Male contraception: prospects for the new millennium

W.M. Hair, F.C.W. Wu

Department of Medicine, University of Manchester, Manchester M13 9WL, UK

Asian J Androl  2000 Mar; 2: 3-12

Keywords: contraception; male contraceptive agents; male contraceptive devices; gonadotropins; testosterone; androgen

Abstract

1 Introduction

Table 1. Current contraceptive prevalence in couples of reproductive age and the typical first year failure rates of the individual methods.

(Adapted from United Nations Populations Division 1994 & Hatcher et al 1989^[2,3])

2 Current Methods

Coitus interruptus and periodic abstinence are associated with unacceptably high failure rates and their popularity is on the decline in modern contraceptive practice (Table 1). The only two current reliable methods available to men (condoms and vasectomy) are based on historical practices developed from the 16th and 19th centuries respectively.

2.1 Vasectomy

A detailed discussion on this surgical method of male sterilisation is outside the scope of this review. However, since the 1960s, vasectomy has played an increasingly important role as the principal method for male contraception in men who have completed their family. Some 45 million men are estimated to have undergone vasectomy. The single most important advantage of the method is the very high efficacy (1-2 failures per 1000 procedures). Complications include haematoma or infection in 5%, recanalisation in up to 3% and sperm granulomata varying from 3-75%, with no reported mortality. Vasectomy has at various times been linked to increased disease risks (atherosclerosis, diabetes, immunological disorders) but has generally been shown to be a reassuringly safe^[5]. Retrospective surveys have suggested a modest increased predisposition to prostatic^[6] and testicular tumours in vasectomised men in the USA. However, the reported relationships were weak and have not been universally observed. On the basis of current data, no changes in vasectomy practice are warranted although ongoing prospective studies should further clarify this situation^[7].

Results of vasectomy reversal are highly variable depending on the time interval since the original procedure, the skill and experience of the operator and the type of procedure. In general, much more favourable results are obtained with microsurgical techniques within 2 years after vasectomy. Potential patients should expect to achieve patency rates of 80% and pregnancy rates of 60% if reversal is within 5 years after vasectomy. Two main factors limit the wider acceptability of surgical vasectomy: the need for skin incisions and the uncertainty of reversibility. New techniques such as no-scalpel vasectomy and percutaneous transluminal vas occlusion have been or are being developed to make the procedure simpler, less invasive as well as more predictably reversible^[8].

2.2 Condoms

3 Experimental approaches

3.1 Hormonal approach

The poor basic understanding of the complex intratesticular regulatory mechanisms underlying normal spermatogenesis makes it difficult to identify specific testicular targets for pharmacological disruption.  Since both T and FSH are required for normal spermatogenesis, currently the most realistic way to suppress spermatogenesis is via the endocrine suppression of pituitary gonadotrophic drive to the testis thereby abrogating Leydig cell steroidogenesis and nullifying FSH simultaneously (See Figure 1). The consequent depletion of intratesticular testosterone and loss of FSH action will result in a collapse of spermatogenesis characterised by a block in spermatogonial maturation and disruption of premeiotic stages of spermatogenesis without affecting stem cells^[9,10]. Maintenance of spermatogonial stem cell population ensures that hormonal suppression of spermatogenesis is invariably reversible. However, the need to induce total inhibition of T production from the testis^[11] invariably creates a systemic hypoandrogenic state. This dictates the need for exogenous T replacement to maintain extratesticular secondary sexual functions such as sex drive, potency and androgen-dependent metabolic functions on bone, muscle and haemopoiesis. Although there are no data available, physiological replacement doses of exogenous T administered systemically are unlikely to raise intratesticular testosterone to an extent that arrest of spermatogenesis induced by gonadotrophin suppression will be prevented.

figure 1

Selective suppression of FSH is not a viable approach to achieve the contraceptive target of azoospermia or severe oligozoospermia. Active or passive immunisation against FSH has produced only modest suppression spermatogenesis in subhuman primates^[12]. Males with inactivating mutations of FSH receptor gene^[13] and transgenic mice with FSH beta knockout have either only moderately impaired or normal spermatogenesis. These results are consistent with current view that T and FSH act synergistically and may substitute for each other at a variety of phases during spermatogenesis. The physiological feedback inhibition by gonadal sex steroids on hypothalamic GnRH and pituitary gonadotrophin secretion is well established (Figure 1). The efficacy of female hormonal contraceptives suggest that exogenous sex steroids may also be the most likely candidates to achieve gonadotrophin suppression in men. Studies performed in the 1970s showed that either androgens alone or progestogens combined with androgens were indeed effective in the suppression both of gonadotrophins and spermatogenesis. Azoospermia was achieved in 40%-80% of normal Caucasian men (with the remainder becoming severely oligozoospermic) without producing unacceptable side effects or impairment of sexual function^[14].

3.1.1 Androgens alone

As the prototype for further study, the androgen-only approach was chosen because of the well-documented safety of T in many years of clinical use in hypogonadal men, its economy as a single agent in achieving both gonadotrophin suppression and maintaining sexual function simultaneously and the familiar albeit suboptimal pharmacokinetics of available preparations.

3.1.1.1 T Enanthate

Between 1986 and 1990, the first ever study to examine the contraceptive efficacy of induced azoospermia was carried out in 271 healthy volunteers from 10 centres in 7 countries using T enanthate 200 mg weekly^[15]. A total of 157 azoospermic men entered the 12 month efficacy phase during which continued weekly TE injections were the only form of contraception used. One pregnancy occurred during 1486 months of exposure giving a Pearl rate (pregnancy per 100 couples using method for one year) of 0.8 with 95% confidence intervals of 0.02-4.5. This affirmed the important principle that suppression to azoospermia by hormonal method can confer contraceptive efficacy comparable with female contraceptive and substantially better than the condom.

While azoospermia appears to be the logical target for optimally effective contraception, a substantial minority of men remains oligozoospermic despite suppression of gonadotrophins to undetectable levels. The fertility of these subjects with residual spermatogenesis needs to be defined in order to assess the overall contraceptive efficacy of the hormone approach. In the second efficacy trial conducted by the WHO between 1990 to 1994^[16], 349 out of 358 (98%) of healthy men from 15 centres in 9 countries were suppressed to azoospermia or oligzoospermia (<5 million/mL) with TE 200 mg im weekly. They accumulated a total of 283.5 years of exposure, during which there were 9 pregnancies. The risk of pregnancy was directly correlated with sperm concentrations (Table 2). No pregnancies occurred in 230 man-years of azoospermic exposure but the failure rate was high at sperm densities above 3 million/mL. With sperm densities between 0.1 to 3.0 million /mL, 4 pregnancies occurred during 49.5 years of exposure yielded a Pearl rate of 8.1 (2.2-20.70 per 100 person-years. The Pearl rate of the method as a whole, including all men with sperm densities below 3 million/mL (i.e. azoospermia to 3 million/mL), was 1.4 (0.4-3.7) per 100 person-years. This is comparable to the typical first year failure rate of modern female reversible contraceptives (OCP, injectables, medicated IUDs) and is superior to the condom (12 per 100 person-years), withdrawal (18 per 100 person-years) and periodic abstinence (20 per 100 person-years). Ninety-eight percent of Asian and 95% of Caucasian men suppressed to 3 million/mL, or less, indicating that the vast majority of men are able to achieve this oligozoospermic threshold of contraceptive efficacy. These two trials using a prototype regime established the important principle that hormonal suppression of spermatogenesis can provide effective reversible contraception for men and provided benchmark results on which future contraceptive studies will be compared. The incidence of side effects (acne, weight gain, changes in sex drive and mood) was low apart from acne (29.3%) and the cumulative annual discontinuation rate was 9.7%^[17].

Table 2. Mean (95% confidence intervals) pregnancy rates according to different sperm concentrations suppressed by testosterone enanthate 200 mg im weekly while couples are not using any other contraceptive methods. (Adapted from WHO 1995^[16]).

HDL-cholesterol and total cholesterol decreased by 18% and 6% respectively while haematocrit increased by 6%. These effects reflect the high peak and markedly fluctuating levels of T produced by weekly intramuscular injections of a supraphysiological dose of T enanthate rather than an inherent feature of hormonal male contraception. Moreover, the requirement for weekly painful injections is impractical and unacceptable as a method of contraception. For these reasons, improved methods or formulations for long-acting, stable delivery of lower doses of testosterone are crucial for the continued development of male hormonal contraceptives.

3.1.1.2 T implants

Surgical implantation of T pellets subcutaneously is a popular method of physiological androgen replacement in some countries^[18]. At doses of 600 to 800 mg, relatively stable but progressively declining levels of testosterone within the physiological range can be maintained for 4-6 months. Following a single administration of a supraphysiological dose of 1200 mg to normal men, azoospermia can be induced with similar efficacy but apparently fewer side effects than weekly intramuscular TE^[19]. Extrusion of T pellets occurs in 8.5% of procedures in experienced hands. The feasibility of maintaining spermatogenesis suppression and the acceptability of repeated T implantation remain to be established.

3.1.1.3 T undecanoate

T undecanoate is an ester with a long aliphatic side chain that increases its lipid solubility and facilitates absorption into intestinal lymphatics. Because of the improved oral bioavailability, T undecanoate was originally formulated in arachis oil for orally-administered androgen replacement. Early attempts to use oral T undecanoate for male contraceptive spermatogenesis suppression, however, were unsuccessful^[20]. Recently, T undecanoate has been re-formulated in castor oil for intramuscular injections. A single dose of 1000 mg T undecanoate achieving a prolonged half-life of 33.9 days in hypogonadal men compared with 4.5 days for 250 mg of T enanthate^[21]. A multi-centre, contraceptive dose-finding study using intramuscular T undecanoate (in tea seed oil) 500-1000 mg 4-6 weekly has recently been completed in China. T undecanoate (TU) 1000 mg was found to induce reversible azoospermia in all 12 subjects treated, whilst 11 of the twelve receiving TU 500 mg also achieved azoospermia^[22].  

3.1.1.4 T buciclate

T-17-trans-4-n-butyl-cyclohexylcarboxylate (T buciclate), a long-acting ester of testosterone developed jointly by the WHO and NICHD, USA, is formulated as an aqueous suspension of finely-milled crystals (10-15 m particle size) and administered as intramuscular injections. Both 600 and 1000 mg in single-dose injections raised plasma T gradually in hypogonadal men into the low normal range and maintaining stable concentrations for 16 and 20 weeks respectively (mean residence time65 days)^[23]. A single dose of 1200 mg of testosterone buciclate produced azoospermia in 3 out of 8 eugonadal men whose plasma testosterone remained within the physiological range^[24].

3.1.1.5 MENT

7-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen which is not 5-reduced but is aromatised to 7-methyl-oestradiol. In the castrated rat, MENT is four times more potent than T in maintaining ventral prostate and seminal vesicle weights but ten to twelve times more potent in maintaining muscle mass and in suppressing gonadotrophins. The favourable therapeutic index of MENT, presumably conferred by the lack of DHT stimulation of accessory sex glands, has also been confirmed in castrated monkeys^[25]. However MENT was also shown to be 10 times more potent than T in decreasing HDL- and total cholesterol. As a result of its increased potency and tissue selectivity, MENT has the potential advantage of being used at relatively low doses (one-tenth that of T) to suppress gonadotrophin secretion and maintain adult sexual functions and muscle mass without stimulating the prostate^[26]. The lower doses (and smaller mass of steroid) may also permit sufficient drug to be delivered by subdermal implants, skin patches or gels. This selective androgen receptor modulator (SARM) is currently being further investigated as a potential agent for androgen replacement and male contraception. Single intramuscular injection of 2-8 mg of micronized MENT to healthy men showed suppression of gonadotrophins without side effects^[27]. Subcutaneous implants containing 115 mg of MENT acetate  (2 implants per subject) have recently been shown to maintain sexual behaviour and mood in hypogonadal men over a 6 week period^[28].

3.1.1.6 19-Nortestosterone

19-Nortestosterone (19-NT) or nandrolone is an anabolic steroid with not only a higher affinity for the androgen receptor than T, but is also a potent progestogen. 19-NT hexoxyphenylproprionate injected every 3 weeks for 3 months induced suppression of gonadotrophins and testosterone and achieved azoospermia in 6 out of 12 volunteers without any symptoms of androgen deficiency^[29]. If 19-NT can maintain essential androgen dependent functions without producing undesirable metabolic, prostatic and behavioural effects with more prolonged exposure, a 19-NT ester offers potential as a single agent anti-fertility formulation.

3.1.2 Combined hormonal male contraceptive

From the recent experience with various androgen-only regimens, it is likely that supraphysiological levels of testosterone are required to produce maximal suppression of spermatogenesis. The elevation in plasma T concentrations, especially with high post-injection peak levels produced by the suboptimal pharmacokinetics of current T esters such as enanthate or cypionate, are therefore likely to produce dose-dependent androgen-related side effects (vide supra). The theoretical possibility of increased risks for benign prostatic hyperplasia, prostatic carcinoma, cardiovascular disease in later years and behaviour disturbances (e.g. increased aggression) also raises concerns that cannot be easily allayed without long-term surveillance data. It seems prudent to consider an alternative approach in which the primary anti-gonadotrophic agent is non-androgenic while testosterone is deployed in lower physiological replacement doses. 

3.1.2.1 Progestogen and androgen combination

Progestogens are potent inhibitors of gonadotrophin secretion in men and may also suppress spermatogenesis directly^[30]. They can act synergistically or additively with androgens thus permitting lower doses of each steroid to be combined with possibly greater efficacy than when either compound is used alone. Incorporating progestogens will also have the added advantage that any direct stimulatory effects exogenous androgens may have on spermatogenesis can be minimised or even antagonised. The synthetic third-generation progestogens derived from 19-NT (e.g. levonorgestrel, desogestrel, gestodene and norgestimate) are highly potent and effective in g doses in inhibiting ovulation in the combined female contraceptive pill. The comparatively low mass of drug required allows long-acting (2-5 years) subdermal implants such as Norplant (levonorgestrel, Wyeth) and Implanon (etonogestrel, Organon) to be successfully used for female contraception. Their value in male hormonal contraception remains to be established.  

Early studies in 1970s an 1980s using depot medroxyprogesterone acetate (DMPA) danazol, norethisterone acetate and levonorgestrel combined with sub-replacement doses of testosterone established that these compounds can be used safely for 12-24 months in normal men but spermatogenic suppression was variable. Recent studies combining progestogens with higher doses of T have yielded more encouraging results.

3.1.2.1.1 DPMA plus T

DMPA (200 or 100 mg) and T enanthate (250 or 100 mg) at monthly intervals for 4 months suppressed spermatogenesis to azoospermia in 19 out of 20 Indonesian men^[31]. The high efficacy of hormone suppression in Indonesian men was confirmed by a larger 5centre study showing that DMPA, when combined with either 3-weekly 19-NT or weekly T enanthate, was effective in inducing azoospermia in 97% of subjects after 6 months^[32]. A single administration of 300 mg of DMPA combined with 800 mg of T implants induced azoospermia in 9 out of 10 Caucasian men^[33]. A single studies showed that combination regimes of progestogen and androgen can be highly effective.

3.1.2.1.2 Levonorgestrel plus T

Oral levonorgestrel 500 g combined with intramuscular T enanthate 100 mg/week induced azoospermia in 12 of 18 (67%) men^[34]. Reducing the dose of levonorgestrel to 250 and 125 g daily produced similar results. Oral desogestrel 150-300 g daily combined with intramuscular T enanthate 50-100 mg/week suppressed 18 of 24 (75%) men to azoospermia^[35]. There is some indication that an optimised combination (e.g. desogestrel 300 g daily with T enanthate 50 mg weekly) can induce azoospermia in all men, although the overall results from these studies with small number of subjects suggest that progestogen-androgen combinations may not be significantly more effective than testosterone alone. The combination regimes also decreased HDL-cholesterol indicating that 19-NT-derived oral progestogens exert significant effects of their own on lipid metabolism in men independent of T.

3.1.2.1.3 CPA plus T

Cyproterone acetate is a synthetic steroid with both anti-androgenic and progestational properties. It has been used in Europe for the treatment of hirsuitism (Dianette, Schering) and prostate cancer. Recent studies showed that oral cyproterone acetate is highly effective in suppressing spermatogenesis to azoospermia in nearly all subjects in a dose-dependent manner (12.5 to 100 mg daily) when supplemented by intramuscular T enanthate^[36]. No changes in lipids but a small decrease in haematocrit was observed. The anti-androgenic properties of cyproterone acetate may account for the superior results of this combination compared to other combinations or androgens alone. Clinical trials of this combination are planned.

3.1.2.2 GnRH analogues and androgens

Sex steroids are unlikely to be entirely free from side effects due to the widespread distribution of their receptors and the broad range of physiological actions in many non-reproductive tissues. Abolition of gonadotrophin secretion can be achieved via blockade of GnRH action on the GnRH receptors which are virtually exclusively expressed in the anterior pituitary gonadotrophs only. This approach offers unique specificity of action confined to the pituitary-gonadal axis and offers the prospect of hormonal male contraception with freedom from non-reproductive side effects.

Continuous administration of superactive agonistic analogues of the natural GnRH decapeptide initially stimulates gonadotrophins followed by down-regulation of the GnRH receptors. Long-acting depot preparations of GnRH agonists have been developed for use in the treatment of prostate cancer, endometriosis, fibroids, precocious puberty and IVF. The potential of GnRH agonists (with T replacement) to reduce sperm production has been explored in 12 clinical studies^[37]. Only 23% of subjects achieved azoospermia and there was evidence that this modest efficacy can be further blunted by the simultaneous use of exogenous androgen replacement. Inadequate doses of the agonists and persistence of FSH are two possible reasons for their relative ineffectiveness. GnRH agonists have virtually been abandoned in the last decade as a potential candidate for male contraception due to the availability of GnRH antagonists.

GnRH antagonists compete for the GnRH receptors with greater affinity and slower dissociation rates than native GnRH^[38]. They are capable of reversibly suppressing gonadotrophins more completely and rapidly than other compounds. GnRH antagonists, with either simultaneous or delayed introduction of T replacement, suppressed spermatogenesis to azoospermia in 35 out of 40 (88%) men within 6-8 weeks^[39-41]. Local histamine reaction has, however, been reported with some antagonists. Compared to most sex steroid-based regimens, GnRH antagonists produce more rapid and complete suppression of spermatogenesis. However, because of the low biopotency, milligram amounts of these peptides are required to be administered daily to achieve adequate gonadotrophin suppression in man. They are complex compounds containing several synthetic amino acids and are currently expensive to produce^[42]. For these reasons, current GnRH antagonists are unlikely to be developed as practical and economic contraceptive agents. In future, the pursuit of non-peptide orally active GnRH antagonists via novel technologies such as conformational analysis of GnRH receptor-ligand interactions and combinatorial chemistry may produce more suitable compounds for fertility regulation. 

3.1.3 Heterogeneity of response to hormonal suppression of spermatogenesis

A striking finding from the studies described is the marked individual difference within and between population groups in the extent of spermatogenic arrest in response to gonadotrophin suppression. This is a key issue which bears on the general acceptance and wider applicability of hormonal male contraception.

3.1.3.1 Heterogeneity within population groups

Within Caucasian populations, sex steroids induce rates of azoospermia (responders) ranging from 40% to 70% with the remainder becoming oligozoopermic (partial responders). No major difference in physical or hormonal characteristics or pharmacokinetics and pharmacodynamics between the responders and partial responders have been identified. One possibility is the extent of residual androgenic stimulation in the seminiferous tubules and this is supported by evidence that partial responders exhibit higher 5-reductase activity during treatment^[43]. Data in rats showed that Leydig cells continue to secrete small amounts of T after hypophysectomy^[44] and elimination of this persistent intratesticular androgen action is important in achieving maximal spermatogenesis blockade^[11].

3.1.3.2 Heterogeneity between population groups

One of the surprising findings from the WHO trials was that Asian (Chinese, Indonesian and Thai) men showed a consistently higher rate of spermatogenic suppression (90%) when compared with European or American (74%) men^[16]. Baseline anthropometric characteristics, biochemical, endocrine and semen parameters or the levels of T and gonadotrophins during treatment do not explain the inter-ethnic heterogeneity in spermatogenic (and other tissue e.g. liver enzymes and lipid metabolism) response to sex steroids^[17]. Caucasians and Chinese men residing in the USA have higher levels of androgenic steroid precursors, which serve as substrates for 5-reduced metabolites compared to Chinese in China^[45]. There is however no inter-ethnic difference in 5-reductase activity. This raises the interesting possibility of an environmental or dietary origin to these population differences. Greater sensitivity of LH to exogenous T infusion^[46] and lower daily sperm production rates^[47] in Asians compared to Caucasians have recently been reported. Whether these differences are responsible for the heterogeneity in suppression of spermatogenesis is currently unclear.

3.2 Non-hormonal approach

Serendipity has played its role in uncovering fertility suppressing side effects of compounds developed for other uses. The majority of these have not showed promise and indeed many have unacceptable levels of toxicity.

3.2.1 Testicular anti-spermatogenic agents

Gossypol, the plant pigment from cottonseed oil, was tested as a potential orally active male contraceptive in over 9000 men in China in the 1970s. Because of the high incidence of irreversible infertility and unacceptable side effects such as hypokalaemia, gossypol is no longer regarded as a candidate for male fertility regulation.

The modest antifertility side effects of sulphapyridine has led to a search for analogous but more potent compounds which are inhibitors of dihydrofolate reductase. This revealed that the anti-malarial drug pyrimethamine at high doses reversibly abolished fertility in male rats. It is hoped that chemical modifications to the basic diaminopyrimidine structure would improve the testicular selectivity of these compounds^[48].

3.2.2 Post-testicular epididymal agents

-Chlorohydrin and 6-chloro-6-deoxyglucose are both metabolised to 3-chlorolactaldehyde, the S-enantiomer of which has the same absolute stereochemistry as R-glyceraldehyde, the substrate for the glycolytic enzyme glyceraldehydes-3-phosphate dehydrogenase. These compounds inhibit oxidative metabolism of glucose and other sugars in the spermatozoa resulting in loss of sperm motility. Unfortunately, the serious adverse effects of these compounds on the nervous system and bone marrow precluded further development^[49].

Triptolide and tripdiolide are oxygenated diterpine epoxide compounds purified from the plant Tryptergium wilfordii whose extract has been used as a traditional Chinese medicine in the treatment of inflammatory and dermatological diseases.

Initial animal studies showed triptolide induced infertility but immunosuppressive effects were apparent at five to twelve times the antifertility dose^[50]. Recent studies in the rat have demonstrated that triptolide exerts its antifertility via post-testicular mechanisms on epididymal spermatozoa. There is evidence that triptolide inhibits calcium influx into spermatozoa which is required for the acrosome reaction and sperm hyperactivated motility. Interestingly, nifedipine, the common anti-anginal and anti-hypertensive drug which blocks L-type calcium channels and calcium dependent ATPase in many tissues including spermatozoa has been shown to reversibly impair in vitro rat sperm motility and in vitro fertilisation in man. More specific blockade of sperm membrane calcium channels may open new avenues for male contraception.

Ketoconazole can accumulate in the seminal plasma and inhibit sperm motility directly after ejaculation. The sperm-immobilising properties of ketoconazole in vitro reside in the imidazole structure^[51].  Substituted imidazole compounds are currently being developed as inhibitors of sperm motility i.e. spermicides which could be administered orally rather than topically.

3.3 Physical agents

Chronic mild testicular hyperthermia (1-2) can be produced by close apposition of the testes to the inguinal rings with the use of tight-fitting underpants or slings applied to the scrotum. Changes in semen parameters were observed in some^[52,53] but not other studies^[54]. The inconsistent suppression of spermatogenesis and sperm quality produced by induced scrotal hyperthermia is unlikely to provide effective contraception.

4 Conclusion

In the last decade, research in hormonal male contraception has firmly established the principle that suppression of spermatogenesis by exogenous sex steroids can offer effective and reversible contraception. T combined with progestogens appears to be the most likely approach for product development initially. GnRH antagonists and T, though highly effective, remain for the moment impractical and expensive. The main obstacles are the current lack of satisfactory androgen formulations and the incomplete suppression of spermatogenesis in a significant minority of men. New androgens with improved pharmacokinetics (stable blood levels and long duration) and more selective biological actions (preferential action on pituitary, CNS and muscle over testis, prostate and liver) are being actively sought to overcome these hurdles. With the recent entry of the pharmaceutical industry into this area, it is anticipated that hormonal male contraceptive products for clinical use will become imminently available. This should encourage renewed efforts in basic research to improve understanding of molecular regulation of spermatogenesis and epididymal function so that novel antifertility agents with more specific actions on the post-meiotic or post-testicular targets can be identified. New pharmacological methods together with improved condoms and methods of vas occlusion should offer men increased choice and ample opportunities to continue to share the responsibility of family planning in the new millennium.

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Correspondence to: Dr W. Morton Hair, now in MRC Reproductive Biology Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, EH3 9ET, U.K.
Tel: +44-131-229 2575  Fax: +44-131-228 5571
e-mail: m.hair@ed-rbu.mrc.ac.uk
Received 2000-02-14     Accepted 2000-02-24