The current state of male hormonal contraception

    The current state of Male hormonal contraception Jing H. Chao, Stephanie T. Page PII: DOI: Reference:

S0163-7258(16)30020-1 doi: 10.1016/j.pharmthera.2016.03.012 JPT 6884

To appear in:

Pharmacology and Therapeutics

Please cite this article as: Chao, J.H. & Page, S.T., The current state of Male hormonal contraception, Pharmacology and Therapeutics (2016), doi: 10.1016/j.pharmthera.2016.03.012

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ACCEPTED MANUSCRIPT P&T #22819

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The Current State of Male Hormonal Contraception

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Jing H. Chao, MDa and Stephanie T. Page, MD, PhD, Professora

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a. Division of Metabolism, Endocrinology and Nutrition, University of Washington,

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Seattle, Washington

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Corresponding author: Stephanie T. Page Mailing Address:

Box 35646

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1959 NE Pacific St.

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UWMC

Seattle, WA 98195

Telephone: 206-685-3781

Fax Number: 206-616-0499

E-mail address: [email protected] (Stephanie T. Page)

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ACCEPTED MANUSCRIPT Abstract: World population continues to grow at an unprecedented rate, doubling in a mere

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50 years to surpass the 7-billion milestone in 2011. This steep population growth

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exerts enormous pressure on the global environment. Despite the availability of numerous contraceptive choices for women, approximately half of all pregnancies

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are unintended and at least half of those are unwanted. Such statistics suggest that

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there is still a gap in contraceptive options for couples, particularly effective reversible contraceptives for men, who have few contraceptive choices. Male

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hormonal contraception has been an active area of research for almost 50 years. The fundamental concept involves the use of exogenous hormones to suppress

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endogenous production of gonadotropins, testosterone, and downstream spermatogenesis. Testosterone-alone regimens are effective in many men but high

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dosing requirements and sub-optimal gonadotropin suppression in 10-30% of men limit their use. A number of novel combinations of testosterone and progestins have been shown to be more efficacious, but still require further refinement in delivery systems and a clearer understanding of the potential short- and long-term side effects. Recently, synthetic androgens with both androgenic and progestogenic activity have been developed. These agents have the potential to be single-agent male hormonal contraceptives. Early studies of these compounds are encouraging and there is reason for optimism that these may provide safe, reversible, and reliable contraception for men in the near future.

Keywords: male contraception, testosterone, spermatogenesis, testis

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ACCEPTED MANUSCRIPT Table of Contents 1. Introduction

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2. Testosterone as a single agent for male hormonal contraception

b. Testosterone undecanoate

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a. Testosterone + Levonorgestrel

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3. Testosterone and progestin combinations

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a. Testosterone enanthate

b. Testosterone + Etonogestrel

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c. Testosterone + Norethisterone Enanthate d. Testosterone + Depomedroxyprogesterone Acetate

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e. Testosterone + Nestorone or Cyproterone Acetate f. Other testosterone delivery methods with or without a progestin

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4. Gonadotropin-releasing hormone antagonists 5. Inhibitors of Intratesticular Testosterone Synthesis 6. Synthetic Androgens for Hormonal Contraception a. 7-Alpha-methyl-19-nortestosterone b. Dimethandrolone undecanoate

7. Conclusion

Abbreviations: GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, folliclestimulating hormone; WHO, World Health Organization; TE, testosterone enanthate; TU, testosterone undecanoate; DMPA, depomedroxyprogesterone acetate; HDL,

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ACCEPTED MANUSCRIPT high-density lipoprotein; NETE, Norethisterone enanthate; CPA, Cyproterone acetate; DHT, dihydrotestosterone; MENT, 7-Alpha-methyl-19-nortestosterone;

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DMAU, Dimethandrolone undecanoate.

1. Introduction

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Women have long been the target population for family planning and have had a

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variety of reversible contraceptive choices available for over 50 years. Despite a multitude of female contraceptive options, the world continues to witness a

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dramatic rise in its population, reaching 7.3 billion in 2015. Recent surveys reveal men’s desire to take part in family planning and an interest in a reversible hormonal

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contraceptive for men, as well as women’s willingness to trust their male partners to use a contraceptive (Glasier, et al., 2000; Martin, et al., 2000). However, men’s

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current contraceptive options are limited to condoms and vasectomy. Although perfect use of condoms is associated with a low contraceptive failure rate (2%) and is an effective way to protect against sexually transmitted diseases, “typical use” of condoms leads to a high pregnancy rate of 17% per year (Kost, Singh, Vaughan, Trussell, & Bankole, 2008; J. Trussell, 2011). Vasectomy has evolved to become a safe and well-tolerated outpatient procedure and is associated with a contraceptive failure rate of less than 1% when azoospermia is achieved. However, vasectomy is intended for permanent contraception and remains difficult and expensive to reverse. Thus, the quest for an effective and reversible male contraceptive has continued.

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ACCEPTED MANUSCRIPT The central principle underlying male hormonal contraception involves the reversible suppression of the hypothalamic-pituitary-testicular axis, resulting in

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suppression of spermatogenesis. Such a strategy is analogous to the principles

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underlying effective, reversible, hormonal female contraceptives. In women, exogenous progesterone, or a synthetic progestin, inhibits the pulsatile secretion of

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gonadotropin-releasing hormone (GnRH) from the hypothalamus, greatly

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diminishing the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. Decreased FSH inhibits follicular

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development and estrogen production, ameliorating the LH surge, and resulting in anovulation. The addition of estrogen to progesterone further suppresses

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gonadotropin production via negative feedback and simultaneously provides circulating estrogen to peripheral tissues. Similarly, in men exogenous progestins

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decrease GnRH, LH and FSH production, and exogenous testosterone further suppresses gonadotropins while providing circulating androgen to maintain secondary sexual characteristics (A. Glasier, 2010; Anna Glasier, 2010). Within the testes, LH stimulates Leydig cell production of testosterone and FSH supports Sertoli cells which foster spermatogenesis. Both LH and FSH are required for quantitatively and qualitatively normal spermatogenesis. In healthy men, the hypothalamic-pituitary-testicular axis is regulated by testosterone and, to a lesser extent, inhibin B, through a negative feedback circuit to the hypothalamus and the pituitary gland (Anderson, Wallace, Groome, Bellis, & Wu, 1997; Hayes, Pitteloud, DeCruz, Crowley, & Boepple, 2001). This negative feedback mechanism forms the foundation of all male hormonal contraceptives. Exogenous testosterone, with or

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ACCEPTED MANUSCRIPT without a progestin, suppresses pituitary release of LH and FSH, thereby depriving the testes of the signals required to produce testosterone. Both a high intratesticular

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testosterone concentration and FSH signaling to the Sertoli cells are needed for

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normal spermatogenesis. The hypothalamus-pituitary-testicular axis and its

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hormonal feedback circuits are summarized in Figure 1.

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Exogenous sex steroids may impact spermatogenesis both through disruption of the hypothalamic-pituitary-gonadal axis and via direct testicular effects of either the

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parent hormone or one of its active metabolites. Testosterone is metabolized to two important active steroid hormones. Approximately 1% of testosterone is

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aromatized to circulating estradiol (E) by aromatase in men, and another 1% is reduced by 5α-reductase to dihydrotestosterone (DHT), a very potent androgen.

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Since testicular Leydig cells are the site of testosterone production, and the testes express aromatase and 5α-reductase, the intratesticular concentrations of testosterone, estradiol and DHT are 10-100 fold higher than those in the circulation. Normal spermatogenesis requires a high concentration of intratesticular testosterone, and intratesticular estradiol and DHT may also play a role (Page et al., 2011). Moreover, androgen, estrogen and progesterone receptors are all expressed in the testes; thus, it is possible that exogenous steroids or synthetic steroids could have direct testicular effects that further inhibit (or support) spermatogenesis.

Spermatogenesis takes place continuously within the testes of men and is a linear progression in which a spermatogonium undergoes divisions and a series of

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ACCEPTED MANUSCRIPT structural changes and eventually evolves into a haploid sperm over approximately 72 days (see Figure 2). Consequently, 2-3 months’ time is usually required before

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the full contraceptive effect of exogenous hormones can be achieved. This amount

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of time is similar to that required for vasectomy to reach full contraceptive efficacy. Healthy men with normal reproductive function produce sperm concentrations

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exceeding 14 million per ml of ejaculate (Cooper, et al., 2010). An ideal hormonal

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contraceptive would render the ejaculate free of sperm, a condition known as “azoospermia.” However, early efficacy studies of male hormonal contraceptives

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demonstrated that “severe oligozoospermia”—a sperm concentration ≤1 million per ml of ejaculate, is associated with a risk of pregnancy of ~1% per year (World

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Health Organization Task Force on Methods for the Regulation of Male, 1996), which is similar to the efficacy of modern female hormonal contraceptives(Moreau,

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Trussell, Rodriguez, Bajos, & Bouyer, 2007). Therefore, severe oligozoospermia is viewed as a reasonable goal for novel male hormonal contraceptives (Aaltonen, et al., 2007).

This review summarizes recent advances in the development of an effective hormonal male contraceptive, including the challenges that remain, as well as promising agents that have the potential to be introduced into the marketplace in the next decade. Non-hormonal pharmacological agents for male contraception, which aim at disrupting spermatogenesis or preventing the union of sperm and egg are also actively under development but will not be discussed within the scope of this review.

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2. Testosterone as a single agent for male hormonal contraception

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Testosterone esters are derivatives of testosterone with a long chain carbon moiety added at the seventeenth carbon position (17C). Esterification of testosterone

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increases its solubility in oil, and injectable testosterone esters in oil are slowly

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metabolized to testosterone in vivo by endogenous esterases, greatly enhancing their half life compared to aqueous injectable and oral testosterone. Moreover,

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exogenous testosterone, in contrast to synthetic androgens, provides both androgenic and estrogenic support to peripheral tissues (via aromatase), and these

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hormonal effects are important in for male health, particularly in tissues such as bone, fat and the brain (Finkelstein, et al., 2013). Similarly, exogenous testosterone

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undergoes 5α-reduction to DHT. There have been concerns that increased concentrations of serum T and DHT might contribute to an increased risk of prostate disease. However, appropriately powered randomized controlled trials to test this hypothesis have not been done, and currently available data are inconclusive (Endogenous Hormones and Prostate Cancer Collaborative, Roddam, Allen, Appleby, & Key, 2008; Page, et al., 2011). Such concerns underscore the need for male hormonal contraceptive regimens, which might be used over many years, to utilize exogenous hormones dosed to achieve serum concentrations in the normal physiologic range for healthy men. a. Testosterone enanthate

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ACCEPTED MANUSCRIPT Testosterone enanthate contains a seven carbon chain at the 17C position. The World Health Organization (WHO) was among the first to pioneer studies of male

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hormonal contraception and to examine contraceptive efficacy in couples in the

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1980s and early 1990s. WHO performed two large multicenter trials in couples using intramuscular testosterone enanthate (TE) 200mg weekly as their only form

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of contraception and demonstrated TE is an efficacious, safe, and reversible

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contraceptive for men, at least over the short term. Ninety-five percent and 98% of the men achieved either azoospermia or oligozoospermia (<3 million sperm per ml

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of ejaculate) in these trials ("Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for

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the regulation of male fertility," 1990; World Health Organization Task Force on Methods for the Regulation of Male, 1996). Of the men who became azoospermic, 0-

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0.8 pregnancies per 100 person-years were seen in the first trial and none in the second trial. Subjects resumed normal sperm production following the discontinuation of testosterone injections. Although these men experienced no serious adverse events and maintained good quality of life and sexual function, they found weekly injections inconvenient and painful, had some undesirable side effects such as acne likely associated with supraphysiolgic testosterone levels, disliked the delay of 3-4 months before becoming azoospermic or oligozoospermic, and still had a chance to conceive when the sperm concentration failed to suppress below 1 million per ml. In addition, there were concerns regarding the long-term safety of this high dose of exogenous testosterone, a dose that is roughly twice the normal

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ACCEPTED MANUSCRIPT level of testosterone produced in healthy men. These properties make TE, at this

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supraphysiologic dose, a less desirable single-agent contraceptive.

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b. Testosterone undecanoate

The advent of a long-acting testosterone depot—testosterone undecanoate (TU)

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administered once every 8-12 weeks (Behre, Abshagen, Oettel, Hubler, & Nieschlag,

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1999; Zhang, Gu, Wang, Cui, & Bremner, 1998), circumvents the inconvenience of weekly injections that made TE an impractical choice for male contraception. TU

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contains an 11-carbon chain at the 17C position, with longer carbon chains generally increasing the solubility and slowing the release of the compound

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compared to shorter-chain esters when given intramuscularly. A phase II efficacy trial using monthly injections of 500mg of TU in 308 Chinese men found 299 men

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achieving azoospermia or oligozoospermia within 6 months (Y. Q. Gu, et al., 2003). Of the men whose sperm concentrations were suppressed <3 million sperm per ml of ejaculate, 296 entered the efficacy phase, in which they, and their partners, used TU as their sole method of contraception for one year. During the efficacy phase, reappearance of sperm was observed in 6 men, and this resulted in one pregnancy, giving an overall contraceptive efficacy rate of 94.8%. Subsequently, a phase III trial enrolling 1045 Chinese men and administering monthly injections of 500mg of TU achieved azoospermia or severe oligozoospermia in 95% of the men within 6 months (Y. Gu, et al., 2009). Of the men whose sperm concentrations were suppressed to <1 million sperm per ml of ejaculate, 855 entered the efficacy phase with their partners, during which 9 pregnancies occurred, giving a similar overall

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ACCEPTED MANUSCRIPT efficacy rate of 94%. Possible explanations for failure to suppress spermatogenesis to < 1 million sperm per ml of ejaculate in the remaining 5% of men include

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incomplete gonadotropin suppression from variations in androgen action and/or

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androgenic support of spermatogenesis from the high concentrations of serum testosterone (that is, from high concentrations of circulating testosterone perhaps

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penetrating the testes and supporting low levels of sperm production). Several

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studies have observed that higher doses of testosterone may be associated with lower degrees of sperm suppression (M. C. Meriggiola, Costantino, Bremner, &

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Morselli-Labate, 2002).

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The use of TU as a male contraceptive appears well tolerated and safe, as demonstrated by the high study-completion rates associated with both trials.

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Common side effects associated with TU include discomfort at the injection site, acne, mood swings, and a small decrease in testicular volume. Long-term use of testosterone as part of a contraceptive regimen may require monitoring of complete blood count because testosterone is associated with an increase in hemoglobin concentration in a dose-related manner. Of note, while TU is used widely in Europe and Asia for testosterone replacement, TU has only recently been approved for use in the United States, and its use in the United States continues to require a “risk evaluation and mitigation strategy” (REMS) for prescribing physicians and administration by qualified healthcare providers because of FDA’s concerns for possible injection-related pulmonary oil microemboli.

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ACCEPTED MANUSCRIPT Although testosterone-only contraceptive regimens have been effective in achieving high rates of azoospermia and oligozoospermia in Asian men (90-98%) they are less

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effective in Caucasian men who achieve goal sperm indices only ~60% of the time

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(Handelsman, Farley, Peregoudov, & Waites, 1995). The reason for this disparity in the efficacy of sperm suppression across different ethnicities is not well understood,

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and baseline differences in androgen receptor sensitivity, androgen metabolism,

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and testicular structure have been proposed, but none of these have been definitively determined to be causal (Ilani, Liu, Swerdloff, & Wang, 2011). In

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addition, a proportion of men across all ethnicities do not achieve maximal sperm suppression with testosterone alone for reasons that remain unclear. The addition

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of a progestin to testosterone has been found to induce more consistent suppression of spermatogenesis in both Caucasians and Chinese men (Kinniburgh, et al., 2002).

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Therefore, combination therapy for male contraception is superior to testosterone alone (see below).

3. Testosterone and progestin combinations Androgens alone do not adequately suppress spermatogenesis, and progestins available to date do not provide adequate androgenicity at non-gonadal tissues when given as single-agent contraceptives. Thus, multiple dual-agent regimens have been evaluated as male hormonal contraceptive “regimens” in an effort to increase effectiveness while minimizing side effects. The addition of a progestin to testosterone achieves faster and more persistent suppression of spermatogenesis

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ACCEPTED MANUSCRIPT across different ethnicities (Liu, et al., 2006), possibly through increased inhibition of gonadotropin secretion, and also spares the use of supraphysiologic doses of

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testosterone. Progestins have a wide range of androgenicity, antiandrogenic effects,

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and progestin potencies. More androgenic progestins are more effective at suppressing LH (Attardi, Koduri, & Hild, 2010) and could allow for lower doses of

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testosterone in combined regimens. In contrast, antiandrogenic progestins could, in

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theory, have direct testicular effects in suppressing spermatogenesis. In fact, recent work demonstrated the presence of intratesticular progesterone and androgen

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receptors that such compounds may interact with (Lue, et al., 2009; Lue, et al., 2013). Furthermore, the side effect profiles of the various available progestins vary

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according to their degree of androgenicity in men just as they do in women. Thus, the bioactivity and delivery mode of the progestin are important properties to

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consider when developing and comparing the effectiveness of various testosteroneprogestin male contraceptive regimens. Further research in this area is ongoing in an effort to optimize the progestins included in these regimens.

a. Testosterone + Levonorgestrel Levonorgestrel is a synthetic progestin with high androgenic potency. Initial proofof-concept studies involving the addition of oral levonorgestrel to testosterone aimed at improving sperm suppression and used higher doses of levonorgestrel but considerably lower doses of testosterone compared to that used in the initial WHO studies. An initial study of 36 healthy men demonstrated more rapid suppression of spermatogenesis, with 94% of the men achieving oligozoospermia, using the

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ACCEPTED MANUSCRIPT combination of testosterone enanthate (100 mg IM weekly) and levonorgestrel (500 mcg daily), compared to 61% of men on testosterone alone (Bebb, et al., 1996).

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However, high dose oral levonorgestrel resulted in a significant decrease in HDL-

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cholesterol and increase in weight in the testosterone-levonorgestrel group. This levonorgestrel dose-dependent effect of weight gain and HDL-cholesterol

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suppression was obviated in subsequent studies using much lower doses of

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levonorgestrel, while the synergistic suppression of testosterone and levonorgestrel on spermatogenesis was maintained (Anawalt, et al., 2005; Herbst, Anawalt, Amory,

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Matsumoto, & Bremner, 2003). Levonorgestrel given as an implant has also been studied in combination with TU in 62 Chinese men and, when combined with high-

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dose TU, was found to be 90% and 100% effective in achieving azoospermia and oligozoospermia, respectively (Gui, et al., 2004). When levonorgestrel and TU

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implants were used in both Chinese and non-Chinese men, suppression to severe oligozoospermia were similar at 90% and 89%, respectively (Wang, et al., 2006). This combination was well-tolerated with the most common side effects being acne and an increase in hemoglobin concentrations and showed no significant effects on HDL-cholesterol. Levonorgestrel buciclate, as a long-acting injectable progestin, is currently in development (Sharma, Pal, Griffin, Waites, & Rajalakshmi, 2007). Like the levonorgestrel implants, levonorgestrel buciclate injections are expected to have less impact on HDL-cholesterol than oral levonorgestrel because delivery through injections help avoid first pass effects through the liver.

b. Testosterone + Etonogestrel

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ACCEPTED MANUSCRIPT Etonogestrel is a relatively less androgenic progestin and is the active metabolite of desogestrel, one of the progestins found in combined oral contraceptive pills for

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women. A pilot study demonstrated effective suppression of spermatogenesis using

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the combination of depot testosterone and etonogestrel implants, with 93% of men developing severe oligozoospermia with minimal metabolic side effects (Anderson,

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Kinniburgh, & Baird, 2002). Subsequently, a multicenter study of 130 men

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examined the effect of etonogestrel implants plus testosterone decanoate over 48 weeks. Approximately 90% of men in the two arms receiving higher doses of

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testosterone decanoate (an average of 100mg weekly) in addition to the etonogestrel implants achieved severe oligozoospermia (Brady, et al., 2006).

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Subsequently, a large double-blind, placebo-controlled international study of 354 men was performed using improved formulations of TU and etonogestrel implants,

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with standardized sperm analysis across the centers. Ninety-four percent of men reached severe oligozoospermia in the groups receiving high-dose etonogestrel (Mommers, et al., 2008). While mild side effects commonly associated with testosterone-progestin regimens were seen—such as weight gain, mood changes, acne, and sweating—they were well-tolerated. Furthermore, no significant change in HDL- or total cholesterol was observed with this non-oral regimen.

c. Testosterone + Norethisterone Enanthate Norethisterone enanthate (NETE) is a second-generation progestin with both antiandrogenic and antiestrogenic properties (Garza-Flores, et al., 1991) and is available as a long-acting injectable female contraceptive. Single-doses of NETE

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ACCEPTED MANUSCRIPT resulted in sustained suppression of gonadotropins in men (Kamischke, Diebacker, & Nieschlag, 2000). A phase II clinical trial using intramuscular TU with either

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intramuscular or oral NETE for 24 weeks showed sperm suppression to

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azoospermia or severe oligozoospermia in all enrolled subjects (Kamischke, et al., 2002). In a 48-week dose- and interval-finding trial, TU and NETE injected at 8-

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week intervals were optimally associated with a 90% rate of azoospermia (M. C.

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Meriggiola, et al., 2005). Similarly, in a separate multi-center study, TU and NETE administered every 8 weeks maximally suppressed gonadotropins and

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spermatogenesis (Qoubaitary, et al., 2006). The combination of TU and NETE injections was well tolerated with reversible side effects including increase in body

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weight and hemoglobin concentrations and decreases in HDL-cholesterol. With promising results from these trials, the WHO and CONRAD conducted a

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multinational phase II trial of 250 couples using TU and NETE, with an efficacy phase of 1 year in men whose sperm concentration suppressed below severe oligozoospermia (<1 million/ml). Unfortunately, in April 2011, WHO and CONRAD announced their decision to terminate the Phase II study early because several side effects—particularly depression, mood changes, and increased libido—were observed more frequently than previously anticipated, and this raised concerns whether TU-NETE could be developed and marketed successfully as a male contraceptive regimen. Despite the early termination, initial reports show a high contraceptive efficacy rate of TU-NETE, and the full report that is yet to be published will provide valuable information on the feasibility and acceptability of a combined androgen-progestin hormonal male contraceptive method (C. Meriggiola, 2013).

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d. Testosterone + Depomedroxyprogesterone Acetate

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Depomedroxyprogesterone Acetate (DMPA), when given intramuscularly, is a long-

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acting progestin that is 97% effective in preventing pregnancies when used as a female hormonal contraceptive (James Trussell, 2007). An Australian contraceptive

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efficacy study utilizing DMPA established the proof-of-principle for using depot

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androgen-progestin combinations as male contraceptive (Turner, et al., 2003). This study enrolled 55 men and administered testosterone implants every 4-6 months

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and DMPA 300mg intramuscularly every 3 months, with the latter being the same DMPA dose as that used for female contraception. Fifty-three men achieved severe

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oligozoospermia for 2 consecutive months and entered the contraceptive efficacy phase with their partners. There were no pregnancies, resulting in a contraceptive

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failure rate of 0-8% (with a confidence range appropriate for the small trial), superior to the first year failure rate of condoms. In a similar study conducted in 30 Chinese men, TU was administered with or without DMPA, and the addition of DMPA increased the rate of sustained azoospermia or severe oligozoospermia to 100% of men (Y. Q. Gu, et al., 2004). In a separate study, transdermal testosterone gel was combined with DMPA 300mg intramuscularly every 3 months, and 90% of the 44 men achieved severe oligozoospermia (Page, et al., 2006). No serious adverse event was reported in any of the three studies; however, reversible weight gain and a mild decrease in HDL-cholesterol were common to all three studies, while a reversible increase in hemoglobin concentration was only associated with the depot or injectable forms of testosterone. These studies demonstrate that the

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ACCEPTED MANUSCRIPT addition of DMPA to testosterone may be a potent, longer acting, and effective male

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contraceptive combination with few side effects.

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Of note, there is current controversy as to whether use of hormonal contraceptives, and DMPA in particular, may increase rates of HIV transmission in some settings

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(Polis, et al., 2014). Large trials designed to test the impact of hormonal

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contraceptive use in women on HIV transmission are currently underway. As hormonal contraceptive regimens for men proceed in development, such long-term

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studies in men may be warranted as well.

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e. Testosterone + Nestorone or Cyproterone Acetate Nestorone is a 19-norprogesterone derivative and one of the most potent progestins

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in development when administered parenterally. It has higher progestational activity compared to levonorgestrel and progesterone, demonstrates near-absent androgenic activity even at high doses, and induces profound gonadotropin suppression (Kumar, Koide, Tsong, & Sundaram, 2000). Thus, nestorone has appeal as part of male contraceptive regimens with the potential for minimal side effects associated with significant gonadotropin and testicular suppression.

The effectiveness of simultaneous use of nestorone and testosterone transdermal gels was assessed in a study that enrolled 99 men, and the gel combination was found to be 88-89% effective at achieving severe oligozoospermia, with serum testosterone maintained in the normal range throughout the treatment period (Ilani,

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ACCEPTED MANUSCRIPT et al., 2012). This study further showed that LH concentrations following 4 weeks of treatment were 97% sensitive in predicting subjects who would achieve sperm

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concentrations of < 1 million per ml at 24 weeks of drug administration (Roth, Ilani,

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et al., 2013). Such a “benchmark”, if widely applicable to other products in the pipeline, will help streamline the conduct of future male hormonal contraception

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trials. No serious adverse events were observed using the combination of nestorone

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and testosterone transdermal gels (Ilani, et al., 2012). Despite mild side effects— such as acne, weight gain, a reversible decrease in HDL-cholesterol, and a mild

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increase in fasting serum glucose that remained in the normal range, a majority of the men reported satisfaction with the combination of testosterone and nestorone

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gels (Roth, et al., 2014). Further development of a single gel containing both steroids for use in men, sponsored by the National Institutes of Health, is currently

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underway. Such a product would represent the first self-administered reversible male hormonal contraceptive to be evaluated in a Phase II trial.

Cyproterone acetate (CPA) is a potent anti-androgen and progestin approved for treatment of prostate cancer in Europe and, when combined with a low-dose ethinyl estradiol, as a female hormonal contraceptive. When tested as a potential male hormonal contraceptive, CPA was first combined with TE and proved to induce rapid and profound suppression of spermatogenesis (M. C. Meriggiola, Bremner, Costantino, Di Cintio, & Flamigni, 1998). However, the need for weekly injections of TE made this regimen undesirable. Subsequently, CPA was combined with longacting TU given once every 6-8 weeks and shown to effectively suppress 100% of

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ACCEPTED MANUSCRIPT the 24 men studied to severe oligozoospermia within 12 weeks. Thereafter, sperm suppression was maintained for another 32 weeks by either TU alone or TU+CPA (M.

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C. Meriggiola, et al., 2003). This regimen was very well tolerated. The addition of

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the anti-androgenic CPA resulted in a lower testosterone level and also obviated the slight and reversible increase in total prostate volume seen in the TU-alone group in

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the maintenance phase. Despite this combination showing promise, injectable CPA

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has not been approved for use in the United States and is no longer available for

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clinical investigation.

f. Other testosterone delivery methods with or without a progestin

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The mode of delivery of testosterone impacts it’s effectiveness, peak concentrations, and side effect profile. In addition, some methods of administration are likely

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preferred over others for different populations of contraceptive users. In some surveys, oral agents have been preferred by potential users (A. Glasier, 2010; Glasier, et al., 2000). Methyltestosterone can be administered orally but is associated with significant hepatoxicity. Testosterone undecanoate is approved for use outside the United States for treatment of male hypogonadism but requires twice daily dosing to maintain physiologic serum testosterone concentrations. A new formulation of oral TU has more promising single-dosing pharmacokinetics (Yin, et al., 2012). Oral TU is associated with elevated serum concentrations of dihydrotestosterone (DHT), which some have argued may raise the risk of prostate disease (see Section 5 below), although other data suggest that increases in serum DHT have little impact on the prostatic hormonal milieu (Page, et al., 2011). These advances in oral

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ACCEPTED MANUSCRIPT testosterone delivery make it possible that some time in the next decade an oral

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“male pill” containing testosterone plus a progestin may be on the horizon.

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Transdermal testosterone, a self-applied treatment modality, is available in the forms of patches and gels and has been used to treat male hypogonadism with

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success. As noted above, and expanded below, testosterone transdermal gels have

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been used effectively in combination with progestins. In contrast, even when combined with a progestin, currently available testosterone patches have not been

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effective for male contraception, with fewer than 50% of men suppressing their sperm concentrations to <1 million sperm per ml of ejaculate (Buchter, et al., 1999;

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Gonzalo, et al., 2002). This insufficient suppression of spermatogenesis is likely caused by the low-normal serum concentrations of testosterone achieved with

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patches, leading to incomplete suppression of the LH and FSH. In addition, skin irritation occurs frequently at the patch application sites and led to patch discontinuation in 24% of men in one study (Hair, Kitteridge, O'Connor, & Wu, 2001).

Several proof-of-concept studies have shown testosterone transdermal gels having potential as male hormonal contraceptive when combined with a progestin and having high rates of acceptability (Amory, Page, Anawalt, Matsumoto, & Bremner, 2007; Roth, et al., 2014). The combination of testosterone gel with nestorone has been described above and was shown to lead to severe oligozoospermia in 88-89% of men with minimal adverse effects (Ilani, et al., 2012). In another study,

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ACCEPTED MANUSCRIPT testosterone gel combined with DMPA injections resulted in severe oligozoospermia in 90% of men treated for 24 weeks (Page, et al., 2006). The testosterone gel-

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progestin combination is associated with minimal side effects, with mild acne being

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the most common, affecting 21% of men on treatment (Ilani, et al., 2012) likely due in part to the favorable pharmacokinetics of these products which provide more

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stable serum levels of testosterone without large peaks (Hadgraft & Lane, 2015).

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Skin irritation associated with testosterone gels appears milder and less common compared with that associated with testosterone patches, although there have not

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been head to head studies. Sexual function was preserved during treatment, and a majority of the men reported satisfaction with the testosterone gel-DMPA regimen

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(Amory, et al., 2007). Potential disadvantages of daily transdermal products include compliance with daily application and the potential of interfering with men’s

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routine, as they need to take care with washing to avoid transferring the gel to female partners and children.

Testosterone can also be administered by subdermal implant , a method originally developed in 1937. Testosterone pellets have near-ideal depot properties—with each implant lasting 3-6 months and achieving steady serum testosterone concentrations. As a result of these properties, their clinical use as androgen replacement therapy greatly rose in the 1990s (Handelsman, Mackey, Howe, Turner, & Conway, 1997). Testosterone pellets for male contraception were initially explored in a pilot study of 9 men treated for 2 months. All men achieved severe oligozoospermia or azoospermia (Handelsman, Conway, & Boylan, 1990). As noted

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ACCEPTED MANUSCRIPT above, a proof of principle study using testosterone implants every 4 months and DMPA intramuscularly every 3 months achieved severe oligozoospermia and

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azoospermia in 96% of the 55 men enrolled, and observed no pregnancies in 35.5

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person-years studied (Turner, et al., 2003). Another two studies examined the suppression of spermatogenesis using testosterone-etonogestrel implants and

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found an overall rate of azoospermia in 85% among the 98 men (Anderson, Van Der

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Spuy, et al., 2002; Kinniburgh, et al., 2002). The testosterone pellet and progestin combinations have been well-tolerated with pellet extrusion as the most common

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adverse effect. Importantly, no significant side effects, including alterations in lipid profiles seen in some studies using injections and transdermal preparations, were

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observed with these depot regimens, although long-term clinical studies are needed

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to further investigate the safety of various testosterone-progestin implants.

4. Gonadotropin-releasing hormone antagonists Although 80-90% of men achieved severe oligozoospermia or azoospermia with the aforementioned hormonal combinations, a small number of men experienced persistent or rebound spermatogenesis. These men showed little to no significant differences in their degree of gonadotropin suppression compared to men who achieved adequate sperm suppression (Amory, Anawalt, Bremner, & Matsumoto, 2001; Handelsman, et al., 1995; McLachlan, et al., 2004; Wallace, Gow, & Wu, 1993). One hypothesis to explain persistent spermatogenesis in this setting is that in some men gonadotropin production continues at a low level, below the limit of detection of standard gonadotropin assays. Although GnRH agonists have been shown to

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ACCEPTED MANUSCRIPT suppress gonadotropins in men, they induce an initial spike in gonadotropin production and, as a result, fail to suppress spermatogenesis effectively (Behre,

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Nashan, Hubert, & Nieschlag, 1992). On the contrary, GnRH antagonists inhibit

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gonadotropin secretions without this effect, leading to a rapid decline in FSH and LH

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levels within hours of administration (Pavlou, et al., 1986).

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Early studies with the short-acting GnRH antagonists as adjuncts to male hormonal contraceptive treatment were disappointing. Studies of the peptide Nal-Glu showed

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that it failed to increase the rate of azoospermia when combined with TE (Bagatell, Matsumoto, Christensen, Rivier, & Bremner, 1993). As induction agents, results

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were mixed. The Nal-Glu and TE combination led to azoospermia in 12 weeks, and following the discontinuation of Nal-Glu, TE alone achieved lasing suppression on

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spermatogenesis for 20 additional weeks (Swerdloff, et al., 1998). On the contrary, although cetrorelix and 19-nortestosterone combination was successful at inducing azoospermia by 12 weeks in 6 of 6 men, 19-nortestosterone failed to maintain azoospermia or severe oligozoospermia following the discontinuation of cetrorelix. The need for daily subcutaneous injections with these shorter-acting GnRH agonists and incidents of minor injection-site reactions raise concerns for poor contraceptive adherence on these agents.

A longer-acting GnRH antagonist, acyline, suppresses serum testosterone concentration to castrate level for 15 days following a single injection (Herbst, et al., 2004) and allows for a more feasible schedule for a possible contraceptive.

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ACCEPTED MANUSCRIPT However, a study of 38 men treated with testosterone gel and intramuscular DMPA assessed acyline as part of an induction phase and did not find the inclusion of the

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GnRH antagonist accelerating spermatogenic suppression or improving rates of

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severe oligozoospermia (Page, et al., 2006). Another longer-acting GnRH antagonist, degarelix, has been developed in recent years to treat prostate cancer. Studies

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showed that degarelix leads to rapid suppression of testosterone to castrate level

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within 1-3 days and may be administered as a subcutaneous depot every 28 days (Klotz, et al., 2008). However, degarelix has yet to be tested as a possible adjunct to

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an androgen as male contraceptive.

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Additional agents are in development, including oral formulations and other longeracting injectables or implants. In theory, these newer agents could be combined

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with an exogenous androgen to spare the use of a progestin and potentially minimize progestin-associated metabolic side effects. Initial studies of oral acyline showed efficacy but unfavorable pharmacokinetics for once daily dosing (Amory, et al., 2009). A more promising non-peptide oral GnRH antagonist, TAK-385 appears more promising (MacLean, Shi, Faessel, & Saad, 2015). Further studies are needed to assess and optimize the incorporation of GnRH antagonists, in conjunction with an effective androgen, into male contraceptive regimens.

5. Inhibitors of Intratesticular Testosterone Synthesis It has been proposed that one mechanism whereby some men fail to fully suppress spermatogenesis is the persistence of intratesticular testosterone

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ACCEPTED MANUSCRIPT production despite maximal gonadotropin suppression (Page, Amory, & Bremner, 2008). Indeed, studies in LH receptor knock out mice suggest that non-LH

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dependent androgen production is sufficient to support spermatogenesis in rodents

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and that doses of exogenous testosterone sufficient to suppress gonadotropins in these animals also activate spermatogenesis (Oduwole, et al., 2014). Although such

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findings have not been reproduced in humans, Roth et al. have shown that intra-

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testicular testosterone production in men can be further decreased with inclusion of a steroid synthesis inhibitor, ketoconazole, beyond that observed with a GnRH

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antagonist alone (Roth, Nya-Ngatchou, et al., 2013). These observations raise the possibility of a male contraceptive regimen that includes an inhibitor of the final

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steps of androgenesis and an exogenous testosterone (to maintain peripheral androgen effects). Drugs that inhibit CYP17A1, such as abiraterone, have recently

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been developed for the treatment of castration-resistant prostate cancer (Gomez, Kovac, & Lamb, 2015) and effectively further lower testosterone production. Current CYP17A1 inhibitors concomitantly lower serum cortisol, an unacceptable side effect for a contraceptive. However, inhibitors with increased selectivity for enzymes further down the androgen synthetic pathway (that is, selective for c17,20 lyase over 17βhydroxylase), with less mineralocorticoid inhibition, are currently in development for the treatment of prostate cancer. Such agents, if truly selective in vivo, might have utility for male hormonal contraception as well if used in conjunction with exogenous androgens.

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ACCEPTED MANUSCRIPT 6. Synthetic Androgens for Hormonal Contraception A major area of male hormonal contraceptive development has been recent

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progress in the synthesis and clinical testing of novel steroid compounds. These

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derivatives of 19-nortestosterone have been designed to retain the androgenic effects of testosterone, increase serum half-life without increasing the risk of

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hepatotoxicity, while retaining the activities of important testosterone metabolites

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(Cook & Kepler, 2005). In men, approximately 1-5% of testosterone is metabolized to DHT, a very potent androgen, via conversion by 5α-reductase, and a similar

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percentage of testosterone is converted to estradiol via aromatase. However, the relative amounts of these biologically active metabolites vary considerably among

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tissues, dependent upon the expression of these respective enzymes. For example, conversion of testosterone to DHT is considerable within the prostate gland, where

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5α-reductase type II is highly expressed (Bartsch, Klein, Schiemann, Bauer, & Voigt, 1990). Similarly, aromatase is expressed in adipose tissue and bone, and estradiol is known to be important in maintenance of bone health, body composition, and sexual function in men (Finkelstein, et al., 2013). Synthetic androgens designed for male hormonal contraception aim, therefore, to be both potent androgens and progestins, while minimizing side effects associated with alterations in changes in DHT and estradiol concentrations.

a. 7-Alpha-methyl-19-nortestosterone 7α-methyl-19-nortestosterone (MENT) is a synthetic androgen five times more potent than testosterone in vitro. MENT is resistant to 5α-reductase but susceptible

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ACCEPTED MANUSCRIPT to aromatase and is converted into an estrogen capable of stimulating the estrogen receptor (Anderson, Wallace, Sattar, Kumar, & Sundaram, 2003). Therefore, in

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theory, MENT could spare the prostate from androgen-stimulated enlargement

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while maintaining other physiological androgen- and estrogen-dependent functions. MENT has been tested for androgen replacement in hypogonadal men and results

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suggest that, indeed, it may be prostate-sparing in vivo (Anderson, et al., 2003).

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However, whether it can maintain bone mineral density and provide adequate

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estrogen-related bioactivity remains to be seen.

As a male contraceptive, the evaluation of MENT has been stymied by difficulties

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with the development of the implant itself. Initial studies were promising. In an initial study evaluating 1, 2 or 4 MENT implants in 35 men over 6-12 months, with

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each implant releasing approximately 400 μg of MENT per day, 4 implants were successful at inducing azoospermia or severe oligozoospermia in 9 of 11 men for 12 months (von Eckardstein, et al., 2003). Subjects’ spermatogenesis returned to normal levels within 3 months of implant extraction, demonstrating reversibility. The implants were well-tolerated with no severe adverse events, few complaints related to pain at implant sites, and expected reversible increases in hemoglobin concentration. In subsequent studies, MENT implants have been combined with etonogestrel or levonorgestrel implants (Nieschlag, Kumar, & Sitruk-Ware, 2013). However, oligozoospermia was not maintained in men receiving MENT in these studies due to a decline in MENT level throughout the study period (Walton, Kumar, Baird, Ludlow, & Anderson, 2007). These disappointing results, therefore, appeared

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ACCEPTED MANUSCRIPT to be related to problems with the MENT implants themselves, not the drug per se. Therefore, reformulated MENT implants that provide sufficient and more consistent

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drug delivery are in development and may lead to more satisfactory contraceptive

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effects. MENT remains a promising agent in the development of a male hormonal

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contraceptive.

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b. Dimethandrolone undecanoate

Dimethandrolone undecanoate (DMAU: 7α, 11β-dimethyl-19-nortestosterone 17β-

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undecanoate) is a potent 19-norandrogen with dual androgenic and progestational activities to maximize gonadotropin suppression. Therefore, DMAU and its active

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metabolite, DMA, could, in theory, act as a single-agent male hormonal contraceptive. In addition, DMA/DMAU does not appear to be 5α-reduced, suggesting, like MENT, it

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may be a “prostate-sparing” androgen (Attardi, Hild, et al., 2010). An early study in rabbits demonstrated the potential for DMAU as an orally active single-agent male hormonal contraceptive. The majority of rabbits in the two highest-dosing groups developed severe oligozoospermia after 13 weeks of treatment, and 7 of 9 rabbits became reversibly infertile in a subsequent mating trial (Attardi, Engbring, Gropp, & Hild, 2011). A study in rats also showed favorable changes in body composition and maintenance of bone mineral density associated with the use of DMAU (Attardi, Marck, Matsumoto, Koduri, & Hild, 2011), important pre-clinical results as in vitro investigations have suggested that DMA/DMAU may not be aromatizable (Attardi, et al., 2008).

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ACCEPTED MANUSCRIPT A Phase 1 trial of single, escalating doses of DMAU administered orally to 10 healthy men has had encouraging results. Importantly, no adverse effects were seen with

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single doses of DMAU up to 800mg. Significant suppression of serum gonadotropins

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and sex hormone concentrations was observed 12 hours after single doses of DMAU were administered with food at doses above 200mg (Surampudi, et al., 2014). This

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first-in-man study, therefore, showed that a single dose of DMAU up to 800mg is

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safe and surprisingly bioactive at the pituitary level. The bioavailability of oral DMAU administered in the fasting state was poor, as active DMA was detectable in

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only 40% of men after the 800mg dose, but when given with food, both DMA and DMAU were detectable in serum for more than 12 hours. Efforts to improve DMAU

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delivery by oral or intramuscular administration are currently underway with support from the Contraceptive Development Branch of the Eunice Kennedy Shriver

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National Institute of Child Health and Human Development.

6. Conclusion

Limiting population growth is a critical environmental and humanitarian challenge for the current millennium. Contraceptive choices for couples increase the opportunity for family planning and can improve maternal health. Many men are willing to and interested in becoming more active participants in contraception. Male hormonal methods are effective in the vast majority of men and have the potential for non-contraceptive health benefits for their users; however, these need to be optimized. Recent advances in the development of potential “single-agent” male hormonal contraceptives, as well as delivery systems that are user-driven,

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ACCEPTED MANUSCRIPT such as pills and gels, hold promise to provide reversible contraceptive options for men in the next decade, but major challenges remain. In particular, streamlined

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regimens with minimal side effects and a greater understanding of the physiologic

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basis underlying those men who fail to adequately suppress spermatogenesis could help move the field forward. To successfully overcome these challenges and

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develop safe and efficacious male hormonal contraceptives, funding from

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government and non-government agencies for clinical testing is critical. In the past, pharmaceutical companies have supported major, randomized clinical trials in this

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area, both with the provision of drug supplies and funding. However, that support has not been forthcoming in recent years, perhaps from a perception of increased

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regulatory barriers and increased financial investment required for drug development, greatly stymying progress in the development of male hormonal

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contraceptives. Despite continued support from the NIH, funding for ongoing research remains limited.. Close collaboration with industry and non-governmental organizations would help expedite the delivery of male contraceptives to men and their female partners and give couples increased options for control of their own fertility.

Conflict of Interests: The authors, JHC and STP, declare that there are no conflicts of interest. STP is supported by the Robert D. McMillen Professorship in Lipid Research. STP has received support in the form of drug supply for investigator-initiated studies from Besins Healthcare (Brussels, Belgium) and Abvie (North Chicago, IL, U.S.A.). 31

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Attardi, B. J., Hild, S. A., Koduri, S., Pham, T., Pessaint, L., Engbring, J., Till, B., Gropp, D., Semon, A., & Reel, J. R. (2010). The potent synthetic androgens, dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11betamethyl-19-nortestosterone, do not require 5alpha-reduction to exert their maximal androgenic effects. J Steroid Biochem Mol Biol, 122, 212-218. Attardi, B. J., Koduri, S., & Hild, S. A. (2010). Relative progestational and androgenic activity of four progestins used for male hormonal contraception assessed in vitro in relation to their ability to suppress LH secretion in the castrate male rat. Mol Cell Endocrinol, 328, 16-21. Attardi, B. J., Marck, B. T., Matsumoto, A. M., Koduri, S., & Hild, S. A. (2011). Longterm effects of dimethandrolone 17beta-undecanoate and 11beta-methyl-19nortestosterone 17beta-dodecylcarbonate on body composition, bone mineral density, serum gonadotropins, and androgenic/anabolic activity in castrated male rats. J Androl, 32, 183-192. Attardi, B. J., Pham, T. C., Radler, L. C., Burgenson, J., Hild, S. A., & Reel, J. R. (2008). Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11betamethyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase. J Steroid Biochem Mol Biol, 110, 214-222. Bagatell, C. J., Matsumoto, A. M., Christensen, R. B., Rivier, J. E., & Bremner, W. J. (1993). Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus T alone as potential male contraceptive regimens. J Clin Endocrinol Metab, 77, 427-432. Bartsch, W., Klein, H., Schiemann, U., Bauer, H. W., & Voigt, K. D. (1990). Enzymes of androgen formation and degradation in the human prostate. Ann N Y Acad Sci, 595, 53-66. Bebb, R. A., Anawalt, B. D., Christensen, R. B., Paulsen, C. A., Bremner, W. J., & Matsumoto, A. M. (1996). Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab, 81, 757-762. Behre, H. M., Abshagen, K., Oettel, M., Hubler, D., & Nieschlag, E. (1999). Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol, 140, 414-419. Behre, H. M., Nashan, D., Hubert, W., & Nieschlag, E. (1992). Depot gonadotropinreleasing hormone agonist blunts the androgen-induced suppression of spermatogenesis in a clinical trial of male contraception. J Clin Endocrinol Metab, 74, 84-90. Brady, B. M., Amory, J. K., Perheentupa, A., Zitzmann, M., Hay, C. J., Apter, D., Anderson, R. A., Bremner, W. J., Pollanen, P., Nieschlag, E., Wu, F. C., & Kersemaekers, W. M. (2006). A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Hum Reprod, 21, 285-294. Buchter, D., von Eckardstein, S., von Eckardstein, A., Kamischke, A., Simoni, M., Behre, H. M., & Nieschlag, E. (1999). Clinical trial of transdermal testosterone

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