Abstract
Spermatogenesis and folliculogenesis involve cell–cell interactions and gene expression orchestrated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH regulates the proliferation and maturation of germ cells independently and in combination with LH. In humans, the requirement for high intratesticular testosterone (T) concentration in spermatogenesis remains both a dogma and an enigma, as it greatly exceeds the requirement for androgen receptor (AR) activation. Several data have challenged this dogma. Here we report our findings on a man with mutant LH beta subunit (LHβ) that markedly reduced T production to 1–2% of normal., but despite this minimal LH stimulation, T production by scarce mature Leydig cells was sufficient to initiate and maintain complete spermatogenesis. Also, in the LH receptor (LHR) knockout (LuRKO) mice, low-dose T supplementation was able to maintain spermatogenesis. In addition, in antiandrogen-treated LuRKO mice, devoid of T action, the transgenic expression of a constitutively activating follicle stimulating hormone receptor (FSHR) mutant was able to rescue spermatogenesis and fertility. Based on rodent models, it is believed that gonadotropin-dependent follicular growth begins at the antral stage, but models of FSHR inactivation in women contradict this claim. The complete loss of FSHR function results in the complete early blockage of folliculogenesis at the primary stage, with a high density of follicles of the prepubertal type. These results should prompt the reassessment of the role of gonadotropins in spermatogenesis, folliculogenesis and therapeutic applications in human hypogonadism and infertility.
Highlights
We summarize the information on the gonadotropin-driven regulation of spermatogenesis and folliculogenesis, and present results from our studies on patients with genetic defects in LHβ and follicle stimulating hormone receptor (FSHR), as well as on genetically modified rodent models
The increased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) causes the development of a second wave of Leydig cells, and the appearance of a peak of T at levels close in magnitude to those observed at puberty
The direct action of FSH and LH are produced through specific G protein-coupled membrane receptors (GPCR), FSHR [17] and LH receptor (LHR) (LHCGR in humans) [18,19,20], expressed respectively in the Sertoli cells of the testes and granulosa cells of the ovaries or in the Leydig cells of the testes and thecal and luteal cells of the ovaries [5,21,22,23,24]
Summary
The most important of these regulatory pathways involves the hypothalamic-pituitary-gonadal (HPG) axis, which coordinates essential functions through the action of the heterodimeric glycoproteins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the maintenance of high intratesticular testosterone (ITT) concentration. The increased secretion of LH and FSH causes the development of a second wave of Leydig cells, and the appearance of a peak of T at levels close in magnitude to those observed at puberty. This event, called “mini-puberty”, is short-lived, and its role is poorly understood. The third wave starts at puberty and lasts for the rest of a man’s life
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