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
Keywords:
testosterone;
progesterone; male contraceptive agents; gonadorelin; spermatogenesis;
spermatogenesis-blocking agents
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.
References
[1]
Heller CG, Nelson WO, Hill TB, Henderson E, Maddock WO, Jungck EC,
et al. Improvement
in spermatogenesis following depression of the human testis with testosterone.
Fertil Steril 1950; 1: 45.
[2] Reddy PRK, Rao JM. Reversible
antifertility action of testosterone propionate in human males.
Contraception 1972; 5: 295-301.
[3] Nieschiag E, Hoogen H, Bolk M, Schuster H, Wickings EJ. Clinical
trial with testosterone undecanoate for male fertility control.
Contraception 1978; 18: 607-14.
[4] Steinberger E, Smith KD. Testosterone:
a possible reversible male contraceptive. Contraception
1977; 16: 261-8.
[5] Matsumoto AM. Is
high dosage testosterone an effective male contraceptive agent.
Fertil Steril 1988; 50: 324-8.
[6] Knuth UA, Behre H, Belkien L, Bents H, Nieschiag E. Clinical
trial of 19-nortestosterone-hexoxyphenylpropionate (Anadur)
for male fertility regulation. Fertil Steril 1985; 44: 814-21.
[7] Handeisman DJ, Conway AJ, Boyian LM. Suppression
of human spermatogenesis by testosterone
implants. J Clin Endocrionol
Metab 1992; 75: 1326-32.
[8] Sundaram K, Kumar N, Bardin CW.
7-alpha-methyl-nortestosterone (MENT):
the optimal androgen for male contraception.
Ann Med 1993; 25: 199-205.
[9] Wallace EM, Aitken RJ, Wu FC.
Residual sperm function in oligozoospermia induced by testosterone
administered as a potential steroid male contraceptive. Int
J Androl 1992; 15: 416-24.
[10] Wallace EM, Gow SM, Wu FC.
Comparison between testosterone-induced azoospermia
and oligozoospermia in a male contraceptive study. I:
Plasma luteinizing hormone, follicle stimulating
hormone, testosterone, estradiol, and inhibin concentrations.
J Clin Endocrinol Metab 1993; 77: 290-3.
[11] Anderson RA, Wu FC. Comparison between testosterone-induced azoospermia
and oligozoospermia
in a male contraceptive study. II.
Pharmacokinetics and pharmacodynamics of once weekly
administration of testosterone. J
Clin Endocrinol Metab 1996; 81: 896-901.
[12] Anderson RA, Wallace AM, Wu FC. Comparison
between testosterone-induced azoospermia and oligozoospermia
in a male contraceptive study. III.
Higher 5 alpha-reductase activity in oligozoospermic men administered
supraphysiological doses of testosterone.
J Clin Endocrinol Metab 1996; 81: 902-8.
[13] Anderson RA, Wallace AM, Kicman AT, Wu FC. Comparison
between testosterone -induced azoospermia and oligozoospermia
in a male contraceptive study. IV. Suppression
of endogenous testicular and adrenal androgens. Hum
Reprod 1997; 12: 1657-62.
[14] Anderson RA, Kelly RW, Wu FC.
Comparison between testosterone-induced azoospermia
and oligozoospermia in a male contraceptive study. V. Localization
of higher 5 alpha-reductase activity to the reproductive
tract in oligozoospermic men administered
supraphysiological doses of testosterone. J
Androl 1997; 18: 366-71.
[15] Arsyad KM. Sperm function in Indonesian men treated with testosterone.
Int J Androl 1993; 16: 355-61.
[16] Aribarg A, Sukcharoen N, Chanprasit Y, Mgeamvijawat J, Kriangsinyos
R. Suppression of spermatogenesis by testosterone
in Thai men. J
Med Assoc Thai 1996; 79: 624-9.
[17] Sukcharoen N, Aribarg A, Kriangsinyos R, Chanprasit Y, Ngeamvijawat
J. Contraceptive
efficacy and adverse effects of testosterone
in Thai men. J Med Assoc Thai
1996; 79: 767-73.
[18] Cao J, Yuan J, Jin W. Clinical
trial of antifertility method with testosterone
in normal men. Chin Med J 1996; 76: 335-7.
[19] Rates of testosterone-induced suppression to severe oligozoospermia
or azoospermia in two multinational clinical studies.
World Health Organization Task force on Methods for
The Regulations of Male Fertility.
Int J Androl 1995; 18: 157-65.
[20] Handelsman DJ, Farley TM, Peregoudov A, Waites GM.
Factors in nonuniform induction of azoospermia by testosterone
in normal men. World
Health Organization Task Force on Methods for the Regulation
of Male Fertility. Fertil
Steril 1995; 63: 125-33.
[21] Wu FC, Farley TM, Peregoudov A, Waites GM.
Effects of testosterone
in normal men: experience
from a multicenter contraceptive efficacy study. World
Health Organization Task Force on Methods for the Regulation
of Male Fertility. Fertil
Steril 1996; 65: 626-36.
[22] Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia
in normal men. Feritl Steril 1996; 65: 821-9.
[23] Zheng WY, Wreford NG, Royce P, de Krester DM, McLachian RI. Stereological evaluation
of human spermatogenesis after suppression by testosterone treatment:
heterogeneous pattern of spermatogenic impairment. J
Clin Endocrinol Metab 1998; 83: 1284-91.
[24] Behire HM, Baus S, Kliesch S, Keck C, Simoni M, Nieschiag E. Potential
of testosterone buciciate for male contraception: endocrine
differences between responders and nonresponders. J
Clin Endocrinol Metab 1995; 80: 2394-403.
[25] Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A
clinical trial of injectable testosterone undecanoate as a
potential male contraceptive in normal Chinese men. J
Clin Endocrinol Metab 1999; 84: 3642-7.
[26] Ge YF, Huang YF, Zhang GY, Wang XH, Xu JP. Studies on apoptosis of
spermatogenic cells in normal fertile men treated with supraphysiological
doses of testosterone undecanoate. Asian J Androl 1999; 1:155-8.
[27] Brenner, Bernstein GS, Roy S, Jecht EW, Mishell DR. Administration
of norethandrolone and testosterone as a contraceptive agent
for men. Contraception
1975; 11: 193-207.
[28] Ulstein M, Netto N, Leonard J, Paulsea CA. Changes
in sperm morphology in normal men treated with danazol
and testosterone. Contraception
1975; 12: 437-44.
[29] Paulsen CA, Leonard JM. Clinical
trials in reversible male contraception. I. Combination of
danazol plus testosterone. 1977 Monograph March 15.
[30] Barfield A, Melo J, Coutinho E, Alvarez-Sanchez F, Faundes A, Brache
V, et al. Pregnancies associated with sperm concentrations
below 10 million/ml in clinical studies of a potential male
contraceptive method, monthly depot medroxyprogesterone acetate
and testosterone esters. Conctraception 1979; 20: 121-7.
[31] Frick J, Danner G, Kunit G, Joos H, Kohle R. Spermatogenesis
in men treated with
injections of medroxyprogesterone acetate combined with testosterone.
Int J Androl 1982; 5: 246-52.
[32] Wu FC, Aitken RJ. Suppression
of sperm function by depot medroxyprogesterone acetate
and testosterone in
steroid male contraception. Fertil
Steril 1989; 51: 691-8.
[33] Soufir JC, Jouannet P, Marson J, Soumah A. Reversible
inhibition of sperm production and gonadotrophin
secretion in men following combined oral medroxygprogesterone
acetate and percutaneous testosterone treatment.
Acta Endocrinol (Copenh) 1983; 102: 625-32.
[34] Guerin JF, Rollet J. Inhibition
of spermatogenesis in men using various combinations of oral
progestagens and percutaneous
or oral androgens. Int J Androl 1988;
11: 187-99.
[35] Pangkahila W. Reversible
azoospermia induced by an androgen-progestin combination regimen
in Indonesian men. Int
J Androl 1991; 14: 248-56.
[36] Comparison of two androgens plus depot-medroxyprogesterone acetate
for suppression to
azoospermia in Indonesian men.
World Health Organization. Task
Force on Methods for the Regulation of Male Fertility. Fertil Steril 1993;
60: 1062-8.
[37] Handelsman DJ, Conway AJ, Howe CJ, Turner L, Mackey MA. Establishing
the minimum effective dose and additive effects of depot progestin
in suppression of human spermatogenesis by a testosterone depot.
J Clin Endocrinol Metab 1996: 81: 4113-21.
[38] Buchter D, von Eckardstein S, von Eckardstein A, Kamischke A, Simoni
M, Behre HM, et al.
Clinical trial of transdermal testosterone and oral levonorgestrel
for male contraception. J
Clin Endocrinol Metab 1999; 84: 1244-9.
[39] Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A
lower dosage levonorgestrel and testosterone combination effectively
suppresses spermatogenesis and circulating gonadotropin levels
with fewer metabolic effects than higher dosage combinations.
J Androl 1999; 20: 407-14.
[40] Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto
AM. 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
1996; 81: 757-62.
[41]
Roy S, Chatterjee S, Prasad MRN, Pandey DC. Effects
of cyproterone acetate on reproductive function in normal human
males. Contraception
1976, 14: 403-20.
[42] Roy S, Chatterjee S. Studies
with cyproterone acetate for male contraception. J
Steroid Biochem 1979; 11: 675-80.
[43] Meriggiola MC, Bremner WJ, Paulsen CA, Vaidiserri A, Incorvaia L,
Motta R, et al. A
combined regimen of cyproterone acetate and testosterone as
a potentially highly effective male contraceptive.
J Clin Endocrinol Metab 1996; 81: 3018-23.
[44] Meriggiola MC, Bremner WJ, Costantino A, Di Cintio G, Flamigni C. Low
dose of cyproterone acetate and testosterone
for contraception in men. Hum Reprod 1998; 13: 1225-9.
[45] Swerdloff RS, Handelsman DJ, Bhasin S. Hormonal
effects of GnRH agonist in the human male: an approach to male
contraception using combined androgen and GnRH agonist treatment. J
Steroid Biochem 1985; 23: 855-61.
[46] Swerdloff RS, Steiner BS, Bhasin S.
Gonadotropin-releasing hormone (GnRH) agonists in male
contraception. Med
Biol 1986; 63: 218-24.
[47] Bouchard P, Garcia E. Influence
of testosterone substitution on sperm suppression by LHRH agonists. Horm
Res 1987; 28; 175-80.
[48] Paviou SN, Brewer K, Farley MG, Lindner J, Bastias MC, Rogers BJ,
et al. Combined
administration of a gonadotropin-releasing hormone antagonist and testosterone
in men induces reversible azoospermia without loss of libido. J
Clin Endocrinol Metab 1991; 73: 1360-9.
[49] Tom L, Bhasin S, Salameh W, Steiner B, Peterson M, Sokol RZ,
et al. Induction
of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing
hormone antagonist and testosterone. J
Clin Endocrinol Metab 1992; 75: 476-83.
[50] Bagatell CJ, Matsumoto AM, Christensen RB, Rivier JE, Bremner WJ.
Comparison of a gonadotropin releasing hormone antagonist
plus testosterone (T) versus T alone as potential male contraceptive
regimens. J Clin Endocrinol Metab 1993; 77: 427-32.
[51] Swerdloff RS, Bagatell CJ, Wang C, Anawalt BD, Berman N, Steiner
B, et al. Suppression
of spermatogenesis in man induced by Nal-Glu gonadotropin releasing
hormone antagonist and testosterone
(TE) is maintained by TE alone.
J Clin Endocrinol Metab 1998; 83: 3527-33.
[52] Moudgal NR, Murthy GS, Prasanna Kumar KM, Martin F, Suresh R, Medhamurthy
R, et
al. Responsiveness of human male volunteers to immunization with ovine
follicle stimulating hormone vaccine: results of
a pilot study. Hum Reprod 1997; 12: 457-63.
[53] Udayakumar TS, Tyagi A, Rajalakshmi M, Das SN, Hashim S, Bajaj JS.
Changes in structure and function of prostate by long-term
administration of an androgen, testosterone
enanthate, in rhesus monkey (Macaca mulatta). Anat Rec 1998; 252: 637-45.
[54] Tyagi A, Rajalakshmi M, Jeyaraj DA, Sharma RS, Bajaj JS. Effects
of long-term administration of testosterone enanthate on glucose
metabolism in rhesus monkey. Contraception 1999; 59: 333-7.
[55] Tyagi A, Rajalakshmi M, Bajaj JS, Kumar VM. Effects of long-term
treatment with testosterone enanthate in rhesus monkeys: I.
Pharmacokinetics of testosterone, testicular volume and liver
metabolism of testosterone. Int J Androl 1999; 22: 139-47.
[56] Tyagi A, Rajalakshmi M, Jeyaraj DA, Sharma RS, Bajaj JS. Effects
of long-term use of testosterone enanthate. II. Effects on lipids, high
and low density lipoprotein, cholesterol and liver function parameters.
Int J Androl 1999; 22: 347-55.
Correspondence
to: Prof P.R.K. Reddy, President of Society of Andrology: India,
School of Life Sciences, University of Hyderabad, Hyderabad-500 046, India.
Tel +91-40-301 022 Fax +91-40-301 0120
e-mail:
prkrsl@uohyd.ernet.in
Received
2000-02-14 Accepted 2000-02-27
|