The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis

Abstract

Spermatogenesis is thought to critically depend on the high intratesticular testosterone (T) levels induced by gonadotropic hormones. Strategies for hormonal male contraception are based on disruption of this regulatory mechanism through blockage of gonadotropin secretion. Although exogenous T or T plus progestin treatments efficiently block gonadotropin secretion and suppress testicular T production, only Ϸ60% of treated Caucasian men reach contraceptive azoospermia. We now report that in luteinizing hormone receptor knockout mice, qualitatively full spermatogenesis, up to elongated spermatids of late stages 13-16, is achieved at the age of 12 months, despite absent luteinizing hormone action and very low intratesticular T (2% of control level). However, postmeiotic spermiogenesis was blocked by the antiandrogen flutamide, indicating a crucial role of the residual low testicular T level in this process. The persistent follicle-stimulating hormone action in luteinizing hormone receptor knockout mice apparently stimulates spermatogenesis up to postmeiotic round spermatids, as observed in gonadotropin-deficient rodent models on folliclestimulating hormone supplementation. The finding that spermatogenesis is possible without a luteinizing hormone-stimulated high level of intratesticular T contradicts the current dogma. Extrapolated to humans, it may indicate that only total abolition of testicular androgen action will result in consistent azoospermia, which is necessary for effective male contraception. T he circulating gonadotropins and intratesticular androgens and paracrine factors form the regulatory network of development and function of the male reproductive organs and functions, including spermatogenesis (1). Spermatogenesis is a complex cyclic process, where germ cells undergo mitotic divisions (spermatogonia), meiosis (spermatocytes), and morphological differentiation (spermatids, spermiogenesis) in a delicately regulated spatiotemporal fashion in the seminiferous epithelium. The production of an appropriate number of spermatozoa is considered to depend critically on stimulation of the testes by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (1).The mechanisms by which LH and FSH regulate spermatogenesis continue to be of interest in research on male reproductive endocrinology, infertility, and contraception. The need for LH and FSH in the maintenance of normal spermatogenesis remains a matter of debate (1-3), with different interpretations arising from different experimental models. LH receptor (LHR) is expressed in Leydig cells, and, on ligand binding, it stimulates their steroidogenesis (4). It remains a dogma that the high intratesticular level of T is indispensable for the onset, maintenance, and completion of spermatogenesis in the adult testis and for its restoration after experimentally induced azoospermia.Numerous studies have reported that both FSH and T are required for quantitatively and qualitatively normal spermatogenesis in a variety of mamma...

Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice

“…However, these constant low levels of testosterone did not impair spermatogenesis, consistent with similar findings in the LH receptor KO mice, where intratesticular testosterone is suppressed to 2% of wild type, yet LH-independent autonomous steroidogenesis is sufficient to maintain spermatogenesis (30).…”

“…It is known that testosterone is essential for normal spermatogenesis, but questions remain about the minimum levels required, which varies by species. In mice, only minimal amounts of testosterone are required to maintain spermatogenesis (30), whereas suppression of steroidogenesis in rat, monkey, and human is the basis for the first generation of hormonal contraceptives (31). In addition, studies performed with female PACAP Ϫ/Ϫ mice showed that fertility is affected in these animals (32), raising the possibility that PACAP is likely to be an important regulator of reproductive functions in both males and females.…”

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

“…In conclusion, poorly developed secondary sex characteristics and infertility are observed in both sexes. Further detail about the phenotype of this model are in our previous reports (Zhang et al, 2001a;Zhang et al, 2003;Zhang et al, 2004;Pakarainen et al, 2005c;Pakarainen et al, 2005b;Pakarainen et al, 2005a).…”

Lack of vasoactive intestinal peptide reduces testosterone levels and reproductive aging in mouse testis

“…At the age of 4 months, the VIP KO mice display very low testosterone and lower FSH levels when compared with WT. These two factors are essential for the maintenance of spermatogenesis (Simoni et al 1999, Zhang et al 2003.…”