Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Clinical Trials in Male Nieschlag E J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 227-238

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Clinical Trials in Male Hormonal Contraception *

E. Nieschlag

Research has established the principle of hormonal male contraception based on suppression of gonadotropins and . All hormonal male contraceptives use , but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Clinical trials concentrate on testosterone combined with , , or depot-medroxyprogesterone acetate. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of and etonogestrel in suppressing spermatogenesis in volunteers. J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1): 227–38. Keywords: male contraception, testosterone, norethisterone, clinical trials

 1. Introduction ceptable to large segments of the popula- and also cause a disturbance in sexual tion in industrial nations, and would thus activity. are the oldest barrier 1.1. The Rationale for Hormo- contribute to further stabilization of method available. However, when using nal Male Contraception population dynamics. It might also help condoms, conception rates are relatively The invention of the “pill” for women developing countries whose exponential high, with 12 out of 100 couples con- was undoubtedly one of the most signifi- population growth endangers economic, ceiving during the first year of use (Pearl cant medical, social and cultural events social and medical progress. Last but not index = 12). use has increased of the 20th century [1]. While nature has least, male contraception can be consid- since the beginning of the AIDS epi- sweetened procreation with the pleas- ered an outstanding issue in the political demic, but more for protection from HIV ures of sex to guarantee human repro- field of gender equality infection and other sexually transmitted duction, the pill was the culmination of a diseases than for contraceptive purposes millennial-long development of meth- 1.2. Choices For the Male [3]. is a safe and relatively ods to disentangle procreation from sex For the male, there are ways to eliminate simple surgical method for male contra- and has had a substantial impact on soci- both procreation and sex at the same ception. The rate of unwanted pregnan- ety, e.g., on family planning, morality time. Such methods have been used in cies after vasectomy is less than 1%. The and demography, not to mention eco- the past and are still being practiced on a drawback to vasectomy is that it is not nomic and political impact. An equiva- limited scale. has been em- easily reversible. Achieving fatherhood lent pharmacological male method is not ployed since ancient time to destroy en- after vasectomy requires either surgical yet available. emies by abolishing their ability to re- reversal or extraction from a tes- produce and transmit their genes. Until ticular biopsy and intracytoplasmatic Female contraception is very effective. the end of the imperial period in China sperm into the ovum. Only Nevertheless, 50% of the 1,000,000 con- (1912), men were willing to sacrifice about 50% of these men will become fa- ceptions occurring every day worldwide their testicles (and often with them their thers in the end. remain unplanned, of which 150,000 are lives) in return for high-ranking posi- terminated by abortion, an intervention tions and political influence at the em- Given the disadvantages of these me- that will end fatally for 500 of these peror’s court. Meanwhile, in the West, chanical male methods, what then are women. Although improved distribution up until almost the same time, some the prerequisites for an ideal male con- and utilization of female contraceptive promising boys were forced to give up traceptive? It should methods might ameliorate this situation, their manhood for the sake of preserving the contribution of a their prepubertal voice and achieving – be applied independently of the is well worth considering. Men enjoy the fame as singers, often without success sexual act, pleasures of sex, but can do little to con- [2]. Abstinence is a less bloody means of – be acceptable for both partners, tribute to the tasks of family planning – a eliminating procreation, but few men are – not interfere with , , or pharmacological male contraceptive is willing to give up both sex and procrea- sexual activity, surely long overdue. tion for extended periods of time, let – have neither short- or long-term toxic alone their entire lives. side effects, Moreover, the risks of contraception – have no impact on eventual offspring, would also be more fairly shared be- Traditional male methods of contracep- – be rapidly effective and fully revers- tween women and men. Representative tion such as periodic abstinence or coitus ible, surveys have shown that a pharmaco- interruptus are associated with a rela- – be as effective as comparable female logical male contraceptive would be ac- tively high rate of unwanted methods.

*Reprint with permission from: Contraception 2010; 82: 457–70. © 2010 Elsevier Inc. All rights reserved.

Correspondence: Prof. Eberhard Nieschlag, MD, Centre of Reproductive Medicine and Andrology of the University, WHO Collaboration Centre for Research in Male Reproduction, Domagkstr. 11, D-48149 Münster/Germany; e-mail: [email protected]

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 227 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Clinical Trials in Male Hormonal Contraception

For the past 40 years, hormonal ap- basis on which hormonal approaches to summary, it should be noted that in all proaches to male contraception have male contraception rest. Its goal is to these many clinical trials, only very few been tested clinically. In the following, suppress spermatogenesis and to reduce untoward side effects were reported, in- these developments will be reviewed sperm concentration, if possible, to cluding mild acne and moderate weight taking the above prerequisites into ac- or at least to a sperm con- gain as a more frequent symptom, the count. centration low enough to provide contra- latter due to the anabolic effect of testo- ceptive protection (≤ 1×106 sperm per sterone. A recently performed placebo-  2. Principle of Hormonal mL ejaculate). controlled clinical trial for male contra- ception demonstrated that several symp- Male Contraception Sperm production and secretion of tes- toms previously ascribed to the Of all the different experimental ap- ticular testosterone are so closely inter- regimen used, also occur in the placebo proaches and pharmacological methods woven that it has remained impossible to group [55]. Minimal serious adverse tested so far for male contraception, hor- interrupt spermatogenesis by hormonal events were registered in this multitude monal methods come closest to fulfilling means without inhibiting pro- of trials. In all studies, sperm counts re- the criteria set out above. The endocrine duction. Inhibition of follicle-stimulat- turned to normal levels as a review of feedback mechanism operating between ing hormone (FSH) alone, e.g., by anti- major studies also revealed [61] so that hypothalamus, pituitary and testes is the bodies, leads to reduction of sperm con- one of the prime goals of male hormonal centration but not to azoospermia, as contraception, i.e., reversibility, is met. monkey studies have shown. Suppres- However, long-term studies extending sion of both FSH and luteinizing hor- over three or more years have not yet mone (LH) would indeed lead to been performed. Incidentally, it is worth azoospermia, but would also induce mentioning that results from animal symptoms of which studies have contributed little to the de- affects libido, potency, male role be- velopment of male hormonal contracep- havior and general metabolic processes tion, except in the case of GnRH ana- (erythropoesis, protein, mineral and logues using non-human primates. On bone metabolism). For this reason inhi- the contrary, humans have provided bition of gonadotropins will always ne- models for fertility control in wildlife cessitate androgen administration. [62].

Thus, the principle of hormonal male  3. Clinical Trials to Date contraception is based on (1) suppression of LH and FSH, 3.1. Alone (2) depletion of intratesticular testoster- 3.1.1. one and atrophy of spermatogen- Soon after testosterone was synthesized esis, and and became available for clinical use in (3) substitution of peripheral testoster- the late 1930s, its spermatogenesis-sup- one to maintain androgenicity. pressing effect was recognized [63], but not until the 1970s did investigations At first sight, testosterone itself would start to exploit this phenomenon for be the steroid of choice as it simultane- male contraception. As in most hormo- ously suppresses the gonadotropins and nal male contraceptive studies to date, in maintains androgenicity. However, stud- the early studies, sperm concentrations ies showed that by administration of tes- and counts were used as surrogate pa- tosterone alone, azoospermia could only rameters for efficacy. be achieved in two-thirds of Caucasian men, so that another gonadotropin-sup- The first efficacy study of testosterone- pressing agent must be added to inter- based hormonal male contraception was rupt spermatogenesis as completely as sponsored by the World Health Organi- possible. Gonadotropin-releasing hor- zation (WHO) [5] and included 10 mone (GnRH) analogues and several centers on four continents. Healthy fer- different steroid combinations and deliv- tile participants were given 200 mg of ery systems such as oral, , the longer-acting testosterone enanthate subcutaneous and intramuscular (im) weekly by im injection. One hundred have been examined. Each has its re- fifty-seven men (70%) reached azo- spective merits and drawbacks (Fig. 1B ospermia after 6 months of treatment Figure 1. Schematic representation of the endocrine and C). and entered the efficacy phase for a fur- mechanism controlling testicular function (A). (B) the ther year, during which no other contra- principle of hormonal male contraception using Table 1 provides an overview of clinical ceptive was used by the couple. Only testosterone. (C) the principle of hormonal male contraception using testosterone plus a gestagen trials for male hormonal contraception one pregnancy was reported in this first (adapted from [2]). based on . At the outset of this proof-of-principle study. Although the

228 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Clinical Trials in Male Hormonal Contraception (< 1 Mio/ml [n]) (< 3 Mio/ml [n]) rom [4]) 0.1 or 0 ??? (n) spermia spermia 0.1 or 4 0 0.1 or 5 0 ≤ ≤ ≤ azoospermia azoospermia azoospermia g/4 weeks 6 0 4 g/4 weeks 1 2 1 mg/4 weeks 1 0 0 A 100 mg im/4 weeks im/4 mg 100 A 6 4 0 None 10 – 3 None 7 4 1 NoneNoneNone 3 5 6 – 0 4 – 0 1 ± GnRH antagonist im/4 weeks None 855 – 43 im/6 weeks im/6 im/week 200 mg/4 weeks DMPA 10 0 0 im/week 3000 mg/4 weeks DMPA 7 2 0 im/week mg/4 weeks 100 DMPA 10 0 0 mg/weeks or 300 mg/8 weeks 150 DMPA 28 1 1 g/4 weeksg/4 mg/4 weeks 150 4 0 0 mg im/week mg/ 4weeks 150 DMPA 8 1 0 mg im/week mg/4 weeks 150 DMPA 4 3 1 0 mg im/4 weeks None 284 6 6 0 mg im/4 weeks None 11 1 0 0 mg im/3 weeks 250 mg im/6 weeks DMPA 43 2 0 0 mg im/week mg im/4 weeks 100–150 DMPA 11 ets 800 mg/16 weeksets 800 mg/16 weeks 300 mg im/12 DMPA 49 2 0 ortestosterone 250 mg im/6 weeks DMPA 6 4 2 opionate 4 rods weeks im/4 mg 100 DMPA 2 0 0 250 mg/2 weeks 75 mg/2 weeks 5 0 0 19-Nortestosterone200 mg im/3 weeks 200 mg im/3 weeks 250 mg im/6 weeks DMPA 44 1 0 MENT implants, 3 doses CaucasianCaucasian 19-N im/week mg 250 TE m 200 DMPA Caucasian TE Republic Caucasian 500 m TE CaucasianCaucasian im/week mg 250 TE T-Pr DMP Caucasian im/week 200 mg TE 150 DMPA Republic DominicanRepublic Caucasian TE 250 mg im/week 200 mg TE m 100 DMPA Caucasian Caucasian mg 1000 TU Not stated mg/day T gel 100 weeks 300 mg/12 DMPA 31 2 3 Caucasian one im mg 1000 TB Caucasian im/week mg 100 TE 8 Dominican TE 250 5 Caucasian im/week mg TE 100 898 Chinese TU*500 mg subjects 2] 12 Chinese mg im/4 weeks TU*1000 None 12 0 0 [12] 12 Chinese TU*50 [27] 10 Indonesian TE 250 mg [27] 10 Indonesian mg TE 100 [23] 5 [22] 10 Dominican TE 500 [21] 11 Brasilian TE 20 [23] 4 [20][20] 12 6 [28] 53 Unknown T-Pell 06 [30] 38 989 [25] 12 04 [29] 30 Chinese TU*1000 en,1989 [26] 10 Overview of studies on hormonal male contraception using either testosterone alone or in combination with progestins (updated f of studies Overview al.,1982 al.,1982 al.,1977 al.,1977 Pangkahila, 1991 Pangkahila, Handelsman et al.,1996 [8] 10stated Not mg800 T-Pellets immg 300 once DMPA 9 0 1 Pangkahila, 1991 Pangkahila, WHO, 1993WHO, 1993WHO, Knuth et al.,1 Aitk and Wu [24] [24] 45 45 Indonesian Indonesian 20 TE Frick et Frick Faundes et al.,1981 Faundes Melo and Coutinho, 1977 Frick et Frick Frick et Frick et Frick Gu et al., 2003Gu et al., 2009DMPA et al., 1977Alvarez-Sanchez [18] [16] [17] Brenner et al., 1977 305 [19] Chinese TU*50 3 Alvarez-Sanchez et al., 1977Alvarez-Sanchez Brenner et al., 1977 [18] 10 [19] 6 von Eckardstein et al., 2003 Eckardstein von [15] 35 McLachlan et al., 2002McLachlan [14] 5stated Not 200 TE im/weekmg None 4 Page et al., 20 Page Kamischke et al., 2000Kamischke [13] 14 Zhang et al., 1999 [1 Turner et al., 2003 Turner Gu et al., 20 Table 1. 1. Table alone Testosterone 1990WHO, et al., 1995Behre Handelsman et al., 1992Handelsman et al., 1996Handelsman et al., 1996Meriggiola et al., 1996 et al., 1996Bebb [7] 1996 [8]WHO, [6] [8]Zhang et al., 1999 [5] [9] 9 10 8 10 271 [10] Unknown Unknown Unknown [11] Mixed 18 mg 1200 T-Pellets mg400 T-Pellets mg800 T-Pellets 225 TE 200 mg im/week None Mixed None None None TE 200 mg im/week None 5 0 157 4 et al., 2002McLachlan 4 157 0 ?? [14] 0 5 0 29 ?? 0 stated Not 0 200 TE im/weekmg 8 immg 300 once DMPA 5 Reference, yearReference, no. Ref. of Number origin Ethnic dose Androgen dose Progestin AzoospermiaOligozoo- Severe Oligozoo-

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 229 Clinical Trials in Male Hormonal Contraception rom [4]) (< 1 Mio/ml [n]) (< 3 Mio/ml [n]) 19 (n) spermia spermia p.o./day 5 0 0 g/6 weeks 13 1 0 g/6 weeks 13 1 0 g/6 weeks 13 0 0 p.o./day 6 3 0 p.o./day 0 4 2 2,5 mg p.o./day 3 2 0 LNG 250 mcg p.o./day 8 4 2 LNG 500 mcg p.o./dayLNG 500 mcg p.o./day 2 12 ? 2 ? 3 LNG 125 mcg p.o./dayLNG 125 11 5 1 LNG 250 mcg p.o./day 14 2 0 /6 weeks /6 p.o./day mg 10 NETA 12 2 0 /6 weeks/6 400 m NETE /6 weeks/6 200 m NETE /6 weeks/6 200 m NETE /week mg 100 CPA mg/day (LNG) 2 rods Jardelle 0 0 0 im/6 weeks im/6 im/4 weeks im/4 g/8 weeks 200 mg/6 weeks NETE 9 g/6 weeks 20 and 2 mg p.o./day CPA 13 11 – g/4 weeksg/4 LNG 250 mcg p.o./day 1 ? 1 mg/12 weeksmg/12 weeks 200 NETE mg/12 3 mg/6 weeks LNG 250 mg p.o./day 17 – 1 0 or 1000 mg/8 weeks mg/8 0 or 1000 LNG 4 implants 31 5 4 0 mg im/week Norplant II 4 rods 13 1 0 -Gel 250 mg/day-Gel 250 mg/day LNG 30 mcg p.o./day (LNG) 1 rod Jardelle 0 0 0 0 1 0 -Gel 250 mg/day (LNG) 4 rods Jardelle 0 0 0 250 mg im/4 weeks Sino-Implant 2 rods 6 0 1 implants/15-18 weeksimplants/15-18 LNG 4 implants 13 – – estoderm TTS 2estoderm Norplant II 4 rods 7 5 2 estoderm TTS 2TTS estoderm mcg p.o./day LNG 125 5 1 1 TU 750 mg/8 weeks 250 mg/8 weeks NETE 5 2 1 patches/day patches/day ed mg/week TE 100 LNG 31 mcg or 62 mcg/day 25 13 2 Caucasian im mg 1000 TU CaucasianCaucasian 200 mg TE im/week mg 100 TE Caucasian mg 1000 TU Caucasian im mg 1000 TU Caucasian 200 m TE Caucasian im/week mg 100 TE CaucasianCaucasian im mg TE 100 im/week mg TE 100 1 CPA Caucasian im mg 1000 TU Caucasian im/week mg 100 TE Caucasian T Caucasian im mg 1000 TU 8 Caucasian 1000 TU 10 Mixed mg/8 weeks TU 1000 250 mg/8 weeks NETE 10 21 Chinese subjects [9] 5 Caucasianim/week mg 100 TE p.o./day mg 50 CPA 3 0 1 [42] 10 Caucasian m TU 1000 [43] 10 Mixed [34] 20 Mixed T [34] 15 Mixed T [44][45][46] 5 9 24 Caucasian Caucasianim/week mg 100 TE Caucasian im/week mg TE 100 m TU 1000 p.o./day mg 25 CPA 5 mg CPA 5 0 0 [35][35] 5 8 Caucasian Caucasian DHT 500 DHT-Gel [34][35] 14 5 Mixed Caucasian TE 10 DHT [45] 7 Caucasian im/week 200 mg TE 5 mg CPA [35][36] 7 41 Caucasian Chinese DHT TU*50 [39] 18 Chinese TU*500 Overview of studies on hormonal male contraception using either testosterone alone or in combination with progestins (updated f of studies Overview 02 [41] 14 02 [41] 14 02 [41] 14 996 [9] 5 05 [37] 41 Mix 1998 [44] 5 999 [33] 16 Chinese TU 1999 [32] 18 1999 [32] 18 al., 20 al., 20 al., 20 al., 2001 [40] 14 2006 [38] 19 1980 [31] 5 1980 [31] 5 Meriggiola et al., 2005 Qoubaitrary et al., 2006 Reference, yearReference, no. Ref. of Number origin Ethnic dose Androgen dose Progestin AzoospermiaOligozoo- Severe Oligozoo- Gaw Gonzalo et al., 2002 Gaw Kamischke et Kamischke Fogh et al., Fogh et al., 1996Bebb et al., Anawalt [10] 18 acetate Cyproterone Meriggiola et al., 1996 Gaw Gonzalo et al., 2002 Gaw Kamischke et al., 2000Kamischke [13] 14 et Kamischke Table 1 (continued). 1 (continued). Table (LNG) et al., Fogh et al., Anawalt Meriggiola et al., 1 Meriggiola et al., Meriggiola et al., 1998 Meriggiala et al., 2003 Meriggiola et al., 2002 Pöllänen et al., 2001 Pöllänen et al., 2001 Wang et al., Wang Gaw Gonzalo et al., 2002 Gaw Pöllänen et al., 2001 Kamischke et Kamischke Ersheng et al., 1 Meriggiola et al., 2002 Pöllänen et al., 2001 Gui et al., 2004 et al., 20 Anawalt Wang et al., 2007 Wang (NETE) enanthate Norethisterone et Kamischke

230 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Clinical Trials in Male Hormonal Contraception rom [4]) 125100 – – ≈ ≈ (< 1 Mio/ml [n]) (< 3 Mio/ml [n]) -methyl-19-nortestosterone. α (n) spermia spermia oate in castor oil; MENT, 7 oate in castor oil; MENT, mcg p.o./daymcg p.o./day 6 7 0 1 1 0 mcg p.o./day 8 0 0 mcg p.o./day 4 1 0 mcg p.o./day 15 0 0 mcg p.o./daymcg p.o./daymcg p.o./daymcg p.o./day 4mcg p.o./day 4 8 6 5 3 1 0 2 0 1 0 0 0 0 mcg p.o./day 3 0 0 mcg p.o./day 11 2 0 anon (ENG) 2 rods 9 4 0 onogestrel implants low doseonogestrel implants low – Implanon (ENG) 1 rod 9 1 3 DSG 75 mcg p.o./day 0 1 0 p.o./day mg p.o./day 10 NETA 7 2 3 g/12 weeksg/12 Etonogestrel implants 11 2 – /week/week DSG 300 DSG 150 im/weekim/weekim/week DSG 150 im/week DSG 300 DSG 150 DSG 300 0 mg/12 weeks0 mg/12 DSG 300 mcg p.o./day 18 0 0 0 mg/12 weeks0 mg/12 mcg p.o./day DSG 150 11 2 2 mg/10 weeksmg/10 Et 250 mg/day250 5 mg p.o./day NETA 4 1 0 250 mg/day250 mg p.o./day 10 NETA 5 0 0 250 mg/day250 20 mg p.o./day MPA 5 0 1 ets 400 mg/12 weeksets 400 mg/12 mcg p.o./day DSG 150 9 0 0 ets 400 mg/12 weeksets 400 mg/12 mcg p.o./day DSG 150 9 0 1 ets 400 mg/12 weeksets 400 mg/12 DSG 300 mcg p.o./day 8 0 0 ets 400 mg/12 weeksets 400 mg/12 DSG 300 mcg p.o./day 8 0 0 oderm TTS 2 patches/dayoderm LNG 250 mcg p.o. later 500 mcg 2 3 0 -Gel 250 mg/day None 0 0 0 ellets 400 mg/12 weeksellets 400 mg/12 weeksellets 400 mg/12 DSG 150 DSG 150 ellets 400 mg/12 weeks ellets 400 mg/12 ellets 400 mg/12 weeksellets 400 mg/12 weeksellets 400 mg/12 Impl DSG 300 ellets 400 mg/12 weeksellets 400 mg/12 DSG 150 ENT implants Etonogestrel implants 3 5 – ndropatch 2 patches/day ndropatch 2 patches/dayndropatch 2 patches/dayndropatch 150 DSG 300 DSG ndriol 240 mg p.o./day None 1 0 0 estoderm TTS 2 patches/dayestoderm None 5 0 1 Andriol 160 mg mg Andriol 160 Andriol 80 mg p.o./day mg p.o./day 12,5 CPA 1 3 2 TU 750 mg/12 weeksTU 750 mg/12 weeks mg/12 TU 1000 Etonogestrel implants high dose – stated weeks T pellets 400 mg/12 Etonogestrel implants 9 2 – CaucasianCaucasianCaucasian im mg 50 TE Caucasian mg TE 100 Caucasian mg TE 100 Caucasian im mg 50 TE mg TE 100 mg TE 100 Caucasian Caucasian T-P Caucasian A Caucasian T-P Caucasian Test Caucasian Caucasian m 600 pellets T Caucasian A 10 Caucasian M 112 Caucasian 750 TU subjects [49][49][50] 8 7 9 Caucasian Caucasian Black T-P T-P T-Pell [35] 2 Caucasian DHT [57] 5 Caucasian gel T [50] 11 Mixed T-Pell [57] 5 Caucasian gel T [50] 8 Black T-Pell [57][58] 8 8 Caucasian Caucasian gel T [50] 12 Mixed T-Pell [59][59] 6 7 Caucasian Caucasian A A [52][52] 15 18 Caucasian Chinese T-P 40 T-Pellets [52] 18 Chinese 40 T-Pellets [52] 13 Caucasian T-P [53] 9 Not Overview of studies on hormonal male contraception using either testosterone alone or in combination with progestins (updated f of studies Overview 02 [34] 19 Mixed T 02 [51] 14 02 [51] 14 1988 [57] 13 2008 [55] 134 1978 [56] 7 200020002000 [48] [48] [48] 7 8 8 1999 [60] 12 al., 1997 2007 [54] 16 999 [59] 4 19991999 [47] [47] 8 8 1999 [47] 7 Reference, yearReference, no. Ref. of Number origin Ethnic dose Androgen dose Progestin AzoospermiaOligozoo- Severe Oligozoo- Table 1 (continued). 1 (continued). Table (DSG) or etonorgestrel Desogestrel et al., Wu et al., Wu et al., Anawalt et al., Anawalt et al., Anawalt Kinniburgh et al., 2001 Kinniburgh et al., 2001 Anderson et al., 2002 Guerin and Rollet, Pöllänen et al., 2001 testosterone undecan TU, TU*, testosterone undecanoate in tea seed oil; ; TB, TE, testosterone enanthate; Wu et al., Wu Guerin and Rollet, 1988 Guerin and Rollet, Anderson et al., 2002 Guerin and Rollet, 1988 Guerin and Rollet, Anderson et al., 2002 Guerin and Rollet, 1988 Guerin and Rollet, Anderson et al., 2002 Meriggiola et Hair et al., 1 Anderson et al., 20 Anderson et al., 20 Hair et al., 1999 Hair et al., 1999 et al., Büchter Kinniburgh et al., 2002 Kinniburgh et al., 2002 Gaw Gonzalo et al., 20 Gaw Kinniburgh et al., 2002 Kinniburgh et al., 2002 Brady et al., 2004 Mommers et al., Self applicable et al., Nieschlag Walton et al., Walton

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 231 Clinical Trials in Male Hormonal Contraception efficacy of this study was very high, it 3.1.3. Testosterone Undecanoate [16]. However, reappearance of sperm cannot be used to determine the overall Initially, testosterone undecanoate was occurred in six men during the efficacy efficacy of testosterone alone as a con- studied as an oral preparation in volun- phase; one pregnancy was attributed to traceptive because only men who be- teers of Caucasian origin [56]. Subjects “sperm rebound”. Side effects observed came azoospermic could enter the effi- were given a daily dose of 240 mg over a in subjects were all typical of elevated cacy phase while the others were ex- period of 12 weeks, but only one out of testosterone serum levels. The largest ef- cluded. seven volunteers reduced sperm output ficacy study to date was also performed sufficiently for contraception. This low in China, based on a loading dose of In order to clarify the question whether effectiveness is probably due to the short 1000 mg followed by monthly injections men developing oligozoospermia can be half-life of testosterone undecanoate of 500 mg testosterone undecanoate. considered infertile, a second worldwide when given orally. Even if administered Eight-hundred ninety-eight men entered multicenter efficacy study involving 357 four times a day, the peaks are not suffi- the efficacy phase during which only 9 couples followed [11]. In this study, cient to suppress gonadotropins consist- were recorded. This repre- azoospermia again proved to be a most ently and thereby to achieve azoosper- sents a pregnancy rate of 1.1 per 100 per- effective prerequisite for contraception. mia. son-years [17]. Thus, in China, testoster- If sperm concentration, however, failed one undecanoate provides better protec- to drop below 3 × 106/mL ejaculate, re- While testosterone undecanoate had tion against pregnancy than condom use. sulting pregnancy rates were higher than been developed as an oral preparation in Although injection intervals of four when using condoms. When sperm con- Europe, it was turned into an injection in weeks appeared to be an achievement centrations decreased below 3 × 106/mL, China, using tea seed oil as a vehicle and over the weekly injections of testoster- which was the case in 98% of the par- is used as such in China for hypogonad- one enanthate, the participants in a Chi- ticipants, then protection was not as ism and in trials for male contraception. nese study considered the frequency of effective as for azoospermic men, but Back in Europe, the half-life of this injections the most inconvenient part of was better than that offered by condoms Chinese preparation could be extended this regimen [67]. Would testosterone (Fig. 2). even further when dissolved in castor oil undecanoate in castor oil also be used in and is now available for clinical use in China, this complaint could certainly be Even if these WHO studies represented a 1000 mg depot injections [66]. overcome. breakthrough by confirming the princi- ple of action, they did not offer a practi- In the clinical trials in China, testoster- In a first contraceptive trial of testoster- cable method. For a method requiring one undecanoate alone administered one undecanoate in castor oil, 1000 mg weekly im injections is not acceptable every 4 weeks resulted in azoospermia in was injected into 14 Caucasian volun- for broad use. Moreover, several all Chinese men who received a dose of teers at 6-week intervals. Eight of 14 months, often up to one year, are re- 1000 mg and in azoospermia or severe men achieved azoospermia [13]. Al- quired before sperm production reaches oligozoospermia in 95% of Chinese men though this rate of azoospermia is not significant suppression. For this reason, who received a dose of 500 mg during a different from that achieved with testo- current research is concentrating on the 4–6-month suppression phase [12]. In sterone enanthate alone, the longer in- development of long-acting testosterone the ensuing phase III study involving jection interval represents a significant preparations and on methods to hasten 305 couples, an efficacy phase followed advantage. A later pharmacokinetic the onset of effectiveness. the suppression phase, and no pregnan- study concluded that 8-week intervals of cies were initiated by men exhibiting 1000-mg injections would be sufficient 3.1.2. Testosterone Buciclate azoospermia or severe oligozoospermia for contraceptive purposes [43]. As long-acting testosterone preparations appeared more promising in terms of practicability and acceptability, WHO and the NIH initiated a synthesis pro- gram for such preparations [64] through which the long-acting testosterone ester testosterone buciclate was identified. This molecule showed a half-life of 29.5 days when tested in hypogonadal men, much longer than the 4.5 days of testo- sterone enanthate [65]. Suppression of spermatogenesis was comparable to that of weekly testosterone enanthate injec- tions, reaching azoospermia in three out of eight volunteers after a single injec- tion of 1200 mg of testosterone buciclate [6]. Despite its promising pharmaco- kinetic profile, no industrial partner could be found to undertake develop- Figure 2. Contraceptive efficacy of testosterone enanthate (250 mg/weekly) in 364 volunteers: pregnancy rates per ment of this preparation. 100 person-years in relation to sperm concentration (adapted from [11]).

232 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Clinical Trials in Male Hormonal Contraception

Considering that 10- to 14-week inter- with gestagen implants is currently be- 3.3. Androgens Plus Gestagens vals of 1000 mg testosterone unde- ing investigated by the Population Coun- The potency of gestagens to suppress canoate are required for substitution of cil. gonadotropins is well known from fe- hypogonadal men, about one third more male contraceptives where gestagens ef- testosterone is required for contracep- 3.2. Androgens Combined With fectively supplement . Numer- tion in normal volunteers. GnRH Analogues ous studies combining androgens (main- 3.2.1. GnRH Agonists ly testosterone) with various gestagens 3.1.4. Testosterone Pellets The pituitary-inhibiting effects of GnRH have been performed over the past 4 dec- Pellets consisting of pure testosterone agonists are well known from their use ades in order to identify a regimen suited are used for substitution in hypogonad- in females and in the therapy of prostate for male contraception (Fig. 3). ism in some countries. In male contra- cancer. After an initial phase of gonado- ceptive studies, the sperm suppressing tropin stimulation, they suppress gona- Unfortunately, a systematic comparison effect was comparable to weekly testo- dotropins and, consequentially, intrates- of the different gestagens with regard to sterone enanthate injections [68]. The ticular testosterone by GnRH receptor their contraceptive potency in males has disadvantage of minor surgery required down-regulation. However, trials for never been performed. Even worse, a for insertion under the abdominal skin is hormonal male contraception in which Cochrane Review analyzing 45 clinical compensated for by their low price. mostly testosterone was added showed trials came to the conclusion that the Spontaneous extrusion may be a disad- that sperm numbers were only insuffi- studies comprised too small numbers of vantage. ciently reduced, thus rendering these volunteers so that significant differences agonists unsuitable as male contracep- between the various steroid combina- 3.1.5. 19-Nortestosterone tives [70]. tions could not be detected [75]. Moreo- When searching for preparations with ver, not all studies observe strict criteria longer lasting effectiveness, 19-nor- 3.2.2. GnRH Antagonists for randomized controlled trials. How- testosterone-hexoxyphenylpropionate GnRH antagonists lack the effect of ini- ever, it should be kept in mind that many was tested. Its spectrum of effects is very tial gonadotropin release as they com- of these trials were performed as proof similar to that of testosterone and it has petitively inhibit pituitary GnRH of principle and not necessarily as trials been used as an since receptors, thus leading to a more imme- for registration with the regulatory au- the 1960s. The 19-nortestosterone ester diate onset of azoospermia. This could thorities. In addition, single centers are injected every 3 weeks enabled azo- be demonstrated by small clinical stud- financially and logistically unable to ospermia to be reached by as many men ies using various GnRH antagonists in cope with the numbers of volunteers and as by testosterone enanthate. Thus, the addition to a testosterone preparation criteria demanded by regulatory agen- 19-nortestosterone ester is as effective [71]. Out of 47 volunteers participating cies. Stimulated by researchers and by as testosterone enanthate but allows in various clinical trials with different public demand, the pharmaceutical in- a longer interval between injections GnRH-antagonists, azoospermia was dustry finally performed a trial fulfilling [69]. achieved in 39 subjects and oligo- the Cochrane criteria – and left the field! zoospermia ≤ 1×106 sperm per mL [55] In the following, important studies Although effective in suppressing sper- ejaculate occurred in one additional vol- are briefly summarized to highlight the matogenesis and without any notable unteer, while only three men maintained cumbersome and often frustrating devel- side effects in the studies, it could not be sperm concentrations above 3×106/mL opment (Table 1). determined whether this synthetic an- ejaculate. Of the more recently devel- drogen would have any unwanted effects oped GnRH antagonists, acycline has The gestagens used in these studies de- with long-term use. The lack of negative been tested in male contraceptive trials. rive either from 19-nortestosterone or reports from widespread use of 19- Although acycline given alone had a po- from 17-hydroxyprogesterone and are nortestosterone in athletes cannot be tent gonadotropin-suppressing effect all being used in female contraceptives taken as evidence for its clinical applica- [72], the addition of acycline to a combi- (Fig. 3). tion as systematic evaluations in athletes nation of testosterone gel plus depot have not been published. medroxyprogesterone acetate (DMPA) 3.3.1. Depot Medoxyprogesterone did not increase the suppression of Acetate 3.1.6. 7α-Methyl-19-Nortestosterone sperm achieved by the steroids alone From early studies in the 1970s initiated The synthetic androgen 7α-methyl-19- [30]. by the WHO and the Population Coun- nortestosterone (MENT) offers an ap- cil, DMPA emerged as a gestagen with proximately 10-fold higher potency to Despite these encouraging results, the great potential in male contraception suppress pituitary gonadotropins than requirement for daily or weekly injec- [76]. The combination of DMPA with does testosterone. In contrast to testo- tions and the high costs of the available 19-nortestosterone in 3-week intervals sterone, there is no 5α-reduction so that preparations have hindered the further first tested in Caucasians [25] was espe- effects on the prostate could be minimal. development of GnRH antagonists for cially promising in Indonesian men [24]. A first dose-finding study showed that hormonal male contraception. Promis- MENT administered in subcutaneous ing attempts to use the GnRH antago- One of the very few efficacy studies aim- implants was as effective as testosterone nists only to initiate azoospermia and ing at pregnancy rates also used DMPA, given alone [15]. The potential of these then maintain this by androgens alone however, in combination with testoster- implants either alone or in combination were not pursued further [73, 74]. one pellets [28]. In this Australian study,

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53 of 55 volunteers suppressed to 3.3.2. Levonorgestrel sponded equally well to testosterone pel- azoospermia and during the 1-year effi- Oral levonorgestrel, when combined lets alone [38]. cacy phase, no pregnancy occurred. with testosterone enanthate im slightly However, the discontinuation rate in this enhanced the effect of testosterone When MENT implants were combined study was high and onset of and recov- enanthate alone [10]. Similarly, when with levonorgestrel implants in different ery from azoospermia took several combined with testosterone undecanoate doses, a clear dose-dependent effect months. im the additional effect of oral levo- could be observed, but it remains unde- remained marginal in Cauca- termined whether implants with suffi- In order to test whether one of the two sian men [13] but seemed to increase ef- ciently long duration can be manufac- steroid entities could be self-adminis- fectiveness in Chinese men [39]. tured; non-biodegradable implants that tered, the addition of a testosterone have to be removed surgically from the transdermal gel to the DMPA injections In a comparative study, when levonor- implantation site when contraceptive (300 mg/3 months) was tested [30]. The gestrel implants were combined with protection is no longer required appear results were comparable to those from testosterone pellets, an additive effect of impractical for widespread use unless trials where DMPA was combined with levonorgestrel was seen in Caucasian they can be left in situ for long periods injectable testosterone. men, but not in Chinese men who re- [77].

3.3.3. Norethisterone The injectable depot preparation nor- enanthate (NETE) and the orally effective (NETA) are hydrolyzed to release the active compound norethisterone, which can be 5α-reduced to 5α-norethisterone and aromatized to ethinyl . While norethisterone has strong andro- genic activity (~ 10% of testosterone), 5α-noresthisterone also shows anti- androgenic properties.

Of 14 men who received 200 mg NETE combined with 1000 mg testosterone undecanoate every 6 weeks, 13 achieved azoospermia [40]. Further investigations showed that the injection intervals could be extended to 8 weeks [42] or that testo- sterone undecanoate could be combined with oral NETA without loss of effec- tiveness [41]. Based on these findings, together with CONRAD, WHO is plan- ning a phase II efficacy study invol- ving 400 couples in 8 centers worldwide [78].

3.3.4. The orally effective cypro- terone acetate (CPA) has strong gesta- genic properties. In early studies com- bining oral CPA with testosterone en- anthate injections, the sperm-suppress- ing effects were considerable, but the antiandrogenic effects (e.g., reflected by decreased hematocrit) were undesirable. However, when combining 1000 mg tes- tosterone undecanoate every 6 weeks with 20 mg CPA daily initially, followed by only 2 mg CPA/day, the initial sup- pression of spermatogenesis could be Figure 3. Gestagens derived from either testosterone (A) or (B) in trials for male hormonal maintained and antiandrogenic effects contraception. prevented [46].

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3.3.5. Desogestrel and Etonogestrel Worldwide, one quarter of all couples lion. Less developed countries bear the Desogestrel is an orally effective gesta- practicing contraception rely on male onus of this enormous population gen which becomes active after conver- methods, albeit with varying preferences growth while the population in industri- sion to etonogestrel. Etonogestrel can be and the proportion of men practicing alized nations is largely stable – due to administered directly as an implant (Im- contracep-tion is increasing. Thus, in the use of contraceptive methods. The popu- planon). In combination with testoster- Netherlands, the percentage of vasect- lation explosion creates minimal sur- one enanthate or testosterone pellets, omized men whose wives were of repro- mountable ecologic and economic prob- desogestrel showed good suppression of ductive age rose from 2% to 10.5% from lems. Medical progress has decisively spermatogenesis [47, 49]. Etonogestrel 1975 to 2008 and from 8% to 12.2% in lowered mortality, particularly of chil- implants combined with testosterone pel- the USA; the highest rates of vasect- dren, so that life expectancy worldwide lets s.c. resulted in a high azoosper- omized men are found in the United is currently 64.2 years for men and 68.6 mia rate, although it took up to 28 weeks Kingdom and in New Zealand. World- years for women. Ever more people to reach this goal in some individuals wide, however, only 2.7% of men are reach reproductive age. If medical pro- [53]. vasectomized. gress allows increasing number of peo- ple to achieve reproductive age, causing In the first (and so far last) industry- Similarly, the use of condoms for contra- overpopulation, then medicine must also sponsored trial, Organon and Schering ception varies from country to country provide contraceptive methods in order decided to test etonogestrel implants with a worldwide average of 5.7%. It is to maintain or restore a balance between with testosterone undecanoate injections to be expected that the percentage of reproduction and death. It has become in various combinations [55]. This study men willing to practice contraception clear that the Millennium Development involved 354 volunteers in seven treat- varies between cultures and with meth- Goals cannot be achieved with the cur- ment groups receiving either placebo ods available. According to asurvey in rent level of population growth [82]. It or 750–1000 mg testosterone unde- Hongkong and Shanghai 10 years ago, goes without saying that a newly devel- canoate every 10–12 weeks with two half the men interviewed were willing to oped male contraceptive would not sud- doses of etonogestrel for 42–44 weeks. take a daily contraceptive pill; in Edin- denly resolve population problems, but a Ninety percent of treated men suppres- burgh and Capetown two thirds were male method could contribute to the sed spermatogenesis to ≤ 1×106/mL eja- willing to do so [79, 80]. After almost 50 resolution, especially as research into fe- culate. years of female oral contraception, the male methods for contraception is simi- attitude of men towards new methods of larly on the decline [83]. In addition, Although the combination of an implant male contraception has changed. World- women increasingly demand that men with injections may not appear too wide, surveys showed men willing to use share the responsibility and risks of fam- attractive for practical use, the study pharmacological contraceptive methods ily planning and men, on the other hand, had a high success rate and could have [81] (Fig. 4). want to regain some of the reproductive formed the basis for a phase III effi- power they surrendered to women since cacy study. Unfortunately, both compa-  5. Responsibility For the the advent of modern female contracep- nies discontinued their male contracep- tives [84, 85]. This should be reason tion programs when they were taken Development of Contra- enough for the pharmaceutical industry over by other firms who were at that ceptives to actively develop male contraceptives. stage not interested in male contracep- The world population has tripled in the While a large proportion of clinical re- tion. last 50 years and is approaching 7 bil- search is driven by the pharmaceutical

 4. Acceptability of Male Contraception One of the reasons why the pharmaceuti- cal industry has not continued to further develop a male contraceptive at this stage may be doubts about the possible acceptability of such a pharmacological method. However, recently, public inter- est in male methods for contraception has notably grown. It is increasingly ex- pected that men share with their partners not only the advantages but also the risks of family planning. As risks tend to in- crease with duration of use, sharing con- traception between men and women would reduce dangers for each partner. Population conferences and women’s world forums have explicitly called for Figure 4. Multinational male fertility control survey among 9342 men who were asked the question: „If available, new male contraceptive methods. would you be willing to use the new male fertility control method?“ (adapted from [81]).

236 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) Clinical Trials in Male Hormonal Contraception industry, in the case of male contracep- 9. Meriggiola MC, Bremner WJ, Paulsen, et al. A combined 30. Page ST, Amory JK, Anawalt BD, et al. Testosterone gel regimen of cyproterone acetate and testosterone enanthate combined with depot-medroxyprogesterone acetate is an ef- tion, industry fails. Without the long- as a potentially highly effective male contraceptive. J Clin fective male hormonal contraceptive regimen and is not en- range perspective and endurance of in- Endocr Metab 1996; 81: 3018–23. hanced by the addition of a GnRH antagonist. J Clin Endocrinol Metab 2006; 91: 4374–80. stitutions and organizations such as 10. Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of 31. Fogh M, Corker CS, McLean H. Clinical trial with levonor- NICHD, CONRAD, Population Coun- levonorgestrel and testosterone induces more rapid and effec- gestrel and testosterone enanthate for male fertility control. cil, WHO, some medical research coun- tive suppression of spermatogenesis than testosterone alone: Acta Endocrinol 1980; 95: 251–7. a promising male contracep-tive approach. J Clin Endocr 32. Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A cils and few foundations, male contra- Metab 1996; 81: 757–62. lower dosage levonorgestrel and testosterone combination ception would long have been aban- 11. World Health Organization Task Force on Methods for the effectively suppresses spermatogenesis and circulating gona- Regulation of Male Fertility. Contraceptive efficacy of testo- dotrophin levels with fewer metabolic effects than higher doned. The principle and effectiveness sterone-induced azoospermia and oligozoospermia in normal dosage combinations. J Androl 1999; 20: 407–14. of hormonal male contraception has men. Fertil Steril 1996; 65: 821–9. 33. Ersheng G, Cuihong L, Youlun G, Lamei L, Changhai H. In- been demonstrated in many studies. The 12. Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A clini- hibiting effects of Sino-implant plus testosterone undeca- cal trial of injectable testosterone undecanoate as a potential noate on spermato-genesis in Chinese men. Reprod Contra- fact that the majority of clinical trials on male contraceptive in normal Chinese men. J Clin Endocrinol ception 1999; 10: 98–105. hormonal male contraception have been Metab 1999; 84: 3642–7. 34. Gaw Gonzalo IT, Swerdloff RS, et al. Levonorgestrel im- plants (Norplant II) for male contraception clinical trials: com- 13. Kamischke A, Plöger D, Venherm S, von Eckardstein S, von published in high-ranking journals is bination with transdermal and injectable testosterone. J Clin Eckardstein A, Nieschlag E. Intramuscular testosterone unde- Endocr Metab 2002; 87: 3562–72. important. This emphasizes the high pri- canoate with or without oral levonorgestrel: a randomized ority the scientific community attributes placebo-controlled feasibility study for male contraception. 35. Pöllänen P, Nikkanen V, Huhtaniemi I. Combination of sub- Clin Endocrinol 2000; 53: 43–52. cutaneous levonorgestrel implants and transdermal dihydro- to these endeavors. Investigators are so testosterone gel for male hormonal contraception. Int J 14. McLachlan RI, O’Donnell L, Stanton PG, et al. Effects of Androl 2001; 24: 369–80. convinced of the validity of the concept testosterone plus medroxyprogesterone acetate on semen of hormonal male contraception that quality, reproductive hormones and germ cell populations in 36. Gui YL, He CH, Amory JK, et al. Male hormonal contracep- normal young men. J Clin Endocrinol Metab 2002; 87: 546–56. tion: suppression of spermatogenesis by injectable testoster- they drafted recommendations for regu- one undecanoate alone or with levonorgestrel implants in Chi- 15. von Eckardstein S, Noe G, Brache V, et al. International nese men. J Androl 2004; 25: 720–7. latory approval for male hormonal con- Committee for Contraception Research, The Population Coun- 37. Anawalt BD, Amoory JK, Herbst KL, et al. Intramuscular cil. A clinical trial of 7 alpha-methyl-19-nortestosterone im- traception at their annual summit meet- testosterone enanthate plus very low dosage oral levonor- plants for possible use as a long-acting contraceptive for gestrel suppresses spermatogenesis without causing weight ings (since 1997) [86]. Little more is re- men. J Clin Endocrinol Metab 2003; 88: 5232–9. gain in normal young men: a randomized clinical trial. J quired to convince industry to bring this 16. Gu YQ, Wang XH, Xu D, et al. A multicenter contraceptive Androl 2005; 26: 405–13. development to fruition. efficacy study of injectable testosterone undecanoate in 38. Wang C, Wang XH, Nelson AL. Levonorgestrel implants healthy Chinese men. J Clin Endocr Metab 2003; 88: 562–8. enhanced the suppression of spermatogenesis by testoster- 17. Gu Y, Liang X, Wu W, et al. Multicenter contraceptive effi- one implants: comparison between Chinese and non-Chinese Comparing the situation with the devel- cacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab 2006; 91: 460–70. opment of the female pill, the lack of men. J Clin Endocrinol Metab 2009; 94: 1910–5. 39. Wang C, Cui YG, Wang XH, et al. Transient scrotal hyper- 18. Alvarez-Sanchez F, Faundes A, Brache V, Leon P. Attain- thermia and levonorgestrel enhance testosterone-induced public advocacy for male contraception ment and maintenance of azoospermia with combined spermatogenesis suppression in men through increased germ is striking. Male contraception lacks monthly injections of depot medroxyprogesterone acetate and cell apoptosis. J Clin Endocrinol Metab 2007; 92: 3292–304. prominent advocates as the development testosterone enanthate. Contraception 1977; 15: 635–48. 40. Kamischke A, Venherm S, Plöger D, von Eckardstein S, 19. Brenner PF, Mishell Jr DR, Bernstein GS, et al. Study of Nieschlag E. Intramuscular testosterone undecanoate and of female contraception benefited from medroxyprogesterone acetate and testosterone enanthate as norethisterone enanthate in a clinical trial for male contracep- personalities such as Margaret Sanger a male contraceptive. Contraception 1977; 15: 679–91. tion. J Clin Endocrinol Metab 2001; 86: 303–9. 41. Kamischke A, Heuermann T, Krüger K, et al. An effective 20. Frick J, Bartsch G, Weiske WH. The effect of monthly de- (1879–1966) and Katherine McCormick hormonal male contraceptive using testosterone undecanoate pot medroxyprogesterone acetate and testosterone on human with oral or injectable norethisterone preparations. J Clin (1875–1967). Hormonal male contra- spermatogenesis. II. High initial dose. Contraception 1977; 15: Endocr Metab 2002; 87: 530–9. ception requires similar advocacy to fi- 669–77. 42. Meriggiola MC, Costantino A, Saad F, et al. Norethiste- nally result in a marketable product. 21. Melo JF, Coutinho EM. Inhibition of spermatogenesis in rone enanthate plus testosterone undecanoate for male con- men with monthly injections of medroxyprogesterone acetate traception: effects of various injection intervals on sperma- and testosterone enanthate. Contraception 1977; 15: 627–34. togenesis, reproductive hormones, testis, and prostate. J Clin 22. Faundes A, Brache V, Leon P, Schmidt F, Alvarez-Sanchez F. Endocrinol Metab 2005; 90: 2005–14. References: Sperm suppression with monthly injections of medroxypro- 43. Qoubaitary A, Meriggiola C, Ng CM, et al. Pharmacokinet- gesterone acetate combined with testosterone enanthate at a 1. Benagiano G, Bastianello C, Farris M. Contraception: a so- ics of testosterone undecanoate injected alone or in combina- high dose (500 mg). Int J Androl 1981; 4: 235–45. cial revolution. Europ Contracept Reprod Health Care 2007; tion with norethisterone enanthate in healthy men. J Androl 12: 3–12. 23. Frick J, Danner C, Kunit G, Joos H, Kohle R. Spermatogen- 2006; 27: 853–67. esis in men treated with injections of medroxyprogesterone 2. Nieschlag E, Behre HM, Wieacker P, Meschede D, 44. Meriggiola MC, Bremner WJ, Costantino A, Di Cintio G, acetate combined with testosterone enanthate. Int J Androl Kamischke A, Kliesch S. Disorders at the testicular level. In: Flamigni C. Low dose of cyproterone acetate and testosterone 1982; 5: 246–52. Nieschlag E, Behre HM, Nieschlag S, editors. Andrology: male enanthate for contraception in men. Hum Reprod 1998; 13: reproductive health and dysfunction, 3rd ed. Springer, Heidel- 24. World Health Organization Task Force on Methods for the 1225–9. berg, 2009; 194–238, chap. 13. Regulation of Male Fertility. Comparison of two androgens 45. Meriggiola MC, Costantino A, Bremner WJ, Morselli- Labate AM. Higher testosterone dose impairs sperm suppres- 3. April K, Köster R, Schreiner W. Wie effektiv schützen plus depot-medroxyprogesterone acetate for suppression to sion induced by a combined androgen-progestin regimen. J Kondome vor einer HIV-Übertragung? Med Klinik 1993; 88: azoospermia in Indonesian men. Fertil Steril 1993; 60: 1062– Androl 2002; 23: 684–90. 304–11. 8. 25. Knuth UA, Yeung CH, Nieschlag E. Combination of 19-nor- 46. Meriggiola MC, Costantino A, Cerpolini S, et al. Testoster- 4. Kamischke A, Nieschlag E. Progress towards hormonal one undecanoate maintains spermatogenic suppression in- male contraception. Trends Pharmacol Sci 2004; 25: 49–57. testoster-one-hexyoxyphenylpropionate (Anadur) and depot- medroxyprogester-one-acetate (Clinovir) for male contracep- duced by cyprot-erone acetate plus testosterone undecanoate 5. World Health Organization Task Force on Methods for the tion. Fertil Steril 1989; 51: 1011–8. in normal men. J Clin Endocrinol Metab 2003; 88: 5818–26. Regulation of Male Fertility. Contraceptive efficacy of testo- 26. Wu FC, Aitken RJ. Suppression of sperm function by 47. Wu FCW, Balasubramanian R, Mulders TMT, Coelingh- sterone-induced azoospermia in normal men. Lancet 1990; Bennink HJT. Oral combined with testosterone as 336: 955–9. depotmedroxyprogesterone acetate and testosterone enan- thate in steroid male contraception. Fertil Steril 1989; 51: a potential male contraceptive: additive effects between 6. Behre HM, Baus S, Kliesch S, Keck C, Simoni M, Nieschlag 691–8. desogestrel and testosterone enanthate in suppression of E. Potential of testosterone buciclate for male contraception: spermatogenesis, pituitary-testicular axis, and lipid metabo- endocrine differences between responders and 27. Pangkahila W. Reversible azoospermia induced by an an- lism. J Clin Endocr Metab 1999; 84: 112–22. drogen-progestin combination regimen in Indonesian men. Int nonresponders. J Clin Endocr Metab 1995; 80: 2394–403. 48. Anawalt BD, Herbst KL, Matsumoto AM, Mulders TM, J Androl 1991; 14: 248–56. 7. Handelsman DJ, Conway AJ, Boylan LM. Suppression of Coelingh-Bennink HJ, Bremner WJ. Desogestrel plus testo- human spermatogenesis by testosterone implants. J Clin 28. Turner L, Conway AJ, Jimenez M, et al. Contraceptive effi- sterone effectively suppresses spermatogenesis but also Endocr Metab 1992; 75: 1326–32. cacy of a depot progestin and androgen combination in men. J causes modest weight gain and high-density lipoprotein sup- Clin Endocrinol Metab 2003; 88: 4659–67. 8. Handelsman DJ, Conway AJ, Howe CJ, Turner L, Mackey pression. Fertil Steril 2000; 74: 707–14. MA. Establishing the minimum effective dose and additive ef- 29. Gu YQ, Tong JS, Ma DZ, et al. Male hormonal contracep- 49. Kinniburgh D, Anderson RA, Baird DT. Suppression of sper- fects of depot progestin in suppression of human sperma- tion: effects of injections of testosterone undecanoate and matogenesis with desogestrel and testosterone pellets is not togenesis by a testosterone depot. J Clin Endocrinol Metab depot medroxyprogesterone acetate at eight-week intervals in enhanced by addition of finasteride. J Androl 2001; 22: 88– 1996; 81: 4113–21. Chinese men. J Clin Endocrinol Metab 2004; 89: 2254–62. 95.

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 237 Clinical Trials in Male Hormonal Contraception

50. Anderson RA, Van Der Spuy ZM, Dada OA, et al. Investiga- nal male contraception: an integrated analysis. Lancet 2006; tion of GnRH antagonist and 19-nortestosterone cannot be tion of hormonal male contraception in African men: suppres- 367: 1412–20. maintained by 19-nortestosterone alone in normal men. Hum sion of spermatogenesis by oral desogestrel with depot testo- 62. Barfield JP, Nieschlag E, Cooper TG. Fertility control in Reprod 2001; 16: 2570–7. sterone. Hum Reprod 2002; 17: 2869–77. wildlife: humans as a model. Contraception 2006; 73: 6–22. 75. Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, 51. Anderson RA, Kinniburgh D, Baird DT. Suppression of sper- 63. Heckel M. Production of oligospermia in a man by the use Schulz KF. Steroid hormones for contraception in men (re- matogenesis by etonogestrel implants with depot testoster- of . Proc Soc Exp Biol Med 1939; 40: view). Cochrane Database Syst Rec 2007; 004316. one: potential for long-acting male contraception. J Clin 658–9. 76. Barfield A, Melo J, Coutinho E, et al. Pregnancies associ- Endocr Metab 2002; 87: 3640–9. 64. Waites GMH. Development of methods of male contracep- ated with sperm concentrations below 10 million/ml in clini- 52. Kinniburgh D, Zhu H, Cheng L, Kicman AT, Baird DT, tion: impact of the World Health Organization Task Force. cal studies of a potential male contraceptive method, monthly Anderson RA. Oral desogestrel with testosterone pellets in- Fertil Steril 2003; 80: 1–15. depot medroxyprogesterone acetate and testosterone esters. duces consistent suppres-sion of spermatogenesis to Contraception 1979; 20: 121–7. azoospermia in both Caucasian and Chinese men. Hum 65. Behre HM, Wang C, Handelsman DJ, Nieschlag E. Phar- 77. Liu PY, Swerdloff RS, Wang C. Recent methodological ad- Reprod 2002; 17: 1490–501. macology of testosterone preparations. In: Nieschlag E, Behre HM (eds). Testosterone: action, deficiency, substitution, 3rd vances in male hormonal contraception. Contraception 2010; 53. Brady BM, Walton M, Hollow N, Kicman AT, Baird DT, ed. University Press, Cambridge, 2004; 405–44. 82: 471–5. Anderson RA. Depot testosterone with etonogestrel implants 78. WHO. Controlled trials register NET-EN plus TU as a male result in induction of azoospermia in all men for long-term 66. Nieschlag E. Testosterone treatment comes of age: new contraceptive (WHO-HRP ID A25165). (accessed 2005-11-29). contraception. Hum Reprod 2004; 19: 2658–67. options for hypogonadal men. Clin Endocrinol 2006; 65: 275– 81. http://www.who.int/reproductive-health/rhl/a25165.html 54. Walton MJ, Kumar N, Baird DT, Ludlow H, Anderson RA. 67. Zhang L, Shal IH, Liu Y, Vogelsong KM, Zhang L. The ac- 79. Anderson RA, Baird DT. Progress towards a male pill. IPPF 7á-Methyl-19-nortestosterone (MENT) vs testosterone in com- Med Bull 1997; 31: 3–4. bination with etonogestrel implants for spermatogenic sup- ceptability of an injectable, once-a-month male contraceptive in China. Contraception 2006; 73: 548–53. pression in healthy men. J Androl 2007; 28: 679–88. 80. Martin CW, Anderson RA, Cheng L, et al. Potential impact 68. McLachlan RI, McDonald J, Rushford D, Robertson DM, of hormonal male contraception: cross-cultural implications 55. Mommers E, Kersemaeker WM, Elliesen J, et al. Male Garrett C, Baker HW. Efficacy and acceptability of testoster- for development of novel preparations. Hum Reprod 2000; 15: hormonal contraception: a double-blind, placebo-controlled one implants, alone or in combination with a 5alpha-reduct- 637–45. study. J Clin Endocrinol Metab 2008; 93: 2572–80. ase inhibitor, for male contraception. Contraception 2000; 62: 81. Heinemann K, Saad F, Wiesemes M, White S, Heinemann 56. Nieschlag E, Hoogen H, Bölk M, Schuster H, Wickings EJ. 73–8. L. Attitudes toward male fertility control: results of a multina- Clinical trial with testosterone undecanoate for male fertility 69. Knuth UA, Behre HM, Belkien L, Bents H, Nieschlag E. control. Contraception 1978; 18: 607–14. tional survey on four continents. Hum Reprod 2005; 20: 549– Clinical trial of 19-nortestosterone-hexoxyphenylpropionate 56. 57. Guerin JF, Rollet J. Inhibition of spermatogenesis in men (Anadur) for male fertility regulation. Fertil Steril 1985; 44: 82. All Party Parliamentary Group on Population. Development using various combinations of oral progestagens and percuta- 814–21. neous or oral androgens. Int J Androl 1988; 11: 187–99. and Reproductive Health. Return of the population growth fac- 70. Behre HM, Nashan D, Hubert W, Nieschlag E. Depot gona- tor: its impact upon the Millennium Development Goals. 58. Meriggiola MC, Bremner WJ, Costantino A, Pavani A, dotropin-releasing hormone agonist blunts the androgen-in- House of Commons, London, 2007. Capelli M, Flamigni C. An oral regimen of cyproterone acetate duced suppression of spermatogenesis in a clinical trial of and testosterone undecanoate for spermatogenic suppression male contraception. J Clin Endocr Metab 1992; 74: 84–90. 83. Strauss JF, Chaudhuri G. The accelerated pace of pharma abandonment of research and development in family planning in men. Fertil Steril 1997; 68: 844–50. 71. Nieschlag E, Kamischke A, Behre HM. Hormonal male con- and fertility: will reproductive health technology be frozen in traception: the essential role of testosterone. In: Nieschlag E, 59. Hair WM, Kitteridge K, Wu FCW. A new male contracep- time? Fertil Steril 2007; 87: 717–8. tive pill/patch combination-oral desogestrel and transdermal Behre HM (eds). Testosterone: action, deficiency, substitution, testosterone: suppression of gonadotropins and spermatogen- 3rd ed. Cambridge University Press; 2004; 685–714. 84. Darroch JE. Male fertility control – where are the men? Contraception 2008; 78: S7–S17. esis in men. The Endocrine Society’s 81st Annual Meeting; 72. Page ST, Amory JK, Bremner WJ. Advances in male con- June 12–15; San Diego, CA, USA. Poster P3-374; 1999. traception. Endocr Rev 2008; 29: 465–93. 85. Meriggiola MC, Cerpolini S, Bremner WJ, et al. Accept- 60. Büchter D, von Eckardstein S, von Eckardstein A, et al. 73. Swerdloff RS, Bagatell CJ, Wang C, et al. Suppression of ability of an injectable male contraceptive regimen of Clinical trial of a transdermal testosterone and oral spermatogenesis in man induced by Nal-Glu gonadotropin re- norethisterone enanthate and testosterone undecanoate for levonorgestrel for male contraception. J Clin Endocr Metab leasing hormone antagonist and testosterone enanthate (TE) men. Hum Reprod 2006; 21: 2033–40. 1999; 84: 1244–9. is maintained by TE alone. J Clin Endocr Metab 1998; 83: 86. Nieschlag E. 10th Summit Meeting Group. 10th Summit 61. Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, 3527–33. Meeting consensus recommendations for regulatory approval Wang C. Hormonal Male Contraception Summit Group. Rate, 74. Behre HM, Kliesch S, Lemcke B, Nieschlag E. Suppression for hormonal male contraception, October 22–23, 2006. Con- extent and modifiers of spermatogenic recovery after hormo- of spermatogenesis to azoospermia by combined administra- traception 2007; 75: 166–7.

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