How to prepare for the ‘SHBG’ test: rules for taking it

Sex hormone-binding globulin (SHBG) rarely interests patients on its own, but without it testosterone and estradiol cannot be assessed correctly. This protein is synthesised in the liver and ‘holds’ sex hormones in the blood, determining what proportion of them is available to tissues. The editorial team explains how to prepare for the test and what can shift its result.

What SHBG is and why it is measured

SHBG is a glycoprotein produced by the hepatocytes of the liver. It binds dihydrotestosterone and testosterone with high affinity, and estradiol somewhat more weakly. Hormone bound to SHBG practically does not enter cells, so the concentration of this protein determines how much ‘working’ hormone is available to the tissues.

The review by Hammond (2011) describes SHBG not only as a transport protein but also as a regulator of the bioavailability of sex steroids and their metabolic clearance. Changes in its level are often a marker of the general metabolic state: liver function, insulin sensitivity, thyroid function.

Most often the test is ordered together with total testosterone in order to calculate free testosterone or the free androgen index. The Endocrine Society guideline (Bhasin et al., 2018) recommends assessing the free hormone precisely when changes in SHBG are suspected — for example, in obesity, diabetes, old age, liver or thyroid disease.

In women, SHBG is used when examining for hyperandrogenism and polycystic ovary syndrome: a low globulin level enhances the action of androgens even with normal total testosterone. Epidemiological data (Ding et al., 2009) also link low SHBG with a higher risk of type 2 diabetes in men and women.

In the sports community, SHBG is of interest as part of the ‘hormone panel’ — to understand whether a low testosterone is truly low or is a consequence of reduced globulin.

Rules for taking the test

The daily fluctuations of SHBG are much smaller than those of testosterone — this is confirmed by the data of Brambilla and colleagues (2009). However, in practice the globulin is almost always taken together with testosterone, so the preparation rules are the same: morning draw, fasting, after your usual sleep.

Blood is taken from a vein, usually between 7:00 and 10:00–11:00. The last meal is 8–12 hours before. Strict fasting is needed primarily for testosterone, but a shared sample helps avoid discrepancies between indicators.

• have SHBG and testosterone done from the same draw and in the same laboratory;
• in the morning, fasting, only water;
• no alcohol or intense training in the 24 hours before the test;
• do not take it during an acute illness;
• inform the doctor about all medications, hormonal agents and biotin.

SHBG is measured by immunoassay, so biotin in high doses can potentially distort the result — the FDA has warned about this. If you take ‘hair and nail’ vitamin complexes, check with the laboratory whether a break is needed.

Since the SHBG level changes gradually — over weeks rather than hours — what matters is not the ‘perfect day’ but a stable state of the body. A test taken during a period of sharp change in weight, diet or hormone intake will reflect precisely that transitional period.

Conditions that alter SHBG levels

The concentration of the globulin is affected by a number of physiological and pathological conditions. Knowing them is important, because a deviation in SHBG is often not a ‘test problem’ but a clue about another disorder.

Thyroid function is one of the strongest regulators: thyroid hormones stimulate the synthesis of SHBG in the liver. Therefore in hyperthyroidism the globulin is high, and in hypothyroidism — reduced. If SHBG has changed unexpectedly, the doctor often orders TSH.

Insulin suppresses SHBG synthesis, so in people with obesity and insulin resistance the globulin level is usually low. Weight loss and improved insulin sensitivity, on the contrary, gradually raise SHBG.

Age also matters: in men SHBG rises with the years, which partly explains why total testosterone in older men may look normal while the free level is reduced. Pregnancy, on the contrary, is accompanied by a significant rise in globulin under the influence of estrogens.

Medications, hormones and nutrition

Among medications, oral estrogens, in particular combined oral contraceptives, as well as enzyme-inducing anticonvulsants, raise SHBG most strongly. Androgens, anabolic steroids and glucocorticoids lower it. You must inform the doctor about everything you take; you should not discontinue prescribed drugs on your own before the test.

Nutrition affects SHBG indirectly — through body weight, insulin and energy balance. Prolonged fasting or very low-calorie diets raise the globulin; stable nutrition within your usual calorie intake gives a more representative result.

For athletes during ‘cutting’ periods this is important: a test taken at the end of a strict diet will show a different hormonal profile than during a normal training period. It is worth telling the doctor about the current phase of preparation.

How to read the result together with other tests

SHBG on its own is rarely a diagnosis. Its significance is revealed in combination with total testosterone: calculation by the formula of Vermeulen and colleagues (1999) makes it possible to assess the free fraction, which better reflects androgen status when the globulin deviates.

SHBG reference intervals depend on sex, age and method, so rely on your laboratory's norm. The result is usually expressed in nmol/L.

If SHBG is low, the doctor may look for signs of insulin resistance, hypothyroidism or ascertain the intake of androgens. If it is high — check thyroid and liver function, the intake of estrogens or anticonvulsants.

The Endocrine Society position statement on testosterone measurement (Rosner et al., 2007) emphasises that the quality of the free hormone calculation depends on the accuracy of both indicators. Therefore a stable laboratory and identical draw conditions are the key to correct trend tracking.

Editorial conclusions

SHBG is an ‘invisible’ regulator of sex hormones. Without it, total testosterone can either hide a deficiency or create the illusion of a problem.

The daily fluctuations of the globulin are small, but it is taken together with testosterone — so, in the morning, fasting, in a stable state, with the doctor informed about medications, hormones and biotin.

Deviations in SHBG often point to the state of the thyroid, liver, carbohydrate metabolism or to the intake of hormonal drugs, so they are interpreted by a doctor in the context of other tests.

We also advise reading our materials on preparing for the total and free testosterone and estradiol tests.

References

1. Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011;85(3):431–441.
2. Selby C. Sex hormone binding globulin: origin, function and clinical significance. Ann Clin Biochem. 1990;27(Pt 6):532–541.
3. Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361(12):1152–1163.
4. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666–3672.
5. Rosner W, Auchus RJ, Azziz R, et al. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92(2):405–413.
6. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
7. Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94(3):907–913.