Targeting Gonadotropin Receptor Genes: Reproductive Biology, Aging, and Related Health Implications

Abstract

This review highlights observations gleaned from recent reports on the deletion of FSH and LH receptors in mice. Gonadal differentiation does not depend on the presence of gonadotropin receptors but development is affected to varying degrees in both sexes. In both knockouts the null females are infertile with severely underdeveloped gonads and accessory structures. Sexual maturity and/or pubertal delay occur depending on the sex and knockout. Male null FSH-R mice have reduced fertility but null LH-R males are sterile due to cryptorchid testes and deficient spermatogenesis. In null FSH-R females hormonal imbalances are due to deficient estrogen and hyperandrogenemia. LH-R deficient females have low estrogen and testosterone. Females in both knockouts display phenotypes such as obesity, bone deficiency, and changes in brain structure and function in addition to manifestation of different types of reproductive tract tumors. Both types of mice represent good models for testing hormone replacement therapy in different combinations. The FSH-R heterozygous females could also be useful for studying age-dependent phenotypes.

FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women

“…However, mice with partial loss of Fsh-r gene develop a phenotype similar to that observed in null Fsh-r knockout mice, even though, in the former case, the development of this peculiar phenotype is age dependent. This observation suggests that a partial loss in the cell surface expression of FSHR may be associated with an age-dependent occurrence of related biological changes (33).…”

“…The first nine exons encode the extracellular domain of the receptor, whereas exon 10 of FSHR encodes the C-terminal end of the extracellular domain, the entire transmembrane domain, and the intracellular domain that is fundamental for signal transduction. Residue 680 is located in the intracellular, C-terminal domain of the receptor, in a region which is highly variable among the three glycoprotein hormone receptors (FSHR, LH receptor, and TSH receptor) (32,33). To date, the functional role of residue 680 has yet to be characterized, but studies in women with normal ovarian function demonstrated that this SNP in exon 10 modulates FSHR function and the cellular response to FSH administration.…”

“…These differences in ovarian response of women with the 'resistant' variant of the FSHR are subtle and do not impair the capacity of their follicles to ovulate. However, only in the case of pharmaceutical stimulation does the difference become clinically evident (22,23,(32)(33)(34)(35)(36)(37). Interestingly, the hormonal profile of postmenopausal women is characterized by increased FSH serum levels which chronically stimulate FSHresponsive tissues, including bone, with a greater extent than in premenopausal women.…”

FSHβ knockout mouse model: a decade ago and into the future

“…In parallel to our work with the FSH ligand null model, Drs. Sairam and colleagues [37, 38] and Abel et al [39] have significantly contributed to the role of FSH signaling in gonads using their FSH-receptor knockout mouse models. Recent work with FSH action in bone has ignited research interests in many labs.…”

Differential time course of FSH/FSH receptor complex endocytosis within sertoli and germ cells during rat testis development

“…FSH is a key hormone of spermatogenesis (Sofikitis et al, 2008) and its essential role has been demonstrated by the use of knock-out mouse models for the FSH b-subunit and the FSH-receptor (Sairam and Krishnamurthy, 2001;Danilovich and Sairam, 2005). Spermatogenesis is dependent upon the presence of the somatic Sertoli cells that produce essential elements required for germ cell proliferation and differentiation (Griswold, 1998).…”