Human Reproduction vol.9 no.4 pp.
586-590, 1994
REVIEW
Male contraception: hormonal, mechanical and other
Frank H.Comhaire
University Hospital Ghent, Department of Internal Medicine,
Section Endocrinology, De Pintelaan 185, 9000 Ghent, Belgium
Methods of male contraception that have been developed so
far have mainly focused on the inhibition of spermatogenesis
through suppression of the hypothalamo- pituitary secretion
of gonodotrophins, and simultaneous supplementation with
androgens. These methods include the use of combinations
of progestogens or luteinizing hormone-releasing hormone
antagonists and testosterone derivatives, or high dose
testosterone. Though effective contraception can be obtained,
side-effects and/or the high cost of treatment limit the
widespread use of these approaches. Inhibition of sperm
maturation in the epididymis, or direct interference with
spermatogenic cells or the cells of Sertoli by e.g. gossypol have
been abandoned because of toxic side-effects. Voluntary
sterilization by vasectomy is the most commonly used method
of male contraception, but its surgical nature, problematic
reversibility and suspected link with subsequent prostate
cancer render the method far from ideal. Non-surgical vas
occlusion may overcome some of these problems, but data
on long-term side-effects and reversibility are lacking. New
contraceptive developments should focus on interfering with
highly specific aspects of spermatogenesis such as unique
enzymatic processes and intercellular communication through
cytokines, or application of antibodies against antigens of the
epididymis or the spermatozoa. Only through better
understanding of normal and pathological spermatogenesis
will it be possible to develop an acceptable male contraceptive.
Key words: androgens/contraception/LHRH analogues/male
reproduction/progestins
Introduction
As a result of the introduction and refinement of effective and
acceptable methods of female contraception, the demand for male
contraception has remained rather limited. The motivation of men
to adhere to long-term medication for contraceptive purposes may
be low. Many men have been motivated to undergo voluntary
sterilization once in a lifetime (Population Reports, 1992). They
may be willing to follow contraceptive treatment during a limited
period of time, provided this does not cause any inconvenience
to their daily life, decrease their 'virility', or affect their physical
well being. Ideally, the contraceptive effect should be immediate
and reversibility should be rapid and complete (Swerdloff et al.,
1989).
586
Until now no such contraceptive method has been available
(Waites, 1993). This is remarkable since spermatogenesis is
probably a more vulnerable process than ovulation (Giwercman
and Skakkebaek, 1992). We suggest that this paradox can be
explained by our insufficient knowledge of the intimate
mechanisms regulating spermatogenesis and perhaps, the poorly
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inspired approach to male contraception. The latter has basically
involved the same techniques as female contraception, namely
to suppress pituitary secretion of gonadotrophins and supplement
the gonadal hormones, or to block gamete transportation.
Future research in male contraception should probably focus
on interfering with the intra-testicular micro-ecosystem and its
paracrine and autocrine regulation by cytokines, such as growth,
migration and differentiation factors, with specific genetic
expression of haploid cells (Niederbergen et al., 1993), or with
unique metabolic pathways.
Endocrine regulation of spermatogenesis
For the better understanding of the methods used in hormonal
male contraception it is desirable to summarize the mechanism
of endocrine regulation of spermatogenesis. Figure I depicts the
complex system of stimulation and feedback regulation of
testicular function. Pulsatile secretion of luteinizing hormone-
releasing hormone (LHRH) stimulates the production and release
of the gonadotrophins luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) by the pituitary. These stimulate
respectively the production and secretion of testosterone by the
Leydig cells, and the production of multiple substances by the
cells of Sertoli (Ritzen et al., 1989). Testosterone exerts a
negative feedback on the hypothalamus where it is aromatized
to oestradiol. Inhibin is secreted by the cells of Sertoli and inhibits
the secretion of FSH by the pituitary. The intimate mechanisms
of intra-testicular endocrine and paracrine regulation and secretion
are incompletely understood (de Kretser, 1988; Risbridger and
de Kretser, 1989), but it is evident that many substances such
as hormones, enzymes, other proteins and cytokines play a role
in the cross-talk between Leydig cells, peritubular cells,
spermatogenic epithelium and cells of Sertoli.
After spermatozoa have been released into the lumen of the
seminiferous tubules, they are transported to the rete testis and
pass through the epididymis. During this passage, spermatozoa
undergo multiple changes of their membrane composition and
of their metabolic activity, resulting in activation of motility.
Spermatozoa are stored in the epididymis and in the ampulla of
the vas deferens. During the first fraction of ejaculation these
spermatozoa are expelled together with the secretions of the
prostate, and the second fraction of the ejaculate contains mostly
the secretory products of the seminal vesicles. The ejaculation
© Oxford University Press

NEUROTRANSMITTERS
CORTEX ENDORPHINS
(PROLACTIN)
STRESS
EXERTION
NUTRITION
LEYD1G CELL
CHOLESTEROL .— P
0 • \ 5o(reductase —
RJ I (aromatase) — •-E,
aromatase
Fig. 1. Hormonal regulation of spermatogenesis. E2 = oestradiol, LHRH = luteinizing hormone-releasing hormone, LH = luteinizing
hormone, FSH = follicle-stimulating hormone, P5 = pregnenolone, T = testosterone, 5a-DHT = 5a-dihydrotestosterone, ABP =
androgen-binding protein, R = receptor.
process is controlled by the sympathetic nervous system and the
activity of the accessory sex glands is androgen dependent.
Hormonal male contraception
Melo and Coutihno (1977) have reported reversible suppression
of spermatogenesis by means of a combination of a progestogen-
inhibiting pituitary secretion of gonadotrophins, and an androgen
to supplement testosterone deficiency. The treatment was
administered by monthly intra-muscular injections and resulted
in temporary azoospermia. Immediate side-effects were reported
to be minimal, but data on long-term application are lacking.
Several variant versions of this approach have been applied,
including different doses of progestogen, percutaneous or oral
delivery of the androgen, or the use of anabolic steroids (Hedman
etal, 1988; Pangkahila, 1991; Nieschlag et al., 1992). Different
rates of azoospermia are achieved in men of different ethnic
groups during treatment with these contraceptive steroids (Waites,
1993).
Suppression of gonadotrophin secretion with simultaneous
androgen supplementation can be obtained by the injection of
supra-physiological doses of testosterone derivatives (Swerdloff
et al., 1979). Severe or even complete suppression of spermato-
genesis is obtained, but 'escape' may occur, possibly due to the
direct stimulatory effect of testosterone on spermatogenesis. In
Male contraception
HYPOTHALAMUS
Downloaded from http://humrep.oxfordjournals.org/ at Pennsylvania State University on May 11, 2016
SERTOLI CELL
Inhibin \
ABP (+>
5«DHT-{+>
SPERMATO-
--O GENESIS
— substances - « -
addition, the side-effects of supra-physiological serum
concentrations of testosterone must be considered, including
weight gain, gynaecomastia, lowering of high density
lipopoprotein cholesterol concentration and potentially increased
risk of atherogenesis, as well as prostatic hyperplasia (Bardin
etal., 1991).
The advent of LHRH agonists has initiated studies combining
their down-regulating effect on gonadotrophin secretion with
testosterone supplementation. Results of this approach were
disappointing since the agonist seemed to blunt the suppressive
effect caused by the androgen (Behre et al., 1992).
The latter did not take place when LHRH antagonists were
used, and testosterone substitution was initiated after complete
suppression of the gonadotrophin secretion was obtained (Pavlou
et al., 1989, 1991). The recent development of a long-acting
testosterone ester (testosterone buciclate; Behre and Nieschlag,
1992) and biodegradable testosterone microcapsules (Bhasin et
al., 1992), which lack the initial peak release of testosterone,
opens new avenues for male contraception. Provided that a
suitable long-acting formulation of the LHRH antagonist can be
developed which is free of side-effects, this approach may yield
an acceptable method of hormonal male contraception. The
remaining inconveniences are the relatively long duration needed
for full sperm recovery, the high cost of the treatment, and the
reduction of testicular volume. Also, available methods of
587
F.H.Comhaire
androgen supplementation do not mimic the nyctohemeral
variations of serum testosterone, the possible physiological
implication of which is unknown.
Obstruction of sperm transport
Vasectomy is a reliable and widely accepted method of male
contraception, or rather, sterilization (Population Reports, 1992).
Open surgical vasectomy causes minor discomfort and is rarely
complicated by local bleeding, inflammation or infection (Huber
et al., 1986). Some patients complain of persistent dull aching
due to the formation of epididymal granulomas. All men develop
antisperm antibodies. Although these do not seem to cause
systemic damage (Tang et al., 1988), they hinder spontaneous
conception after vasectomy repair. Vasectomy reversal is
surgically feasible in the majority of cases, but does not always
result in restoration of fertility (Johnson, 1972). The latter is
particularly uncommon when the vasa have been obstructed for
over 5 years. Most disturbing, however, are recent reports on
the higher probability of prostate carcinoma in vasectomized men
(Guess, 1990; Giovannucci et al., 1992, 1993a,b; Healy, 1993).
This problem seems to occur eight or more years after vasectomy,
and becomes more prominent as the time interval increases. It
is unknown which pathogenetic mechanisms are involved, but
inflammatory cytokines such as interleukin-6 may play a role
(Siegall et al., 1990). The controlled case studies on which the
suspicion of increased prevalence of prostate cancer is based need
to be interpreted with caution (Farley et al, 1993), since the
occurrence of the disease is common among the control cases,
and the reported increase in prevalence is rather low.
Non-surgical vasectomy uses the injection of a polyurethane
elastomere plug into the vasa deferentia through a percutaneous
puncture (Zhao, 1990). This technique is perhaps rather delicate,
but is certainly more acceptable and less traumatic than surgical
vasectomy. It should also be easier to remove the plug and to
restore sperm passage (Zhao et al., 1992a). The polyurethane
elastomere is not, however, considered entirely safe with regard
to possible carcinogenesis, although the evidence to support this
is very weak (Chen et al., 1992). Therefore, attempts have been
undertaken to inject silicone rubber into the vasa (Zhao et al.,
1992b). Although this method is technically feasible, occurrence
of vas occlusion has been slow. In addition, sperm antibodies
may also occur after non-surgical vas occlusion, and the risk of
late complications needs to be explored.
Inhibition of epididymal function
The spermatozoa which are present in the rete testis lack in-vivo
fertilizing capacity, which is acquired during their passage
through the epididymis. Inhibition of epididymal function has
been attempted as a method of male contraception. Chlorinated
sugars such as a-chlorohydrin were found to be highly effective
in animal experiments (Tsang et al., 1981; Ford and Waites,
1986), but their use in the human male is excluded because of
neurotoxicity. Epididymal function largely depends on high local
concentration of testosterone and its 5a-reduced derivative 5a-
dihydrotestosterone. Attempts were made to apply a low dose
of the anti-androgen cyproterone acetate in order to inhibit
588
epididymal maturation of the spermatozoa. This approach was
not successful. Animal experiments suggest that inhibition of 5a-
reductase activity by Finasteride is also ineffective in this respect.
Gossypol and related substances
Spermatogenesis can be blocked by means of substances which
appear to be toxic to the spermatogenic epithelium, such as crude
cotton seed oil containing gossypol, or other chemical substances
including nitrofurane derivatives and sulphasalazine. The effect
of gossypol on spermatogenesis is dramatic, but its reversibility
after discontinuation is only partial (Liu et al., 1987; Liu and
Lyle, 1987). In addition, toxic side-effects with hypokalaemia
have been reported. On the other hand, long-term use of
nitrofurane derivatives may lead to interstitial pulmonary fibrosis,
and sulphasalazine presents side-effects which make its use for
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long-term male contraception inappropriate.
Studies on the multiglycoside extract of the plant Triptergynium
wilfordii (Qian, 1987), as well as with other compounds such
as imidazoles and pyrimethamine are presently underway, but
data on side-effects, reversibility and effectiveness are lacking
at the present time.
Future developments
Testicular function involves many and complex interactions,
which are configured into a micro-ecosystem. This implies that
minute changes in any of the elements can impair the whole
system. The role of cytokines in maintaining the blood —testis
barrier, Leydig cell function (Verhoeven and Cailleau, 1986;
Verhoeven et al., 1988) and of substances regulating cell
migration, differentiation and release, as well as cell to cell
interactions are presently being investigated. Much can be learned
from other systems such as that of tumour cell invasion where
similar mechanisms are possibly involved (Van Roy and Mareel,
1992). There is a long list of cytokines the roles of which need
elucidation. It is foreseeable that some of these may play a critical
role in the unique process of normal spermatogenesis (Bosmans
et al, 1993; Hakovirta et al, 1993; Hussenet et al, 1993;
Shimoya et al., 1993). Antagonists of such substances may lead
to inhibition of particular steps in spermatogenesis, or migration
of the spermatogenic cells through the inter-Sertoli cell matrix.
It may be feasible to produce such an antagonist by means of
biotechnology, and to link it to a specific carrier molecule which
should transport and deposit the substance into the seminiferous
tubules.
Similarly, one can try to identify antisperm antibodies causing
male infertility and to produce and bind them to a carrier
molecule. Another logical approach could be the generation of
antibodies against specific antigens of the epididymis (Kirchhoff
et al, 1993). Either passive or active immunization could be
considered as a method to impair epididymal sperm maturation.
Particular steps of the metabolic pathway during
spermatogenesis could be targeted, e.g. the 'x' isoenzyme of
lactodehydrogenase (LDHx) which plays a key role in the
carbohydrate metabolism of the spermatogenic epithelium
(Zinkham, 1972).
It seems reasonable to assume that these approaches can lead
to more specific, rapidly effective and innocuous methods of male

contraception. In addition, the better knowledge of mechanisms
underlying normal spermatogenesis could reveal some hitherto
unknown causes of idiopathic oligozoospermia.
Conclusion
Both hormonal and mechanical methods for male contraception
suffer from major drawbacks making them hardly acceptable for
universal application. The most recent developments include the
combination of an LHRH antagonist and a long-acting
testosterone preparation with sustained androgen release. This
combination may yield an acceptable method of hormonal
contraception, at least for the near future. It is, however, only
through the better understanding of the intimate mechanisms of
spermatogenesis itself that more adequate methods of male
contraception will develop. More efforts should be directed
toward studies of the cellular biology of spermatogenesis,
epididymal function, and inter-cellular communication if we want
to have better male contraceptives available in the 21st century.
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Received on July 7, 1993; accepted on December 17, 1993

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