Hypothalamic Pituitary Testes Axis

Brain Androgen Receptor Testes




The endocrinology of spermatogenesis and male hormonal contraception: Open arrows denote promotion of spermatogenesis; dashed lines denote inhibition of spermatogenesis and hormone production.
A, Diagram of the naturally occurring, normal state;
B, Diagram of the impact of hormonal contraceptive interventions on the reproductive axis.

The hypothalamic-pituitary-testicular axis is a classic endocrine loop, with negative feedback of downstream products playing the pivotal regulatory role in maintaining homeostasis. Testicular production of both hormones and sperm is exquisitely regulated by gonadotropins produced by the pituitary, whereas gonadotropin production is under the direct control of pulsatile GnRH secretion from the hypothalamus. In turn, steroid and peptide hormones produced in the testes provide inhibitory signals to the pituitary and hypothalamus.

It has been known for over 25 yr that both temporal and quantitative changes in GnRH secretion disrupt testicular function. GnRH secretion from the hypothalamus is directly related to pulsatile release of LH and FSH in the peripheral circulation; thus, disrupters of GnRH secretion and action are potential contraceptive targets.

Over the last 5 yr there have been rapid advances in understanding of the neuroendocrine control of reproduction upstream of GnRH, and these too represent potential new contraceptive targets that have yet to be tested. Moreover, the negative feedback of testosterone and estradiol on GnRH secretion is mediated via inhibition of kisspeptin.

Negative feedback to the pituitary and hypothalamus is critical to maintain endocrine homeostasis in the male. Testosterone is the main testicular steroid, but significant aromatase activity in the testicle and peripheral tissues results in production of estradiol as well. Testosterone clearly inhibits kisspeptin transcription and GnRH and gonadotropin secretion. Some of this inhibition is estrogen independent, but estradiol seems to play an important role in steroid negative feedback in the male, particularly by decreasing LH production.

Aromatase inhibition results in significant increases in LH and FSH secretion in normal men; normal levels can be restored with estradiol supplementation in a nonlinear fashion, with higher estradiol levels having increasingly less effect on circulating gonadotropin and testosterone levels. Moreover, both aromatase inhibition and medical castration result in similar increases in FSH, despite markedly decreased testosterone levels with medical castration compared with aromatase inhibition; this suggests that, at least acutely, FSH regulation is more dependent on estradiol than testosterone.

In contrast, dihydrotestosterone (DHT), a nonaromatizable androgen, is a poor inhibitor of gonadotropin production in the male when given at or near physiological doses, and 5 -reductase blockade with finasteride or dutasteride, which lowers serum DHT concentration by as much as 95%, fails to alter gonadotropin levels. However, with chronic administration and supraphysiological dosing, exogenous DHT inhibits both LH and FSH secretion despite concomitant suppression of testosterone and estradiol, demonstrating that aromatization is not an absolute requirement for negative feedback.

Like other sex steroids, progesterone is expressed in the male as well as the female, albeit at lower levels. The precise role of progesterone in normal male physiology is unknown, but progesterone receptors have been demonstrated in the male hypothalamus, pituitary, and reproductive tract.

Progestins enhance male hormonal contraceptive efficacy when combined with androgens, an effect attributed to increased hypothalamic-pituitary suppression of gonadotropin secretion directly or through the androgen receptor. Brady et al. compared the effects of progesterone and the synthetic progestin, desogestrel, on gonadotropin secretion and GnRH responsiveness in normal men. Although both progestins decreased LH and FSH secretion, only progesterone decreased the LH response to GnRH. These results demonstrate that progesterone affects gonadotropin secretion through progesterone receptors and provide evidence for such inhibition at both the hypothalamic and pituitary levels.

However, the effects of exogenous progestins on spermatogenesis are greater than can be accounted for by enhanced suppression of gonadotropins alone. Therefore, it has been suggested that progestins may act directly on the testes. Exploitation of testicular progestin action is an additional mechanism whereby specific progestins could be formulated as male contraceptives.

Finally, the nonsteroidal testicular product inhibin B contributes to hormonal feedback in the male. Inhibin B is a dimeric molecule consisting of and β subunits and a member of the TGF-β family. Inhibin B is predominantly produced by Sertoli cells, and inhibin B levels correlate with Sertoli cell number. Indeed, although inhibin B levels rise acutely with FSH administration, chronic FSH and spermatogenic suppression results in only a 25% decline in levels, suggesting FSH-independent inhibin B production.

Negative feedback by inhibin B on FSH production has been demonstrated in 1) normal men, where inhibin B and FSH exhibit an inverse relationship; 2) castrate men with very high FSH levels compared with normal men rendered medically castrate; 3) men with testicular disorders; and 4) male infertility where low inhibin B levels are associated with increased levels of FSH.

Aside from its role in regulating FSH production and as an indicator of Sertoli cell function, no clear role for inhibin B in testicular physiology or spermatogenesis has been established. Theoretically, exogenous inhibin B in conjunction with androgens might further suppress FSH and be an adjunct in a male hormonal contraceptive regimen. However, to date recombinant inhibin B has not been available for clinical studies, and recent investigations suggest that incomplete FSH suppression may not be pivotal to persistent spermatogenesis in men undergoing male hormonal contraceptive treatment.

Because progestins inhibit the secretion of gonadotropins from the pituitary, several progestins have been combined with testosterone to improve its contraceptive effect by augmenting suppression of gonadotropins. Testosterone/progestin regimens were first tested for male hormonal contraception in the 1970s. Over the following 35 yr, efficacy of testosterone-progestin-based regimens has greatly improved.The use of progestins in men can be associated with side effects such as weight gain, additive suppression of serum HDL cholesterol, and perhaps increases in proinflammatory cytokines associated with increased cardiovascular risk; thus, current protocols aim to minimize these adverse effects.

Early studies of progestins focused on demonstrating improved sperm suppression compared with testosterone alone, while subsequent studies have aimed at minimizing the doses involved or optimizing the delivery strategy. A randomized, controlled trial of 0.5 mg of oral levonorgestrel with 100 mg of weekly TE showed that the combination was superior to TE alone in achieving azoospermia (67 vs. 33%) by 6 months in Caucasian men. Furthermore, the proportion of subjects achieving a sperm concentration of less than 3 million/ml was 94% in the combination group compared with 61% in the TE-alone group. The combination regimen resulted in greater weight gain and further decreases in HDL cholesterol when compared with the TE-alone group, side effects which have been minimized without compromising effectiveness by lowering the dose of levonorgestrel in subsequent studies .

In summary, the contraceptive effect of most of the progestins is fairly similar, although smaller doses may be more efficacious for some progestins compared with others and their side effect profiles likely vary. Combinations all result in azoospermia rates of almost 90%. As a result, many researchers now feel that one of these combinations is the most likely to result in a clinically useful contraceptive method.



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