Eur J Endocrinol. 2017 Apr;176(4):393-404. doi: 10.1530/EJE-16-0834.

Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.

Grasa MD1,2,3, Gulfo J1, Camps N1, Alcalá R1, Monserrat L1, Moreno-Navarrete JM4,5,3, Ortega FJ4,5,3, Esteve M1,2,3, Remesar X1,2,3, Fernández-López JA1,2,3, Fernández-Real JM4,5,3, Alemany M6,2,3.

1 Department of Biochemistry and Molecular Biomedicine; Faculty of BiologyUniversity of Barcelona, Barcelona, Spain.
2 Institute of BiomedicineUniversity of Barcelona, Barcelona, Spain.
3 CIBER Obesity and NutritionBarcelona/Girona, Spain.
4 University Hospital ‘Dr. Josep Trueta’Girona, Spain.
5 Girona Institute of Biomedical Researchand Hospital of Girona ‘Dr. Josep Trueta’, Spain.
6 Department of Biochemistry and Molecular Biomedicine; Faculty of BiologyUniversity of Barcelona, Barcelona, Spain malemany@ub.edu.

Abstract

OBJECTIVE:

Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.

DESIGN:

Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m2).

METHODS:

SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones.

RESULTS:

Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.

CONCLUSIONS:

The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity. © 2017 European Society of Endocrinology.

PMID:28077498

 

Additional comment on SHBG function according to the available data

In spite of the existence of proteins transporting exclusively androgens in a number of mammal tissues and blood, in humans SHBG has been found to bind both androgens and estrogens. However, there are patent reasons why a single protein, SHBG, could not act as transporter, regulator, inducer opf tissue binding and in fact coordinator of the levels and availability of both active androgens and active estrogens. The levels of each group of steroid hormones is quite different according to sex, age, inflammatory status and a number of physiological and pathologic conditions. However, changes in protein levels are much less extensive. Steroid hormones compete for the SHBG binding sites, but their actual specific binding to the plasma protein is widely different for estradiol and testosterone. In the case of estradiol, binding proportion was far from the physiological level at which SHBG may participate in the control of the hormone levels. SHBG in plasma has been found to be fairly well correlated with testosterone, but not with estradiol.

In addition, different (that is structurally, chemically, different) molecular species of SHBG are commonly present in human plasma, and are largely the consequence of cleavage of part of the protein chain or also carbohydrate chains, by well-regulated mechanisms that have been postulated to modulate SHBG function.

The correlation of hormone binding abilities of normal-weight and obese men and women plasma SHBG with the Western blot measurements of their relative abundance showed that the ratio of protein to binding sites is constant only in normal weight individuals, being grossly altered in the obese, affecting differently the binding of testosterone and estradiol, despite their circulating levels being only slightly changed.

We concluded that there should be at least two “SHBGs”, one more specific (and regulatory) of testosterone and the other doing the same for estrogens. Unfortunately, binding is seldom used in modern studies of SHBG, largely based on immunoreactivity of the molecule, generated under conditions in which the possible differential reactivity against the different molecular weight SHBGs was not even considered. It is suggested, then, to widen our knowledge of this important regulatory agent helping control the availability of circulating active estrogen and androgen by refining the methodology (in part available) to distinguish between at least two SHBG forms, the androgen-prone SHBG and the estrogen-prone SHBG, based on their differential affinity to bind testosterone or estradiol. Only then, the data on SHBG will make sense, since what most studies measure now is the immunoreactivity of the SHBG chain, largely irrespective of its binding (and thus, regulating) abilities.