Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

GJ Manetti and SC Honig

Disclosures

Int J Impot Res. 2010;22(3):159-170. 

In This Article

Review of Hypothalamic–Pituitary–Gonadal Axis and Spermatogenesis

An understanding of the endocrinology of male reproduction, specifically the male hypothalamic–pituitary–gonadal axis and the basics of spermatogenesis is required to understand the methodologies used for male contraception.

The hypothalamic–pituitary–gonadal pathway is regulated through negative feedback by downstream products as summarized in Figure 1. Spermatogenesis is regulated by the pulsatile release of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus of the hypothalamus, which stimulates the anterior pituitary to episodically release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH stimulates the Leydig cells to produce testosterone, which has a local effect on the interstitium and seminiferous tubules and results in sperm production and maturation. This effect is manifested by very high intratesticular testosterone compared with the bloodstream. FSH exerts its effect directly on the Sertoli cells to promote spermatogenesis. Testosterone and estradiol (converted through aromatase in the testis interstitium) are direct negative feedback modulators of GnRH, LH and FSH. Aromatase inhibition increases FSH levels suggesting that FSH regulation is more dependent on estradiol than testosterone.[5,6]

Figure 1.

Endocrinology of spermatogenesis. The hypothalamic–pituitary–gonadal axis.

Other substances have a role in this important neuroendocrine negative feedback pathway. Studies have shown that kisspeptins, a group of amino-acid peptides, and their G-protein-coupled receptor (GPR54) have a critical function in the secretion of GnRH and the negative feedback of testosterone and estradiol on the hypothalamus. Administration of kisspeptin has been shown to increase GnRH secretion in neuronal cell lines.[7] Furthermore, although acute administration of kisspeptin seems to increase LH, FSH and testosterone secretion, chronic administration lowers serum LH levels in monkeys.[8,9] Manipulation of the kisspeptin–GPR54 pathway represents another potential target for future male contraceptive therapy.[8]

Complex interplay between testosterone, FSH and other factors is important for normal spermatogenesis. Sertoli cells are part of the seminiferous tubules that are activated by FSH and function to provide the optimal environment for the developing sperm cells throughout spermatogenesis. Inhibin B represents a nonsteroidal substance released by Sertoli cells after puberty and functions as a negative feedback on FSH secretion. Inhibin B could potentially be another indirect target to suppress spermatogenesis. However, the role of inhibin in FSH suppression and spermatogenesis is unclear, as low levels of inhibin are still present with LH-receptor mutations and chronic FSH administration.[8,10,11] Progesterone receptors are seen in the hypothalamus, pituitary and testis. It appears that progesterone affects gonadotropins via the hypothalamic–pituitary–testis axis, however, they may function directly on the testis as well.[12,13]

It is clear that in normal sperm-producing men, intratesticular testosterone levels are 100-fold higher than in serum.[14–18] Interestingly, LH-receptor-deficient mice can support some level of spermatogenesis, but use of an androgen receptor antagonist such as flutamide will suppress spermatogenesis completely.[19–21] The role of dihydrotestosterone, a potent metabolite of testosterone, in spermatogenesis appears to be less clear. A decrease in dihydrotestosterone levels does not seem to cause a significant drop in sperm production.[22]

On a cellular and receptor level, androgen receptors are found in multiple cell sites within the testes, specifically immature germ cells, smooth muscle cells, myoid cells, Sertoli and Leydig cells. Cell-specific effects on androgen receptors may affect spermatogenesis. In Sertoli cell and Leydig cell androgen receptor-specific knockout mice, spermatogenesis is impaired.[23–26] In contrast, androgen receptors on germ cells and myoid cells appears to be less important in spermatogenesis as knock out models in these situations, do not impair spermatogenesis in a major way.[23,27] Compounds that are cell specific and influence Sertoli and Leydig cell androgen receptors could potentially be an excellent site of future male contraceptive thoughts. As described earlier, complete blockage of the androgen receptor with flutamide suppresses spermatogenesis.[28] Molecules that follow this pathway, but may be more specific and do not have the significant negative side effects of flutamide, may be valuable potential contraceptive targets.

Spermatogenesis is hormone dependent. Spermatogonia divide in 16-day intervals to form B spermatogonia, which will differentiate and progress through spermatogenesis. Other B spermatogonia will renew to form new precursor stem cells. Type B spermatogonia that differentiate will divide mitotically to form primary spermatocytes and these will undergo meiosis to secondary spermatocytes and round spermatids. The round spermatids will then undergo a process of conformational change into mature spermatids. In this process, they will undergo extensive changes in cytoplasm and nucleus, form an acrosome, flagellum and cytoplasmic organelles undergo changes to form a mature spermatozooan. This process requires approximately 64 days. High levels of intratesticular testosterone are required for this to occur. Hypophysectomy results in testis atrophy, but not complete depletion of germ cells, and blocks maturation and causes interference with germ cell proliferation.[29] When testosterone microspheres are injected into the testes of GnRH agonist-treated rats, almost completely normal spermatogenesis occur.[30]

Based on this data, the roles of FSH and LH are not completely clear in the renewal of spermatogenesis. It appears that high intratesticular testosterone will initiate and maintain qualitative spermatogenesis. This can be initiated by LH stimulation or exogenous hCG; however, the role of FSH is less clear. Men with FSH receptor defects can be fertile, although spermatogenesis appears to be significantly impaired. FSH also can initiate spermatogenesis in pubertal men and reinitiate sperm production in animals that have undergone hypophysectomy. In patients with hypogonadotropic hypogonadism, FSH provides for optimized spermatogenesis in some but not all cases. It appears that the combination of FSH and high intratesticular testosterone is important for normal sperm production.[31] It appears that suppression of gonadotropins has a direct effect on germ cell apoptosis and this is the mechanism of suppression.[32] All these data are valuable as we evaluate the effects of different agents as male contraceptives.

Endocrinological treatment strategies for male contraception are listed in Table 1 and are shown in Figure 2. Taking advantage of disruption of negative feedback mechanisms and interruption of normal pulsatile release of hormones are the mainstay of therapeutic options.

Figure 2.

Male hormonal contraceptive (MHC) regimens (compromising androgens alone or in combination with progestins or GnRH antagonists) act to inhibit the hypothalamic–pituitary–testicular axis. Exogenous testosterone (T) must be administered to maintain virilization and suppress GnRH, FSH and LH levels and thereby intratesticular androgen production (testosterone and dihydrotestosterone (DHT) (percent baseline levels following MHC administration are shown in brackets). Reduction in Sertoli cell FSH and androgen receptor (AR) activation results in marked inhibition of spermatogenesis, mainly the maturation of type A pale (Ap) to type B (B) spermatogonia and of sperm release (spermiation). MHC agents that have undergone some assessment in humans include progestins, GnRH antagonists, 7α-methyl-19-nortestosteone (MENT) and 5α reductase inhibitors with their sites of actions marked. Potential but untrialled MHC agents (selective androgen response modulators (SARMs) that target inhibition of the Sertoli cell AR, FSH-R antagonists, agents to inhibit spermiogenesis and spermiation) appear in hatched boxes. Germ-cell subtypes include type A pale spermatogonia (Ap); type B spermatogonia (B); leptotene–zygotene spermatocytes (L-Z); pachytene spermatocytes (PS); steps 1–2 round spermatids (rST); steps 3–6 elongating spermatids (El), steps 7–8 elongated spermatids (Eld) and spermatozoa (S). Source: Matthiesson and McLachlan.[42] Reprinted with permission from Oxford University Press.

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