Indian Journal of Experimental Biology Vol. 43. November 2005. pp. 1032-1041
Review Article
Male contraception: Expanding reproductive choice
M RajaJakshmi" Department of Reproductive Biology. All India Institute of Medical Sciences. New Delhi 110 029. India
The development of steroid-based oral contraceptives had revolutionized the availability of contraceptive choice for women. In order to expand the contraceptive options for couples by developing an acceptable. safe and effective male contraceptive. scientists have been experimenting with various steroidal/non-steroidal regimens to suppress testicular sperm production. The non-availability of a long-acting androgen was a limiting factor in the development of a male contraceptive regimen since all currently tested anti-spermatogenic agents also concurrently decrease circulating testosterone levels. A combination regimen of long-acting progestogen and androgen would have advantage over an androgen-alone modality since the dose of androgen required would be much smaller in the combination regimen. thereby decreasing the adverse effects of high steroid load. The progestogen in the combination regimen would act as the primary anti-spermatogenic agent. Currently. a number of combination regimens using progestogen or GnRH analogues combined with androgen are undergoing trials. The side effects of long-term use of androgens and progestogens have also undergone evaluation in primate models and the results of these studies need to be kept in view. while considering steroidal regimens for contraceptive use in men. Efforts are also being made to popularize non-scalpel vasectomy and to develop condoms of greater acceptability. The development of contraceptive vaccines for men. using sperm surface epitopes not expressed in female reproductive tract as source. still requires considerable research efforts.
Keywords: Androgens. Condom. Male contraception. Progestogens. Spermatogenesis
The steadily expanding population in developing article reviews the recent developments in the area of countries is now of global concern due to its impact male contraception and highlights the research done on health and societal dynamics. The development of by Indian scientists. oral contraceptives for women initiated a revolution in It may be argued that research efforts for contraceptive options. While this was a major developing male oriented methods are not a priority landmark in expanding contraceptive choice for since men are reluctant to opt for contraception, but women, a similar breakthrough ha~ not taken place in published data show that men form 26% and 11 % of the field of male contraception. contraceptive users (adopting vasectomy, and condom New contraceptive options for men, both hormonal use, respectively) in developed and developing and non-hormonal, are required urgently since regions of the world I. Even in a setting like India vasectomy, withdrawal and condom use are where the contraceptive use of condom and inadequate and have many limitations, which are well vasectomy by men is a dismal 5% (ref. 2), it was known. Attempts to use unique sperm surface found possible to enhance male involvement by using 3 epitopes that are not expressed in the female appropriate intervention strategies . It is also likely reproductive tract as source to develop contraceptive that the contraceptive choice of men from different vaccines for men have not yielded any major socio-cultural environments and age groups may be successful lead. Increasingly, t-fforts are being different, thus requiring a wider spectrum of options. focused on the development of hormonal agents that Major attempts to develop an effective male would induce adequate level of spermatogenic contraceptive have focused on different aspects of suppression that is not compatible with fertility. This sperm development, maturation and transport. The present review will focus on research efforts towards *Presebt address-National Academy of Mecical Sciences. Ansari (1) prevention of sperm deposition, (2) prevention of Nagar, New Dellhi 110 029. India sperm transport and, (3) inhibition of Phone: 26589289; 26589326; Fax: 26588992 E-mail: [email protected] spermatogenesis. RAJALAKSHMI: MALE CONTRACEPTION 1033
Prevention of spenn deposition insertion techniques were tested. A high level of Condoms contraceptive efficacy was obtained with two SHUG 9 Condoms have been in use as a barrier method to devices . In Indonesia, removable vas occlusion has prevent sperm deposition in the female tract since been achieved by injection of Medical Grade Silicone lO 1564 when Pallopio used a sheath for "use against Rubber (MSR) which cures-in-place to form plugs . venereal disease and numerous bastard offspring". The rate of azoospermia, six months after MSR vas The history of condom use and research on the occlusion was 98.27% compared to 100% in the development of new generation of condoms have vasectomy series. 4 been reviewed earlier ,5. The partial blocking of vasal lumen by injection of The coating of condoms with microbic ides was copper resulted in loss in functional capacity of the presumed to reduce HIV transmission in women. The spermatozoa. Insertion of copper wire into the vas nonionic detergent nonoxynol-9 (N 9), which was caused decapitation of spermatozoa and resulted in considered a spermicide, has been in use for coating infertilityll but the effectiveness decreased with time, condoms. But, the use of vaginal sponges containing probably due to erosion of the copper wire12 The N 9 was found to increase the risk of HIV infection in polymer, Styrene Maleic Anhydride (SMA), when 6 female sex workers in Kenya . This was attributed to injected into the lumen of the vas deferens in dimethyl the cell membrane disrupting action of N 9, which sulphoxide is reported to be an effective method of acts as an irritant in the epithelium of penis and male contraception 13. Phase I and II clinical trials vagina in approximately 56% of women who were using the RISUG (trade name of SMA) have been using N 9 suppositories four times per day for two completed. Mishra et aZ 14 have reported focal weeks? It is clear that the use of spermicides degeneration of seminiferous epithelium in testis of microbicides would have a significant impact on the langur monkeys following long-term (540 days) vas role of male and female condoms in contraception and occlusion with SMA. prevention of transmission of se.'ually transmitted diseases. Inhibition of spennatogenesis Hormone-based approach to male contraception Prevention of sperm transport The development of hormone-based male Contraceptive options for men which are currently contraceptive is based on the premise that the available are vasectomy and condom use. Of these, suppression of gonadotrophin production will result in vasectomy or male sterilization is a cheap and an the inhibition of spermatogenesis. Gonadotrophin effective method of preventing sperm transport production can be suppressed by the use ctf (1) through the vas deferens. Improvement to the method . steroidal agents like androgen, progestogen, estrogen of traditional vasectomy is the "non-scalpel" or combination of these, and (2) by the use of non technique. Various aspects of post-vasectomy steroidal agent/>. Among the non-steroidal agents, complications, vasectomy reversal (vasovasostomy) GnRH agonists and antagonists have been evaluated and pregnancy rate, and long-term health extensively. Suppression of gonadotrophins results in consequences of vasectomy and safety have been decrease in androgen production leading to clinical 8 reviewed earlier . manifestations of androgen deficiency. To offset such In attempts to interfere with sperm passage through androgen insufficiency, external androgen the vas deferens, sclerosing agents like quinacrine, supplementation is required. Combination regimens ethanol, and silver nitrate have bt;~n introduced into using androgen supplementation need careful the vasal lumen resulting in . sclero<;is, inflammation, monitoring of the dose of androgen since higher doses and fibrosis. The occlusion thus induced was may directly sti'mulate spermatogenesis. In irreversible and in some cases, retrugrade flow of the combination reg~mens, a relatively smaller dose of agent resulted in testicular atrophy. Intra-vasal androgen is required compared to the androgen-only injection of polyurethane or silicone rubber resulted in modality since the anti-spermatogenic action is plug formation by polymerization in situ. Since in situ achieved mainly by the non-androgen component of polymerization may be accompanied with the release the combination regimen, which suppresses of potentially toxic compounds, Zaneveld and gonadotrophin se.::retion by interfering with negative associates used preformed soft hollow silicone plug feedback control at the pituitary and hypothalamus called SHUG. Several different SHUG devices and (eg. exogenous steroids) or directly by inhibiting the 1034 INDIAN J EXP BIOL, NOVEMBER 2005
effect of GnRH on the pituitary ,ego use of GnRH men with sperm count between 0.1 to 3 million/~'. analogues). None of the c:z )ospermic men in 230.4 persons years of efficacy phase reported the occurrence of Androgen-alone regimen pregnancy. Testosterone enanthate These landmark multicenter trials carried out by Clinical trials using an androgen alone for male WHO established the fact that hormonally induced contraception, though carried out f-:Jr the first time by azoospermia is compatible with effective contraception. Indian investigators, is seldom acknowledged. Reddy l5 On the basis of these two studies, it was concluded that and Rao induced uniform azoospermia in men by (1) "hormone regimens that induce azoospermia can injecting testosterone propionate (TP) daily. Since provide highly effective, sustained and reversible male daily administration of TP is not feasible for family contraception with minimum side effects,,1 8 and (2) that, planning purposes, investigator~ used thereafter if most of the men were rendered azoospermic, and the testosterone enanthate (TE) 4,5.16.17. But, the dose of rest severely oligozoospermic by a hormonally based TE used and schedule of administration were not agent, this would provide a sustained, reversible level of comparable among the differen~ studies. Further, contraception with an overall level of efficacy similar to some of the investigators have used different doses of . that of the combined oral contraceptive pill for the TE during the induction and maintenance phases to 22 women. minimize the dose of the drug and thereby reduce the The pharmacokinetic profile of TE, with sharp adverse effects. These studies hdicated that the increase in testosterone levels after injection followed androgen-alone modality IS able to induce by an expone mal fall and short duration of action, spermatogenic suppression in men to verifying were major disadvantages in its use for clinical degrees depending on the protocol of drug use. Using purposes. The need for a long-acting androgen or a standardized protocol, WHO conducted a ten-center improved deliv~ry systems led to the pre-clinical seven-country contraceptive effilacy study using evaluation of a number of promising compounds and weekly injections of TE. No other method of evaluation for alternate drug delivery systems. These contraception was used once spem:' ('ounts decreased include testosteone buciclate, injectable testosterone to a preset level. The results of this large study undecanoate, 7 a. methyl 19-nor testosterone (MENT), showed that during 1486 months .)f efficacy period, testosterone j>elbts, and transdermal and buccal only one pregnancy occurredl8. T!1e' cumulative life modes of androgt:.ti delivery. table to achieve azoospermia was only 64.5%. Two interesting observations made out of this study were: Testosterone buciclate (1) the variable response in achievement of Preclinical evaluation of the pharmacokinetics and azoospermia within six months of ex~osure to weekly pharmacodynami(,s of testosterone buciclate (TB) in injections of TE, and (2) differences in contraceptive castrated rhesus' monkeys showed it to be the longest 23 responses in men of Caucasian (60%) and Chinese 3 acting testostero . · ester available ,24. It was alst) (91 %) origin to weekly injections of TE. Subsequent effective in suppr3c;sing spermatogenesis to azoospermia l9 20 studies also confirmed that androgen alone • or in . 21 • or to severe oligozoospermia, when combined with the combination with progest06ens Induced long-acting pr:g' '\togen, levonorgestrel butanoate4.25. azoospermia in a greater percent•. ge of Asian men The dose of TB 'vas sufficient to maintain circulating than in Caucasian subjects. Body s ·zt.. or pretreatment androgen levels in the physiological range. But, TB is basal levels of endocrine and semen i. rofile were not not available for clinical use due to difficulties in !'elated to these ethnic differences in responses. The formulation and Possible toxicity. When given alone to precise reason for such differences in ethnic response adult bonnet moiiteys at multiple sites, TB decreased to steroids still needs to be identified. . sperm count ~ testicular volume and adversely The contraceptive efficacy of testosterone affected sperm m>turation, even though the circulati!'g induced oligozoospermia was e\ aluated in a 15- levels of testostd )ne were at the upper limit of the 326 center study undertaken by WHO in which TE- physiological raJ 6. • > 6 induced suppression of sperm co m~ to 3 x 10 ImJ was taken as the cut-off limit to enter the efficacy Testosterone undecanoate 22 phase • Four pregnancies were reported during Testosterone undecanoate (TU) has been 49.5 person-years of contraceptive efficacy phase in considered for Img as an orally active preparation, RAJALAKSHMI: MALE CONTRACEPTION 1035 but was not considered suita,ble for use in the effects of administration of non-aromatisable contraceptive formulations. Following oral use, androgens like DHT and androstanediol were marked fluctuations in serum testosterone levels and evaluated in rhesus monkeys35.36. In these treated only partial suppression of gonadotrophin levels animals, spermatogenesis progressed only to occurred. Consequently, spermatogenic suppression spermatid level in some tubules, while adjacent that occurred was not compatible with the needs of tubules, showed qualitatively normal effective contraception. spermatogenesis. The absence of ejaculatory response When dissolved in tea seed oil for injection, TU with increase'n duration of administration of these was found to have favourable pharmacokinetics in non-aromatisable androgens was a major drawback of 28 castrated monkeys27 and hypogonadal men . this regimen DHT/androstanediol treatment Contraceptive efficacy studies showed that 1000 decreased circulating levels of .testosterone, but FSH mg/4w TU induced azoospermia in all 12 Chinese levels were near normal, which may explain the men whereas a 500 mg/4w -lose resulted in reason for only partial suppression of 20 azoospermia in 11112 men . The mean time to spermatogenesis. ~hort-term or long-term exposure to azoospermia was 12-16 weeks of TU injections. A DHT suppressed plasma testosterone and LH in large efficacy study using TU in 308 men showed that men37,38 • in nine men, spermatogenesis was not suppressed to a sperm concentration of 3 x 106/ml or lower within six Alternate testosterone delivery systems months. Pregnancies were not reported when sperm Alternate drug delivery modalities were explored concentration remained below 3 x 106/ml29. But, the by investigators for the delivery of testosterone. These 39 same authors reported that when TU was given alone include subdermal fused testosterone implants , at 1000 mg/8w for 24 weeks, only 67% of men transdermal delivery of testosterone intended for 40 41 attained azoospermia30. The disadvantage of TU is the scrotal or non-scrotal application and buccal 42 large diluent volume of 8ml needed for injection. delivery of testosterone . The rtsults of these studies When dissolved in castor oil, the diluent volume for have been reviewed earliel. These modalities of TU is 4ml, as developed by Jenapharm. androgen delivery have inherent limitations like: (1) preparation of scrotal skin for patch adhesion, (2) skin 7a-methyl-19-nor testosterone (MENT) irritation in patches with an alcohol base resulting in On the basis of stimulation of ventral prostate high discontinuation rate, (3) decreased adherence weight, MENT, a synthetic androgen, has a potency when patches are applied over a wider area, and 31 which is 4-5 times greater than that of testosterone . (4) visibility. MENT does not undergo Sa-reduction but can be aromatized, and it · is not bound by SHBG and is Progestogen-alone regimens rapidly cleared from the circulation. Two MENT acetate implants inserted in hypogonadal men Progestogens have been tested to assess their supported sexual behavior similar to TE32. MENT (25 potential to suppress spermatogenesis, either alone or Jlg) delivered through silastic implants in bonnet in combination with androgen. Progestogens bind to monkeys decreased sperm count to oligozoospermia, their receptors and suppress gonadotrophin but increasing the dose supported spermatogenesis33 . production, besides direct effects on testis by MENT has the advantage that it is only twice as inhibiting androgen biosynthesis and androgen action. potent as testosterone in stimulating prostate growth Progestogens used for male contraception include whereas its potency in suppressing gonadott:ophin derivatives of 19 nor-testosterone (norethindrone secretion and stimulating anabolic activity is ten times acetate, norgestrel, norethisterone enanthate, more than testosterone34. ethinodiol diacetate), or 17 hydroxyprogesterone derivatives obained by acetylation of 17 hydroxy Non-aromatisable androgens -- dihydrotesto group (medroxyprogesterone acetate). New sterone (OUT) and androstanediols progestogens like desogestrel, gestodene and The aromatization of administered testosterone norgestinate are LNG derivatives. Progestational resulting in increased levels of estradiol thereby compounds like levonorgestrel possess inherent leading to unwanted side effects was considered androgenic activity25, while norethindrone, undesirable for male contraceptiofl. In view of this, norethinodrel <".'1 J ethinodiol diacetate show weak 1036 INDIAN J EXP BIOL, NOVEMBER 2005 estrogemclty. These properties of the progestogens nor-testosterone, a higher percentage of subjects would influence their mode of action when used at became azoospermic (96.7%), compared to trials in 21 high doses for suppressing spermatogenesis. In Caucasian men , similar to the ethnic differences in contrast, progestogens like medroxyprogesterone response of men to TE. Treated subjects showed acetate (MPA) obtained by substitution at the 17 and gynaecomastia and weight gain. But, the adverse 6 positions of progesterone molecule are devoid of effects on serum lipoproteins59 and delay in androgenic and estrogenic activities. restoration of spermatogenesis due to accumulation of Clinical trials carried out by the International DMPA in the adipose tissue60 are of concern in the Committee for Contraceptive Research of the use of the regimen for contraception. Population Council, USA using progesterone alone or DMPA has also been used in association with in combination with androgen showed that percutaneously applied testosterone or DHT; DMPA azoospermia could be achieved only in 87 of the 191 plus percutaneous androgen induced effective subjects43 . It was clear that the dose of progestogen suppression of spermatogenesis54, but the side effects used needs to be increased significantly for effective in female partner (hirsutism) due to absorption of contraception. Further, the androgen deficiency androgen from the male partner led to the termination induced needs to be compensated by use of androgen of this regimen. Use of transdermal testosterone supplementation. patches for testosterone delivery also was not acceptable due to allergic skin reactions which were Progestogen-androgen combination regimens quite severe in some subjects61 . In combination regimens using progestogen and androgen, the progestogen acts as the primary anti Levonorgestrel-androgen combination regimen spermatogenic agent by suppressing gonadotrophin 19 nor-testosterone-derived progestogens like production and action, which is potentiated by levonorgestrel are potent gonadotrophin inhibitors. androgen co-administration progestogens, in addition Levonorgestrel has been used orally and as implants to their anti-gonadotrophic effects, also exert direct in women. In men, orally administered levonorgestrel effects on testis including inhibition of 44 (LNG; 500 mg/day) combined with weekly injections steroidogenesis , inhibition of LH receptor of TE (100 mg) induced azoospermia in 67% of expression and function45 and on spermatozoa via the . 46 subjects compared to only 33% azoospermia induced non-genomIc progesterone receptor . in TE plus placebo group62. Levonorgestrel, being a very potent gonadotrophin suppressor was more Medroxyprogesterone acetate (MPA)-androgen effective in suppressing spermatogenesis when combination regimens combined with androgen than the androgen-alone Clinical trials have been conducted since 1965 to modality. However, the inherent androgenicity of identify the most effective combination levonorgestrel demonstrated by classical ventral regi mens4.17 ,47 . A consensus has eluded on the dose, prostate assa/5 requires careful titration of the dose schedule, and duration of administration, and on the of the progestogen and androgen in the combination identity of the progestogen-androgen combination regimen to ensure that spermatogenesis remains fully regimen that would induce uniform azoospermia. The suppressed. This was evident in the dose finding contraceptive efficacy of MPA has been evaluated in studies carried out in bonnet monkeys using long many clinical trials; the androgen of choice included acting levonorgestrel butanoate (LNG-B) and TB25. TE48.53 , TU54, testosterone cypionate55, Among the three doses used, 1 mglkg of LNG-B co methyltestosterone56 or 19 nor-testosterone20,57. Of administered with 40 mg TB on days 0 and 60 evoked these androgen preparations used, injectable TU maximum suppression of spermatogenesis to appears most promising. Use of a higher initial azoospermia or to severe oligozoospermia, while loading dose (1000 mg) of DMPA with 250-500 mg androgen levels were maintained in the physiological TE resulted in 80-100% of men achieving range25. Thus, the overall androgenic status of the azoospermia, but the lower maintenance doses used subject appears crucial when progestin-androgen were unable to maintain azoospermia with return of combination regimens are evaluated for suppression spermatogenesis49,51,58. In the WHO conducted study of spermatogenesis. Another cause of concern is the in Indonesia using 250 mg DMPA plus 200 mg TEl19 androgen related side effects like decrease in HDL- RAJALAKSHMI: MALE CONTRACEPTION 1037 cholesterol, weight gain and acne62. Injectable TU in action of testosterone and is metabolized to ethinyl combination with oral LNG induced azoospermia in estradiol and 5a. NET. In bonnet monkeys, only 50% of subjects, possibly due to the high spermatogenesIs could be arrested by 0.8 mg/day 63 30 androgen levels . Gui et al assessed the NET-en and estradiol valerate, (0.0 I 5mg/d) contraceptive efficacy of LNG implants (75 mg each) administered .via Alzet mini pumps69. Preliminary in Chinese men combined with TU injections. data indicated the high efficacy of TV and NET-en Insertion of four LNG implants followed 4 weeks regimen using varying doses of NET -en and mode of 70 later by TU (1000 mg/8w) for 24 weeks resulted in application • The results showed that injection of greater number of men attaining azoospermia (90%), TU/6w combined with 400 mg NET-enl6w is an compared to men with similar LNG load but only 500 effective contraceptive modality to suppress mg TU/8w (62%) or TU (1000 mg/8w) alone (67%), spermatogenesis. But side effects included increase in highlighting the greater efficacy of the combination body weight, erythrocytes, hemoglobin and regimen. Adverse effects including changes in serum haematocrit and decrease in HDL-cholesterol and chemistry were not observed. alkaline phosphate.
Desogestrel-androgen combination regimen Cyproterone acetate-androgen combination Desogestrel is a potent orally active progestogen. regimens Desogestrel at 300 mg, po daily, combined with 500 65 Cyproterone acetate (CPA) is an anti-androgen as mg TFlw or 150 mg, po, daily desogestrel + 100 mg well as a progestogen and has been in clinical use for 64 TEJw resulted in azoospermia in all treated men, but treatment of hypersexuality, acne and hirsutism in the number of subjects involved was small. women and prostate cancer in men. Use of CPA for Decreasing the dose of desogestrel or increasing the male contraception requires androgen substitution to 65 66 dose of TE or use of testosterone pellets did not offset androgen deficiency caused by its strong anti result in uniform induction of azoospermia. It is androgenicity. This was evident in the results of essential to use a larger number of subjects in such clinical trials conducted in 1970's using CPA alone. clinical trials to reach reliable conclusions, which is The marked suppression in spermatogenesis achieved evident in the results of the two-center study by CPA was attributed to its direct effects on testis in (Edinburgh and Shanghai) using 150 or 300 mg addition to its progestational activity since CPA desogestrel po, daily for 24 weeks with 400 mg competitively inhibits binding of testosterone and testosterone pellets sc on day one and at 12 weeks. DHT to the androgen receptor. Azoospermia was achieved in greater proportion of The first combination regimen of CPA and TE was men (28/28) in the 300 mg desogestrel group eva Iuat ed m· Iangur mook eys 71 '.72 Spermatogenesls . compared to the 150 mg group67 (22131). was suppressed to azoospermia or to severe Surprisingly, a trend towards greater spermatogenic oligozoospermia. All metabolic parameters were suppression was seen in the Caucasian group than in normal. Chinese men, in contrast to the results of the WHO When CPA was combined with the long-acting conducted TE studyl8. Whether this would be androgen TB, uniform azoospermia was induced substantiated in a closely monitored multicentre study 73 without any adverse effects • T,ese studies proved similar to the WHO study remains to be seen. The fall that the dose and type of androgen used are critical in in HDL-cholesterol in Caucasian men was an adverse the induction and maintenance of azoospermia. side effect not reported by Chinese subjects. Since the active agent of desogestrel is Combination of 25-100 mg/d CPA (oral) with 100 mg/w TE resulted in rapid onset of azoospermia in all etonogestrel, the contraceptive efficacy of 74 75 etonogestrel implants (releasing approximately 50 mg subjects . . The fall in body weight, hemoglobin of the drug/day) combined with testosterone pellets concentration and haematocrit was attributed to the 68 was compared , however uniform azoospermia was anti-androgenicity of CPA. In these studies, CPA did not induced. not cause adverse effects on liver function parameters or HDL-cholesterol. At a relatively low dose of 12.5 Norethisterone-androgen combination regimen mg CPNd, in combination with TV, spermatogenesis Norethisterone enanthate (NET-en) is a was suppressed in men76. Cyproterone acetate is thus progestogen with approximately 15% of the androgen a promising compound for evaluation as a male 1038 INDIAN J EXP BIOL, NOVEMBER 2005
contraceptive agent in combination with an androgens developed and being evaluated for this appropriate androgen, since CPA is capable of purpose should maintain steady-state physiological inducing a greater degree of s4Ppression of levels of circulating hormone for relatively long spermatogenesis at a relatively shorter duration of period of time on the other hand, they should not time, possibly due to its antagonistic role in evoke any adverse side effects on systemic and suppressing even residual intra-testicular testosterone. metabolic functions; further, they should be long 4 acting and affordable . Estrogen-testostenme combination regimens Androgens for use in male contraception should be While estradiol enhances spermatogenic evaluated extensively for their long-term effects on suppression caused by testosterone, the side effects of cardiovascular, liver and prostate functions. Androgens estradiol restrict the application of this modality for cause major shifts in lipoprotein fractions in the blood 83 contraceptive purposes. At best, this approach is of and act as risk factors for ischemic heart disease ,84 . academic interest only. High levels of triglycerides in blood have been linked to 85 a high incidence of cardiovascular disease • Androgens GnRH analogues for male contraception are also known to increase liver transaminases in Asians It was felt that the abolition of gonadotrophin and have been implicated in the occurrence of 86 secretion by interference with the action of GnRH on hepatocellular carcinoma ,87. Adult rhesus monkeys gonadotrophin would be a more direct approach for kept under controlled dietary conditions and exposed spermatogenic suppression than the steroidal continuously to 50 mg TE once in 14 days for 32 approach based on interference with the negative months showed alterations in lipid profile with increase 88 feedback action on gonadotrophin secretion. in LDL
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