMAU in a powder formulation from 25 to 800 mg, fasting or following high-fat meal (50% calories as fat). With a high-fat meal, authors found considerable, dose-escalating absorption of DMAU and suppression of gonadotropins (12 h later) from 200 mg upwards [ 45 ]. In a follow-up 2017 study, authors evaluated daily DMAU absorption at doses up to 400 mg daily and effects on estrogen and T levels [ 44 ]. Similarly, they found improved absorption with high-fat meals and suppression of estrogen and T in the absence of any serious side effects [ 44 ].

In a placebo-controlled, double-blinded, randomized phase I trial, Thirumalai et al. 2019 [ 43 ] investigated safety, tolerability, and adverse events associated with oral DMAU over 28 days of treatment, as well as pharmacokinetics, pharmacodynamics, hormonal changes, and sperm counts. The study found suppression of T at even the lowest dose of DMAU and dose-dependent suppression of LH and FSH, theoretically sufficient to suppress spermatogenesis with treatment for 10 weeks [ 57 ]. No serious side effects were observed; several participants reported decreased libido or erectile dysfunction, particularly at the highest tested dose, but participants did not report this affecting their sexual or erectile satisfaction [ 43 ]. Of note, DMAU was taken after a meal containing 25–30 g of fat, reflecting a typical Western diet but approximately half the fat content of the Ayoub et al. 2017 study [ 44 ]. In a secondary analysis of this trial’s samples and data, Thirumalai et al. 2021 found dose-dependent suppression of T and estrogen as well as an increase in a marker for bone formation over 28 days [ 67 ]. In another secondary analysis comparing metabolic effects of DMAU and 11β-MNTDC (discussed below), Yuen et al. 2021 found that DMAU caused a mean weight gain of 1.2 or 2.0 kg with 200 or 400 mg daily dosing, respectively, and mild lipid changes, but there were no serious adverse effects or signs of overt insulin resistance [ 46 ]. Collectively, these analyses indicate that orally dosed DMAU is well-tolerated and shows promise as a male contraceptive.

Today, there are two ongoing trials with DMAU, run by Drs. Christina Wang, MD, out of the University of California Los Angeles and Stephanie Page, MD, PhD, out of the University of Washington [ 41 , 42 ]. Per ClinicalTrials.gov, both are reportedly still recruiting. The first is a phase I trial comparing a single injection of intramuscular (80-800 mg) vs. subcutaneous (50-200 mg) DMAU and is primarily assessing safety, pharmacodynamics, and hormonal suppression in healthy males [ 41 ]. Completion is estimated for December 2024. The second is a phase II trial primarily investigating the ability of orally dosed DMAU with or without a low dose of levonorgestrel (a progestin) to suppress spermatogenesis after 12 weeks treatment; secondary outcomes include hormonal suppression, serious adverse events, systemic symptoms, and tolerability [ 42 ]. Ideally, these ongoing studies will shed further light on the optimal route and dose of DMAU administration to guide efficacy trials.

11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC)

11β-MNTDC is a testosterone derivative active at both AR and PR; it does not undergo aromatization and therefore lacks estrogenic effects [ 48 , 61 , 65 ]. Like DMAU, 11β-MNTDC is a pro-drug and is converted to 11β-methyl-19-nortestosterone (11β-MNT), which is structurally similar to DMA [ 68 ]. However, 11β-MNT’s affinity for AR and PR is more balanced than that of DMA (which favors AR), so side effect profiles may vary [ 48 ]. In preclinical animal studies, 11β-MNTDC was shown to effectively suppress serum gonadotropins [ 65 ] and exert even less liver toxicity than other androgens, including DMAU [ 63 ].

Several clinical trials have investigated 11β-MNTDC. The first major human trial was directed by Drs. Wang and Page and published in 2019 [ 48 ]. Twelve healthy adult males were given a single oral dose of 100-800 mg 11β-MNTDC with a high-fat meal or fasting, then assessed for pharmacokinetics, adverse effects, serum gonadotropins, and T levels. Like DMAU, 11β-MNTDC absorption was improved with high-fat meal, treatment was overall well-tolerated, and T was suppressed in a dose-dependent manner from 200 mg upwards [ 48 ]. Gonadotropin levels were not significantly reduced with a single dose, but this was addressed in a follow-up study published in 2020 [ 47 ]. This randomized, placebo-controlled phase II trial was again directed by Drs. Wang and Page, and participants received a daily oral dose of 200 or 400 mg 11β-MNTDC for 28 consecutive days. 11β-MNTDC was taken after a meal containing 25–30 g of fat [ 47 ], a more typical fat content per meal than in the previous trial [ 48 ]. Ultimately, 11β-MNTDC was well-tolerated; participants reported no serious adverse events, no one discontinued the trial due to side effects, and all reported side effects were mild or moderate. The most common sides effects were headache, acne, and decreased libido in 16% of participants [ 47 ]. Mood symptoms were reported, but they were comparable to those seen with currently available female estrogen-containing contraceptives [ 69 – 71 ]. 11β-MNTDC caused dose-dependent suppression of LH and FSH, and more participants in the 400 mg group had suppression to LH and FSH levels < 1.0 IU/L, the threshold at which spermatogenesis will be suppressed in nearly 90% of participants [ 57 ].

Efficacy trials are still needed for 11β-MNTDC, but between the two clinical trials and a secondary analysis comparing metabolic effects of DMAU and 11β-MNTDC (DMAU discussed above), 11β-MNTDC demonstrated acceptable safety profiles. Levels of T, estradiol, and sex hormone binding globulin (SHBG) were all suppressed, but these changes did not correlate with side effects or changes in serum chemistries [ 46 – 48 ]. 11β-MNTDC slightly increased participant weight and serum low-density lipoprotein (LDL) cholesterol levels, but there were no serious adverse events or signs of overt insulin resistance [ 46 ]. Results-to-date warrant clinical trials evaluating efficacy and safety using a larger number of participants.

Non-hormonal methods

Several non-hormonal methods show promise in the field of male contraception, and two are either near human study or recently began human trials. In theory, these methods lack hormonal side effects, such as acne or mood symptoms, as well as the societal stigmas and false beliefs associated with hormonal contraception in the United States [ 6 , 72 ]. The non-hormonal methods showing the most potential or closest to market, particularly those that inhibit spermatogenesis, motility, or vas deferens passage, will be discussed in greatest depth.

Spermatogenesis

All-trans retinoic acid (RA), also known as tretinoin, is derived from vitamin A and plays global roles in cell growth and development. RA plays essential roles in spermatogenesis and acts through binding the retinoic acid receptor alpha (RARA) located in the testes [ 73 , 74 ]. The first human trial targeting RARA was conducted over 60 years ago with the non-selective RA biosynthesis inhibitor WIN 18,446 [ 75 ]. Sixty men were treated for one year, and spermatogenesis was suppressed in all participants throughout. However, off-target effects including inhibition of aldehyde dehydrogenase 2 in the liver unfortunately lead to a severe disulfiram-like reaction, effectively making the drug unmarketable [ 75 ]. Since then, the pharmaceutical company Bristol-Myers Squibb (BMS) designed and, with other labs, demonstrated effective, reversible suppression of spermatogenesis in mice with the pan-antagonist BMS-189,453 [ 76 – 78 ]. Theoretically, reversible alpha-selective agents would effectively and safely suppress sperm production without the systemic side effects of pan-antagonists. In other words, this would be an ideal method of contraception. Early attempts, most notably BMS-189,532 and BMS-189,614, lacked the efficacy of the pan-antagonist (WIN 18,446) by oral, intravenous, or intraperitoneal routes [ 79 ], but RARA remains a strong potential target for male contraception.

Bromodomains are amino acid segments in proteins that facilitate specific protein-protein interactions and a wide variety of cellular functions [ 80 , 81 ]. One of these bromodomains, bromodomain testis-specific protein (BRDT), is required for spermatogenesis, and males with BRDT gene mutations are infertile with abnormal sperm morphology and impaired motility [ 82 , 83 ]. Like RARA inhibition, specific inhibition of BRDT would theoretically suppress sperm production without the systemic effects of pan-inhibitors or hormonal methods. Indeed, inhibition of BRDT has been shown to effectively suppress spermatogenesis in male rodents using the small molecule JQ1 [ 84 ]. In this study, JQ1 was safe, reversible, and lacked obvious transgenerational effects, but authors noted potential off-target binding that could be reduced or prevented through design of more specific molecular inhibitors [ 84 ]. Progress has been made in the search for more specific BRDT inhibitors [ 85 – 88 ], but the compounds have yet to be tested in vivo and are therefore far from human trials.

Males express distinct testis-specific serine/threonine kinases (TSSK) that play spermatogenic roles in spermatids [ 89 ]. Mice with TSSK1 and TSSK2, TSSK3, or TSSK 6 deletions and human males with TSSK2 mutations are infertile, suggesting potential non-hormonal targets for contraception [ 90 – 93 ]. Of these, research into TSSK2 has shown the most progress. Since generation of enzymatically active, isolated TSSK2 [ 94 ], several inhibitors have demonstrated potent in vitro inhibition of TSSK2 [ 95 ]. To our knowledge, these inhibitors have yet to undergo in vivo study.

In order to reach and fertilize oocytes, sperm must travel through the female reproductive tract. This quality is termed motility , and immotile sperm are a major contributor to male-factor infertility [ 96 ]. Theoretically, by targeting enzymes or receptors that play essential roles in motility and are present only in sperm, one may reversibly immobilize sperm without systemic side effects. Eppin is an enzyme made in the testes that binds to the surface of sperm to play essential roles in motility [ 97 ]. Both immunization against eppin and molecular inhibition using the inhibitor EP055 has been shown to significantly, transiently reduce sperm motility [ 98 , 99 ]. Although these studies were both done with small sample sizes and much work is needed before eppin inhibition may see clinical trials, no severe side effects were noted in these animal studies, suggesting that eppin may hold promise as a non-hormonal target [ 100 ].

In a similar vein as eppin, soluble adenylyl cyclase (sAC) is an intracellular signaling molecule needed for sperm capacitation, motility, and acrosome formation [ 101 – 103 ]. Several compounds have been tested in preclinical in vitro studies and shown to effectively inhibit sAC in mouse and human sperm [ 101 , 104 ]. Indeed, sAC inhibition stands as a strong candidate for male contraception, and two recent studies have been conducted by Drs. Lonny Levin, PhD, and Jochen Buck, MD, PhD, out of Weill Cornell Medicine.

The first study by the Levin-Buck lab intricately compared capacitation and motility of sperm from sAC null mice and from healthy, wild type mice [ 105 ]. In vitro, they demonstrated that sAC plays essential roles in capacitation. In vivo, sAC null mice mated similarly to wild type mice, but their sperm were unable to migrate through the female reproductive tract. Essentially, these sperm were immotile [ 105 ]. Improving on the inhibitors mentioned above [ 102 ], a recent, well-designed study by the Levin-Buck lab investigated the new compound TDI-11,861; they demonstrated that a single oral or intraperitoneal dose of TDI-11,861 acutely inhibits sAC in mice, impairing capacitation and motility [ 103 ]. Importantly, the mice in this study had no changes in behavior, no obvious toxicity, and no pregnancies when treated within 2.5 h of mating [ 103 ]. With completion of this proof-of-concept study, authors anticipate additional safety and transgenerational studies to follow.

Calcium plays several signaling roles in sperm, including modulation of motility through activating sAC [ 96 ]. Extracellular calcium enters sperm flagella, the organelle that propels sperm, primarily through the cell type-specific cation channel of sperm (CatSper) [ 106 ]. Studies nearly 15 years ago demonstrated that immunologic inhibition of CatSper significantly suppresses sperm motility [ 107 ]; since, several compounds (RU1968 and HC-056456) have demonstrated effective inhibition of CatSper in vitro [ 108 , 109 ] and preliminarily in vivo [ 110 ]. Several new compounds have been identified, synthesized, and tested on human sperm in vitro with excellent efficacy and safety profiles, at least on a cellular level [ 111 ]. Additional in vivo animal studies are anticipated.

Slowpoke homolog 3 (SLO3) is the main potassium channel in sperm and has functions directly related to calcium signaling and the CatSper channel [ 112 , 113 ]. Like CatSper, SLO3 is specific to sperm and has functions essential for male fertility, making it an ideal target for male contraception [ 114 – 116 ]. A highly specific inhibitor of SLO3, VU0546110, has been identified and shown in vitro to inhibit sperm motility and acrosome reactions [ 117 ]. Better yet, at least one compound (termed “7 a” by Carlson et al. 2022) has been identified that blocks both SLO3 and CatSper, indicating potential for synergistic inhibition of sperm motility [ 111 ].

Vas deferens occlusion

The final target we wish readers to know about is physical obstruction of the vas deferens, termed ‘vas occlusion’, via gel injection to physically disrupt sperm during passage through the vas deferens. The benefits of this approach include fast installation (i.e. a quick injection at an outpatient visit) and relatively fast onset of action. A major barrier has been reversibility, but once overcome this approach may hold strong potential in male contraception. Several distinct polymers have been studied, including two styrene compounds termed “reversible inhibition of sperm under guidance” (RISUG) in India [ 118 – 120 ] and Valsalgel in the United States [ 121 – 123 ], and silicone and polyurethane compounds in the People’s Republic of China [ 124 , 125 ]. The most recent trial of RISUG showed high contraceptive efficacy and a favorable safety profile [ 120 ], but human trials demonstrating reversibility of RISUG are needed. Despite these setbacks, one newer compound is being investigated in an ongoing clinical trial [ 126 ]. This new compound is a proprietary hydrogel, named ADAM by its founding company, Contraline Inc. of Charlottesville, Virginia. The trial started enrolling in late 2022 with a planned 25 total male participants through June 2025; ADAM injections will be done at the Epworth Freemasons Hospital in Melbourne, Australia. The primary outcome is adverse events, and secondary outcomes include percentage of participants achieving azoospermia and any serious adverse events [ 126 ].

Limitations of the study

This review is subject to several limitations. The clinical trials discussed above are ongoing, and results have yet to be peer-reviewed and published. This does not yet allow for data-driven conclusions. Although this narrative review focuses on the most recent and ongoing studies of male contraception, authors recognize that it is not comprehensive. As mentioned above in Materials and Methods, several compounds were excluded because they failed to progress to human trials, failed after reaching human trials, or are in early preclinical stages. For these, we advise readers to explore several well-written reviews by Thirumalai and Amory [ 127 ], Long et al. [ 128 ], or the University of California San Diego urology department [ 129 ] that include many of these discontinued approaches.

It is long overdue that male partners share the burden of family planning, and it is the authors’ hope that this will soon be a possibility. Ultimately, we feel that two of the methods discussed above—NES/T and DMAU—show the greatest potential for male contraception in the next decade. However, as clinical trials range from early planning stages to data collection stages, it may be several years before we see the efficacy and safety data needed to apply for FDA approval. In particular, the ongoing phase IIb NES/T trial results will not be published before 2025, and this is the method farthest along ‘the pipeline.’

Despite their many theoretical advantages to hormonal contraception, the non-hormonal targets are further from practical application. Authors recognize that there are many obstacles to reaching human studies, let alone late-stage clinical trials. Clinical trials require years of time, meticulous study, and financial support, and many compounds that perform well in pre-clinical animal studies fall short in human trials. The tools needed to efficiently design and study these non-hormonal targets are relatively young. However, they are already being employed to design and test strong drug candidates. As a society we now possess not only the scientific knowledge, technology, and clinical infrastructure needed to overcome these challenges, but also the social drive. With so many strong candidates, it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.

Acknowledgements

Abbreviations.

Authors’ contributions

First author EJL and senior author KAH conceived and wrote this review paper. EJL created Fig. 1 using BioRender.com. GFLQ and KLP assisted with literature search and interpretation. All authors approved the final version of this manuscript.

This manuscript was supported by the University of South Dakota Sanford School of Medicine Department of Obstetrics and Gynecology.

Availability of data and materials

Declarations.

The authors declare that they have no competing interests.

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