The SHBG Gene

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The human gene that encodes SHBG is found on the short arm of chromosome 17, comprises 8 exons, and spans 3 kb of genomic DNA (10) and is expressed at high levels in the liver. SHBG gene expression in testicular Sertoli cells produces androgen-binding protein (ABP), with an identical AA sequence but variant glycosylation. SHBG is also expressed in placenta, endometrium, brain, and prostate. So far, not

Table 1

Factors That Influence Circulating Sex Hormone-Binding Globulin Levels

Increase

Decrease

Aging

Prepubertal development

Growth hormone deficiency Obesity

Estrogens

Androgen deficiency Hyperthyroidism

Hyperinsulinema

Glucocorticoids

Androgens

Progestins

Hypothyroidism

Growth hormone excess

Familial

Hepatitis Porphyria much is known about the regulation of the SHBG promoter. Hammond and coworkers reported that the proximal promoter contains a sequence partially homologous with the consensus binding-site for hepatic nuclear transcription factors (hNF). Members of this family are highly expressed in the liver, and the SHBG promoter is activated by HNF-4 in HEPG2 hepatoma cells (11).

The hormonal control of SHBG in plasma is complex. Table 1 lists those factors that are known to decrease or increase plasma SHBG levels. Only insulin (12-14) and thyroxine (15) influence SHBG levels through effects on steady state mRNA levels. One study examined SHBG mRNA levels in orchidectomized monkeys treated with testosterone (16). Whereas testosterone lowered circulating SHBG levels, SHBG mRNA rose, indicating posttranscriptional control. How other factors increase or decrease circulating SHBG levels remains unknown.

SHBG is developmentally regulated, with high levels in newborns that decline in childhood to pubertal levels in both sexes (17,18). Growth hormone (GH) is unlikely to be responsible for this regulation, because an age-related decline, albeit across higher levels, was observed in children with idiopathic hypopituitarism (19). SHBG also declined with age in two siblings with complete androgen insensitivity, implying that the change with maturation is not androgen dependent (20).

Plasma SHBG levels are lower in adult men than in women, presumably because of suppression by androgens and stimulation by estrogens. SHBG levels increase as men grow older (21,22) but are reduced in elderly women (23). The rise in SHBG in elderly men has been attributed to GH deficiency (24), and the decline through menopause has been attributed to a predominating effect of estrogen deficiency.

Glass et al. (25) first reported that circulating testosterone levels are reduced in obese men, and many subsequent studies have confirmed that total testosterone levels decrease as body mass index increases. Because men and women who are hyperandro-genic gain weight predominantly in the abdomen, it is mechanistically interesting to

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