Megan R. Sax, MDa, Zoran J. Pavlovic, MDb, Ashley S. Kim, MDc, Alan H. DeCherney, MDd
aUniversity of Cincinnati, Department of Obstetrics and Gynecology
bRush University, Department of Obstetrics and Gynecology
cKaiser Permanente Los Angeles Medical Center
dProgram in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892 USA
Although male hormonal contraception has been under investigation since the 1970s, there is currently no method approved for use by the United States Food and Drug Administration. The most promising formulations have only minor adverse effects and return of fertility has been demonstrated in all individuals studied, yet clinical trials have been terminated early due to changes in mood and libido. In parallel to the development of contraception, investigators in Behavioral Endocrinology have discovered multiple sex steroid derivatives that are associated with anxiety and mood disorders. Although the proposed mechanisms are not well understood, targeting these pathways with medications such as allopregnanolone and 5-a reductase inhibitors has demonstrated promising results in both men and women. It is interesting to consider how results of studies in women with premenstrual dysphoria, postpartum depression, and perimenopause mood disorders may be extrapolated into improving the development of male hormonal contraception.
Sex steroids have been shown to influence the response to stress and cognitive processes in men and women, and when there is an imbalance of these steroid hormones or their derivatives, mood disorders may result.1,2 Behavioral Endocrinology is a field of medicine that studies these potential derangements and aims to identify hormonal elicitors and substrates relevant to endocrine-related mood disorders to develop potential treatment and management options. Within this field, there is increasing research being conducted on neuroactive steroids, which are derivatives of cholesterol synthesized in the brain, and steroids synthesized in the adrenal glands to ultimately act on receptors in the brain.3
Many neuroactive steroids have been associated with anxiety and mood changes including pregnanolone, allotetrahydroDOC, DHEA, DHEA-S, and testosterone, but the most robust data has been regarding the action of allopregnanolone (ALLO), a 3-a reduced metabolite of progesterone, on the GABAA receptor in the brain.3 Neuroendocrine studies of ALLO in menstrual cycle and pregnancy-related mood disorders have provided significant information to illustrate neurobiological disturbances as a result of changes in gonadal steroids and their derivatives.3,4 Furthermore, medications like brexanolone (an IV formulation of allopregnanolone) or the 5-a reductase inhibitor dutasteride that alter neurosteroid levels directly or indirectly have the potential to ameliorate mood disorders in men and women.1,5,6
With evidence of hormonal derivatives playing a role in mood disorders, it’s not surprising that hormonal contraceptives have varying degrees of psychiatric side effects depending on their unique formulation. For instance, among studies in women using hormonal contraception, androgenic progestins have been noted to more frequently cause mood disturbances, especially among women with underlying mood disorders.7 Research regarding hormonal contraceptive mood disturbances in men has not been as robust as there are no male hormonal contraceptive methods available for commercial use in the United States; however, clinical trials in male hormonal contraception have been terminated early for concern for adverse effects on mood and libido.8 For this reason, it is crucial to consider and further investigate the implications of sex steroids and corresponding neuroactive steroid derivatives in hormonal contraceptive development for men and women.
Male Hormonal Contraception: A Work in Progress
Although male hormonal contraception (MHC) has been under investigation since the 1970s, there remains no MHC method approved by the United States Food and Drug Administration (FDA) despite evidence for safe and efficacious methods including oral pill, injectable, and transdermal gel formulations.8-11 Most formulations work via feedback suppression of gonadotropin secretion to decrease sperm concentration to less than or equal to 1 million sperm per milliliter semen, a level shown to have an efficacy rate of 97-100% and pregnancy rate of approximately 1% per year, which is similar to efficacy and pregnancy rates cited with perfect use of combined hormonal contraceptive pills in females.11,13 Although testosterone alone may achieve this level of severe oligospermia, androgen-progestin formulations appear to be more reliable with progestin additives available in various methods: etonogestrel (implant), norethistrone enanthate (injectable), medroxyprogesterone acetate (injectable), nestorone (gel).13,14 In multiple clinical trials, MHC has been shown to be effective, reversible, and safe with return of fertility in all men studied.12
Among recent clinical trials, the trial of an injectable by Behre, et al., in 2016 stands out as a significant landmark for developing future efficacy and safety trials.8 This trial was the first large-scale, international trial of a combination regimen involving 200mg norethisterone enanthate combined with 10000mg testosterone undecanoate administered every 8 weeks. Within 24 weeks of medication initiation, 95.5% of participants achieved adequate oligospermia (sperm concentration of £1mil/mL) with a recovery rate of 94.8% within 52 weeks of medication cessation.8 Overall, adverse effects were rare with the most common complaints being acne, pain at the injection site, increased libido, and mood disorders, however an external review committee mandated early cessation of the trial with expedited transition of all active participants to recovery phase. This review committee ultimately determined the risks posed to the study participants outweighed potential benefits with greatest concern regarding potential mood changes, depression, injection site pain, and increased libido.8 Despite early cessation, this trial was significant in demonstrating high contraceptive efficacy, comparable to that of female oral contraceptive methods. Surprisingly, even after being made aware of the early termination of the study intervention, more than 75% of participants reported being willing to use this method if available.8
Female counterparts have similarly endured side effects of hormonal contraceptive methods that remain in circulation, such as irritability, fatigue, and depression being more often associated with contraceptives containing progestin components.15 Specifically, more androgenic progestins have been shown to have greater adverse effects on mood.6 Studying mood disorders at times of hormonal changes has provided insight into proposed mechanisms by which neuroactive steroids may attribute to mood and sexual dysfunction both in nature and as a hormonal contraceptive side effect.
Neuroendocrinology and Mood Disorders
Progesterone and its derivatives have biological versatility, with potentially significant impact on mood at points of hormonal transitions in women such as menarche, peripartum, and menopause, but have also been found to have an impact on mood in men as well.16 There is increasing evidence to suggest many of these neuroendocrine-related mood disorders may be due to the inhibitory system in the brain regulated by the GABAA receptor.18 Activators of the GABAA receptor include the progesterone metabolites allopregnanolone (ALLO) and pregnanolone, as well as benzodiazepines, barbiturates, and alcohol. Some studies have demonstrated that progesterone metabolites, especially ALLO, may induce depressive and anxiogenic effects when concentration is fluctuating, rather than with discrete elevation or reduction in serum level.18 Additionally, this effect is variable among patients, and may be subjective based on an individual’s expression of GABAA receptor sensitivity or α- and/or δ-subunits.16 One method that has allowed for GABAA receptor sensitivity measurement in women is saccadic eye velocity (SEV). Utilizing SEV, Backstrom, et al. were able to demonstrate a GABAergic deficiency in women with premenstrual dysphoric disorder (PMDD) by diminished sensitivity to progesterone metabolites, or other GABAergic agents in comparison to healthy controls.19 Some additional studies have expanded on this finding to demonstrate restored sensitivity at the GABA receptor with selective serotonin reuptake inhibitors (SSRIs) by increasing synaptic serotonin.18
In addition to SSRIs, continuous exposure to combined hormonal contraceptives may also ameliorate mood symptoms in cases of PMDD.18 In the luteal phase of the menstrual cycle, when the cells of the ovulated follicle become the corpus luteum and secrete progesterone, peak progesterone production rises until seven to eight days after the LH surge.18 This progesterone may be metabolized to ALLO and other neuro active steroids, potentially resulting in PMDD symptoms. When hormonal methods like combined hormonal contraceptive pills are used to suppress ovulation, these symptoms resolve or be less severe by impeding cyclic production of progesterone and ovarian-derived ALLO.18
Neuroactive Steroids: The Cause and the Solution
Investigations in neuroactive steroid interventions on GABAergic neural pathways have had promising results in treatment for anxiety and depression.5,20 Brexanolone, an intravenous formulation of ALLO, has specifically been shown to have a reduction in postpartum depression and was FDA-approved for this purpose in 2019.5 This formulation allosterically enhances GABAA receptor function, increasing GABAergic inhibition. Clinical trials have demonstrated effects in postpartum depression as soon as 60 hours after infusion initiation, with depression measured by the HAMILTON Rating Scale for Depression (HAM-D). Due to rapid plasma clearance, this drug formulation requires continuous infusion, however effects appear to last up to 30 days following administration. The lasting effects are thought to be secondary to changes in GABAA receptor expression mediated by changes in subunit phosphorylation and expression of progesterone receptors activated by ALLO.20
Paradoxically, blocking the conversion of progesterone to ALLO has also proven to be an effective intervention to improve mood in women with PMDD.6 In a trial by Martinez, et al., neuroactive steroid levels were stabilized by blocking the conversion of progesterone to ALLO with administration of the 5-a reductase inhibitor dutasteride. This randomized, placebo-controlled, cross-over trial, evaluated mood response in two intervention groups: low-dose dutasteride (0.5 mg/day) and high-dose dutasteride (2.5 mg/day). All women were evaluated in clinic during follicular and luteal phases of each menstrual cycle and were also required to complete a daily rating form (DRF) to document symptoms of irritability, sadness, and anxiety. In the low-dose group, plasma levels of ALLO were not suppressed from follicular to luteal phases and no significant effect was noted via DRF; however, the high-dose group experienced a statistically significant reduction in PMDD symptoms (such as irritability, sadness, anxiety, food cravings, and bloating) and ALLO levels correspondingly remained stable from follicular to luteal phase.6 Dutasteride had no effect on mood in the control subjects who did not have PMDD and received dutasteride.
Although clinical trials of ALLO administration with brexanolone or blocking the production of ALLO with dutasteride continue to have success in female participants, no such studies have been published in male human subjects. On the other hand, the adrenal androgen dehydroepiandrosterone (DHEA), a precursor to androsterone, has been studied in both sexes.1 Ben Dor and colleagues demonstrated antidepressant and libido-enhancing effects of DHEA in men and women with midlife depression in a randomized controlled 6-week trial of DHEA. In their study, depression severity was quantified by the Center for Epidemiologic Studies Depression Scale (CES-D).1 Their results demonstrated significantly increased levels of androsterone after DHEA administration in both men and women who exhibited clinically improved mood, as demonstrated by corresponding CES-D depression score.
Implications in Hormonal Contraceptive Development
The use of hormonal contraceptives in women with PMDD has been shown to ameliorate mood disorders by stabilizing neuroactive steroid levels through ovulation suppresion.20 For this reason, some evidence suggests that the greatest efficacy in treating women with PMDD is with continuous combined hormonal contraceptives to suppress follicle development and achieve more stable hormone levels.18 However, women on different types contraceptives with varying progestins can still experience mood disorders that may lead to premature discontinuation of contraception. Behavioral endocrinology research in patients who experience hormonally-related mood changes can be utilized to guide future research in these patients as well as in the clinical trials of MHC. The possibility of concurrent use of neuroactive steroids such as brexanolone or medications targeting sex steroid pathways like 5-a reductase inhibitors have had promising results in combating potential adverse effects on mood and should be further investigated in collaboration with MHC methods. Although an individual’s response to sex steroid derivatives is highly contextualized and subjective, it is this dysregulation that may one day allow for the development of commercially available MHC.
Studies examining neuroactive steroid effects on mood are crucial to the development of hormonal contraceptives in males as prior male hormonal contraceptive trials have been limited by concern for adverse side effects on mood. Examining the neurobiological implications of fluctuating sex steroid derivatives in disorders like PMDD, postpartum depression, and midlife depression, investigators may extrapolate results to further develop male hormonal contraception without predisposing men to affective dysregulation.
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