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Cited by 13Sperm and Testicular FunctionHormonal and reproductive studiesGenetic Associations and Epidemiology

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age

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Grigorova, Marina, Punab, Margus, Poolamets, Olev, Adler, Mart, Vihljajev, Vladimir, Laan, Maris·2017·Journal of the Endocrine Society
DOI 10.1210/js.2017-00050PMC PMC5686641
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Abstract

Context: Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men. Objective: To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T. Design, Patients: Groups differing in general and reproductive parameters: young men (n = 540; 19.3 ± 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 ± 6.0 years), and male partners of pregnant women (n = 324; 31.9 ± 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia. Main Outcome Measure(s): Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons. Results: Associations with serum SHBG levels were robust for SHBG −68 G>A [rs1799941; meta-analysis: P = 3.7 × 10−14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 × 10−11; −3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 × 10−4, −12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 × 10−4; −2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 × 10−5; −1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 × 10−3; −2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927. Conclusions: Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.

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  • For the rare homozygous AA genotype of rs1799941, an increase in both serum SHBG and T was observed as opposed to the reference genotype.

    “Second, for the rare homozygous AA genotype of rs1799941, an increase in both serum SHBG and T was observed as opposed to the reference genotype [66, 69, 72, 73].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [66]

    The Results section (“Common SHBG Variants Coregulate Circulating SHBG and Total T”; page not provided) reports higher SHBG and total testosterone in rs1799941 A-allele carriers. It also reports higher SHBG for an AA/CC genotype combination than for GG/TT, but that comparison includes a second variant. The supplied text does not directly establish that AA homozygotes have higher levels of both measures than the reference GG genotype considered alone. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • rs12150660 and rs6258 are located within the SHBG locus and both show a relevant association with SHBG concentration.

    “Additionally, as rs12150660 and rs6258 are located within the SHBG locus, a relevant association with SHBG concentration was demonstrated for both SNPs [65–67].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [66]

    The Methods (D. Genetic Analysis; page not provided) identify rs6258 as an SHBG variant, and the Results report its association with serum SHBG levels (P = 1.2 × 10⁻⁴). The paper does not report rs12150660 or establish its location or association with SHBG concentration, so it supports only one of the two SNPs in the claim. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • For rs6258, a rare missense polymorphism in exon 4 of SHBG, lower concentrations of T were observed for the CT vs CC genotype.

    “For the second SNP, rs6258, a rare missense polymorphism located in exon 4 of SHBG, lower concentrations of T were observed for the CT vs CC genotype.”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [66]

    Results §2.C identifies rs6258 as a rare C>T missense variant in SHBG and reports substantially lower total testosterone in heterozygous carriers than in wild-type carriers, supporting the CT-versus-CC comparison. Our copy does not specify that rs6258 is in exon 4 (page numbers unavailable). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Analysis of genome-wide association data of more than 8000 men identified that two SNPs within the SHBG locus are independently associated with serum T concentrations.

    “Analysis of genome-wide association data of more than 8000 men identified that two SNPs within the SHBG locus are independently associated with serum T concentrations.”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [66]

    The Results section, “Common SHBG Variants Coregulate Circulating SHBG and Total T” (page unavailable), identifies two SHBG variants with low linkage disequilibrium and relates their genotypes to circulating SHBG and T. But the Methods, “Genetic Analysis” (page unavailable), describes targeted genotyping in 1,505 men, not a genome-wide analysis of more than 8,000 men; the cited paper also does not establish the claimed independent associations with T in such a dataset. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • For rs727428, the T allele accounted for a decrease in both SHBG and T levels, without affecting calculated free T.

    “For a third SNP in the SHBG locus, rs727428, the T allele accounted for a decrease in both SHBG and T levels, without affecting calculated free T [66, 68].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [66]

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Authors
Grigorova, M., Punab, M., Poolamets, O., Adler, M., Vihljajev, V., & Laan, M.
Affiliations
  • University of Tartu (EE)
  • Tartu University Hospital (EE)
Corresponding author
Laan, Maris
ORCID
Venue
Journal of the Endocrine Society
Publisher
The Endocrine Society
Published
2017-04-11
Volume
1
Issue
6
Pages
560-576
ISSN
2472-1972 (ISSN-L)
DOI
10.1210/js.2017-00050
PMC
PMC5686641
OpenAlex
W2606865606
Cited by
13
References
2
Citations by year
2025: 1 · 2024: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1
FWCI
1.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the Endocrine Society (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
sex hormone-binding globulin, testosterone, male infertility, genetic variants, GCKR, SLCO1B1, JMJD1C, luteinizing hormone, follicle-stimulating hormone, free testosterone, semen parameters, reproductive hormones

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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