Hormonal contraception for human males: prospects
P.R.K. Reddy
School of Life Sciences, University of Hyderabad, Hyderabad-500 046, India
Asian J Androl 2000 Mar; 2: 46-50
Abstract
Development of an ideal hormonal contraceptive for man has been the goal of several research workers during the past few decades. Suppression of pituitary gonadotropic hormones, which in turn would inhibit spermatogenesis while maintaining normal libido and potentia has been the approach for a contraceptive agent. Intramuscularly administered and orally active testosterone or testosterone in combination with progesterone have been shown to cause inhibition of spermatogenesis resulting in azoospermia in normal men. Similarly testosterone has been used in combination with gonadotropin releasing hormone antagonists and agonists to inhibitpituitary gonadotropic hormone release. Immunological approach to neutralize the circulating levels of follicle stimulating hormone has also been shown to cause inhibition of spermatogenesis. The available literature shows that testosterone causes reversible azoospermia without any significant side effects in Asian population effectively and appears to be a promising chemical for control of fertility in man.
1 Testosterone as a contraceptive
In earlier studies testosterone supplementation for improvement of sperm count was tried in oligospermic patients. In such treatment patients at first became azoospermic before an improvement in spermatogenesis was observed[1]. Reddy and Rao[2] utilized this observation to suggest, for the first time, that testosterone can be used for control of fertility in normal human males. They showed that injecting testosterone propionate at a dose of 25 mg per day for 60 days caused total inhibition of spermatogenesis in volunteers since they became azoospermic. Complete recovery of sperm counts was achieved after 150 days of cessation of treatment with testosterone propionate. When these experiments were carried out, effective orally acting testosterone was not available and hence these authors suggested that it might be possible to develop a suitable orally active testosterone and bring down the dose of testosterone by combining it with progesterone. Following this study testosterone undecoate was used as an orally active hormone to control fertility in human males[3]. However, it was observed that only one volunteer out of seven became azoospermic after treatment with 80 mg of testosterone undecoate three times a day for 10-12 weeks. It was adduced that the levels of testosterone administered as testosterone undecoate were probably not in circulation for periods long enough to suppress pituitary gonadotropins due to their rapid metabolism. Long acting injectables, testosterone enanthate (TE)[4,5] and 19-non-testosterone-hexoxy-phenylpropionate[6] were tried for control of fertility. In both of these studies sperm output was inhibited while virility was maintained. It was further suggested that testosterone treated subjects exhibited reduction in sperm penetration of ova as assessed by zona pellucida-free hamster ova penetration test[5]. A number of studies followed these observations to investigate the feasibility of using testosterone as a possible contraceptive in human males. With a view to deliver testosterone in a sustained form in the body, testosterone pellets were implanted under the skin lining the abdominal wall[7]. In a similar study[8] 7-alpha-methyl nortestosterone (MENT) was also shown to be an effective androgen for contraception which can be used as a sub-dermal implant. Men treated with testosterone implants also showed suppression of sperm output resulting in azoospermia. In a series of experiments it was shown that injection of 200 mg of testosterone enanthate intramuscularly every week caused azoospermia in about 50% of Caucasian volunteers[9-14]. Contrary to these observations, in all seven Indonesian men, 100 mg of TE injected every week intramuscularly, induced azoospermia[15]. Similarly TE caused azoospermia in Thai[16-17]and Chinese[18] volunteers. A multi-center study initiated by World Health Organization confirmed this heterogeneity of individual susceptibility to testosterone[19-23]. Other esters of testosterone with better pharmacokinetics, like testosterone buciclate[24] and testosterone undecanoate[25] were also shown to cause suppression of spermatogenesis without any serious side effects. Further it was observed in a recent study conducted in China[26] that testosterone undecoate causes apoptosis of spermatogenic cells in men, in addition to its gonadotropic hormone inhibitory effect on the pituitary, which enhances its inhibitory effect on spermatogenesis.
2 Use of testosterone in combination with progestrones as contraceptives
With a view to lower the dose of testosterone, progesterone or its analogs were given additionally orally or in the form of injections to human males to suppress pituitary gonadotropic hormones while maintaining their libido and potentia. Norethandrolone in combination with testosterone[27] or danazol and testosterone[28,29] were shown to cause reversible inhibition of spermatogenesis in normal men. Monthly injections of depot medroxyprogesteroneacetate (DMPA) and testosterone or medroxyprogesterone acetate in combination with sub-dermal implants of testosterone caused reduction of sperm in 5 out of 9 patients to less than 1 million/mL of semen[30]. Similar observations on inhibition of spermatogenesis was observed in other studies when medroxyprogesterone acetate and TE were injected in normal men[31,32]. Oral administration of medroxyprogesterone acetate and percutaneous injection of TE showed good inhibition of spermatogenesis with no side effects[33,34]. In an Indonesian study[35] twenty normal healthy men were treated with 100 mg each of DMPA and TE or with 200 mg DMPA plus 250 mg of TE monthly. It was observed that both steroid regimens were equally effective in suppressing spermatogenesis 2.5 months after onset of treatment and full recovery was achieved after 2 months of cessation of treatment. Though a transient decrease in libido was observed in about 25% of patients during the first month of recovery, probably due to the prolonged effect of DMPA, no other side effects were noticed and the induction of azoospermia was uniform in all treated men. This study was further extended by a WHO sponsored multi-center study involving 96 normal healthy volunteers in Indonesia[36]. It was observed that both TE and 19-nor-testosterone in combination with DMPA cause azoospermia and this effect was reversible after stopping the treatment. It was further suggested[37] that sustained availability of 6 mg/day of TE in combination with DMPA enhances the spermatogenic suppression with negligible side effects, to pave the way for the development of a progestin/androgen combination contraception for males. Orally active progesterone, levonorgesterel, in combination with injectable TE was also studied as a contraceptive for men[38-40]. It was shown that, long acting levonorgestral in combination with TE is advantageous compared to DMPA. Other effective pituitary gonadotropin suppressants like cyproterone acetate (CA) were used either alone[41,42] or in combination with TE to suppress spermatogenesis[43,44]. However, in view of the effect of CA being anti-androgenic, higher dose of testosterone may be needed to maintain libido and potentia.
3 Gonadotropin-releasing hormone agonists and antagonists for fertility control in males
After deciphering of the structure of gonadotropin-releasing hormone (GnRH) several of its agonists and antagonists were prepared in various laboratories to study their efficacy as inhibitors of gonadotropic hormone production. Since continuous treatment with GnRH causes desensitization of pituitary gonadotrophs, which turns off the secretion of gonadotropic hormones, spermatogenesis is inhibited. In an earlier study[45,46] it was shown that daily subcutaneous injection or infusion with GnRH in combination with TE caused decline in mean sperm count to 85%. Similar study with a depot preparation of GnRH agonist in combination with low dose TE also showed marked azoospermia[47]. Gonadotropin-releasing hormone antagonists were also tested in combination with testosterone[48-51]. In all of these studies it was observed that suppression of spermatogenesis was achieved to varying degree. However, since both gonadotropin-releasing hormone agonists and antagonists need to be administered subcutaneously, every day, such a mode of treatment will be difficult. In addition, both GnRH agonists and antagonists will be expensive to be used by a large number of population.
4 Immunological methods for contraception in men
In view of the dependence of spermatogenesis on follicle stimulating hormone (FSH) in humans, an effective method to immunize circulating levels of FSH was tried in men[52]. It was demonstrated that human volunteers respond to ovine follicle stimulating hormone and produce antibodies, which are capable of neutralizing bioactivity of human FSH and such antibodies were shown to be specific. However, the efficiency of this method in causing total azoospermia or rendering the residual sperm incapable of fertilization needs further confirmation.
5 Conclusion
The work conducted at several centers shows that administration of testosterone esters cause reversible azoospermia in human males in two months. However, the effect of testosterone appears to differ in various ethnic populations. While testosterone caused successful, 100% azoospermia in volunteers in India, Indonesia, Thailand and China, such inhibition in all volunteers was not noticed in Caucasian populations. These studies also show that the dose of testosterone can be brought down to about 6-8 mg by supplementing with progestational compounds. However, an effective combination drug which would cause functional azoospermia in all populations still needs to be developed. In addition the implications of inhibiting pituitary gonadotropin synthesis and release for extended periods of time needs further investigation. It is important to study the effect of long term inhibition of pituitary gonadotropins, for about 2-5 years and side effects caused, if any, need to be investigated. In one of such studies TE was given once every 14 days for a total of 32-33 months in rhesus monkeys[53-56]. Some changes in prostate gland[53],glucose metabolism[54], liver metabolism[55] and lipid profile[55] was observed. The authors in these studies were of the opinion that these changes could be due to increased bio-availability of testosterone as TE was injected intramuscularly. A modified orally active testosterone in combination with an orally active progesterone analog with good pharmacokinetics needs to be developed for contraception in men. The available literature shows that there are bright possibilities to develop an orally acting testosterone/progestin combination drug for the control of fertility in human males.
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