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Cited by 109Ovarian function and disordersSexual Differentiation and DisordersHormonal and reproductive studies

Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction

Hogeveen, Kevin N., Cousin, Patrice, Pugeat, Michel, Dewailly, Didier, Soudan, Benoît, Hammond, Geoffrey L.·2002·Journal of Clinical Investigation
DOI 10.1172/jci0214060
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Abstract

The access of testosterone and estradiol to target tissues is regulated by sex hormone–binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non–protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband's maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband's paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to hyperandrogenism and ovarian dysfunction.

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  • Abnormal levels of SHBG and mutations altering the affinity for its ligands are associated with androgen excess and a PCOS phenotype, but have also been implicated in the pathogenesis of cancer and metabolic dysfunction.

    “Abnormal levels of SHBG and mutations altering the affinity for its ligands are associated with androgen excess and a PCOS phenotype, but have also been implicated in the pathogenesis of cancer and metabolic dysfunction (Hammond, 2016, Hogeveen et al., 2002).”

    From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Hogeveen et al., 2002

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Authors
Hogeveen, K. N., Cousin, P., Pugeat, M., Dewailly, D., Soudan, B., & Hammond, G. L.
Affiliations
  • Western University (CA)
  • Inserm (FR)
  • Centre Hospitalier Universitaire de Lille (FR)
Corresponding author
Hammond, Geoffrey L.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2002-04-01
Volume
109
Issue
7
Pages
973-981
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci0214060
OpenAlex
W4243534847
Cited by
107
References
35
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 3
FWCI
7.02
Type
journal article
Language
en
Open access
closed
Locations
Journal of Clinical Investigation (publishedVersion)
Funders
  • Fondation de France
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
sex hormone-binding globulin, hyperandrogenism, polycystic ovary syndrome, ovarian dysfunction, ovarian failure, hirsutism, missense mutations, glycosylation, protein secretion, single nucleotide polymorphisms, frameshift mutation, compound heterozygosity, pregnancy

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