Sex hormone-binding globulin levels linked with genetic variants in men

Serum sex hormone-binding globulin levels in both fertile and infertile men were associated with four different genetic variants, researchers from Estonia found.

“Despite the rising importance in personalized patient management in the clinical practice, the current understanding of common genetic variation contributing to male reproductive hormone levels is moderate,” Marina Grigorova, PhD, research fellow of human molecular genetics at the institute of biomedicine and translational medicine at the University of Tartu, and colleagues wrote. “So far, there are no acknowledged genetic variants with clear-cut clinical implications that modulate male [testosterone] levels. However, recent genome-wide association studies have extensively targeted the genetic determinants of both circulating total [testosterone] and the key modulator of free [testosterone], sex hormone-binding globulin.”

The researchers analyzed genetic associations between serum levels of sex hormone-binding globulin and testosterone, and seven genetic variants, including variants in GCKR, SLCO1B1, JMJD1C and four variants in the SHBG gene. Grigorova and colleagues reviewed data from men from three groups recruited at the Andrology Center of Tartu University Hospital, Estonia: young men (n = 540; mean age, 19.3 years), patients with severe idiopathic male infertility (n = 641; mean age, 31.6 years) and male partners of women who were pregnant (n = 324; mean age, 31.9 years).

Grigorova and colleagues reported robust associations between serum sex hormone-binding globulin levels and SHBG -68 G>A (meta-analysis, P = 3.7 x10^-4), SHBG +1091 C>T (P = 7.3 x10^-11), SHBG Pro185Leu (P = 1.2 x10^-4) and GCKR Pro446Leu (P = 1.5 x10^-4). Measured testosterone concentrations were correlated with genetically modulated serum sex hormone-binding globulin levels (P < .0001), the researchers wrote. Substitution of SHBG Pro185Leu had an “additional downstream effect” on luteinizing hormone (P = 5.1 x10^-5) and follicle-stimulating hormone (P = 3.4 x10^-3) among infertile men.

“In summary, we have robustly replicated the association with serum sex hormone-binding globulin for four of seven analyzed genetic variants,” Grigorova and colleagues wrote. “Our study alerts to investigations on the role of genetically determined level of [testosterone] in reproductive and general health of aging men, in predisposition to hypotestosteronemia and pharmacogenetics of hormone replacement therapy in male infertility and hypogonadism.” – by Andy Polhamus

Disclosure: The researchers report no relevant financial disclosures.