The combination of low sex hormone-binding globulin (SHBG) and low testosterone usually points to a metabolic problem rather than a purely hormonal one. SHBG is a protein made by the liver that carries testosterone through the bloodstream, and the most common driver of low SHBG is insulin resistance, which also independently suppresses testosterone production. That overlap makes the pairing far more common than you might expect, particularly in people who are overweight or have type 2 diabetes, and it creates a diagnostic headache because standard lab calculations can misjudge how much active testosterone is actually circulating.
What SHBG Actually Does With Testosterone
Most testosterone in your blood is not floating around freely. Roughly two-thirds is bound to SHBG, about a third is loosely attached to albumin, and only around one to three percent circulates unbound. That unbound fraction, called free testosterone, is what enters cells and triggers biological effects. Research has confirmed this “free hormone hypothesis” experimentally: testosterone that is bound to SHBG in the circulation is restricted from entering target tissues and carrying out its functions.1Scientific Reports. Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis Clinical observations in men with unusually high SHBG and primary testicular dysfunction further support the idea that free testosterone, not total testosterone, governs the feedback loop between the brain and the testes.2PubMed Central. Hormonal profiles of men with highly elevated SHBG and primary testicular dysfunction support free hormone hypothesis
This matters because when SHBG is low, a larger share of total testosterone is freed up. In many cases, a man with modestly low total testosterone but also low SHBG can have a perfectly normal amount of free testosterone and feel fine. The situation that concerns clinicians is when both values fall together, because it suggests that something is dragging down testosterone production itself while also hammering the liver’s ability to make SHBG.
Insulin Resistance Is the Most Common Culprit
If you had to pick one condition that best explains the low-SHBG-plus-low-testosterone pattern, it would be insulin resistance. The liver manufactures SHBG, and insulin directly suppresses that production. Cell culture experiments showed decades ago that insulin significantly reduces SHBG output from human liver cells, even when estrogen or thyroid hormones are trying to push it up.3PubMed. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin Large population studies back this up: a Swedish survey found a strong inverse relationship between fasting insulin and SHBG levels in both men and women, independent of age, body mass index, and blood sugar. The researchers concluded that low SHBG functions as a marker for metabolic syndrome.4PubMed Central. Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden
On the testosterone side, insulin resistance and high blood sugar appear to dampen the brain’s signaling to the testes. In men with type 2 diabetes who still had testosterone levels in the normal range, researchers found significantly fewer pulses of luteinizing hormone (LH) compared with healthy controls, and the number of pulses correlated negatively with blood glucose levels.5PubMed. Evaluation of the hypothalamic-pituitary-gonadal axis in eugonadal men with type 2 diabetes mellitus Fewer LH pulses means less stimulus for the testes to produce testosterone. So insulin resistance attacks both ends at once: it tells the liver to make less SHBG and tells the brain to order less testosterone.
Liver Fat and NAFLD
SHBG production depends heavily on what is happening inside liver cells, and one of the clearest disruptors is fat accumulation. When the liver starts building up lipids, a process often driven by excess sugar and refined carbohydrates, it reduces levels of a transcription factor called HNF-4α. That transcription factor is essentially the on-switch for the SHBG gene, so as liver fat goes up, SHBG goes down.6JCI Insight. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene
Clinically, this shows up clearly in people with non-alcoholic fatty liver disease (NAFLD). In patients with type 2 diabetes, SHBG levels dropped in step with the severity of fatty liver on ultrasound, and that relationship held even after adjusting for BMI, waist size, triglycerides, liver enzymes, and insulin resistance.7PubMed. Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes A separate analysis found that the link between low SHBG and NAFLD was stronger than the link between low SHBG and metabolic syndrome as a whole, suggesting that liver fat may be the more direct mechanism.8Scientific Reports. Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients NAFLD affects a large share of people with obesity and diabetes, the same population most likely to also have suppressed testosterone, which is why the two lab findings so often travel together.
Thyroid Problems Can Push SHBG in Either Direction
Thyroid hormones are a potent regulator of SHBG, and they work through the same liver pathway. When thyroid hormone levels are adequate, they increase HNF-4α expression and reduce fat buildup in liver cells, both of which raise SHBG production.9PubMed. Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha Hypothyroidism does the opposite, and clinical data confirms it: SHBG levels are decreased in hypothyroid patients and increased in hyperthyroid patients. When hypothyroid patients were treated with levothyroxine, their SHBG concentrations climbed significantly.10PubMed. Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans
Hypothyroidism also commonly causes fatigue, weight gain, and depressed mood, symptoms that overlap substantially with low testosterone. An underactive thyroid can contribute to both low SHBG and reduced testosterone production, so checking thyroid function is a standard part of working up this lab pattern. Correcting the thyroid deficiency often raises SHBG on its own.
Chronic Inflammationh2>
Ongoing low-grade inflammation, the kind associated with obesity, autoimmune conditions, and chronic illness, also suppresses SHBG through the liver. Tumor necrosis factor alpha (TNFα), a key inflammatory signaling molecule, has been shown to reduce SHBG production by activating an inflammatory pathway that degrades HNF-4α in liver cells.11Molecular Endocrinology. Molecular Mechanism of TNFα-Induced Down-Regulation of SHBG Expression This is significant because many of the conditions already discussed, including obesity, NAFLD, and type 2 diabetes, feature chronically elevated TNFα. The inflammation adds another push downward on SHBG beyond what insulin and liver fat are already doing.
Chronic inflammation also suppresses testosterone through its own pathways, including direct effects on testicular function and disruption of the hypothalamic signaling that controls hormone production. So in someone with a chronic inflammatory condition, both low SHBG and low testosterone can result from the same upstream problem.
Medications and Substances
Several drugs drive SHBG sharply lower. The most dramatic example is anabolic steroid use. In men self-administering testosterone and anabolic steroids, SHBG concentrations dropped by roughly 80 to 90 percent during use and remained suppressed for 16 weeks after stopping.12Journal of Steroid Biochemistry. Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man Oral anabolic steroids are especially potent suppressors because they pass through the liver first. In HIV-positive men treated with testosterone and the oral anabolic agent oxandrolone, both SHBG and total testosterone were far below normal ranges, and one patient saw libido and morning erections return only after stopping the oral steroid.13PubMed. Low sex hormone-binding globulin and testosterone levels in association with erectile dysfunction among human immunodeficiency virus-infected men receiving testosterone and oxandrolone
Other medications can lower SHBG as well. Some progestins, certain glucocorticoids, and insulin-sensitizing drugs all influence SHBG to varying degrees. If you see a sudden shift in your lab numbers after starting a new medication, the drug itself may be the explanation.
Genetics Play a Role Too
Your baseline SHBG level is partly inherited. Specific variants in the SHBG gene influence circulating levels even after accounting for body weight, testosterone, and insulin resistance. In women with polycystic ovary syndrome (PCOS), certain polymorphisms in the SHBG gene were independently associated with SHBG levels after controlling for BMI, unbound testosterone, and insulin resistance markers.14PubMed Central. Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome This means two people with the same metabolic profile can have meaningfully different SHBG levels simply because of their DNA. Genetic variation does not usually explain severely low SHBG on its own, but it sets the baseline that metabolic and hormonal factors then push around.
Symptoms of the Combination
When both SHBG and testosterone are genuinely low and free testosterone is depleted, the symptom picture resembles straightforward testosterone deficiency: reduced sex drive, erectile difficulties, fatigue, loss of muscle mass, increased body fat, and sometimes mood changes. In aging men, free testosterone (which reflects the combined effect of SHBG and total testosterone) was more strongly correlated with muscle strength, bone mineral density, and fat mass than total testosterone alone.15The Journal of Clinical Endocrinology & Metabolism. Measures of Bioavailable Serum Testosterone and Estradiol and Their Relationships with Muscle Strength, Bone Density, and Body Composition in Elderly Men
Sexual function is one area where both SHBG and free testosterone seem to matter independently. In a study of older men, free testosterone correlated with erectile function and orgasmic function after adjusting for age, while SHBG itself was independently correlated (negatively) with orgasmic function.16PubMed. The clinical relevance of sex hormone levels and sexual activity in the ageing male The relationship between very low testosterone and mood is less clear-cut than many people assume. An analysis of national survey data found that in men, very low testosterone was weakly associated with appetite problems, but after adjusting for lifestyle factors like alcohol use, physical activity, and BMI, low total testosterone did not consistently predict overall depression scores.17PubMed Central. Testosterone and specific symptoms of depression: Evidence from NHANES 2011–2016 That does not mean testosterone is irrelevant to how you feel, but it does mean the fatigue and low mood that often accompany this lab pattern may be driven as much by the underlying metabolic condition as by testosterone itself.
In women, the stakes look somewhat different. Low SHBG in postmenopausal women has been shown to predict cardiovascular disease and overall mortality.18The Journal of Steroid Biochemistry and Molecular Biology. Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk This association likely reflects the tight connection between low SHBG and insulin resistance rather than SHBG doing something harmful on its own, but it reinforces the point that a low SHBG value is worth taking seriously as a metabolic warning sign.
Why Lab Calculations Can Be Misleading at Low SHBG
Most labs do not directly measure free testosterone. Instead, they calculate it from total testosterone and SHBG using mathematical formulas. These formulas generally work well in the middle of the normal range, but they become unreliable at the extremes. Specifically, when SHBG is low, the most commonly used calculation (the Vermeulen equation) tends to underestimate free testosterone. That underestimation can lead to overdiagnosis of hypogonadism in obese men, flagging them as testosterone-deficient when their free testosterone is actually adequate.19The Journal of Clinical Endocrinology & Metabolism. Reassessing Free-Testosterone Calculation by Liquid Chromatography–Tandem Mass Spectrometry Direct Equilibrium Dialysis
Different calculation methods also disagree with each other considerably. One comparison of formulas found wide discrepancies among approaches, with equilibrium-binding algorithms systematically overestimating free testosterone compared with direct measurements.20PubMed. Predictive accuracy and sources of variability in calculated free testosterone estimates If your SHBG is notably low, asking your physician about equilibrium dialysis, the gold-standard direct measurement, can give a more accurate picture of your actual free testosterone status. The practical consequence is real: a man whose calculated free testosterone looks borderline-low might not need testosterone therapy at all once a more precise method shows his free levels are within range.
How Weight Loss and Exercise Affect Both Numbers
Because insulin resistance and body fat are the primary drivers of the low-SHBG/low-testosterone pattern, weight loss is one of the most effective interventions. In a trial of overweight postmenopausal women, those who combined diet and exercise had significantly higher SHBG levels at 30 months compared with controls, and the women who maintained their weight loss showed the largest increases in SHBG alongside decreases in free testosterone and free estradiol.21PubMed Central. Long-term Weight Loss Maintenance, Sex Steroid Hormones and Sex Hormone Binding Globulin In premenopausal women, SHBG showed “prominent sensitivity to body mass fluctuations,” rising with weight loss and falling again with weight regain, even when insulin resistance measures remained improved.22PubMed Central. The impact of supervised weight loss and intentional weight regain on sex hormone binding globulin and testosterone in premenopausal women
Exercise appears to contribute beyond what calorie restriction alone achieves. In a trial comparing diet-only weight loss with exercise-focused weight loss (both groups losing similar amounts of weight), the exercise group lost more body fat, had a greater reduction in free testosterone, and showed a trend toward higher SHBG.23PubMed Central. Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial In men, the evidence broadly supports that losing visceral fat through any combination of diet and exercise improves both testosterone output and SHBG levels, largely because it improves insulin sensitivity and reduces liver fat.
Dietary Composition and SHBG
What you eat matters beyond just calories. Diets high in sugar and refined carbohydrates tend to suppress SHBG through the liver lipogenesis pathway described earlier. Conversely, higher-fiber diets and dietary patterns that reduce insulin spikes have been associated with higher SHBG levels. A review of recent evidence concluded that total calorie intake as well as the fat, fiber, and protein content of the diet can all alter plasma SHBG.24PubMed. Recent Advances on Sex Hormone-Binding Globulin Regulation by Nutritional Factors: Clinical Implications
One interesting finding involves ketogenic diets. In a short trial, middle-aged obese men who followed a ketogenic diet for three weeks saw their SHBG rise from about 25 nmol/L to about 31 nmol/L, a meaningful increase. Women on the same diet showed a smaller but still statistically significant rise.25PubMed Central. Three Weeks on a Ketogenic Diet Reduces Free Testosterone and Free Estradiol in Middle-Aged Obese Men and Women Whether this effect persists long-term or is simply a consequence of rapid calorie restriction and weight loss is not fully clear, but it reinforces the tight link between what the liver is metabolizing and how much SHBG it produces.
Low SHBG in Women and PCOS
In women, low SHBG is most clinically significant in the context of polycystic ovary syndrome. SHBG serves as a practical biomarker of hyperandrogenism in PCOS: when SHBG drops, more testosterone circulates freely, contributing to symptoms like acne, excess hair growth, and irregular periods. Low SHBG in PCOS patients is associated with insulin resistance, abnormal glucose and lipid metabolism, and the degree of androgen excess.26PubMed Central. Effect of Sex Hormone-Binding Globulin on Polycystic Ovary Syndrome: Mechanisms, Manifestations, Genetics, and Treatment A woman with PCOS, low SHBG, and testosterone that is technically in the normal range may still experience androgen-driven symptoms because her free testosterone is elevated.
The diagnostic calculation error described earlier runs in the opposite direction for women with PCOS. If the formula underestimates free testosterone when SHBG is low, it can miss hyperandrogenism, leaving women undiagnosed.19The Journal of Clinical Endocrinology & Metabolism. Reassessing Free-Testosterone Calculation by Liquid Chromatography–Tandem Mass Spectrometry Direct Equilibrium Dialysis This makes accurate free testosterone measurement especially important in women being evaluated for PCOS, not just men being evaluated for hypogonadism.
Age-Related Changes in SHBG
SHBG and testosterone follow different trajectories as you get older, and understanding that helps put lab results in context. In men, SHBG declines after childhood to a low point around age 20, stays relatively stable through middle age, then gradually rises from the sixth decade onward.27PubMed. Estimating age-specific trends in circulating testosterone and sex hormone-binding globulin in males and females across the lifespan Total testosterone, meanwhile, remains fairly stable until around age 70 and then drops.28PubMed Central. Bioavailable Testosterone Linearly Declines Over A Wide Age Spectrum in Men and Women From The Baltimore Longitudinal Study of Aging The result is that in older men, rising SHBG can squeeze free testosterone downward even when total testosterone has not changed much. The combination of genuinely low SHBG and low total testosterone in an older man is therefore somewhat unusual and strongly suggests an underlying metabolic or medication-related cause rather than normal aging.
In women, SHBG tends to rise after menopause when estrogen levels fall (since estrogen stimulates SHBG production to some degree). Premenopausal women with low SHBG are far more likely to be dealing with insulin resistance, obesity, or PCOS than with age-related decline.
Environmental Chemicals and SHBG
An emerging area of research involves endocrine-disrupting chemicals, particularly phthalates found in plastics, personal care products, and food packaging. Computational modeling has shown that several common phthalates can dock into the same binding site on SHBG that testosterone normally occupies, sharing a majority of interacting amino acid residues with the natural hormone. Longer-chain phthalates appear to be more potent in this regard.29PubMed Central. Endocrine Disruption: Computational Perspectives on Human Sex Hormone-Binding Globulin and Phthalate Plasticizers Whether this binding displaces testosterone from SHBG in a clinically meaningful way at real-world exposure levels is still being studied. The research is in early stages and based primarily on computer simulations rather than human clinical trials, so it would be premature to attribute any individual’s low SHBG to plasticizer exposure. But it does highlight that SHBG is not just a passive bystander in endocrine disruption, and it may be one of the targets through which environmental chemicals affect hormone balance.