Hormonal profiles of men with highly elevated SHBG and primary testicular dysfunction support free hormone hypothesis

Free hormone hypothesis (FHH) posits that free testosterone crosses plasma membrane to activate intracellular signaling and is biologically active fraction of circulating testosterone. Widely accepted in other fields, FHH has been debated in andrology.

To disentangle the roles of free and total testosterone, we studied men with greatly elevated sex hormone-binding globulin (SHBG) levels and primary hypogonadism, who had marked divergence in total and free testosterone concentrations, in whom elevated gonadotropins provided independent evidence of primary testicular insufficiency.

Prospective hormonal evaluation of men with greatly elevated SHBG.

Total and free testosterone, LH, FSH, symptom ascertainment.

Among 20 men with SHBG>100 nmol/L, 15 met Endocrine Society's criteria for primary hypogonadism: low free testosterone, one or more symptoms/signs, elevated LH and/or FSH. Among 15 men with elevated LH and/or FSH and unequivocally low free testosterone who met the criteria for primary hypogonadism, 4 had total testosterone that exceeded the reference range (>916 ng/dL) and 8 had total testosterone >450 ng/dL, substantially above the lower normal limit.

In men with markedly elevated SHBG, in whom total and free testosterone diverged substantially, low free testosterone was associated with elevated gonadotropins, providing independent evidence of primary testicular insufficiency even when total testosterone levels were above the reference range or substantially above the lower normal limit. Although sample size was small, these illustrative "n-of-1" observations in uncommon patients are consistent with the primacy of free testosterone over total testosterone in the hypothalamic-pituitary-testicular feedback loop to regulate LH and FSH, and support the FHH.