Endocrine control of spermatogenesis in primates

Control of primate spermatogenesis is reviewed in terms of endogenous regulatory mechanisms and endocrine approaches to contraception and treatment of infertility. The role of gonadotropins and steroid hormones in maintaining spermatogenesis in primates is incompletely understood because A) hormonal interactions are complex, and B) most studies have used rodents rather than primates. Feedback control, interaction of LH and testosterone, the role of androgen, androgen in secondary sex organs, regulation of receptor proteins, roles of prolactin and growth hormone, and the breakdown and modification of the endocrine control mechanism are reviewed. The treatment of infertility with GnRH, gonadotropins, and androgen is discussed. Information is included on contraception research using the following methods: immunization against GnRH, use of GnRH analogs, immunization against gonadotropins, induced suppression of FSH secretion or action, and steroid suppression of spermatogenesis. The importance of studying testicular steroid metabolism in primates is stressed. Significant advances in the understanding of endocrine control of spermatogenesis have been made in recent years, but no primate species have been thoroughly studied. Variability between species in endocrine control mechanisms is an important factor in selecting primate models, and it is clear that such models can be valuable in the development of male contraceptives.     

Use of testosterone alone as hormonal male contraceptive

The world population continues to grow rapidly while resources for sustainable living dwindle and manmade ecological problems increase proportionally to the overpopulation. Family planning is required to reduce population growth in developing countries and to stabilize populations in developed countries. Contraception makes abortion superfluous and provides the key to family planning. Women increasingly demand that men share the burden and risks of contraception and ?? as opinion polls show ?? men would be willing to use contraceptives if they were available. Research has established the principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis. All hormonal male contraceptives use testosterone, but in East Asian men, testosterone alone can suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians additional agents are required of which progestins are favoured.     

Use of progestins in male contraception

Hormonal male contraception aims at suppression of spermatogenesis to azoospermia or at least to severe oligoasthenozoospermia, incompatible with the ability to induce a pregnancy. The general principle of this approach is based on interference with the endocrine regulation of spermatogenesis, i.e. the suppression of gonadotropins. Since both FSH (through the Sertoli cell) and LH (through the Leydig cell and testosterone (T)) are required for normal spermatogenesis, both gonadotropins need to be suppressed as strongly as possible. In East Asian men this can be achieved with T alone (preferably in depot preparations such as T undecanoate) but only two-thirds of Caucasian men respond with adequate sperm suppression. Therefore, in Caucasian men additional substances such as GnRH antagonists or progestins are required to suppress the pituitary. Over the past 30 years many combinations of various T preparations with different progestins have been tested in clinical trials. Since self-applicable steroid combinations (e.g. oral levonorgestrel or desogestrel with transdermal T) showed low effectiveness, currently injections and implants are under clinical development. Long-acting intramuscular T esters (e.g. T undecanoate), T pellets or implants (e.g. MENT) are combined with injections of DMPA or noresthisterone enanthate or with implants containing levonorgestrel or etonogestrel. Acute side-effects of these combinations appear to be minimal and tolerable, long-term effects need to be investigated.     

Regulation of testicular function in men: implications for male hormonal contraceptive development

In the adult male, the testes produce both sperm and testosterone. The function of the testicles is directed by the central nervous system and pituitary gland. Precise regulation of testicular function is conferred by an elegant feedback loop in which the secretion of pituitary gonadotropins is stimulated by gonadotropin hormone-releasing hormone (GnRH) from the hypothalamus and modulated by testicular hormones. Testosterone and its metabolites estradiol and dihydrotestosterone (DHT) as well as inhibin B inhibit the secretion of the gonadotropins both directly at the pituitary and centrally at the level of the hypothalamus. In the testes, LH stimulates testosterone synthesis and FSH promotes spermatogenesis, but the exact details of gonadotropin action are incompletely understood. A primary goal of research into understanding the hormonal regulation of testicular function is the development of reversible, safe and effective male hormonal contraceptives. The administration of exogenous testosterone suppresses pituitary gonadotropins and hence spermatogenesis in most, but not all, men. The addition of a second agent such as a progestin or a GnRH antagonist yields more complete gonadotropin suppression; such combination regimens effectively suppress spermatogenesis in almost all men and may soon bring the promise of hormonal male contraception to fruition.     

Contraception hormonale masculine par les androgènes seuls. Acquis et perspectives

There is in France a demand for male contraception. It is possible to respond it using steroids (androgens, progestins). Studies in several countries, including France, have confirmed the contraceptive efficacy of these treatments ?? equivalent to female contraception. Androgens may be indicated, in defined conditions, to couples for which traditional methods of contraception are not suitable. Two obstacles limit widespread use of androgens: risk of a prolonged state of hyperandrogenism and mode of administration by injection. The combination of progestins to low doses of androgens should reduce these drawbacks.     

Male contraception: Another holy grail

The idea that men should participate in family planning by playing an active role in contraception has become more acceptable in recent years. Up to the present the condom and vasectomy have been the main methods of male contraception. There have been and continue to be efforts to develop an acceptable hormonal contraceptive involving testosterone (T) suppression. However the off target affects, delivery of the analogs and the need for T replacement have proven difficult obstacles to this technology. Research into the development of non-hormonal contraception for men is progressing in several laboratories and this will be the subject of the present review. A number of promising targets for the male pill are being investigated. These involve disruption of spermatogenesis by compromising the integrity of the germinal epithelium, interfering with sperm production at the level of meiosis, attacking specific sperm proteins to disrupt fertilizing ability, or interfering with the assembly of seminal fluid components required by ejaculated sperm for acquisition of motility. Blocking contractility of the vas deferens smooth muscle vasculature to prevent ejaculation is a unique approach that prevents sperm from reaching the egg. We shall note the lack of interest by big pharma with most of the support for male contraception provided by the NIH.     

BET proteins: Investigating BRDT as a potential target for male contraception

While many contraception options are available for women, birth control methods for men are limited to condoms and vasectomy. Past research into male contraceptives has focused on hormonal options but the associated side effects have thus far precluded this method from reaching the market. Non-hormonal male contraceptives and vas occlusion have also been explored, but to date no method has progressed past clinical testing. Recent interest in epigenetic research has unveiled a new potential non-hormonal male contraceptive target: the testis-specific bromodomain BRDT. Potent inhibitors for bromodomain-containing proteins are described in the literature, but a BRDT-specific compound has yet to be designed, prepared and tested. The high similarity between bromodomain proteins of the BET family makes development of selective and specific inhibitors both difficult and necessary. Selective inhibition of BRDT by a small molecule is an exciting new target in the search for a new non-hormonal male contraceptive.     

Perspectives of contraceptive choices for men

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, hormonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinical testing. Promising leads have been obtained from testosterone buciclate/undecanoate, alone or in combination with levonorgestrel butanoate or cyproterone acetate, RISUG, an injectable intravasal contraceptive and a few herbal products, particularly the seed products of Carica papaya. It is feasible that an ideal male contraceptive, that meets out all the essential criteria will be made available to the community in the near future.     

Contraception masculine hormonale

The activities of male and female gonades depend on the same pituitary hormones FSH and LH. In the field of contraception, the situations are very different: it is rather easy to disturb maturation then rupture of the dominant follicle, whereas it is much more difficult to inhibit the daily production of more than one hundred millions spermatozoa. Therefore, even in case of efficient inhibition of gonadotrophins, azoospermia is not systematically obtained, and the problem is to appreciate the risk of pregnancy corresponding to a given value of sperm concentration. Molecules used for hormonal male contraception can be classified in two groups: steroids and GnRH analogs. The inhibitory effect of supra-physiological doses of testosterone on sperm production has been well known for a long time. In a preliminary study conducted by World Health Organisation Task Force, 271 volunteers received 200 mg of testosterone enanthate IM once a week: 65% became azoospermic within a 6 months period; the mean sperm concentration in the non azoospermic subjects was 3 millions/ ml. Asiatic men were better responders than caucasian. In a second study recently published, the efficiency of male contraception was tested in 349 men having less than 3 millions/ml: 4 pregnancies occured, corresponding to an overall pregnancy rate of 1.4 per 100 person-years, which reached 8.1% if azoospermic subjects were excluded. The administration during a long period of androgens at a supra-physiological level is not devoid of potential risks. The association of progestagens and androgens allows to give androgens at physiological doses as a supplementation treatment, since the main contraceptive effect is due to the progestagens. Medroxy-progesterone acetate has been widely studied, but others molecules, as Nor-ethisterone or levonorgestrel, are more powerful inhibitors or gonadotrophins and are good candidates for male contraception. On the contrary, all the trials testing the efficiency of GnRH analogs were very disappointing, with or without androgens supplementation. Recent works using GnRH antagonists as Nalglu look promising, since almost all men became azoospermic, however several problems must be resolved (histamine-like side effects; high coast of the treatment). Since androgens are involved in all protocols, it is very important, in order to promote hormonal male contraception, to find some gallenic forms of androgens which allow to avoid injections.     

Male contraception: expanding reproductive choice

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.     

Reversible suppression of pituitary-testicular function by a sustained-release formulation of a GnRH agonist (leuprolide acetate) in dogs

Pituitary-testicular function was studied in 15 dogs following treatment with a sustained-release formulation of a GnRH agonist, leuprolide acetate (LA). Adult male dogs were treated with a single subcutaneous injection of microencapsulated LA (0.1 or 1 mg/kg). Treatment with LA at a dose of 1 mg/kg resulted in decreased (P<0.001) ejaculatory volume and disappearance of morphologically normal spermatozoa within 8 wk and the effect persisted for 6 wk, while the 0.1 mg/kg dose was not adequate to effect suppression of spermatogenesis. The larger dose treatment (1 mg/kg) caused a transient rise in plasma levels of LH and testosterone followed by a marked decline to below the normal level by 2 wk, the low levels being maintained for at least 5 wk, indicating a prolonged effect of LA treatment on pituitary-gonadal axis. Twenty weeks after treatment with LA, a complete return to normal spermatogenesis was observed. The full reversibility of spermatogenesis in the dog after LA treatment suggests that this peptide could be used as a reversible method of male contraception.     

KiSS-1 and GPR54 at the pituitary level: overview and recent insights

Since the stimulatory effect of kisspeptin on gonadotropin secretion is blocked by a GnRH antagonist, it has been suggested that the effect of kisspeptin is manifest exclusively at the level of hypothalamic GnRH secretion. However, kisspeptins are present in ovine hypophysial portal blood suggesting that the pituitary gland may be a target of kisspeptin. Dual fluorescence labeling with a specific mouse monoclonal antibody against LHbeta demonstrates that KiSS-1 and GPR54 are expressed by the gonadotrophs. Different paradigms were designed in animals and in humans in vivo to elucidate its role. However, in vitro studies assessing the direct stimulatory effects of kisspeptins on gonadotropin secretion in the pituitary have given conflicting results, depending on the hormonal (GnRH and/or estradiol) environment of the cells. Kisspeptins alone seem unable to induce the LH surge. It is therefore likely that kisspeptin has a synergic effect with GnRH and estradiol, at both hypothalamic and pituitary levels. However, kisspeptin may also play another role, distinct from that restricted to the reproductive axis. In this paper, we shall also review data on the potential role of kisspeptin in the control of other pituitary functions, e.g. somatotroph and lactotroph. Finally, kisspeptins could act as endocrine/autocrine/paracrine signals in modulating hormonal secretions of the anterior pituitary.     

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis

BackgroundObservational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.ConclusionsThis IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.     

Induction of puberty in a patient with hypogonadotropic hypogonadism: effect of sequentially applied hCG and pulsatile GnRH administration

Pulsatile substitution with GnRH appears to be the therapy of choice in patients with Kallmann's syndrome, a well defined type of hypogonadotropic hypogonadism. We tried to simplify the treatment and to limit the subcutaneous GnRH therapy to the period absolutely necessary to induce spermatogenesis. Therefore we applied in sequence first hCG to stimulate testicular growth and second pulsatile GnRH application to induce spermatogenesis. We herein report that with this mode of therapy testicular growth from infantile to adult size and normal spermatogenesis could be achieved. We conclude that pulsatile GnRH application is a new effective therapy of hypogonadotropic hypogonadism which can be simplified considerably by pretreatment with hCG.     

Pulsatile gonadotropin-releasing hormone treatment of men with idiopathic hypogonadotropic hypogonadism

OBJECTIVES/METHODS: To induce testicular growth and spermatogenesis, 11 patients with idiopathic hypogonadotropic hypogonadism were treated with long-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration. Three patients had a history of undescended testes. Patients who did not respond to therapy with a sufficient increase in serum testosterone or spermatogenesis were offered additional injections with hCG or, after discontinuation of GnRH, either combined therapy with hCG and hMG or recombinant FSH. RESULTS: During treatment testicular volume and serum levels of FSH, LH and testosterone increased. Semen analysis revealed the presence of spermatogenesis in 9 of the 11 patients (8 on GnRH alone and in 1 when hCG/hMG was subsequently instituted), and 7 pregnancies have resulted thus far. CONCLUSION: Pulsatile GnRH therapy is a well-tolerated and effective therapy for the induction of spermatogenesis in some men with idiopathic hypogonadotropic hypogonadism. It appears that a significant fraction of them should be treated for a minimum of 1-2 years to maximize testicular growth and achieve spermatogenesis. Cryptorchidism was a negative prognostic factor.     

Non-surgical methods of contraception and sterilization

The Humane Society of the United States estimates that each year between 8 and 10 million dogs and cats enter shelters and 4-5 million of these animals are euthanized due to lack of homes. Many veterinarians within the United States recommend surgical sterilization for population control in dogs and cats. However, there are non-surgical methods to control reproduction. Pharmacologic methods of contraception and sterilization can be safe, reliable and reversible. Hormonal treatments using progestins, androgens, or gonadotropin releasing hormone (GnRH) analogs act to either directly block reproductive hormone receptor-mediated events, or indirectly block conception via negative feedback mechanisms. Immunocontraception, via vaccination against GnRH, the luteinizing hormone receptor or zona pellucida proteins, is also possible. Intratesticular or intraepididymal injections provide a method for non-surgical sterilization of the male dog and cat. Additional methods have been employed for mechanical disruption of fertility including intravaginal and intrauterine devices and ultrasound testicular ablation. Alternative approaches to surgical sterilization will be reviewed.     

Effects of long-term treatment with the GnrH agonist deslorelin (Suprelorin®) on sexual function in boars

Immunization against GnRH has been proven effective for boar taint removal, and long-term treatment with GnRH analogues has been shown to suppress GnRH dependent reproductive processes in several species. This study was conducted to treat boars (n = 5) with Suprelorin®, i.e., an implant that contains 4.7 mg of the long-acting GnRH analogue deslorelin, and to test the effects on sexual function. Insertion of the implant occurred at the age of 5 weeks and animals were observed until market age at 26-27 weeks. Surgically castrated (n = 4) and intact boars (n = 3) served as controls. Testes growth was markedly reduced and steroidogenesis (testosterone, estrone, estrone sulphate, estradiol 17β) as well as spermatogenesis suppressed in 4 of 5 GnRH treated boars, respectively. The remaining fifth boar resumed testes growth after week 17 of age and had high hormone concentrations when tested at weeks 26 and 27. Restoration of spermatogenesis was observed at 34 weeks of age. There were no effects of treatment on general health, nor were there local inflammatory reactions. Results indicate that suppression of sexual functions in boars due to long-term treatment with the GnRH agonist deslorelin through an implant such as Suprelorin® is possible and can last for several months up to market age; thus it has potential as an alternative to other methods used for boar taint removal. Because the maximum duration of suppression seems to vary between boars, further studies are necessary to refine the treatment.     

The effects of vasectomy on health

The study of possible adverse effects of vasectomy have been mainly focussed on hormonal balance, spermatogenesis, the induction. of auto-immune reactions and cardiovascular changes including the non-fatal myocardial infarction. The review of literature, including our own work on the immunological sequelae of vasectomy, indicates that there is no health hazard following vasectomy. The presence of antibodies to spermatozoa in some individuals, however, may effect future fertility, if reversal is requested.     

Epididymal approaches to male contraception

Today, a vast arsenal of contraceptive methods interfering at different levels of the female reproductive axis is available. This is not the case for men for whom, until now, there is no reliable male reversible method and for whom vasectomy, condom and withdrawal are the only options available. Despite this limited supply, more than one third of all contraceptive methods used worldwide rely on the cooperation of the male partner. Besides developing hormonal approaches to stop sperm production, there may be attractive approaches that will interfere with sperm functions rather than production. Sperm functions are primarily established during post-testicular maturation, with the epididymis accounting for the majority. The purpose of this review is to present some of the promising and/or already abandoned leads that emerge from research efforts targeting the epididymis and its activities as potential means to achieve male post-meiotic contraception.     

Gonadotropin-releasing hormone agonist: a new approach to reversible contraception in female deer

Fertility control offers a potential alternative for controlling an abundance of wild ungulate populations where lethal methods are infeasible or unacceptable. A promising nonsteroidal, nonimmunologic approach to reversible contraception consists of agonist of gonadotropin-releasing hormone (GnRH). We evaluated the effects of the GnRH agonist, leuprolide, on reproduction, the suppression of luteinizing hormone (LH) and progesterone, blood parameters, and reproductive behavior in captive female mule deer (Odocoileus hemionus) during December 1999 through June 2001. Leuprolide, administered as a controlled release formulation (ATRIGEL), was 100% effective in preventing pregnancy for one breeding season. Infertility was achieved by suppressing LH levels, which prevented ovulation and the formation of corpus luteum. Treated females regained normal ovarian function and conceived the following breeding season. Leuprolide had no adverse effects on blood chemistry and hematology, body weight dynamics, or the general health of treated females. In contrast to our predictions, leuprolide did not suppress estrous behavior in female deer during the "normal" breeding period, nor did treated females return to normal ovarian function and exhibit reproductive behaviors during the post-breeding period. This prolonged-release leuprolide formulation offers an alternative approach to reversible contraception in female deer that overcomes some of the problems associated with existing technology.