Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

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REVIEW Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

GJ Manetti1 and SC Honig1,2,3

1Division of Urology, Yale-New Haven Hospital, New Haven, CT, USA; 2Division of Urology, Hospital of Saint Raphael, New Haven, CT, USA and 3Division of Urology, University of Connecticut, Farmington, CT, USA

Traditionally, male contraception has consisted of either barrier methods, such as condoms, or vasectomy. However, in recent years, we have made great strides in the basic science and clinical medicine to better understand the feedback mechanisms and physiology of the male reproductive system. These advances have enabled the development of several nonsurgical, hormonal, reversible, well-tolerated alternatives for male contraception. Men are more likely now than ever to participate in the choice of contraceptive techniques. This review will discuss the current status and recent developments in nonsurgical hormonal male contraception, a field that has been historically limited by social, financial and physiological challenges. International Journal of Impotence Research (2010) 22, 159–170; doi:10.1038/ijir.2010.2; published online 25 March 2010

Keywords: contraception; testosterone; sperm; male infertility; spermatogenesis

Update on male hormonal contraception: study involving 450 women also suggested that is the vasectomy in jeopardy? women would both trust and welcome their male partner to take a more active role in contraception.3 Male contraception has traditionally consisted of Approximately half of all conceptions are un- either barrier methods, such as condoms or vasect- planned, resulting in unintended pregnancies and 4 omy. Vasectomy is a permanent, expensive, surgical subsequent elective terminations. Therefore, it has solution with very low failure rates of 1/2000.1 become quite important to develop less invasive, Condoms are a less desirable option and with more tolerable and more reversible methods of male typical and ideal use results in a 14 and 3% yearly contraception that have a success rate similar or pregnancy rate, respectively. The ideal contracep- better than female hormonal contraception. This tive would be 100% effective, reversible, noninva- review will discuss the current status and recent sive, affordable, with no short- or long-term side developments in male contraception, a field that has effects. been historically limited by social, financial and Men are more likely now than ever to participate physiological challenges. in the choice of contraceptive techniques, although there are notable variations between population groups and cultures.2 Furthermore, an international Review of hypothalamic–pituitary– gonadal axis and spermatogenesis Correspondence: Dr SC Honig, Department of Urology, University of Connecticut, 330 Orchard Street, Suite 164, An understanding of the endocrinology of male New Haven, CT 06511, USA. reproduction, specifically the male hypothalamic– E-mail: [email protected] pituitary–gonadal axis and the basics of spermato- This article has drawn upon material from Honig SC and genesis is required to understand the methodologies Sandlow J. Male contraception and vasectomy. In: Lip- used for male contraception. shultz L, Howards SS, Niederberger CS (eds). Infertility The hypothalamic–pituitary–gonadal pathway is in the Male, 4th edn. Cambridge University Press: Cam- bridge, UK, 2009, pp 474–492, reproduced with permis- regulated through negative feedback by downstream sion. products as summarized in Figure 1. Spermatogen- Received 3 November 2009; revised 23 December 2009; esis is regulated by the pulsatile release of gonado- accepted 24 December 2009; published online 25 March tropin-releasing hormone (GnRH) from the arcuate 2010 nucleus of the hypothalamus, which stimulates the Update on male hormonal contraception GJ Manetti and SC Honig 160 tially be another indirect target to suppress spermatogenesis. However, the role of inhibin in FSH suppression and spermatogenesis is unclear, as low levels of inhibin are still present with LH-receptor mutations and chronic FSH administration.8,10,11 Progesterone receptors are seen in the hypothalamus, pituitary and testis. It appears that progesterone affects gonadotropins via the hypothalamic– pituitary–testis axis, however, they may function directly on the testis as well.12,13 It is clear that in normal sperm-producing men, intratesticular testosterone levels are 100-fold higher than in serum.14–18 Interestingly, LH-receptor-defi- cient mice can support some level of spermatogenesis, but use of an androgen receptor antagonist such as flutamide will suppress spermatogenesis completely.19–21 The role of dihydrotestosterone, a potent metabolite of testosterone, in spermatogen- Figure 1 Endocrinology of spermatogenesis. The hypothalamic– esis appears to be less clear. A decrease in pituitary–gonadal axis. dihydrotestosterone levels does not seem to cause a significant drop in sperm production.22 anterior pituitary to episodically release follicle- On a cellular and receptor level, androgen stimulating hormone (FSH) and luteinizing hor- receptors are found in multiple cell sites within mone (LH). LH stimulates the Leydig cells to the testes, specifically immature germ cells, smooth produce testosterone, which has a local effect on muscle cells, myoid cells, Sertoli and Leydig cells. the interstitium and seminiferous tubules and Cell-specific effects on androgen receptors may results in sperm production and maturation. This affect spermatogenesis. In Sertoli cell and Leydig effect is manifested by very high intratesticular cell androgen receptor-specific knockout mice, testosterone compared with the bloodstream. FSH spermatogenesis is impaired.23–26 In contrast, an- exerts its effect directly on the Sertoli cells to drogen receptors on germ cells and myoid cells promote spermatogenesis. Testosterone and estra- appears to be less important in spermatogenesis as diol (converted through aromatase in the testis knock out models in these situations, do not impair interstitium) are direct negative feedback modula- spermatogenesis in a major way.23,27 Compounds tors of GnRH, LH and FSH. Aromatase inhibition that are cell specific and influence Sertoli and increases FSH levels suggesting that FSH regulation Leydig cell androgen receptors could potentially be is more dependent on estradiol than testosterone.5,6 an excellent site of future male contraceptive Other substances have a role in this important thoughts. As described earlier, complete blockage neuroendocrine negative feedback pathway. Studies of the androgen receptor with flutamide suppresses have shown that kisspeptins, a group of amino-acid spermatogenesis.28 Molecules that follow this path- peptides, and their G-protein-coupled receptor way, but may be more specific and do not have the (GPR54) have a critical function in the secretion of significant negative side effects of flutamide, may be GnRH and the negative feedback of testosterone and valuable potential contraceptive targets. estradiol on the hypothalamus. Administration of Spermatogenesis is hormone dependent. Sperma- kisspeptin has been shown to increase GnRH togonia divide in 16-day intervals to form B secretion in neuronal cell lines.7 Furthermore, spermatogonia, which will differentiate and pro- although acute administration of kisspeptin seems gress through spermatogenesis. Other B spermato- to increase LH, FSH and testosterone secretion, gonia will renew to form new precursor stem cells. chronic administration lowers serum LH levels in Type B spermatogonia that differentiate will divide monkeys.8,9 Manipulation of the kisspeptin–GPR54 mitotically to form primary spermatocytes and these pathway represents another potential target for will undergo meiosis to secondary spermatocytes future male contraceptive therapy.8 and round spermatids. The round spermatids will Complex interplay between testosterone, FSH and then undergo a process of conformational change other factors is important for normal spermatogen- into mature spermatids. In this process, they will esis. Sertoli cells are part of the seminiferous tubules undergo extensive changes in cytoplasm and nu- that are activated by FSH and function to provide cleus, form an acrosome, flagellum and cytoplasmic the optimal environment for the developing sperm organelles undergo changes to form a mature cells throughout spermatogenesis. Inhibin B repre- spermatozooan. This process requires approxi- sents a nonsteroidal substance released by Sertoli mately 64 days. High levels of intratesticular cells after puberty and functions as a negative testosterone are required for this to occur. Hypo- feedback on FSH secretion. Inhibin B could poten- physectomy results in testis atrophy, but not

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 161 Table 1 Male hormonal contraceptive options contraception by 20 years. In 1939, two investigators independently tested testosterone for suppression of Testosterone spermatogenesis.33,34 Since then, female birth con- Testosterone propionate Testosterone enanthate trol pills have dominated the contraceptive market. Testosterone undecanoate It has been difficult to equal or improve on the Testosterone buciclate safety, efficacy and reversibility of female birth 7a-methyl-19-nortestosterone control pills, as the bar has been set quite high. Testosterone gels The failure rate of 1/2000 with vasectomy has set the Dimethandrolone undecanoate has combined testosterone 1 and progesterone properties bar very high as well. In 2007, the 10th summit group published their Testosterone–progestin combinations updated recommendations for regulatory approval Medroxyprogesterone acetate (MPA and depoMPA) for hormonal male contraception. This international Cyproterone acetate Levonorgestrel group was designed to review the status of clinical Desogestrel and etonogestrel development projects for male hormonal contra- Dienogest ception.35 Although much has been published Norethisterone (NET, NETA, nestorone gel) regarding the safety and efficacy of different meth- Testosterone with GnRH analogues ods of hormone-based male contraception, there has GnRH agonists been no clear consensus as to how to measure GnRH antagonists successful suppression of spermatogenesis, inclusion criteria for studies, reversibility of treatment, Selective androgen receptor modulators length of study to determine safety and power of study necessary to prove efficacy. Table 2 lists the complete depletion of germ cells, and blocks recommendations and guidelines for male contra- maturation and causes interference with germ cell ceptive options. The ideal hormone-based male proliferation.29 When testosterone microspheres are contraceptive would be safe, affordable, 100% injected into the testes of GnRH agonist-treated rats, effective, reversible, with no short- or long-term almost completely normal spermatogenesis occur.30 side effects. Such a drug does not exist now. Based on this data, the roles of FSH and LH are There have been several review articles published not completely clear in the renewal of spermatogen- in the past few years on male contraception.8,36–43 esis. It appears that high intratesticular testosterone The purpose of this review was to summarize the will initiate and maintain qualitative spermatogen- published data regarding hormone-based male con- esis. This can be initiated by LH stimulation or traceptive treatment options. exogenous hCG; however, the role of FSH is less clear. Men with FSH receptor defects can be fertile, although spermatogenesis appears to be significantly impaired. FSH also can initiate spermatogen- Testosterone alone esis in pubertal men and reinitiate sperm production in animals that have undergone hypo- In 1939, independent studies on male contraception physectomy. In patients with hypogonadotropic were performed by Heckel33 and McCullagh and hypogonadism, FSH provides for optimized sper- McGurl34 and with short-acting testosterone propio- matogenesis in some but not all cases. It appears that nate. Subsequent studies revealed reversible azoos- the combination of FSH and high intratesticular permia by 60 days in some patients with daily use of testosterone is important for normal sperm produc- 25 mg i.m. testosterone propionate.44 Improved tion.31 It appears that suppression of gonadotropins frequency and dosage were achieved with the has a direct effect on germ cell apoptosis and this is advent of longer-acting testosterone enanthate (TE), the mechanism of suppression.32 All these data are spurring interest in studies with an improved valuable as we evaluate the effects of different delivery frequency. agents as male contraceptives. The WHO (World Health Organization) in con- Endocrinological treatment strategies for male junction with the Contraceptive Research and contraception are listed in Table 1 and are shown Development program conducted two large multi- in Figure 2. Taking advantage of disruption of center studies on TE. In the initial multicenter study negative feedback mechanisms and interruption of conducted in seven countries, subjects received normal pulsatile release of hormones are the main- 200 mg TE i.m. weekly and used no other contra- stay of therapeutic options. ception for 1 year once sperm concentrations fell below 3 million per ml.45 This study revealed that 70% of 271 patients became azoospermic after 6 Hormonal treatment months of treatment. The mean time to azoospermia was 3 months. The azoospermic patients were The concept of male hormonal manipulation for enrolled in a 12-month efficacy phase, where one contraception predated the era of female hormonal pregnancy occurred. Sperm reappeared in the

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 162 Hypothalamus GnRH Exogenous T Progestins

Pituitary Exogenous T Progestins GnRHR GnRH antagonists

↓FSH LH Exogenous T: (1-2%) (<0.4%) Reproductive and Non-reproductive sections

FSH R Antagonists LHR Testis specific Leydig AR inhibition (SARMs) SoR inhibitors Cell FSHR Progestins AR Cholesterol ↓DHT Sertoli cell (30%) 5α reductase Pregnenosone

T MENT (2%) Progesterone Spermatogonial maturation B Androstenedione 17OH Progesterone

Ap L-Z Interstitium meiosis

PS Spermiation rST El Eld Seminiferous epithelium S

Spermiogenesis

Alkylated imino sugars Haploid germ cell targeting

Figure 2 Male hormonal contraceptive (MHC) regimens (compromising androgens alone or in combination with progestins or GnRH antagonists) act to inhibit the hypothalamic–pituitary–testicular axis. Exogenous testosterone (T) must be administered to maintain virilization and suppress GnRH, FSH and LH levels and thereby intratesticular androgen production (testosterone and dihydrotestosterone (DHT) (percent baseline levels following MHC administration are shown in brackets). Reduction in Sertoli cell FSH and androgen receptor (AR) activation results in marked inhibition of spermatogenesis, mainly the maturation of type A pale (Ap) to type B (B) spermatogonia and of sperm release (spermiation). MHC agents that have undergone some assessment in humans include progestins, GnRH antagonists, 7a-methyl-19-nortestosteone (MENT) and 5a reductase inhibitors with their sites of actions marked. Potential but untrialled MHC agents (selective androgen response modulators (SARMs) that target inhibition of the Sertoli cell AR, FSH-R antagonists, agents to inhibit spermiogenesis and spermiation) appear in hatched boxes. Germ-cell subtypes include type A pale spermatogonia (Ap); type B spermatogonia (B); leptotene–zygotene spermatocytes (L-Z); pachytene spermatocytes (PS); steps 1–2 round spermatids (rST); steps 3–6 elongating spermatids (El), steps 7–8 elongated spermatids (Eld) and spermatozoa (S). Source: Matthiesson and McLachlan.42 Reprinted with permission from Oxford University Press.

ejaculate in 11 patients. Once the testosterone was a central role in the discrepancy between the sperm discontinued, the mean time to sperm recovery was suppression rates of Asians and Caucasians. This 3.7 months. Of note, this international study revealed investigation evaluated 40 Caucasian men and that 91% of Asian and 60% of Caucasian patients showed that men with high fat mass had an impaired became azoospermic, suggesting an ethnic difference relative decline in LH and FSH in response to in endocrine response. This difference has been seen testosterone administration (testosterone propionate in subsequent studies. Possible explanations include and testosterone undecanoate (TU)). They suggest fivefold differences a-reductase levels in these that fat content may be important in differences that groups,46 lower baseline testosterone levels, differing occur. Adjustments in the dosing or frequency of susceptibility of the gonadotropic axis to testosterone injections in obese men may overcome this problem. and/or the rate of metabolic clearance of this This may explain why suppression differs in differ- hormone. One recent study by Kornmann et al.47 ent ethnic populations. Although semen analysis was suggest that differences in body fat content may have not performed in this relatively small study, it

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 163 Table 2 The 10th summit meeting on Hormonal Male Contraception (2006) criteria for studies on treatment modalities35

1. Phase 2 studies evaluating efficacy should use WHO sperm concentration parameters and the goal should be suppression o or ¼ to 1 million sperms per ml 2. After cessation of therapy, patients need to be followed until normal fertility is restored (criteria used is 20 million sperms per ml) 3. Inclusion criteria must include men with sperm concentrations 420 million per ml 4. Open-label, noncomparative contraceptive efficacy studies are acceptable if the primary end point is not susceptible to bias, e.g., pregnancy rate 5. For efficacy, two independent phase 3 trials for 1 year from suppression to o1 million per ml should include 200 men/couples per trial 6. For safety, new agents require studies with 300–600 men for 6 months at the intended combination and dose, 100 men exposed for 1 year and 1500 men in phase 1–3 studies at a minimum 7. Long-term safety will be monitored by post-marketing surveillance 8. Laboratory data need to be performed under strict quality control provides insight that may assist in the development formed by the WHO collaborating center and of patient-specific male contraceptives that will be showed moderate suppression of spermatogenesis more universally marketable. at a dose of 1200 mg i.m. per month. This study, The second WHO testosterone study was per- which was conducted in 1995, was among the first formed as a 15-center, 9-country study with 399 to show minimal side effects from this long-acting, volunteers. Among them, 98% suppressed sperma- easily administered testosterone derivative. This togenesis to o3 million sperms per ml with weekly trial helped to set the stage for future investigation 100 mg i.m. TE after induction phase with 200 mg combining long-acting testosterone with progester- i.m. TE.48 There was a significant difference in one derivatives.51 pregnancy rates between azoospermic patients (1.4 Synthetic androgens have been tested as well. A pregnancy per 100 person-years) and patients dose response trial of 7a-methyl-19-nortestosterone between 0.1 and 3 million sperms per ml (8.1 (MENT) was initiated in 35 healthy volunteers to pregnancies per 100 person-years). Approximately assess effects of serum gonadotropins and sperm 25% of patients discontinued the study due to production.52 This synthetic androgen is more personal reasons, dislike of injections or for medical potent than testosterone, is resistant to 5 a-reduction reasons. This study confirmed the relative efficacy and has diffusion characteristics that make it well- of treatment and was the groundwork for further suited for a depot implant. Initial data showed studies with different longer-acting testosterone relatively good efficacy, but typical testosterone- regimens. related side effects. Suvisaari et al.53 and others A phase 2, multicenter study was performed with have shown that MENT has a short half-life and is a longer-acting monthly injections of TU in 380 not suitable for long-term injection and does not Chinese men. Among them, 76% of patients sup- show significant FSH suppression. Dimethandro- pressed enough to enter the initiation phase. If lone undecanoate is another potent synthetic andro- suppression was to azoospermia or o3 million gen with some progestational activity that sperms per ml, there were no pregnancies. However, represents an orally active substance that appears there was reappearance of sperm in azoospermic to suppress LH levels in vitro and in rabbit models. patients, with one pregnancy.49 Structurally similar to MENT, it may be resistant to A phase 3, multicenter study was recently breakdown by 5a-reductase allowing it to maintain performed in 1045 Chinese men undergoing muscle mass without stimulating prostate growth. monthly injections of 500 mg TU in tea seed oil for Preliminary animal data suggest that due to 30 months. All subjects had fathered at least one its combined androgen and progestin effects, child in the past 2 years and had two normal semen dimethandrolone undecanoate may offer a single, analyses. Suppression was defined as azoospermia reversible contraceptive agent for men.54 or o1 million sperms per ml. The cumulative Newer delivery systems have been approved by contraception failure rate was 1.1 per 100 men (nine the US Food and Drug Administration for the pregnancies), 4.8% patients did not achieve sup- treatment of hypogonadism. Whether men would pression and 1.3% of subjects had post-suppression tolerate daily gel application of testosterone may be sperm rebound. Treatment was well tolerated and a barrier to its widespread use, however recent spermatogenesis recovered to normal reference studies combining testosterone gel with other agents levels in all but two subjects following a 15-month will be presented later. recovery period. The authors concluded that Testosterone alone has side effects, including monthly injection of TU is a safe, very effective acne and oily skin, mood changes, increased and reversible contraceptive method in a high hemoglobin and hematocrit, weight gain, decrease proportion of healthy fertile Chinese men.50 in testicular volume, sleep apnea, gynecomastia and Studies with testosterone buciclate, another long- possible effects on cholesterol. There are no long- acting testosterone derivative were initially per- term data with testosterone use and normal men

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 164 regarding prostate symptoms, growth or cancer. In one supplementation to restore exogenous testoster- an era of fear of using medications on relatively one, safety and efficacy may be improved and side healthy individuals, acceptability of routine use effects lessened. may be a major concern, given recent data on medical treatment of menopause with estrogen/ progestin therapy. In addition, anabolic steroids are a controlled substance and regulation Medroxyprogesterone acetate (MPA and of this industry is very strict at this time. Abuse of depot MPA) these drugs could easily become prevalent with its widespread use and availability for Since the 1970s, the contraceptive efficacy of MPA contraception. has been studied.58 Unlike studies on testosterone Although data suggest that testosterone therapy monotherapy, there are few randomized, multi- will create a milieu of oligospermia and/or azoos- center, large population studies evaluating efficacy permia in most cases, its reliability is clearly of testosterone/progestin preparations.59 uncertain at this point. The efficacy bar has been A review of MPA/testosterone preparations set very high with ‘the pill’. Higher efficacy with showed that only 67% of patients receiving MPA fewer short- and long-term side effects will need to with different testosterone preparations achieved be achieved to make use of testosterone alone a azoospermia.60 The 1993 WHO study comparing viable option. In addition, close follow-up with testosterone alone and 19-nortestosterone with de- regular semen analyses is necessary as there may be pot MPA showed consistent azoospermia in 95.6 breakthroughs in sperm suppression. However, the and 97.8%, respectively, in 90 Indonesian men.61 use of testosterone with other agents may have more On the basis of this data, it was not clear if the effect promise. It is not, completely clear why either was from testosterone alone or combination therapy. testosterone alone, or in combination does not Subsequent studies in 55 men with testosterone suppress spermatogenesis completely or why it implants and depot MPA showed suppression to o1 results in evidence of ‘breakthrough’ sperm produc- million sperms per ml in 94% of patients with no tion. Theories suggested are incomplete suppression pregnancies in this suppression subgroup.62 Median of FSH and persistent or episodic incomplete time to counts returning to 20 million sperms per ml suppression of intratesticular testosterone that was 5 months, but return to baseline numbers was allows for low levels of sperm production.42 Recent much longer, suggesting an accumulation of drug in studies have shown increased levels of insulin-like adipose tissue. These studies were conducted in the factor 3 (INSL-3)55 or increased fat content49 in Asian population only. Recently, two papers report- incompletely suppressed patients. ing on the same group of patients studied 38 men with testosterone gel and depot MPA for sperm suppression and evaluated patient acceptability of 63,64 Combination therapy this combination. Over 90% of patients had sperm suppression o1 million per ml, but acceptability was low, with only 45% saying they would Significant side effects and lack of high efficacy with use it if commercially available, one-third of the testosterone alone have pushed researchers toward patients said it would interfere with their daily combination therapy. The goal of combination routine and questionnaire data showing mild therapy is to create sterility effectively while using changes in overall satisfaction with sexual activity a lower-dose testosterone to maintain physiological and ejaculatory function. Interestingly, a subgroup levels and lessen side effects. of patients received GnRH antagonist, but there was no additive effect in terms of sperm suppression. A recent study by the same group looked at factors that Testosterone and progestins might differentiate azoospermic groups from nonazoospermic groups.55 Amory et al. performed a Progestins have been used in multiple small studies retrospective analysis of male hormone contracep- of men for suppression of spermatogenesis and tive studies and found that end of treatment INSL-3 testosterone production. Progestins used alone levels were significantly increased in the nonazoos- result in significant side effects such as loss of permic subgroup.55 INSL-3 is a peptide hormone libido and erectile dysfunction. The mechanism of that appears to be almost exclusively produced by action of progestins is thought to be either negative Leydig cells and can be relatively easily measured in feedback on the pituitary–gonadal axis, inhibition of serum by immunoassay. Although the exact role/ LH receptor expression or direct effects on function of INSL-3 remains unclear, administration sperm.56,57 Progestins alone cannot suppress sper- of this substance to mice has been shown to prevent matogenesis in dosages tolerable for administration apoptosis of male germ cells in the setting of FSH/ and without significant side effects. However, by LH deficiency.65 However, although INSL-3 may combining lower doses of progestins with testoster- be a useful target for refining treatment, further

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 165 investigation is still required to better understand given every 3 months is a very palatable option for and corroborate this interesting association between patients. A multicenter phase 2 trial was initiated in INSL-3 and nonazoospermic men and its potential 2003, but terminated in 2006 by Schering-Organon application to the development of a hormonal for unclear reasons. contraceptive for men. To minimize side effects, MENT has been combined with etonogestrel implants, hoping to decrease the dosage of MENT required to suppress Cryproterone acetate spermatogenesis and eliminate some of the undesirable testosterone-related side effects. However, a 79 Cryproterone acetate is an active antiandrogen with recent study by Walton et al. comparing MENT progestin effects. It has been studied as hormone and testosterone in combination with etonogestrel deprivation for prostate cancer. It has profound implants in healthy men showed that suppression of effects on libido, energy and decrease in hematocrit. spermatogenesis was inconsistent over time in the Multiple studies66–72 have been performed with MENT/etonogestrel group, and still associated with combination cryproterone acetate and TE or TU. persistent undesirable side effects (for example, Doses ranging from 25 to 100 mg per day have reduced libido). suppressed spermatogenesis, but side effects have precluded subsequent studies. It has been postu- lated that antiandrogens may work well to suppress Dienogest the effects of residual intratesticular testosterone not 38 suppressed by other means. Dienogest is a progestin with a lower degree of antiandrogenic and estrogenic activities. Prelimin- ary data suggest that it can suppress gonadotropins Levonorgestrel without adverse side effects.80 A study was conducted in rats using a combination of dienogest and Several small studies60,73–75 have been performed TU monthly injection that showed 100% contra- with levonorgestrel. This progestin is either an ceptive efficacy and complete arrest of spermatogen- oral or implant preparation. Unfortunately, the stu- esis. These data were based on findings of lack of dies performed with combination of levonorgestrel sperm in the rat epididymis and suppression of and testosterone resulted in only partial suppression spermatogenesis in testis tissue. No negative effects 81 of spermatogenesis even in the Asian population. The of lipid profiles were seen. However, there is concept of a two-implant preparation of progesterone/ minimal data available on sperm suppression in testosterone is appealing, but data for efficacy at the humans and further investigation is needed. present time are lacking with this progestin.

Norethisterone, nestorone gel Desogestrel and etonogestrel A depot female contraceptive with similar effects to Desogestrel is a potent oral progestin that is TU makes this combination attractive for male converted to the active agent, etonogestrel. Initial contraception. A study conducted in 1988 showed small studies performed with doses of 75, 150 and suppression with a combination of oral norethister- 300 mg per day showed variable results. A two-center one and TU.82 Subsequent studies have shown high study in Scotland and China with oral desogestrel efficacy in a small group of Caucasian patients (74 300 mg p.o. per day and 400 mg depot testosterone total patients) with either oral or i.m. norethisterone s.c. pellets led to suppression of spermatogenesis and TU.83,84 8-week intervals of treatment had a with azoospermia in 100% men.76 There was noted higher azoospermic rate than 12-week treatment. No to be a rise in high-density lipoprotein and weight short-term changes in the prostate were seen. Long- gain. A subsequent study of 21 African men er-term studies are necessary to better evaluate administered desogestrel and testosterone pellets changes in prostate size, PSA and so on. This showed similar results, but slightly less complete combination is very attractive for a depot, as the 8- suppression with no negative effects on lipoprotein week injection of both testosterone and norethister- or hemoglobin.58 Another study with 15 patients one is highly efficacious in a potentially single taking etonogestrel and testosterone pellets at injection. 3-month intervals resulted in azoospermia in A recent clinical trail by Mahabadi et al.85 showed all subjects by 28 weeks.77 A subsequent larger that transdermal Nesterone and a relatively high study (n ¼ 130) with the same investigators showed dose of testosterone gel (10 g; Testim) had an excellent sperm suppression with combination additive effect on gonadotropin suppression. This testosterone/progesterone implant when used randomized, multicenter, unmasked trial showed monthly.78 The combination of this two-drug pellet that the gel applications were well tolerated with

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 166 few short-term adverse effects. The effects on the immunoneutralization of GnRH would prevent cholesterol were mixed with a small drop in low- endogenous GnRH from binding to its receptors and density lipoprotein and high-density lipoprotein. cause gonadal atrophy in adults, such as spremato- Because Nesterone is a progestin without estrogenic genic arrest and libido loss.94 Several attempts have or androgenic activity, it represents a noteworthy been made to couple mammalian GnRH, a non- candidate to augment the effectiveness of testoster- immunogenic peptide, to carrier proteins such as one alone. A sperm suppression study with this tetanus and diphtheria toxoids to enhance the regimen is planned. bioefficacy of the antibodies produced.95 Anti-GnRH vaccines have been tested for control of prostate cancers in India, in hopes of cutting off androgen 96 Testosterone and GnRH analogues support to prostate cancer cells. Although there have been reports of contraceptive efficacy in male (agonists and antagonists) dogs, there have been no successful structured studies in male nonhuman primates that have Gonadotropin-releasing hormone is released in a 95 carefully evaluated such a contraceptive vaccine. pulsatile manner that is thought to be responsible Other possible vaccine targets include gonadotro- for the episodic release of LH and FSH. GnRH pins and gonadotropin receptors. Human FSH and agonists work by having paradoxical antigonadotro- ovine FSH are the two such candidate antigens. pic effects through the downregulation of GnRH Attempts were made to use hFSH linked to cholera after an initial GnRH surge. GnRH antagonists cause toxin and interleukin to produce effective antibo- competitive inhibition of GnRH receptors. They are dies. The immunization using hFSH caused a familiar to clinicians for regulation of ovulation 75–100% decrease in sperm counts in the ejaculate. induction, treatment of advanced prostate cancer The fertility of male monkeys after hFSH immuniza- and endometriosis. tion was significantly reduced, as described as There have been 12 clinical trials with different loss in spermatozoa ability to penetrating hamster GnRH agonists and testosterone resulting in a ova assay.95 Even though FSH-based vaccines may combined 23% suppression to azoospermia in 106 not lead to azoospermia, there seems to be increas- patients.86,87 It appears that the lack of suppression ing evidence that a reduction in the quality of sperm is related to breakthrough of FSH secretion. There- combined with oligospermia may represent a rea- fore, at this point, this combination has not been sonable marker for male contraception as a measure actively pursued. of infertility. Furthermore, using FSH protein frag- However, trials combining TE and GnRH antago- ments instead of GnRH- or LH-based vaccines does nists seem to have better results. Several studies 88–92 not require exogenous testosterone supplementation dating back to the early 1990s suggest a rapid 95 to maintain accessory gland function and libido. onset of suppression of spermatogenesis to azoos- Periodic vaccination as a method for male contra- permia. This group of studies, each with small ception represents a promising area of research and populations, suggested a good response to this continues to be refined through the use of better combined therapy. When GnRH was stopped, and adjuvant compounds. maintenance was performed with testosterone alone, suppression of spermatogenesis was not maintained.93 Initial trials were with short-acting GnRH antagonists with local side effects such as Selective androgen receptor modulators significant irritation at injection site. With the longer-acting GnRH antagonists available having Selective androgen receptor modulators or SARMs less local side effects, this therapy may take on a mimic the central and peripheral androgenic and more critical role in the future. anabolic effects of testosterone and are being trialed for treatment of prostate disease. Although steroidal SARMs, such as MENT, did not effectively maintain GnRH/Gonadotropin vaccines sperm suppression, recent animal models suggest that nonsteroidal SARMs may hold promise. In rat models, Immunomodulation of the reproductive system of SARM c-6 was found to induce significant suppression animals has been under investigation for many years of spermatogenesis.97 A study on rats showed that a in the area of fertility control in animals such as structurally modified SARM, (S)-N-(4-cyano-3-trifluor- rabbits, mice, cattle and subhuman primates for omethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hy- many years. The ideal target for a male contraceptive droxy-2-methyl-propanamide (S-23), combined with vaccine remains an interesting area of research that estradiol benzoate was an effective and reversible has undergone significant advances due to our regimen for suppressing spermatogenesis in male improved understanding of gonadotropin feedback rats.98 These oral, synthetic nonsteroidal molecules mechanism. As seen in Figure 1, as GnRH stimulates have the potential to mimic steroids and suppress secretion of gonadotropic hormones, it is logical that gonadotropin without unwanted side effects. The

International Journal of Impotence Research Update on male hormonal contraception GJ Manetti and SC Honig 167 animal studies serve as interesting models for testing in on the following criteria listed in Table 1 for studies humans as either primary or adjunctive therapy. on treatment modalities.35 Although these compounds appear to have an interest- Although vasectomy and condoms will likely ing mechanism of action, there have not been any remain very popular options, the hope for a clinical trials with these agents to date. nonsurgical treatment for male contraception will certainly remains possible in the future. Further- more, as men’s participation in the contraceptive process grows and population growth continues to Follow-up semen analysis studies represent a global concern, the demand for safer, cheaper and more reversible methods will increase For a contraception method to be effective and as well. However, the long-term effects and male reliable with a reversible method, follow-up semen health implications of sustained hormonal supple- analysis data need to be readily available. With mentation remain persistent obstacles in the search vasectomy, once one or two post-vasectomy semen for an effective and tolerable ‘male pill’. analyses show no sperm, typically no further follow- up is necessary. However some partners of men may request or require regular semen analysis testing. Historically, this required a doctor’s visit or lab drop Conflict of interest off. Furthermore, as men’s participation in the contraceptive process grows and population growth The authors declare no conflict of interest. continues to represent a global concern, the demand for safer, cheaper and more reversible methods will increase as well. As we move toward this goal, a References useful adjunct to measuring sperm suppression with a contraceptive may be the home immunodiagnostic SpermChecks ContraVac, Charlottesville, VA, USA; 1 Smith JC, Cranston D, O’Brien T, Guillebaud J, Hindmarsh J, Turner AG. Fatherhood without apparent spermatozoa after Vasectomy kit. This home kit uses monoclonal vasectomy. Lancet 1994; 344: 30. antibodies that recognize the sperm-specific acroso- 2 Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. mal protein SP-10. Although the second WHO study Attitudes toward male fertility control: results of a multi- noted a significant difference in pregnancy rates national survey on four continents. Hum Reprod 2005; 20: 549–556. between azoospermic patients and severely oligos- 3 Glasier AF, Anakwe R, Everington D, Martin CW, van der Spuy permic (0.1–3 million sperms per ml) patients, most Z, Cheng L et al. Would women trust their partners to use a male contraceptives target sperm concentrations o male pill? Hum Reprod 2000; 15: 646–649. 1 million sperms per ml. In a cohort study of 144 4 Finer LB, Henshaw SK. Disparities in rates of unintended post-vasectomy semen samples, the device regis- pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006; 38: 90–96. tered a negative result in sperm concentrations of 5 Hayes FJ, DeCruz S, Seminara SB, Boepple PA, Crowley Jr WF. approximately 385 000 sperms per ml. The test was Differential regulation of gonadotropin secretion by testoster- positive in 100% of cases if sperm concentrations one in the human male: absence of a negative feedback were greater than 385 000. More importantly, the effect of testosterone on follicle-stimulating hormone. J Clin device had a negative predictive value of 97% below Endocrinol Metab 2001; 86: 53–58. 99 6 Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates this value. The availability of a home test for easy testosterone’s short term feedback restraint of 24-hour en- confirmation and low-cost follow-up will make this dogenously driven and acute endogenous gonadotropin- a more palatable option to the average couple. releasing hormone stimulated luteinizing hormone and folli- Although this test will not differentiate between cle stimulating hormone secretion in young men. J Clin Endocrinol Metab 2001; 86: 2600–2606. motile and nonmotile sperms (and therefore is not 7 Novaira HJ, Ng Y, Wolfe A, Radovick S. Kisspeptin increases recommended after vasectomy), if we are testing for GnRH mRNA expression and secretion in GnRH secreting a value of less than 1 million sperms per ml, it neuronal cell lines. Mol Cell Endocrinol 2009; 311: 126–134. should be very reliable. 8 Page ST, Amory JK, Bremner WJ. Advances in male contraception. Endocr Rev 2008; 29: 465–493. 9 Seminara SB, Dipietro MJ, Ramaswamy S, Crowley Jr WF, Plant TM. Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonado- Summary tropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 2006; 147: In summary, male hormonal contraception is ap- 2122–2126. proaching the high bar set by ‘the pill’ and 10 Soriano-Guillen L, Mitchell V, Carel JC, Barbet P, Roger M, vasectomy. However, much more work is necessary Lahlou N. Activating mutations in the luteinizing hormone to clarify the best combination therapy, timing, receptor gene: a human model of non-follicle-stimulating hormone-dependent inhibin production and germ cell ma- efficacy, and short- and long-term safety before it turation. J Clin Endocrinol Metab 2006; 91: 3041–3047. will reach phase 3 trials. 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