Impairment of Spermatogonial Development and Spermiation after Testosterone-Induced Gonadotropin Suppression in Adult Monkeys (Macaca fascicularis)¹

Abstract

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...

Role of Antisperm Antibodies in Infertility, Pregnancy, and Potential for Contraceptive and Antifertility Vaccine Designs: Research Progress and Pioneering Vision

“…Hormonal male contraception essentially involves inducing testosterone deficiency via the suppression of gonadotrophin production [226]. Hormonal contraceptives in men act by decreasing spermatogonia production and increasing apoptosis of spermatocytes and spermatids [227]. These effects can be reversed by withdrawing treatment, making hormonal contraceptives an attractive option and this is one of the most powerful advantages for using them as a contraceptive.…”