Serum sex hormone–binding globulin, a determinant of cardiometabolic disorders independent of abdominal obesity and insulin resistance in elderly men and women

Serum sex hormone–binding globulin, a determinant of cardiometabolic disorders independent of abdominal obesity and insulin resistance in elderly men and women

Abstract

Serum sex hormone–binding globulin (SHBG) is related to cardiometabolic disorders; but whether or not this relationship is purely secondary to hyperinsulinemia and/or obesity, which down-regulates SHBG, is unknown. The aim of the study was to investigate the association of SHBG and total testosterone with atherogenic dyslipidemias, metabolic syndrome (MS), and diabetes among predominantly elderly Turkish adults. After appropriate exclusions, 777 randomly selected male and female subjects with available measurements of both variables were eligible and were analyzed cross-sectionally, with diabetic subjects analyzed separately. Free testosterone was calculated. Metabolic syndrome was identified by the modified criteria of the Adult Treatment Panel III. Metabolic syndrome was identified in half the sample, which had a median age of 58 years. The odds of low SHBG concentrations (<45 nmol/L in men, <55 nmol/L in women) for the likelihood of 2 types of dyslipidemias, MS, and diabetes were examined by regression analyses in standard models including age, smoking status, presence of abdominal obesity, and insulin resistance (homeostasis model assessment of insulin resistance). In both sexes, low SHBG was associated independently with high triglyceride/low high-density lipoprotein dyslipidemia and with MS, at significant 2.2- to 4.5-fold odds ratios, independent of waist circumference or homeostasis model assessment of insulin resistance index. Low SHBG among women was additionally associated with the likelihood of hypertriglyceridemia with elevated apolipoprotein B and—at borderline significance—with that of diabetes, again when adjusted for the same confounders. In an elderly population with prevalent MS, low SHBG levels significantly associate with high triglyceride/low high-density lipoprotein dyslipidemia, MS, and, in women alone, diabetes and a dyslipidemia marking small dense low-density lipoprotein particles, all independent of abdominal obesity and insulin resistance. Low SHBG may be an important independent factor for cardiometabolic risk, particularly in women.
Article Outline

The liver produces plasma sex hormone–binding globulin (SHBG), which transports sex steroids and regulates their access to tissues. In overweight children and adults, low plasma SHBG levels are a biomarker of the metabolic syndrome and its associated pathologies. Here, we showed in transgenic mice and HepG2 hepatoblastoma cells that monosaccharides (glucose and fructose) reduce human SHBG production by hepatocytes. This occurred via a downregulation of hepatocyte nuclear factor–4α (HNF-4α) and replacement of HNF-4α by the chicken OVA upstream promoter–transcription factor 1 at a cis-element within the human SHBG promoter, coincident with repression of its transcriptional activity. The dose-dependent reduction of HNF-4α levels in HepG2 cells after treatment with glucose or fructose occurred in concert with parallel increases in cellular palmitate levels and could be mimicked by treatment with palmitoyl-CoA. Moreover, inhibition of lipogenesis prevented monosaccharide-induced downregulation of HNF-4α and reduced SHBG expression in HepG2 cells. Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4α levels, which in turn attenuated SHBG expression. This provides a biological explanation for why SHBG is a sensitive biomarker of the metabolic syndrome and the metabolic disturbances associated with increased fructose consumption.

Reduced levels of circulating sex hormone-binding globulin (SHBG) are implicated in the etiology of sex steroid-related pathologies and the metabolic syndrome. Dietary correlates of serum SHBG remain unclear and were studied in a convenient cross-sectional sample of healthy 30- to 40-y-old women (n = 255). By univariate analyses, serum SHBG correlated negatively with several indices of the metabolic syndrome, such as BMI, waist circumference, hip circumference (r = −0.36 to −0.44; P < 0.0001), fasting serum insulin (r = −0.41; P < 0.0001), serum triglycerides (r = −0.27; P < 0.0001), serum glucose (r = −0.23; P < 0.001), and plasma testosterone (r = −0.19; P = 0.002). Serum SHBG correlated positively with serum HDL-cholesterol (r = 0.33; P < 0.0001), plasma progesterone (r = 0.17; P = 0.007), and dietary intake of β-tocopherol (r = 0.17; P = 0.006), and negatively with that of fructose (r = −0.13; P = 0.04). Principal component analysis (PCA) extracted 12 nutrient factors with eigenvalues > 1.0 from 54 nutrients and vitamins in food records. Multivariate regression analyses showed that the PCA-extracted nutrient factor most heavily loaded with β-tocopherol and linoleic acid (P = 0.03) was an independent positive predictor of serum SHBG. When individual nutrients were the predictor variables, β-tocopherol (P = 0.002), but not other tocopherols or fatty acids (including linoleic acid), was an independent positive predictor of serum SHBG. Circulating insulin (P = 0.02) and waist circumference (P = 0.002), but not serum lipids, were negative independent predictors of SHBG in all regression models. Additional studies are needed in women of other age groups and men to determine whether consumption of foods rich in β-tocopherol and/or linoleic acid may increase serum SHBG concentrations and may thereby decrease the risk for metabolic syndrome and reproductive organ cancer.

Association of vitamin D status with serum androgen levels in men.
Wehr E, Pilz S, Boehm BO, März W, Obermayer-Pietsch B.
Source

Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University Graz, Graz, Austria.
Abstract
OBJECTIVE:

Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D.
DESIGN:

In this cross-sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997-2000).
MEASUREMENTS:

Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmol/l)/SHBG (nmol/l) x 100.
RESULTS:

Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29.9 microg/l) and 25(OH)D-deficient (<20 microg/l) men (P < 0.05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0.05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12.2 microg/l, 15.9 nmol/l and 40.8, respectively) and peak levels in August (23.4 microg/l, 18.7 nmol/l and 49.7, respectively) (P < 0.05 for all).
CONCLUSION:

Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels.

mphatesmpb wrote:
Also, vitamin D levels are associated with decreased SHBG and higher concentrations free androgens.

Foodjobber wrote:These studies are all very interesting.

One concern I have though is the possible negatives of SHBG. For example, it is commonly accepted in places like body building forums (though rarely backed up with citations as far as I've seen), that SHBG reduces the positive impact of androgens on muscle development, libido and erectile function.

Are you aware of any studies that demonstrate whether this actually is the case?

Personally I'm as interested in having a functioning penis as I am in having a healthy head of hair!

That's not really a good thing is it?

I heard that low SHBG in young people doesn't help with their hair loss.

When you say free androgens do you mean DHT as well? If so then if someone who is young and experiencing mpb takes vitamin D, wouldn't they notice an increase in the "itch" that a lot people report when suffering from hair loss?

These studies are all very interesting.

One concern I have though is the possible negatives of SHBG. For example, it is commonly accepted in places like body building forums (though rarely backed up with citations as far as I've seen), that SHBG reduces the positive impact of androgens on muscle development, libido and erectile function.

Are you aware of any studies that demonstrate whether this actually is the case?

Personally I'm as interested in having a functioning penis as I am in having a healthy head of hair! Wink

Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
Chiu KC, Chu A, Go VL, Saad MF.
Source

Division of Clinical Epidemiology and Preventive Medicine, Department of Medicine, University of California-Los Angeles School of Medicine, 924 Westwood Boulevard, Los Angeles, CA 90024, USA. kchiu@mednet.ucla.edu
Abstract
BACKGROUND:

Although the role of vitamin D in type 2 diabetes is well recognized, its relation to glucose metabolism is not well studied.
OBJECTIVE:

We investigated the relation of 25-hydroxyvitamin D [25(OH)D] concentrations to insulin sensitivity and beta cell function.
DESIGN:

We enrolled 126 healthy, glucose-tolerant subjects living in California. Insulin sensitivity index (ISI) and first- and second-phase insulin responses (1stIR and 2ndIR) were assessed by using a hyperglycemic clamp.
RESULTS:

Univariate regression analyses showed that 25(OH)D concentration was positively correlated with ISI (P < 0.0001) and negatively correlated with 1stIR (P = 0.0045) and 2ndIR (P < 0.0001). Multiple regression analyses confirmed an independent correlation between 25(OH)D concentration and ISI (P = 0.0007). No independent correlation was observed between 25(OH)D concentration and 1stIR or 2ndIR. However, an independent negative relation of 25(OH)D concentration with plasma glucose concentration was observed at fasting (P = 0.0258), 60 min (P = 0.0011), 90 min (P = 0.0011), and 120 min (P = 0.0007) during the oral-glucose-tolerance test. Subjects with hypovitaminosis D (<20 ng/mL) had a greater prevalence of components of metabolic syndrome than did subjects without hypovitaminosis D (30% compared with 11%; P = 0.0076).
CONCLUSIONS:

The data show a positive correlation of 25(OH)D concentration with insulin sensitivity and a negative effect of hypovitaminosis D on beta cell function. Subjects with hypovitaminosis D are at higher risk of insulin resistance and the metabolic syndrome. Further studies are required to explore the underlying mechanisms.

mphatesmpb wrote:plasma concentrations of vitamin D are negatively correlated with SHBG.