Current Molecular Pharmacology - Volume 7, Issue 2, 2014

The development of a “male pill” to control fertility is still a major challenge. Although women have several options to play an active role in the couple family planning, men are very limited in terms of contraceptive methods. Several approaches have been proposed to develop a male contraceptive and can be divided in two major groups: hormonal and non-hormonal methods. Within the testis, the somatic Sertoli cell (SC) is known as the “nurse cell” since it provides the physical and nutritional support for the developing germ cells. Moreover, adjacent SCs form the Sertoli/blood testis barrier (BTB), which divides the seminiferous epithelium into the basal and the apical compartments, controlling the passage of substances to the site where germ cells develop. Among the several functions of SC, its metabolism and the production of lactate, acetate and other metabolic factors are essential for the normal occurrence of spermatogenesis. In the last years, several works have highlighted that the metabolic cooperation established between SCs and developing germ cells is compromised in several diseases associated with male subfertility/infertility. Notably, several metabolismassociated proteins are specifically expressed in the testis. Thus, there are several evidences illustrating that the control of male fertility can be achieved by targeting testicular cells metabolism. Herein, we discuss the metabolic cooperation in testis as a potential pharmacological target to counteract subfertility/infertility promoted by several diseases, particularly metabolic diseases. We also discuss how it can contribute to the development of a male contraceptive.

In adulthood, the main function of the testes is the production of male gametes. In this process, Sertoli cells are essential for sustained spermatogenesis, providing the developing germ cells with the physical and nutritional support required. The total number of Sertoli cells in adulthood determines the daily gamete production, since Sertoli cells can support only a limited number of developing germ cells. Considering that Sertoli cell proliferation only occurs during the immature period, proper development and proliferation of the Sertoli cells during the proliferative phase are crucial to male reproductive health in adulthood. The proliferation process of the Sertoli cells is finely regulated by an assortment of hormonal and paracrine/autocrine factors, which regulate the rate and extent of proliferation. In the present review, we discuss the most important hormonal and paracrine factors involved in the regulation of Sertoli cell proliferation, as well as the signaling mechanisms by which they exert their effects.

The general interest in the availability of male contraceptives is on the increase across different cultures and ethnic backgrounds, due in part to the fact that men are now willing more than ever, to share the responsibility of family planning. Despite the expression of interest and tremendous advances in research however, a modern male hormonal contraceptive method has remained an elusive goal. Testosterone (T) alone, or in combination with a progestin currently provides the most promising lead to male hormonal contraception. The principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the endocrine stimulus for the process of spermatogenesis. A serious drawback is the inconsistent suppression among men of different ethnic backgrounds. This has increased the quest for development to include other nonhormonal methods. In reality many obstacles still have to be overcome before an acceptable method is available. In this review, we highlight recent developments in male hormonal contraceptives methods. Based on our recent findings from animal experiment, we shed light on why the method is not achieving the intended results, and suggest possible ways forward.

Exposure of humans and wildlife to pollutants released in the environment is a centre of attention nowadays. Many of these chemicals (generally referred to as environmental pollutants) have been shown to interfere with normal hormonal signalling and biological functions, leading to reproductive disorders or infertility, which has been a matter of concern within the recent decades. The present paper reviews adverse effects of these toxicants on mammalian testes, with emphasis on alteration of steroidogenesis, spermatogenesis, and histopathological effects. From the publications reviewed, it appears that environmental toxicants, especially heavy metals and organic chemicals of synthetic and microbiological origins, disrupt hormone production and action in the mammalian testes. Endocrine disruption leads to disorders of testicular function and thereby compromises the normal phenotypic development of male sexual characteristics, initiation and maintenance of spermatogenesis. The toxicants also induce impairment of testicular cells function, testicular histology, and sperm cells function directly. The release of the toxicants in the environment is still ongoing, despite alarming quantities that already exist in the atmosphere. If appropriate measures are not taken, their impact on the male reproductive function and especially on testicular function will be more serious.

The major post-translational modification in eukaryotes is protein phosphorylation which mediates responses to signals in a myriad of cellular processes. Not surprisingly, many steps in spermatogenesis involve the concerted action of the protein (de)phosphorylation key players, kinases and phosphatases. Phosphoprotein phosphatase 1 catalytic subunit (PPP1C), an evolutionarily conserved Ser/Thr-protein phosphatase, catalyzes the majority of eukaryotic protein dephosphorylation reactions. Three genes, PPP1CA, PPP1CB and PPP1CC, encode four PPP1C isoforms, PPP1CA, PPP1CB, PPP1CC1, and PPP1CC2. After transcription, PPP1CC undergoes tissue-specific splicing, originating a ubiquitously expressed isoform, PPP1CC1 and a testis-enriched and sperm-specific isoform, PPP1CC2 which is essential for completion of spermatogenesis. Highly similar PPP1C isoforms – PPP1CA and PPP1CB – are capable of compensating the loss of Ppp1cc in every tissue except in testis. PPP1C cellular functions depend on the complexes it forms with PPP1C Interacting Proteins (PIPs), which together with the different catalytic subunits, account for PPP1C specificity. This review will focus on the role of the major serine/threonine phosphatase – PPP1C and its holoenzymes in spermatogenesis. Furthermore, current challenges on the protein phosphatases field as targets to male contraception will be addressed.

Breast cancer resistant protein (BCRP, ABCG2) is an ATP-binding cassette (ABC) transporter, which together with two other ABC efflux drug pumps, namely P-glycoprotein (P-gp, ABCB1) and multidrug resistance-related protein 1 (MRP1, ABCC1) is the most important multidrug resistance protein foun d in eukaryotic cells including cells in the testis. However, unlike P-gp and MRP1, which are components of the Sertoli cell blood-testis barrier (BTB), BCRP is not expressed at the BTB in rodents and human testes. Instead, BCRP is expressed by peritubular myoid cells and endothelial cells of the lymphatic vessel in the tunica propria, residing outside the BTB. As such, the testis is equipped with two levels of defense against xenobiotics or drugs, preventing these harmful substances from entering the adluminal compartment to perturb meiosis and post-meiotic spermatid development: one at the level of the BTB conferred by P-gp and MRP1 and one at the tunica propria conferred by BCRP. The presence of drug transporters at the tunica propria as well as at the Sertoli cell BTB thus poses significant obstacles in developing non-hormonal contraceptives if these drugs (e.g., adjudin) exert their effects in germ cells behind the BTB, such as in the adluminal (apical) compartment of the seminiferous epithelium. Herein, we summarize recent findings pertinent to adjudin, a non-hormonal male contraceptive, and molecular interactions of adjudin with BCRP so that this information can be helpful to devise delivery strategies to evade BCRP in the tunica propria to improve its bioavailability in the testis.

Population growth in the last century has raised important social and economic questions. Thus, current methods of fertility control have been under debate for a long period. Birth rates are essentially dependent on several environmental and social factors but women, who are great users of contraceptives, play a major role. Regulation of male fertility has been widely studied in recent years with the aim of developing a new male contraceptive for further inclusion of men’s choice in family planning. Based on the ancient people techniques to control the birth rates, natural products appeared as a promising source for the development of a male contraceptive. Over the years, many plants and their main constituents have been studied in the search for their antifertility properties. Interestingly, some antispermatogenic effects have been reported. Herein, we will discuss the antispermatogenic properties of some natural products. We propose to discuss specific targets and sites of action of the selected natural products. Despite the advances in this field in the last years, the molecular mechanisms by which natural products can control fertility, need to be disclosed to develop an effective, reversible and safe male contraceptive and avoid undesired toxicity in other organs. To date, no natural-based male contraceptive is available in the commercial market, mostly due to the difficulty in reversing the effects of these products in male fertility.

The spermatogenesis is a precisely-timed cellular proliferation that takes place in the seminiferous tubules of testes and is meticulously regulated by gonadotrophins, androgens and temperature. Hormonal, nonhormonal and thermal methods of male contraception have been researched with success; though a clinically viable method is yet to evolve. Testicular sperm lack motility and fertilizing ability, which they gain during their transit through the long epididymal conduit whose distal end serves as a store house of mature sperm in a quiescent state, ready for ejaculation during coitus. Epididymal maturation has been a target for male contraceptive research to avert interruptions of fundamental testicular functions like spermatogenesis and steroidogenesis. However, several experimental successes have not yet yielded a practicable method of fertility regulation. Coitus culminates in the propulsion of epididymal sperm within seconds through the vas deferens into the female vagina and marks the initiation of sperm motility, a vigorous physical activity that is crucial for fertilization. Highly motile spermatozoa have a brief stay in the vagina before starting their ascent in the female reproductive tract. Vaginal spermatozoa have been targeted for contraception since ages. Spermicides and sperm immobilizers inactivate sperm immediately on deposition in the vagina, while they are placed in a rather ‘ex-vivo’ condition outside the body. Their need based usage, minimal systemic involvement; easy application, self-controlled reversibility and potential capability to obliterate sexually transmitted infections add significant value to contraception. We have reviewed here our recent endeavors in this important area of chemical contraception by using designed chemical synthesis approach to inhibit spermatozoa and infection.

Current contraceptive options available to men include withdrawal, condoms, and vasectomy, each of which has its own drawbacks. In this chapter we will describe the pros and cons for each, as well as methodological and product updates. Statistics from the U.S. Centers for Disease Control on acceptance and satisfaction will be included. Advances in vasectomy and reversal will be presented. Methods to develop new contraceptive technologies fall into two categories: hormonal and non-hormonal. Many targets and strategies have been proposed for non-hormonal male contraception within the testis. Targets include structural components in the testis, as well as enzymes, ion channels and other proteins specific to spermatozoa. Here we provide an overview of the spermatogenic mechanisms and proteins that have received research interest to date. We also discuss potential novel targets, such as ubiquitin specific proteases, that warrant greater research emphasis.