The regulation of female reproductive behaviors may involve memories of male pheromone signatures, formed in part by neural circuitry involving the olfactory bulb and hippocampus. These neural structures are the principal sites of adult neurogenesis; however, previous studies point to their independent regulation by sensory and physiological stimuli. Here we report that the pheromones of dominant (but not subordinate) males stimulate neuronal production in both the olfactory bulb and hippocampus of female mice, which are independently mediated by prolactin and luteinizing hormone, respectively. Neurogenesis induced by dominant-male pheromones correlates with a female preference for dominant males over subordinate males, whereas blocking neurogenesis with the mitotic inhibitor cytosine arabinoside eliminated this preference. These results suggest that male pheromones are involved in regulating neurogenesis in both the olfactory bulb and hippocampus, which may be important for female reproductive success.

We recently demonstrated that the sexual development of LH receptor (LHR) knockout mice is normal until birth, but is totally arrested thereafter. To study further the functional defects of LHR knockout mice, the expression of selected Leydig cell-specific genes was studied in (-/-) and control (+/+) mice between birth and adulthood. Testis weights were similar at birth in both types of mice, but after about 3 wk, the (-/-) testes remained significantly lighter, weighing only 18% of (+/+) testes on d 70. Testicular testosterone (T) content on d 1 was also similar in (-/-) and (+/+) testes, but it was 97% reduced by d 70 in the former. Likewise, testicular T production in vitro was similar in neonatal (-/-) and (+/+) testes, but became undetectable in adult (-/-) testes. The mRNA expression of cytochrome P450 side-chain cleavage, 17 alpha-hydroxylase cytochrome P450, 17 beta-hydroxysteroid dehydrogenase type III, 3 beta-hydroxysteroid dehydrogenase I (3 beta HSDI), steroidogenic acute regulatory protein, and relaxin-like factor were similar in newborn (-/-) and (+/+) testes, but became gradually very low/undetectable in (-/-) mice. The only exception was the persistently high expression of 3 beta HSDI in peritubular Leydig precursor and mesenchymal cells of the (-/-) testes at all ages. Immunohistochemistry and Western hybridization studies confirmed the above findings. In conclusion, LH action is not essential for the differentiation and function of mouse fetal Leydig cells, but, with the exception of 3 beta HSDI, the expression of the key genes of endocrine function of adult Leydig cells is dependent on LH signaling.

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...

Testosterone (T) is essential for spermatogenesis, fertility, and maintenance of the male phenotype. We analyzed in hypogonadal LH receptor knockout (LuRKO) male mice whether T treatment can restore their phenotype, spermatogenesis, and fertility. In LuRKO mice, spermatogenesis is arrested at round spermatids, adult-type Leydig cells are absent, T production is dramatically decreased, the animals are cryptorchid, and their accessory sex organs are atrophic. T replacement therapy from 21 d of life for 60 or 120 d in LuRKO mice induced a male phenotype macroscopically indistinguishable from that of wild-type littermates as well as full spermatogenesis and testicular descent. Thus, the absence of LH-dependent prepubertal androgen priming is not necessary for subsequent maturation of the male phenotype. Conspicuously, some abnormalities remained in epididymal histology after T treatment despite normal expression of several epididymis-specific genes in caput epididymis. The mice displayed normal mating behavior, although at lower frequency than wild-type controls. The spermatozoa were able to fertilize oocytes, but their impaired passage from epididymis to uterus was apparent. The mice remained subfertile, because only 9% of all breedings resulted in pregnancy, and only two of 13 mice (15%) were fertile. Moreover, inflammation in epididymides and prostate was found in many T-treated LuRKO mice, which probably impaired sperm transport and contributed to their high rate of subfertility. In conclusion, T replacement initiated prepubertally only partially restores the fertility of LuRKO mice, even though most features of the male phenotype recover. Full fertility may require higher and/or earlier postnatal T exposure or production of other Leydig cell factors lacking in this model.