Genetically Determined Dosage of Follicle-Stimulating Hormone (FSH) Affects Male Reproductive Parameters

Abstract

Context:The detailed role of FSH in contributing to male testicular function and fertility has been debated. We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, −211 bp from the mRNA start) and significantly reduced male serum FSH.Objective:In the current study, the T-allele carriers of the FSHB −211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action.Design and Subjects:We genotyped rs10835638 in the population-based Baltic cohort of young men (n = 1054; GG carriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center.Results:Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10−6; T-allele effect, −0.41 IU/liter), inhibin-B (P = 2.16 × 10−3; T-allele effect, −14.67 pg/ml), and total testosterone (P = 9.30 × 10−3; T-allele effect, −1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 × 10−4; TT genotype effect, −9.47 ml) and increased serum LH (P = 2.25 × 10−2; TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations.Conclusion:We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential.

MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

“…This was then amply confirmed in German and Italian men (62,63). In accordance with the epidemiological and in vitro data reported above, homozygous carriers of the minor allele represent only 1.5% of men with normal semen parameters but have serum FSH levels which are about 25% lower than homozygous, major allele carriers (11,62,64). In addition, this polymorphism is associated with lower testicular volume, lower sperm count, lower testosterone, and higher LH serum levels (11,62,63,64,65).…”

“…One study showed that patients with at least one FSHR c.2039AOG G allele had a significant increase in total sperm count after 3 months of treatment with rFSH (150 IU/thrice per week) (83). Another study considered the FSHB K211GOT genotype and showed that TT homozygotes, representing 25% of men with oligozoospermia and low FSH levels, could significantly benefit from FSH treatment (64). No study has addressed the combination of the two genotypes …”

Hormone-Based Treatments in Subfertile Males

“…Several studies have suggested that hormone levels may be heritable and may predispose individuals to subclinical HH [23,[83][84][85][86][87]. Additionally, polymorphisms in the androgen receptor and trinucleotide repeats may account for a large proportion of the subclinical HH.…”

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

“…SNP‐trait association tests were performed using linear regression, assuming an additive genetic model. In the Baltic cohort, regression testing was adjusted for age, BMI, smoking status, recruitment centre; hormone measurements were additionally corrected for blood sampling hour, and semen parameters were corrected for ejaculation abstinence period according to the analysis settings described previously (Table S1; Grigorova et al ., 2011). In the study group of Estonian idiopathic infertility patients, adjustment for age was applied for all parameters and abstinence period was used as an additional confounder in association tests with semen parameters.…”