Expression Levels of Follicle-Stimulating Hormone Receptor and Implication in Diagnostic and Therapeutic Strategy of Ovarian Cancer.

BACKGROUND: Follicle-stimulating hormone receptor (FSHR) has been shown to be expressed in ovarian cancer. METHODS: Here we have summarized the potential therapeutic and diagnostic implication of FSHR in the ovarian cancers based on a review of the literature. RESULTS: Current research indicates that FSHR comprises several variants: FSHR-1, FSHR-2, FSHR-3 and FSHR-4. Only FSHR-1 and FSHR-3 have biological roles. Although the level of FSHR differs in ovarian cancer tissues, few quantitative correlations have so far been reported on the expression levels of FSHR and carcinogenesis and progression of cancers. CONCLUSION: A comprehensive understanding of the role of FSHR in the ovarian cancers may help the search for novel therapeutic and diagnostic regimens and improve the management of cancer patients.

Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models.

Follicle-stimulating hormone (FSH) is critical for ovarian folliculogenesis and essential for female fertility. FSH binds to FSH receptors (FSHRs) and regulates estrogen production in ovarian granulosa cells to orchestrate female reproductive physiology. Ovarian senescence that occurs as a function of aging results in loss of estrogen production, and this is believed to be the major reason for bone loss in postmenopausal women. Although conflicting, studies in rodents and humans during the last decade have provided genetic, pharmacological, and physiological evidence that elevated FSH levels that occur in the face of normal or declining estrogen levels directly regulate bone mass and adiposity. Recently, an efficacious blocking polyclonal FSHß antibody was developed that inhibited ovariectomy-induced bone loss and triggered white-to-brown fat conversion accompanied by mitochondrial biogenesis in mice. Moreover, additional nongonadal targets of FSH action have been identified, and these include the female reproductive tract (endometrium and myometrium), the placenta, hepatocytes, and blood vessels. In this mini-review, I summarize these studies in mice and humans and discuss critical gaps in our knowledge, yet unanswered questions, and the rationale for developing novel genetic models to unambiguously address the extragonadal actions of FSH.

Comparison of the ovarian and uterine reproductive parameters, and the ovarian mRNA and protein expression of LHR and FSHR between the prepubertal and adult female cats.

This study aimed to evaluate and compare the ovarian and uterine characteristics along with the ovarian mRNA and protein expression of LHR and FSHR between the pre-pubertal and adult female cats. The uterine horns and ovaries were collected from pre-pubertal and adult female cats at their follicular, luteal and interoestrous stages of the oestrous cycle (n = 6/group). Endometrial and myometrial thickness, uterine gland diameter, ovarian weight and type of follicles were analysed. The mRNA and protein expression of LHR and FSHR was analysed by IHC and qPCR, respectively. The ovarian weight of pre-pubertal cats was significantly lower than that of adult cats. No differences were recorded in the numbers of primordial and primary follicles between the study groups, while adult luteal cats had significantly lower numbers of antral follicles compared to pre-pubertal cats. No differences in the ovarian expression of FSHR mRNA, LHR protein or mRNA were found between the pre-pubertal and adult cats, but significantly lower FSHR protein expression was found in pre-pubertal cats compared to adult luteal cats.

Is the kisspeptin system involved in responses to food restriction in order to preserve reproduction in pubertal male sea bass (Dicentrarchus labrax)?

Previous works on European sea bass have determined that long-term exposure to restrictive feeding diets alters the rhythms of some reproductive/metabolic hormones, delaying maturation and increasing apoptosis during gametogenesis. However, exactly how these diets affect key genes and hormones on the brain-pituitary-gonad (BPG) axis to trigger puberty is still largely unknown. We may hypothesize that all these signals could be integrated, at least in part, by the kisspeptin system. In order to capture a glimpse of these regulatory mechanisms, kiss1 and kiss2 mRNA expression levels and those of their kiss receptors (kiss1r, kiss2r) were analyzed in different areas of the brain and in the pituitary of pubertal male sea bass during gametogenesis. Furthermore, other reproductive hormones and factors as well as the percentage of males showing full spermiation were also analyzed. Treated fish fed maintenance diets provided evidence of overexpression of the kisspeptin system in the main hypophysiotropic regions of the brain throughout the entire sexual cycle. Conversely, Gnrh1 and gonadotropin pituitary content and plasma sexual steroid levels were downregulated, except for Fsh levels, which were shown to increase during spermiation. Treated fish exhibited lower rates of spermiation as compared to control group and a delay in its accomplishment. These results demonstrate how the kisspeptin system and plasma Fsh levels are differentially affected by maintenance diets, causing a retardation, but not a full blockage of the reproductive process in the teleost fish European sea bass. This suggests that a hormonal adaptive strategy may be operating in order to preserve reproductive function in this species.

Follicle-Stimulating Hormone Increases the Risk of Postmenopausal Osteoporosis by Stimulating Osteoclast Differentiation.

OBJECTIVE: The objectives of this study were to observe the changes in follicle-stimulating hormone (FSH) and bone mineral density (BMD) in postmenopausal women, to research the relationship between FSH and postmenopausal osteoporosis, and to observe the effects of FSH on osteoclast differentiation in RAW264.7 cells. METHODS: We analyzed 248 postmenopausal women with normal bone metabolism. A radioimmunoassay (RIA) was used to detect serum FSH, luteinizing hormone (LH), and estradiol (E2). Dual-energy X-ray absorptiometry was used to measure forearm BMD. Then, we analyzed the age-related changes in serum FSH, LH and E2. Additionally, FSH serum concentrations were compared between a group of postmenopausal women with osteoporosis and a control group. Osteoclasts were induced from RAW264.7 cells in vitro by receptor activator of nuclear factor kappa B ligand (RANKL), and these cells were treated with 0, 5, 10, and 20 ng/ml FSH. After the osteoclasts matured, tartrate-resistant acid phosphatase (TRAP) staining was used to identify osteoclasts, and the mRNA expression levels of genes involved in osteoclastic phenotypes and function, such as receptor activator of NF-κB (Rank), Trap, matrix metalloproteinase-9 (Mmp-9) and Cathepsin K, were detected in different groups using real-time PCR (polymerase chain reaction). RESULTS: 1. FSH serum concentrations in postmenopausal women with osteoporosis increased notably compared with the control group. 2. RANKL induced RAW264.7 cell differentiation into mature osteoclasts in vitro. 3. FSH increased mRNA expression of genes involved in osteoclastic phenotypes and function, such as Rank, Trap, Mmp-9 and Cathepsin K, in a dose-dependent manner. CONCLUSIONS: The circulating concentration of FSH may play an important role in the acceleration of bone loss in postmenopausal women. FSH increases osteoclastogenesis in vitro.

OCT4 mediates FSH-induced epithelial-mesenchymal transition and invasion through the ERK1/2 signaling pathway in epithelial ovarian cancer.

Our previous study showed that Octamer-binding transcription factor 4 (OCT4) expression was upregulated and significantly associated with histological grade through the analysis of OCT4 expression in 159 ovarian cancer tissue samples, and OCT4 mediated follicle-stimulating hormone (FSH)-induced anti-apoptosis in epithelial ovarian cancer. Nevertheless, whether OCT4 participates in FSH-induced invasion in ovarian cancer is still unknown. Therefore, the present study aimed to define whether FSH-induced ovarian cancer invasion is mediated by OCT4. In present study, we showed that FSH induced not only the epithelial-mesenchymal transition (EMT) and invasive phenotype but also the upregulation of OCT4 expression in a dose- and time-dependent manner in epithelial ovarian cancer cells. In addition, the expression of FSH receptor (FSHR) was upregulated by FSH induction, and knockdown of FSHR inhibited FSH-stimulated OCT4 expression. ERK1/2 signaling pathway participated in the enhanced expression of OCT4 and Snail induced by FSH. We further showed that the activated expression of Snail and N-cadherin, the suppressed expression of E-cadherin and the morphological change of the cells stimulated by FSH were blocked by OCT4-specific small interfering RNA. Moreover, our results showed that OCT4 mediated the increase in invasive capacity induced by FSH in ovarian cancer cells. Taken together, our work reveals that OCT4 is an essential mediator in FSH-induced EMT and invasion in epithelial ovarian cancer and may act as a potential therapeutic target.

Follicle stimulating hormone receptor in mesenchymal stem cells integrates effects of glycoprotein reproductive hormones.

Previously we reported that follicle stimulating hormone (FSH) affects bone degradation in human cells and in follicle stimulating hormone receptor (FSH-R) null mice. Here we describe a FSH-R knockout bone-formation phenotype. We used mesenchymal stem cells (MSCs), osteoblast precursors that express FSH-R, to determine whether FSH regulates bone formation. FSH stimulates MSC cell adhesion 1-3 h and proliferation at 24 h after addition. On the basis of phylogenetic and clinical precedents, we also examined effects of pregnant levels of human chorionic gonadotropin (hCG) on MSCs. We found effects similar to those of FSH, and RNAi knockdown of FSH-R abrogated both FSH and hCG effects on MSCs. In contrast to effects on MSCs, neither FSH nor hCG had significant effects on osteoblast maturation. Also in MSCs, short-term treatment by FSH and hCG altered signaling pathways for proliferation, including Erk1/2 phosphorylation. Our results show augmentation of MSC proliferation by either FSH at menopausal levels or hCG at normal pregnant levels. We conclude that FSH-R participates in regulation of MSC precursor pools in response to either FSH or hCG, integrating the effects of these two glycoprotein hormones.

Interleukin-1 deficiency prolongs ovarian lifespan in mice.

Oocyte endowment dwindles away during prepubertal and adult life until menopause occurs, and apoptosis has been identified as a central mechanism responsible for oocyte elimination. A few recent reports suggest that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the proinflammatory cytokine IL-1 in the age-related exhaustion of ovarian reserve using IL-1α and IL-1ß-KO mice. IL-1α-KO mice showed a substantially higher pregnancy rate and litter size compared with WT mice at advanced age. The number of secondary and antral follicles was significantly higher in 2.5-mo-old IL-1α-KO ovaries compared with WT ovaries. Serum anti-Müllerian hormone, a putative marker of ovarian reserve, was markedly higher in IL-1α-KO mice from 2.5 mo onward, along with a greater ovarian response to gonadotropins. IL-1ß-KO mice displayed a comparable but more subtle prolongation of ovarian lifespan compared with IL-1α-KO mice. The protein and mRNA of both IL-1α and IL-1ß mice were localized within the developing follicles (oocytes and granulosa cells), and their ovarian mRNA levels increased with age. Molecular analysis revealed decreased apoptotic signaling [higher B-cell lymphoma 2 (BCL-2) and lower BCL-2-associated X protein levels], along with a marked attenuation in the expression of genes coding for the proinflammatory cytokines IL-1ß, IL-6, and TNF-α in ovaries of IL-1α-KO mice compared with WT mice. Taken together, IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve in mice, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.

Androgen actions in the ovary: balance is key.

For many decades, elevated androgens in women have been associated with poor reproductive health. However, recent studies have shown that androgens play a crucial role in women's fertility. The following review provides an overall perspective about how androgens and androgen receptor-mediated actions regulate normal follicular development, as well as discuss emerging concepts, latest perceptions, and controversies regarding androgen actions and signaling in the ovary.

Loss of follicle-stimulating hormone receptor function causes masculinization and suppression of ovarian development in genetically female medaka.

FSH, a glycoprotein hormone, is circulated from the pituitary and functions by binding to a specific FSH receptor (FSHR). FSHR is a G protein-coupled, seven-transmembrane receptor linked to the adenylyl cyclase or other pathways and is expressed in gonadal somatic cells. In some nonmammalian species, fshr expression is much higher in the ovary than in the testis during gonadal sex differentiation, suggesting that FSHR is involved in ovarian development in nonmammalian vertebrates. However, little is known of FSHR knockout phenotypes in these species. Here we screened for fshr mutations by a medaka (Oryzias latipes) target-induced local lesion in the genomes and identified one nonsense mutation located in the BXXBB motif, which is involved in G protein activation. Next, we used an in vitro reporter gene assay to demonstrate that this mutation prevents FSHR function. We then analyzed the phenotypes of fshr mutant medaka. The fshr mutant male medaka displayed normal testes and were fertile, whereas the mutant female fish displayed small ovaries and were infertile because vitellogenesis was inhibited. The mutant females also have suppressed expression of ovary-type aromatase (cyp19a1a), a steroidogenic enzyme responsible for the conversion of androgens to estrogens, resulting in decreased 17ß-estradiol levels. Moreover, loss of FSHR function caused female-to-male sex reversal in some cases. In addition, the transgenic overexpression of fshr in fshr mutants rescued FSHR function. These findings strongly suggest that in the medaka, FSH regulates the ovarian development and the maintenance mainly by the elevation of estrogen levels. We present the first FSHR knockout phenotype in a nonmammalian species.

Relative mRNA expression and immunolocalization for transforming growth factor-beta (TGF-ß) and their effect on in vitro development of caprine preantral follicles.

This study aimed to evaluate the immunolocalization and messenger RNA (mRNA) expression for transforming growth factor-beta (TGF-ß) and its receptors (TGF-ßRI and RII), as well as mRNA expression for P450 aromatase and FSH receptor in caprine preantral follicles. The effects of TGF-ß, FSH alone, or in association on the in vitro follicular development were also assessed. Immunohistochemical analyses showed the expression of TGF-ß and its receptors in oocytes of all follicle stages and granulosa cells of primary and secondary follicles. mRNA for TGF-ß receptors and for FSH receptor (FSHR) was present in preantral follicles as well as in oocytes and granulosa cells of antral follicles. Isolated secondary follicles were cultured in α-minimum essential medium (MEM) alone or supplemented with either FSH (100 ng/ml), TGF-ß (10 ng/ml), or TGF-ß + FSH for 18 d. TGF-ß increased significantly oocyte diameter when compared to FSH alone and control. After 18 d of culture, all groups showed a significant reduction in P450 aromatase and FSHR mRNA levels in comparison to fresh control. In contrast, treatment with FSH significantly increased the mRNA expression for TGF-ß in comparison to fresh control and other treatments. In conclusion, the findings showed that TGF-ß and its receptors are present in caprine ovarian follicles. Furthermore, they showed a positive effect on oocyte growth in vitro.

[Bone metabolism by sex hormones and gonadotropins].

Pathophysiology of postmenopausal osteoporosis has been considered due to deficiency of estrogen. However, it has been reported that the rate of bone mass loss during perimenopause is greater than that in postmenopause, probably due to increased FSH. From the recent knowledge of basic research on FSH, FSH can directly stimulate osteoclast formation and accelerate bone resorption. In contrast, FSH transgenic mice exhibit increased bone mass dependent on ovarian function. In this review, the controversies on the function of FSH in bone mass regulation will be discussed.

Effect of adenovirus-mediated up-regulation of α-enolase gene products on follicle-stimulating hormone receptor mRNA and luteinizing hormone receptor mRNA of granular cells from goose F1 follicles.

Enolases are glycolytic enzymes in the glycolytic pathway. In order to evaluate the effect of ENO1 on follicle-stimulating hormone receptor (FSHR) mRNA and luteinizing hormone receptor (LHR) mRNA of primary granular cell from goose F1 follicles, the recombinant plasmid adenovirus carrying ENO1 were constructed and infected the primary culture granular cells. The granular cells were randomly divided into three groups: recombinant adenovirus infected (pAd-CMV-ENO1), empty vector infected (pAd-CMV-Null) and no virus (mock control). The expression levels of FSHR mRNA and LHR mRNA of granular cells were examined by qRT-PCR. The results showed the group pAd-CMV-ENO1 had significantly higher FSHR mRNA expression levels than the other two groups (P < 0.05), but had significantly lower LHR mRNA expression levels than the other two groups (P < 0.05). The results suggested that ENO1 could improve the combination rate between FSH and FSHR to accelerate the proliferation and differentiation and steroidogenesis in poultry gonadal tissues.

Reproductive physiology in young men is cumulatively affected by FSH-action modulating genetic variants: FSHR -29G/A and c.2039 A/G, FSHB -211G/T.

Follicle-Stimulating Hormone Receptor (FSHR) -29G/A polymorphism (rs1394205) was reported to modulate gene expression and reproductive parameters in women, but data in men is limited. We aimed to bring evidence to the effect of FSHR -29G/A variants in men. In Baltic young male cohort (n = 982; Estonians, Latvians, Lithuanians; aged 20.2 ± 2.0 years), the FSHR -29 A-allele was significantly associated with higher serum FSH (linear regression: effect 0.27 IU/L; P = 0.0019, resistant to Bonferroni correction for multiple testing) and showed a non-significant trend for association with higher LH (0.19 IU/L) and total testosterone (0.93 nmol/L), but reduced Inhibin B (-7.84 pg/mL) and total testes volume (effect -1.00 mL). Next, we extended the study and tested the effect of FSHR gene haplotypes determined by the allelic combination of FSHR -29G/A and a well-studied variant c.2039 A/G (Asn680Ser, exon 10). Among the FSHR -29A/2039G haplotype carriers (A-Ser; haplotype-based linear regression), this genetic effect was enhanced for FSH (effect 0.40 IU/L), Inhibin B (-16.57 pg/mL) and total testes volume (-2.34 mL). Finally, we estimated the total contribution of three known FSH-action modulating SNPs (FSHB -211G/T; FSHR -29G/A, c.2039 A/G) to phenotypic variance in reproductive parameters among young men. The major FSH-action modulating SNPs explained together 2.3%, 1.4%, 1.0 and 1.1% of the measured variance in serum FSH, Inhibin B, testosterone and total testes volume, respectively. In contrast to the young male cohort, neither FSHR -29G/A nor FSHR haplotypes appeared to systematically modulate the reproductive physiology of oligozoospermic idiopathic infertile patients (n = 641, Estonians; aged 31.5 ± 6.0 years). In summary, this is the first study showing the significant effect of FSHR -29G/A on male serum FSH level. To account for the genetic effect of known common polymorphisms modulating FSH-action, we suggest haplotype-based analysis of FSHR SNPs (FSHR -29G/A, c.2039 A/G) in combination with FSHB -211G/T testing.

Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: evidence for its ability to support follicular development and ovulation.

FSH signalling through its cognate receptor is critical for follicular development and ovulation. An earlier study had documented thiazolidinone derivatives to activate FSH receptor expressed in CHO cells and rat granulosa cells; however development of this compound for clinical use was halted for unobvious reasons. The objective of the current study is to extend the previous investigations in detail on the ability of thiazolidinone derivative (henceforth referred to as Compound 5) to activate FSH signalling and learn the barriers that preclude development of this derivative for clinical purposes. Our results demonstrate that the Compound 5 in a dose-dependent manner stimulated cAMP production, activated AKT and ERK signalling pathways and induced estradiol production in cultured rat granulosa cells. Compound 5 also caused dose-dependent increase in estradiol production from human granulosa cells. In increasingly more complex in vitro systems, Compound 5 was able to induce the expansion of mouse cumulus-oocyte-complex and support in vitro development of mouse preantral follicle to preovulatory stage and release of oocyte from the follicle. In vivo, the compound stimulated preovulatory follicular development and ovulation in immature rats. Pharmacokinetic and safety investigations reveal poor oral availability and genotoxicity. Together, our results document Compound 5 to act as a FSHR allosteric modulator but have poor pharmacological properties for development of an oral FSH receptor modulator.

Mechanisms in endocrinology: Genetics of FSH action: a 2014-and-beyond view.

OBJECTIVE: To assess the pharmacogenetic potential of FSH for infertility treatment. DESIGN: Review of the literature and genomic databases. METHODS: Single-nucleotide polymorphism (SNP) assessed: rs6166 (c.2039A>G, p.N680S), rs6165 (c.919A>G, p.T307A), rs1394205 (c.-29G>A) in FSHR, and rs10835638 (c.-211G>T) in FSHB. Literature search via PubMed. Blast analysis of genomic information available in the NCBI nucleotide database. Comparison of allele frequency and haplotype distribution using the http://spsmart.cesga.estool. RESULTS: All these SNPs appear first in Homo, result in reduced FSH action, and are present with variable frequencies and combinations worldwide. Stringent clinical studies demonstrate that the FSHR genotype influences serum FSH levels and gonadal response in both sexes. Serum FSH levels depend on the -211G>T SNP, influencing transcriptional activity of the FSHB promoter. Genotypes reducing FSH action are overrepresented in infertile subjects. CONCLUSIONS: Although the clinical relevance of the FSHR polymorphisms alone is limited, the combination of FSHR and FSHB genotypes has a much stronger impact than either one alone in both sexes. About 20% of people are carriers of the alleles associated with lower serum FSH levels/reduced FSHR expression or activity, possibly less favorable for reproduction. Prospective studies need to investigate whether stratification of infertile patients according to their FSHR-FSHB genotypes improves clinical efficacy of FSH treatment compared with the current, naïve approach. A relative enrichment of less favorable FSHR-FSHB genotypes may be related to changes in human reproductive strategies and be a marker of some health-related advantage at the cost of reduced fertility.

Toxicity of cadmium on Sertoli cell functional competence: an in vitro study.

Cadmium (Cd), an ubiquitous environmental metal, mainly used for industrial purposes, may be toxic at level of the reproductive system. Testis tubular-based Sertoli cells (SC), play a major role in constituting the blood-testis barrier and provide a unique microenvironment for the genesis and differentiation of germ cells. Hence SC strictly control sperm qualitative and quantitative parameters. We aimed to assess whether exposure to Cd would adversely affect superior mammal SC viability and function. We isolated and purified SC from pre-pubertal pig testes according to our method and incubated the retrieved cells with three different Cadmium chloride concentrations (5-10-15 microM). Parameters of SC function such as inhibin B and anti-Mullerian hormone (AMH) were depressed by Cd exposure, contrary to what observed in untreated controls. No impairment of the FSH receptor integrity on the SC, as assessed by 17-beta-estradiol production, upon stimulation with FSH, was observed in either 5 microM Cd-treated or untreated controls. Differences, on the contrary, were observed for higher Cd concentrations (10 and 15 mM), in terms of FSH receptor integrity, that was altered, as compared to untreated controls, in terms of lower production of 17-beta-estradiol. In addition, the apoptotic test showed a significant increase of early (ANNEXIN V-/Propidium Iodide+) (AV-/PI+) and late apoptotic cells (AV+/ PI+) in all Cd -treated SC conditions as compared to controls. In conclusion, the Cd -related toxicity on SC, clearly demonstrated by our study, even at low concentrations, is expected to damage spermatogenesis that directly is dependent upon retention of SC viability and function.

Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common complex genetic endocrinopathy. It has high heritability, and twin studies indicate that it is a complex polygenic disorder. Searching for major genes of PCOS is crucial to clarify its molecular pathogenesis. A previous genome-wide association study in Chinese women with PCOS identified a region on chromosome 2p16.3 that encodes the follicle-stimulating hormone receptor (FSHR) genes as a reproducible PCOS susceptibility locus. In the present study, we performed a replication analysis of the association between two common variants of the FSHR gene and PCOS in Northern Chinese Han women. RESULTS: We recruited 384 unrelated PCOS patients and 768 healthy individuals from the Shaanxi province in the northern part of China. Two polymorphisms (Ala307Thr and Ser680Asn) of the FSHR gene and the clinical characteristics of the study subjects were analyzed in the case-control sample. The frequency of FSHR Ala307Thr and Ser680Asn variants along with the haplotype was not significantly different between the PCOS patients and the controls; however, the Ser680 variants may be associated with high levels of FSH and low E2 levels. CONCLUSION: The variant of Ser680 was not associated with PCOS but it may be related to high FSH levels. The present study suggests that the two variants of the FSHR gene are not a causative factor of PCOS in Northern Chinese Han women.

Gonadotropin resistance.

Pituitary gonadotropins are essential for normal reproductive function. LH and FSH exert their effects by acting on G protein-coupled receptors. Pituitary LH and placental hCG share the same receptor (LHCGR). Homozygous or compound heterozygous inactivating mutations of LHCGR are associated with a phenotypic spectrum from female or ambiguous external genitalia due to Leydig cell hypoplasia to micropenis, hypergonadotropic hypogonadism and delayed puberty in genetic males. Testes size is slightly reduced, and testosterone levels are low in affected males. Interestingly, the clinical phenotypes are closely correlated with the severity of the mutation. In females, the phenotype is also variable and can range from primary amenorrhea to oligoamenorrhea, associated with constant infertility. Estradiol and progesterone levels remain in the early to mid-follicular phase, whereas the ovaries are normal or enlarged with cysts. In both sexes, LH levels are increased, whereas FSH is usually normal. Inactivating mutations of FSH receptor are associated with partial to complete premature ovarian failure in women and variable impairment of spermatogenesis and small testes in men. Mutations of the human gonadotropin receptors provide natural models for elucidating the differential effects of LH and FSH on the gonads.

Synergistic effect of follicle-stimulating hormone receptor and androgen receptor gene variants on semen quality.

Follicle-stimulating hormone (FSH), interacting with its receptor (FSHR), participates in the production of spermatozoa and androgens. Androgens exert their effects on male sex determination, development and sperm production by binding to androgen receptor (AR). In the present study, we sought to explore the potential synergistic effects of FSHR and AR gene variants on sperm quality. 200 oligozoospermic and 250 normozoospermic men were examined. DNA was extracted from spermatozoa, and the FSHR 307 (T/A), FSHR 680 (N/S) and AR (CAG)n polymorphisms were genotyped. Their parallel analysis revealed six combined genotypes. A gradual reduction of sperm motility, from long AR allele-Thr307Thr/Asn680Asn carriers to long AR allele-Ala307Ala/Ser680Ser carriers and from short AR allele-Thr307Thr/Asn680Asn carriers to short AR allele-Ala307Ala/Ser680Ser carriers was revealed in normozoospermic men (P < 0.001). Similar associations were observed in oligozoospermic men (P < 0.001). In our series, the synergism of the long AR alleles with the FSHRThr307/Asn680 allelic variant was associated with increased sperm motility, while the synergism of the short AR alleles with the FSHRAla307/Ser680 allelic variant was associated with decreased motility, supporting the significance of these genes in semen quality.