Variability in Sperm Suppression during Testosterone Administration to Adult Monkeys Is Related to Follicle Stimulating Hormone Suppression and Not to Intratesticular Androgens

Abstract

Sex steroid-based male contraceptive regimens do not induce consistent azoospermia. The reason for this variable response is obscure. We used normal adult male monkeys, Macaca fascicularis (n ‫؍‬ 9) as a model of testosterone (T)-induced gonadotropin suppression to understand the basis for variability in spermatogenic suppression during hormonal contraception. As observed in men, T administration to these monkeys induced azoospermia in some animals and variable degrees of spermatogenic suppression in others. Based on their sperm counts, we divided these animals into two groups: azoospermic (azoo; n ‫؍‬ 4) and nonazoospermic (nonazoo; n ‫؍‬ 5) groups. Sperm density, testis volumes, and serum T, bioassayable LH (bioLH), immunoassayable FSH (immunoFSH), bioassayable FSH (bioFSH), and inhibin B were examined every 2 wk during the control period, 20 wk of T administration using SILASTIC brand (Dow Corning Corp.) implants, and recovery. Testes were biopsied for estimation of intratesticular T, dihydrotestosterone, and 5␣-androstane-3␣,17␤-diol. Serum T levels increased 1.5-to 2-fold, leading to decreased bioLH levels (48% of control) and intratesticular T levels (15% of control); neither LH nor intratesticular T levels differed between the azoo and nonazoo groups. In contrast, serum levels of FSH, by both bio-and immunoassay, during T administration were significantly lower in the azoo than in the nonazoo group. These results suggest that the degree of suppression of spermatogenesis is closely related to the degree of suppression of FSH levels and not to the levels of intratesticular androgens or to serum LH. These results imply that FSH plays a key role in supporting spermatogenesis in monkeys in this experimental regimen and suggest that maximal suppression of FSH may be essential to ensure consistent azoospermia in men during hormonal contraception. (J Clin Endocrinol Metab 87: 3399 -3406, 2002) A DMINISTRATION OF exogenous testosterone (T), either alone or in combination with other agents, produces profound suppression of spermatogenesis by inhibition of pituitary gonadotropins and depletion of testosterone within the testis (1-5). This approach is currently being investigated as a method of hormonal contraception for men. A consistent problem associated with T-based contraceptive regimens is that azoospermia is achieved in 40 -90% of men, but a varying degree of spermatogenic suppression is seen within and between various ethnic groups (6, 7). The reason for this variation remains unknown, but it is a critical question in designing and developing future hormonal contraceptives for men.A possible mechanism for such variation could be differences in residual testicular steroidogenesis (8); it remains controversial whether FSH levels in blood are important (5, 9) or not (10, 11) in the maintenance of sperm production in some men. There is a lack of evidence about the potential role of intratesticular androgens in the maintenance of spermatogenesis during hormonal contraceptive regimens. Also, there are very limited ...

Norethisterone enanthate has neither a direct effect on the testis nor on the epididymis: a study in adult male cynomolgus monkeys (Macaca fascicularis)

“…From day 14 on FSH was injected every second day and the dose of hCG was reduced to 25 IU/injection. After this reduction, testosterone levels returned to the normal range and serum FSH levels were comparable to those expected in intact monkeys (20).…”

Differential regulation of rat testicular 5alpha-reductase type 1 and 2 isoforms by testosterone and FSH

“…In both primates (Narula et al 2002) and men , gonadotrophin suppression by exogenous testosterone administration caused a marked reduction in testicular testosterone levels yet maintenance of 5 -reduced androgen levels. It is thought that maintenance of testicular 5 -reduced androgen levels may be responsible for continued low levels of sperm production in the 30% of normal men whose sperm counts do not fall to zero (azoospermia) after testosterone contraceptive treatment (Anderson et al 1996(Anderson et al , 1997.…”

Endocrine correlates of reproductive development in the male tree-shrew (Tupaia belangeri) and the effects of infantile exposure to exogenous androgens

“…The lack of spermatogenic activity in the absence of normally increasing FSH levels and the precise temporal correlation between FSH levels and the progression of germ cell development and growth of the testes in both normal and experimental situations suggest that FSH may play a primary role in the initiation and establishment of spermatogenesis in male tree-shrews. In the development of hormonal contraceptive technologies in human and nonhuman primates, it has been noted that the degree of suppression of spermatogenic activity induced by testosterone is specifically correlated with the degree of inhibition of FSH levels while inadequate suppression of FSH is a potential cause of contraceptive failure (Weinbauer et al, 2001;McLachlan et al, 2002;Narula et al, 2002). The present observation of a chronic androgen suppression of FSH levels in association with an hiatus in spermatogenic activity, together with the reversibility of these effects upon testosterone withdrawal, suggest that the tree-shrew merits specific exploration as a model for the development of steroid-based contraceptive regimens.…”