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.     

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.     

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.     

Recent advances in the pharmacologic regulation of fertility in men.

An updated review of research into contraceptives for men is presented. New concepts of the pharmacologic effects of chemical agents on germinal stem cells and spermatogenic arrest, and the effect of new compounds that act at the post-testicular level but do not affect androgen production are discussed. The latest results of studies on steroidal compounds that inhibit pituitary secretion of gonadotropin and hence result in suppression of spermatogenesis and testosterone secretion are presented. The newer contraceptive pills for men are also evaluated. The major drawback to the development of chemical contraceptives for men is the fear of genetic damage and impotence. New and continued research into this type of contraception is urgently needed.     

Hétérosexualités, corps et care : l’exemple des hommes d’Ardecom

Ardecom (1979?C1986), an association that advocated male hormonal contraception, was set up in France following the 1970s?? feminist movement. By looking at the life of the men who tried out hormonal contraception, we will see how they proposed another model of ??heteromasculinity??. This article refers to interviews and the press coverage in the 1980s?? in which some of them mentioned their experiences.     

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 in felids

Contraceptives are used for reversible reproductive control in genetically valuable wild felids, as permanent reproductive control in generic wild felids, and as an economically practicable means to control feral cats. The progestin contraceptives, megestrol acetate, melengesterol acetate, medroxyprogesterone acetate, and levonorgestrol (administered orally, in implants, or as depot injections), are effective in preventing pregnancy. However, long-term use is associated with endometrial hyperplasia, endometrial cancer, and mammary cancer. Gonadotropin releasing hormone analogs or luteinizing hormone vaccines that achieve contraception by suppressing ovarian or testicular function, do not have the adverse health effects of progestins. However, reliable reversibility has not been demonstrated, and male secondary sex characteristics may be suppressed. Bisdiamines also inhibit spermatogenesis and lower circulating testosterone concentrations in treated male cats. Porcine zona pellucida vaccines are ineffective contraceptives in felids and may cause serious health problems when combined with some adjuvants. Because of the limited availability of non-progestin contraceptives and side effects associated with some agents, widespread application of contraception to felids has been curtailed. More non-steroidal methods of contraception should be tested in the future to provide alternatives for controlling reproduction in felids. Furthermore, all empirical information on contraceptive safety and efficacy should be assembled in a database to provide the knowledge needed by veterinarians and managers to determine benefits/risks of currently available contraceptives in felids, both domestic and wild.     

La contraception pour les hommes — une cause perdue ?

Before the advent of female hormonal contraception, men inWestern European countries had a large share of responsibility for birth control through the use of condoms and the practice of coitus interruptus. Despite these practices, development of hormonal male contraception has not received support from the various players responsible for its finally reaching the market and being distributed: the pharmaceutical industry, the medical profession, international research funding agencies and the media. A deconstruction of underlying, but rarely explicit, representations and values, largely linked to an essentialist reading of gender relations, allows us to understand why male hormonal contraception remains blocked in the quagmire that has prevailed for several decades.     

Factors affecting ever-married men's contraceptive knowledge and use in Nigeria

African men play important roles in the decisions about family life, including fertility and family planning. However, fertility and family planning research and programmes have ignored their roles in the past, focusing only on women's behaviours. Since the 1994 International Conference on Population and Development (ICPD), interest in men's involvement in reproductive health has increased. Unfortunately, data on their knowledge and use of contraception are generally scanty. This paper examines knowledge and use of contraception among ever-married men in Nigeria. A total of 1451 ever-married men aged 18-55 were interviewed in Imo and Ondo States, Nigeria. The findings reveal that men's level of contraceptive knowledge is high in the study areas. About 90% knew at least one method of family planning. Furthermore, the level of contraceptive use among married men is such that men could participate in family planning activities if there were adequate programmes to involve them. Men in the sample areas were found not only to support their spouses' use of contraceptives, but were actually using condoms to delay or prevent pregnancy. Age, education, place of residence, number of living children and being counselled for family planning were identified as key factors determining contraceptive knowledge and use among married men in the study areas. To ensure increased participation of men in family planning, programmes must be designed to educate them on the need for family size limitation and involve them in service delivery, even if only to their male counterparts.     

Barriers to the use of modern contraceptives and implications for woman-controlled prevention of sexually transmitted infections in Madagascar

Globally, unplanned pregnancies and sexually transmitted infections (STIs) persist as significant threats to women's reproductive health. Barriers to the use of modern contraceptives by women might inhibit uptake of novel woman-controlled methods for preventing STIs/HIV. Use of modern contraceptives and perceptions and attitudes towards contraceptive use were investigated among women in Antananarivo, Madagascar, using qualitative research. The hypothetical acceptability of the diaphragm--a woman-controlled barrier contraceptive device that also holds promise of protecting against STIs/HIV--was assessed. Women consecutively seeking care for vaginal discharge at a public health clinic were recruited for participation in a semi-structured interview (SSI) or focus group discussion (FGD). Audiotaped SSIs and FGDs were transcribed, translated and coded for predetermined and emerging themes. Of 46 participating women, 70% reported occasional use of male condoms, mostly for preventing pregnancy during their fertile days. Although women could name effective contraceptive methods, only 14% reported using hormonal contraception. Three barriers to use of modern contraceptives emerged: gaps in knowledge about the range of available contraceptive methods; misinformation and negative perceptions about some methods; and concern about social opposition to contraceptive use, mainly from male partners. These results demonstrate the need for programmes in both family planning and STI prevention to improve women's knowledge of modern contraceptives and methods to prevent STI and to dispel misinformation and negative perceptions of methods. In addition, involvement of men will probably be a critical component of increased uptake of woman-controlled pregnancy and STI/HIV prevention methods and improved health.     

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.     

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.     

Family Planning Knowledge,Attitude and Practice among Married Couples in Jimma Zone,Ethiopia

Background

Understanding why people do not use family planning is critical to address unmet needs and to increase contraceptive use. According to the Ethiopian Demographic and Health Survey 2011, most women and men had knowledge on some family planning methods but only about 29% of married women were using contraceptives. 20% women had an unmet need for family planning. We examined knowledge, attitudes and contraceptive practice as well as factors related to contraceptive use in Jimma zone, Ethiopia.

Methods

Data were collected from March to May 2010 among 854 married couples using a multi-stage sampling design. Quantitative data based on semi-structured questionnaires was triangulated with qualitative data collected during focus group discussions. We compared proportions and performed logistic regression analysis.

Result

The concept of family planning was well known in the studied population. Sex-stratified analysis showed pills and injectables were commonly known by both sexes, while long-term contraceptive methods were better known by women, and traditional methods as well as emergency contraception by men. Formal education was the most important factor associated with better knowledge about contraceptive methods (aOR = 2.07, p<0.001), in particular among women (aOR_women = 2.77 vs. aOR_men = 1.49; p<0.001). In general only 4 out of 811 men ever used contraception, while 64% and 43% females ever used and were currently using contraception respectively.

Conclusion

The high knowledge on contraceptives did not match with the high contraceptive practice in the study area. The study demonstrates that mere physical access (proximity to clinics for family planning) and awareness of contraceptives are not sufficient to ensure that contraceptive needs are met. Thus, projects aiming at increasing contraceptive use should contemplate and establish better counseling about contraceptive side effects and method switch. Furthermore in all family planning activities both wives'' and husbands'' participation should be considered.     

Attractive men induce testosterone and cortisol release in women

Recently, Roney et al. (Roney, J.R., Lukaszewski, A.W., Simmons, Z.L., 2007. Rapid endocrine responses of young men to social interactions with young women. Horm. Behav. 52, 326-33; Roney, J.R., Mahler, S.V., Maestripieri, D., 2003. Behavioral and hormonal responses of men to brief interactions with women. Evol. Hum. Behav. 24, 365-375) demonstrated that men release testosterone and cortisol in response to brief social interactions with young women. The current experiment examined whether women show a similar endocrine response to physically and behaviorally attractive men. 120 women (70 naturally-cycling and 50 using hormonal contraceptives) were shown one of four 20-minute video montages extracted from popular films, depicting the following scenarios: 1) an attractive man courting a young woman (experimental stimulus), 2) a nature documentary (video clip control), 3) an unattractive older man courting a woman (male control), and 4) an attractive woman with no men present (female control). Saliva samples were taken before and after presentation of the stimulus, and were later analyzed for testosterone and cortisol content via enzyme immunoassay. Naturally-cycling women experienced a significant increase in both testosterone and cortisol in response to the experimental stimulus but to none of the control stimuli. Participants taking hormonal contraceptives also showed a significant cortisol response to the attractive man. Women may release adrenal steroid hormones to facilitate courtship interactions with high mate-value men.     

La contraception masculine

Currently available methods of male contraception include condoms and vasectomy, but condoms have a high failure rate and vasectomy is an irreversible method. These methods are also not accepted by all couples. Hormonal methods are based on reversible suppression of gonadotrophin (both LH and FSH) and inhibition of intra-testicular steroid and sperm production. In 1990 and 1996, the WHO published results from two studies using testosterone injections as a method of hormonal contraception. These studies demonstrated, for the first time, that if a hormonal method is able to induce azoospermia or at least severe oligozoospermia, it could constitute an effective method of contraception. Another possible approach consists of using a combination of progestins or other gonadotropin inhibitors together with androgens to ensure more effective suppression of spermatogenesis. The dose of androgens can be lowered to decrease the risk of long-term adverse effects. Ongoing studies are designed to determine the safest and most effective combinations of androgens and progestins. GnRH antagonists interfere with the action of GnRH and suppress gonadotropins and therefore spermatogenesis. Agents acting directly on the testis are often very toxic and frequently induce irreversible effects on spermatogenesis and therefore cannot be used for contraception. Immunocontraception, particularly targeting of antibodies to gamete-specific antigens involved in sperm-egg binding and fertilisation, constitutes a very attractive approach. This is not a new idea, as several immunocontraception trials, using animal model systems, have been reported over recent years. However, the results of these studies have been largely disappointing because immunoneutralisation of a single, gamete-specific antigen appears to be insufficient to induce a significant reduction in fertility and secondly, although systemic immunisation regimes may lead to high serum antibody levels, these levels do not correlate with specific antibody levels in the reproductive tract or with contraceptive efficacy.     

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.     

Gender relations: husband-wife fertility and family planning decisions in Kenya

Although Kenya's fertility rate has declined from 6.7 births per woman in the mid-1980s to 5.4 births per woman in 1993 (NCPD, 1994), population growth is still high, yielding a doubling time of 35 years. This study uses the 1993 Kenya Demographic Health Survey data collected from 1257 couples to examine the socioeconomic and sociodemographic characteristics of married men and women and their communication with their spouses over fertility and family planning decision-making practices. The logistic regression analysis shows that education for both men and women, discussion of fertility and family planning between spouses, male approval of use of contraception and male family size desires are important factors that influence ever-use of family planning.     

Estimate of Venous Thromboembolism and Related-Deaths Attributable to the Use of Combined Oral Contraceptives in France

Purpose

To estimate the number of venous thromboembolic events and related-premature mortality (including immediate in-hospital lethality) attributable to the use of combined oral contraceptives in women aged 15 to 49 years-old between 2000 and 2011 in France.

Methods

French data on sales of combined oral contraceptives and on contraception behaviours from two national surveys conducted in 2000 and 2010 were combined to estimate the number of exposed women according to contraceptives generation and age. Absolute risk of first time venous thromboembolism in non-users of hormonal contraception and increased risk of thromboembolism in users vs. non-users of hormonal contraception were estimated on the basis of literature data. Finally, immediate in-hospital lethality due to pulmonary embolism and premature mortality due to recurrent venous thromboembolism were estimated from the French national database of hospitalisation and literature data.

Results

In France, more than four million women are daily exposed to combined oral contraceptives. The mean annual number of venous thromboembolic events attributable to their use was 2,529 (778 associated to the use of first- and second-generation contraceptives and 1,751 to the use of third- and fourth-generation contraceptives), corresponding to 20 premature deaths (six with first- and second-generation contraceptives and fourteen with third- and fourth-generation contraceptives), of which there were eight to nine immediate in-hospital deaths. As compared to the use of first- and second-generation contraceptives, exposure to third- and fourth-generation contraceptives led to a mean annual excess of 1,167 venous thromboembolic events and nine premature deaths (including three immediate in-hospital deaths).

Conclusions

Corrective actions should be considered to limit exposure to third- and fourth-generation contraceptives, and thus optimise the benefit-risk ratio of combined oral contraception.     

Contraceptive Use and Uptake of HIV-Testing among Sub-Saharan African Women

Despite improved availability of simple, relatively inexpensive, and highly effective antiretroviral treatment for HIV/AIDS, the disease remains a major public health challenge for women in sub-Saharan Africa (SSA). Given the numerous barriers in access to care for women in this region, every health issue that brings them into contact with the health system should be optimized as an opportunity to integrate HIV/AIDS prevention. Because most non-condom forms of modern contraception require a clinical appointment for use, contraception appointments could provide a confidential opportunity for access to HIV counseling, testing, and referral to care. This study sought to investigate the relationship between contraceptive methods and HIV testing among women in SSA. Data from the Demographic and Health Survey from four African countries—Congo, Mozambique, Nigeria, and Uganda—was used to examine whether modern (e.g., pills, condom) or traditional (e.g., periodic abstinence, withdrawal) forms of contraception were associated with uptake of HIV testing. Data for the current analyses were restricted to 35,748 women with complete information on the variables of interest. Chi-square tests and logistic regression models were used to assess the relationship between uptake of HIV testing and respondents'' baseline characteristics and contraceptive methods. In the total sample and in Mozambique, women who used modern forms of contraception were more likely to be tested for HIV compared to those who did not use contraception. This positive association was not demonstrated in Congo, Nigeria, or Uganda. That many women who access modern contraception are not tested for HIV in high HIV burden areas highlights a missed opportunity to deliver an important intervention to promote maternal and child health. Given the increasing popularity of hormonal contraception methods in low-income countries, there is an urgent need to integrate HIV counseling, testing, and treatment into family planning programs. Women on hormonal contraceptives should be encouraged to continue to use condoms for HIV-prevention.     

The presence of endometrial cells in cervical smears in relation to the day of the menstrual cycle and the method of contraception

The presence of endometrial cells in cervical smears was studied in a large series of women participating in a population screening program for cervical cancer, in relation to different time periods of the menstrual cycle and to the method of contraception practiced. In the total group of women studied, endometrial cells were present in an average of 12% of the cervical smears. In women who were menstruating cyclically, the percentage of cervical smears containing endometrial cells was not age dependent. Only in women over 52 years was a lower number of endometrium-positive cervical smears found: in postmenopausal women, 0.6% of smears were found to contain endometrial cells. In menstruating women, the frequency of endometrial cells in cervical smears was highest during the menses. After day four, through the proliferative phase, the percentages of cervical smears containing endometrial cells markedly decreased. During the secretory phase, an average of 2% of the smears contained endometrial cells; in the premenstrual phase (after day 25), the percentages of endometrial cell-positive smears rose again. When related to the method of contraception practiced, significant differences in the percentages of cervical smears with endometrial cells appeared. In women using oral hormonal contraceptives, the average numbers of smears containing endometrial cells for the whole cycle as well as for each period of the cycle were significantly lower. This phenomenon might be due to endometrial atrophy on the basis of prolonged use of oral hormonal contraceptives. In women wearing an intrauterine device, at any moment the frequencies of smears with endometrial cells present were significantly higher than the values found in women using any other method of contraception or not using contraceptives. The evaluation of cells originating from the endometrium requires considerable experience. The identification of endometrial cells can be made with greater confidence when the cytologist is aware of the exact date of the menstrual cycle and of the impact on the presence of endometrial cells in cervical smears caused by different methods of contraception.