No abstract

Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output. Whereas considerable progress has been made toward defining clinically effective combinations, further optimization of androgen-progestin treatment regimens is still required.

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 ...

AIM:To better clarify the main target organs of dimethylarsinic acid toxicity and the role of metallothionein (MTs) in modifying dimethylarsinic acid (DMAA) toxicity. METHODS:MT-I/II null (MT -/-) mice and the corresponding wild-type mice (MT +/+ ), six in each group, were exposed to DMAA (0-750 mg/kg body weight) by a single oral injection. Twenty four hours later, the lungs, livers and kidneys were collected and undergone pathological analysis, induction of apoptotic cells as determined by TUNEL and MT concentration was detected by radio-immunoassay. RESULTS:Remarkable pathological lesions were observed at the doses ranging from 350 to 750 mg/kg body weight in the lungs, livers and kidneys and MT +/+ mice exhibited a relatively slight destruction when compared with that in dose matched MT -/-mice. The number of apoptotic cells was increased in a dose dependent manner in the lungs and livers in both types of mice. DMAA produced more necrotic cells rather than apoptotic cells at the highest dose of 750 mg/kg, however, no significant increase was observed in the kidney. Hepatic MT level in MT +/+ mice was significantly increased by DMAA in a dose-dependent manner and there was no detectable amount of hepatic MT in untreated MT -/-mice. CONCLUSION:DMAA treatment can lead to the induction of apoptosis and pathological damage in both types of mice. MT exhibits a protective effect against DMAA toxicity.

Human male hormonal contraceptive regimens do not consistently induce azoospermia, and the basis of this variable response is unclear. This study used nine adult macaque monkeys (Macaca fascicularis) given testosterone (T) implants for 20 weeks to study changes in germ cell populations in relation to sperm output. Germ cell numbers were determined using the optical disector stereological method. Four animals achieved consistent azoospermia (azoo group), whereas five animals did not (nonazoo group). T-induced gonadotropin suppression in all animals decreased A pale (Ap) spermatogonia to 45% of baseline within 2 weeks, leading to decreased B spermatogonia (32-38%) and later germ cells (20 -30%) after 14 and 20 weeks. Though the reduction in later germ cell types could be primarily attributed to the loss of spermatogonia, the data suggested that some cells were lost during the spermatocyte and spermatid phase of development. B spermatogonial number was more markedly suppressed in azoospermic animals, compared with the nonazoo group, as was the conversion ratio between Ap and B spermatogonia. Abnormal retention of elongated spermatids (failed spermiation) was also prominent in some animals after long-term T administration. We conclude that: 1) the variable suppression of sperm output is attributed to the degree of inhibition of germ cell development from type B spermatogonia onwards, and this is related to the degree of FSH suppression; and 2) inhibition of Ap and B spermatogonial development and of spermiation are the major defects caused by long-term T administration to monkeys. T HE ADMINISTRATION OF exogenous testosterone (T),either alone or in combination with a progestin, reduces the secretion of the pituitary gonadotropins, LH and FSH, and thereby sperm production, and is a promising approach to male contraception (1). A feature of many such contraceptive formulations is the variable induction of azoospermia, ranging from 70 -95%, depending on the regimen and ethnic group under study (1-4). Though sperm counts of less than 3 million per mL may provide adequate contraception (4), there is a general consensus that the reliable induction of azoospermia is important to ensure contraceptive efficacy and the widespread acceptance of male hormonal contraception. An understanding of the biological basis for the variable response is essential to this goal.Although many studies have investigated the effects of hormone suppression on spermatogenesis in the rat (5-7), fewer studies have investigated the effects of FSH and LH/ testicular T suppression on germ cell development in monkeys and man. In monkeys rendered gonadotropin-deficient by hypophysectomy or GnRH antagonist treatment, spermatogonia are the most sensitive germ cell type (8 -11); however, which spermatogonial subtypes are regulated by hormones is controversial (9,(11)(12)(13)(14). A recent study in men receiving weekly injections of T enanthate suggested that the inhibition of spermatogonial development was also the primary lesion in response to go...