What is the Function of Sex Hormone Binding Globulin SHBG?

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Defy Medical TRT clinic doctor
Sex Hormone Binding Globulin...most of the Testosterone in the body is "bound" (SHBG) and can't be used by the body. Only Free or Bioavailable Testosterone can bind to Androgen receptors and be used thus having a high(er) Free T is a good thing. To a point...too low SHBG requires some difference in protocols just as high SHBG has to be handled differently, think dosing and frequency of injections.


SHBG binds testosterone, a great deal of it, and albumin weakly binds it. Free testosterone is that which is unbound, bioavailability is that which is free and weakly bound to albumin.

Gene Devine

Super Moderator
The main function of SHBG is sex-steroid transport within the blood stream and to extravascular target tissues.

SHBG also plays a key role in regulating bioavailable sex-steroid concentrations through competition of sex steroids for available binding sites and fluctuations in SHBG concentrations. Because of the higher affinity of SHBG for DHT and T, compared to E, SHBG also has profound effects on the balance between bioavailable androgens and estrogens.

Increased SHBG levels may be associated with symptoms and signs of hypogonadism in men, while decreased levels can result in androgenization in women.


Men with low SHBG seem to have trouble getting total T up yet usually have high bio available/free T. Is that because the SBHG prevents T from being metabolized? I remember reading somewhere that unbound T has a very short half life. That would mean that our high free/bio available T looks good on paper, but without total T increasing we're not getting the full benefits of TRT.
There's no trouble getting Total T up, its that most of us have to inject EOD. If a low SHBG guy injected E3.5D, his trough would be rather low; i.e., 500s, and it would appear as though Total T is a problem, when it's not. Think of it as how fast T is metabolized, even if that's not totally accurate. Inject EOD and get tested in the 48hr trough and the guy should be fine in regards to Total T.
Low SHBG is not a problem at all, smaller, more frequent injections, if not daily injections, are how it's dealt with. When I was on E3.5D, I was up and down and up and down and up and down, its not a fun ride, as it were. But injecting more often gets the Total T up and keeps it there.


Thanks Vince. Any idea how smaller more frequent injections effect DHT, free, and bio available T? I'd like to keep these in check.


The trend seems to be going to eod with low shbg guys. Just 1 year ago, seems most low shbg guys were on an every 3.5 day protocol. My shbg is always low end of normal and for the 1st couple years of TRT, I was injecting only once a week. As long as I took my AI, I was okay, and did decent with once a week injections. I've been injecting every 3.5 days for a few months now and definitely prefer it. Once a week wasn't very bad, but twice weekly is a smoother ride for sure. I'd imagine eod would be smoother yet. But for me, twice weekly is a comfortable balance I'm happy with for now. You definitely want to educate yourself on shbg because it really influences how much and how often you should inject.
Thanks Vince. Any idea how smaller more frequent injections effect DHT, free, and bio available T? I'd like to keep these in check.

Free and Bio avail T are pretty much the same thing and a high Free T, over lab ranges or 3% or higher is key marker for low SHBG. Obvious correlation if there's less SHBG to bind your T, the higher your Free T will be. You can see some guys post labs with no SHBG test but see their Free T is very high and with near certainty predict they have low SHBG. I've read little to nothing that Free T over range is anything but good. DHT though with EOD (or daily) I have to specifically use a cream daily on the sctorum to raise my DHT so I can't say if I have a DHT problem with 5AR activity, DHT problem related to SHBG, or what the root cause is or was there.


New Member
I'm a new member and have no idea how to get in touch with a moderator...I would like to talk to someone that is very knowledgeable about hpta restart. Nelson Vergel or yourself, can you please contact me

Nelson Vergel

Founder, ExcelMale.com
Testosterone, sex hormone-binding globulin and risk of cardiovascular events

Aims: Testosterone and its binding protein sex hormone-binding globulin have been associated with cardiovascular disease and dysglycaemia. However, information on the prognostic implication in patients at high cardiovascular risk with dysglycaemia is inconsistent. The study objective was to determine whether testosterone and/or sex hormone-binding globulin predict cardiovascular events or death in dysglycaemic patients.

Methods: Dysglycaemic males (with high blood sugar) at high cardiovascular risk (n = 5553) who participated in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial and provided baseline blood samples were studied. Testosterone and sex hormone-binding globulin were measured at baseline and used to estimate free testosterone. Low levels of total and free testosterone were defined as ≤300 ng/dl and ≤7 ng/dl, respectively. Patients were followed for six years for cardiovascular events (defined as the composite of cardiovascular death, non-fatal myocardial infarction or stroke) and all-cause mortality.

Results: The mean total and free testosterone levels were 416.6 ng/dl and 8.4 ng/dl, and low levels were present in 13% and 37% of the patients. The median sex hormone-binding globulin level was 35 nmol/l. In Cox regression models adjusted for age, previous diseases and pharmacological treatment, neither total nor free testosterone predicted cardiovascular events. However, a one-standard-deviation increase in sex hormone-binding globulin predicted both cardiovascular events (hazard ratio 1.07; 95% confidence interval 1.00–1.14; p = 0.03) and all-cause mortality (hazard ratio 1.13; 95% confidence interval 1.06–1.21; p < 0.01).

Conclusion: Sex hormone-binding globulin, but not total testosterone, predicts cardiovascular disease and all-cause mortality in dysglycaemic males at high cardiovascular risk.

Keywords Testosterone, sex hormone-binding globulin, cardiovascular, prognosis, diabetes, glucose intolerance


Nelson Vergel

Founder, ExcelMale.com
SHBG Controls Androgens (Testosterone, etc.) Inside the Cell!

Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.

Nelson Vergel

Founder, ExcelMale.com
We are finding out that SHBG may actually be involved in facilitating the entry of testosterone into cells by activating the androgen receptor. So, it is not a "bad hormone" that only binds testosterone to render it useless.


Nelson Vergel

Founder, ExcelMale.com
Causes of Low and High SHBG
low and high SHBG causes.jpg

Circulating SHBG level as a biomarker of metabolic risk
In epidemiologic studies, low total testosterone levels have been associated with increased risks of diabetes and metabolic syndrome, a cluster of conditions including hypertension, insulin resistance, central obesity, and dyslipidemia, which predispose individuals to an increased risk of cardiovascular disease. In longitudinal analyses, SHBG levels rather than total or free testosterone levels have been independently and prospectively associated with incident diabetes and metabolic syndrome after adjustments for age, adiposity, and comorbid conditions (97, 98). Among children and adolescents, SHBG may also be a biomarker for metabolic syndrome risk (99), and lower levels were more robustly associated with the risk of metabolic syndrome in boys than in girls (100). We do not know whether SHBG is merely a marker of metabolic risk or whether SHBG plays a causal role in the pathophysiology of metabolic disorders such as diabetes and metabolic syndrome.

Source: Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications

Nelson Vergel

Founder, ExcelMale.com
Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Its serum levels are regulated not only by androgens and estrogens but also by thyroid hormones and other metabolic factors. Several disease conditions are accompanied by altered SHBG levels such as hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, and breast as well as prostate cancer. Additionally, several drugs and alcohol consumption influence serum concentrations of SHBG. In some cases, altered SHBG levels are a specific result of the underlying pathology. In others, they merely constitute an epiphenomenon, which still might offer the possibility of using serum measurements of SHBG as surrogate marker. This review article portrays the different disorders associated with altered SHBG levels and discusses the usefulness of SHBG as disease biomarker from a clinicians as well as from an endocrinological researchers point of view.

SHBG and exogenous administered drugs, xenobiotics and alcohol

Numerous drugs influence SHBG serum levels via variation of its hepatic synthesis rate. SHBG synthesis is e as already mentioned above e modulated by sex steroids. Application of estrogenic, progestogenic and androgenic compounds will therefore result in altered SHBG concentrations.

Estrogens cause considerable increases in SHBG levels. The extent is dependent on the route of administration: oral formulations will cause more pronounced effects than transdermal ones as the active component directly accesses the portal system and the liver will be exposed to very high concentrations [10,12,68]. With application of tamoxifen, raloxifene and clomiphene SHBG levels have been observed in both sexes. Hence, selective estrogen receptor modulators generally seem to exhibit agonistic characteristics with respect to SHBG synthesis [12,69]. As well, SHBG elevations in adrenal carcinoma patients treated with mitotane are attributed to the drug's agonistic effects on hepatic estrogen receptors [70]. Progestins on the other hand have been known for a long time to significantly decrease SHBG serum levels [71]. Consequently, SHBG levels in women receiving combination oral contraceptives (COC) depend on the proportion of the contained estrogen and progestin [72]. Application of androgens in male hypogonadism as well as suppression of pituitary gonadotropin release with the testosterone derivative danazol causes

SHBG concentrations to decrease [12,73,74]. A drop of SHBG levels has also been described with the use of the antiandrogen cyproterone acetate. The observation is attributed to its progestogenic properties but might also be due to partly agonistic effects in the liver [12]. Beyond sex steroids,treatment with synthetic glucocorticoids has been associated with decreasing SHBG levels. Findings,however, are inconsistent across different studies and results of in vitro experiments are ambiguous [13].

Another class of drugs influencing SHBG levels are hepatic enzyme inducers like phenobarbital, phenytoin, carbamazepine or rifampicin, which regularly result in elevated SHBG concentrations [10].

The effect has been best investigated in liver enzyme inducing antiepileptic drugs (LEIAED). Increased SHBG concentrations in men on LEIAED therapy contribute to the common hormonal and reproductive disturbances in these patients [75]. In women, LEIAED associated SHBG increase might cause failure of COC by tightly binding progestins and lowering free progestin levels.

Finally, SHBG and drugs are not only interconnected via hepatic synthesis but also by plasma steroid transport. Drugs might exert their effects and side effects by occupying SHBG binding sites and displacing the natural ligands. Furthermore, SHBG has been implied in the transport of xenobiotic ligands in plasma and across cell membranes [13]. Both topics, however, require further research to enable proper judgment of relevance.

Moderate alcohol consumption is associated with slightly but significantly decreased SHBG levels in both sexes in the majority of studies [76,77]. In e non-cirrhotic e alcoholics, however, approximately 3-fold increased SHBG-levels have been described, which might contribute to the hypogonadism often observed in these patients [78]. Beyond that, chronic alcohol ingestion also impairs glycosylation during protein synthesis resulting in SHBG isoforms with altered carbohydrate composition. Withdrawal causes SHBG levels to decrease promptly, but values within reference ranges are only reached after several weeks of abstinence [78].

Awareness of the relation of drugs and SHBG levels helps to explain some effects and side effects of therapy. When not explicitly evaluating gonadal and sexual dysfunction, however, there is no need to determine SHBG in day-to-day routine in patients receiving the respective medication. The connections of SHBG and xenobiotics require more detailed investigations and might constitute a rewarding research area.

Reference: The biomarker sex hormone-binding globulin – From established applications to emerging trends in clinical medicine
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