Sex hormone-binding globulin (SHBG) is a liver-produced protein that binds to testosterone, regulating how much hormone is available to tissues. During testosterone replacement therapy (TRT), SHBG levels typically decrease due to androgen-mediated suppression of hepatic production. This reduction increases the proportion of bioavailable testosterone, which can intensify both therapeutic benefits and potential adverse effects. Understanding SHBG changes during treatment is essential for accurate hormone monitoring and safe prescribing. This article examines how testosterone therapy affects SHBG levels, the clinical implications of these changes, and appropriate monitoring strategies in line with UK guidance.

Understanding SHBG and Its Role in Testosterone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein produced primarily by the liver that plays a crucial role in regulating the availability of sex hormones in the bloodstream. SHBG binds tightly to testosterone and other sex steroids, including oestradiol and dihydrotestosterone (DHT), effectively acting as a transport protein whilst simultaneously controlling the amount of hormone available to tissues.

In the circulation, testosterone exists in three forms: tightly bound to SHBG (approximately 60–70%), loosely bound to albumin (approximately 20–30%), and free or unbound (approximately 1–3%). Only the free and albumin-bound fractions—collectively termed 'bioavailable testosterone'—can readily enter cells and exert biological effects. SHBG therefore functions as a regulatory mechanism, buffering against rapid fluctuations in hormone activity and protecting tissues from excessive androgen exposure.

Several factors influence SHBG production. Oestrogens and thyroid hormones increase SHBG synthesis, whilst androgens, insulin, growth hormone, and obesity tend to suppress it. Liver disease can significantly alter SHBG levels, with chronic liver disease often increasing SHBG. Age also affects SHBG levels, with concentrations typically rising in men as they grow older. Understanding these dynamics is essential when interpreting testosterone measurements, as total testosterone levels may appear normal whilst bioavailable testosterone remains low if SHBG is elevated, or vice versa.

Clinically, measuring SHBG alongside total testosterone provides a more complete picture of androgen status. While the free androgen index (FAI), calculated as (total testosterone ÷ SHBG) × 100, is sometimes used, it is less reliable in men than calculated free testosterone using validated equations (such as the Vermeulen formula). NICE Clinical Knowledge Summary on testosterone deficiency emphasises the importance of considering SHBG when assessing hypogonadism, particularly in men with conditions known to alter SHBG levels, such as obesity, type 2 diabetes, thyroid disorders, or liver disease.

Does SHBG Go Down with Testosterone Treatment?

Yes, SHBG levels typically decrease during testosterone replacement therapy (TRT), though the magnitude of this reduction varies depending on the route of administration, dosage, and individual patient factors. This phenomenon has been consistently documented in clinical studies and represents a predictable physiological response to exogenous androgen administration.

The reduction in SHBG occurs through negative feedback mechanisms. Testosterone and its metabolites suppress hepatic SHBG synthesis, with androgens having a direct inhibitory effect on liver production of this binding protein. When exogenous testosterone is administered, circulating androgen levels rise, signalling the liver to reduce SHBG output. This effect is dose-dependent, meaning higher testosterone doses generally produce greater SHBG suppression.

The extent of SHBG reduction varies considerably between individuals and treatment modalities. Clinical observations suggest decreases in SHBG during testosterone therapy, with the magnitude varying between patients. Injectable testosterone preparations, particularly those producing higher peak levels, may cause more substantial SHBG suppression compared to transdermal formulations that provide steadier hormone delivery.

It is important to note that whilst SHBG reduction is common during testosterone therapy, the clinical significance of this change varies between individuals. The decrease in SHBG during TRT is generally considered an expected adaptive response rather than a pathological change. However, it's worth noting that epidemiological studies have associated low SHBG levels with insulin resistance and type 2 diabetes, though causality remains uncertain. Marked suppression may increase the proportion of free testosterone, potentially intensifying both therapeutic effects and adverse reactions. Individual patient characteristics, including baseline SHBG levels, body composition, and metabolic health, influence how SHBG responds to testosterone treatment and whether this change has clinical significance.

How Testosterone Therapy Affects SHBG Levels

The mechanism by which testosterone therapy reduces SHBG involves direct androgen-mediated suppression of hepatic gene expression. Testosterone and its active metabolite DHT bind to androgen receptors in liver cells, downregulating the transcription of the SHBG gene. This process typically begins within days of initiating treatment, with SHBG levels reaching a new steady state after several weeks of consistent testosterone administration.

Different testosterone formulations affect SHBG to varying degrees. Injectable testosterone esters (such as testosterone enantate or testosterone undecanoate) often produce more pronounced SHBG suppression, particularly when administered at higher doses or shorter intervals. These preparations create fluctuating testosterone levels with higher peaks, which may exert stronger suppressive effects on hepatic SHBG production. Conversely, transdermal gels and patches, which provide more physiological, steady-state hormone delivery, typically cause more modest SHBG reductions.

In the UK, licensed testosterone preparations for replacement therapy include injectable testosterone undecanoate (Nebido), shorter-acting injectable esters, and various transdermal gels and patches. All these formulations generally suppress SHBG to some degree. Oral testosterone undecanoate has limited availability in the UK and, like other testosterone preparations, would typically suppress rather than increase SHBG. It's worth noting that 17-alpha-alkylated oral androgens are not recommended or licensed in the UK for testosterone replacement therapy due to potential hepatotoxicity.

The time course of SHBG changes follows a predictable pattern. Initial reductions are often observed within 2–4 weeks of starting treatment, with maximum suppression typically occurring by 3–6 months. SHBG levels generally stabilise thereafter, provided testosterone dosing remains consistent. If treatment is discontinued, SHBG levels gradually return towards baseline over several weeks to months, though the recovery timeline varies between individuals. Factors such as age, obesity, insulin resistance, and concurrent medications can modulate both the degree and speed of SHBG changes during testosterone therapy.

Clinical Implications of SHBG Changes During Treatment

The reduction in SHBG during testosterone treatment has several important clinical implications that affect both treatment monitoring and patient outcomes. As SHBG decreases, the proportion of free (bioavailable) testosterone increases, even if total testosterone levels remain stable or rise only modestly. This shift in the free-to-bound ratio means that patients may experience more pronounced androgenic effects than total testosterone measurements alone would suggest.

Interpreting testosterone levels becomes more complex when SHBG is suppressed. A total testosterone value that appears within the therapeutic range may actually represent supraphysiological free testosterone if SHBG is markedly reduced. This scenario can increase the risk of adverse effects, including erythrocytosis (elevated red blood cell count), fluid retention, mood changes, and acceleration of benign prostatic hyperplasia. Conversely, in patients with persistently elevated SHBG despite treatment, apparently adequate total testosterone levels may mask insufficient bioavailable hormone delivery.

Clinicians should consider calculating free or bioavailable testosterone using validated equations (such as the Vermeulen formula) that incorporate SHBG values, or directly measuring free testosterone when SHBG changes significantly. This approach provides a more accurate assessment of androgen exposure and helps guide dose adjustments. NICE guidance on testosterone deficiency acknowledges the importance of considering SHBG when interpreting hormone levels, particularly in men with obesity or metabolic syndrome, where SHBG is often already suppressed before treatment begins.

Important safety considerations include monitoring for signs of excessive androgen activity when SHBG falls substantially. Symptoms such as increased aggression, mood instability, significant fluid retention, or rapid haematocrit elevation may indicate that free testosterone levels are excessive, even if total testosterone appears appropriate. Treatment should be paused or reduced if haematocrit exceeds 0.54, with venesection considered in some cases. Baseline and periodic prostate assessment (PSA and digital rectal examination) is essential, with referral to urology if PSA rises significantly or abnormalities are detected.

Patients should be aware that testosterone therapy suppresses fertility by reducing sperm production, making it unsuitable for men actively trying to conceive. Caution is also needed in men with obstructive sleep apnoea or significant cardiac, hepatic, or renal disease due to potential exacerbation of these conditions. Patients should report suspected adverse reactions to their healthcare provider or via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk).

Monitoring SHBG Levels on Testosterone Replacement Therapy

Routine monitoring of SHBG is not universally required for all patients on testosterone replacement therapy, but it provides valuable information in specific clinical scenarios. Current UK guidance, including recommendations from the British Society for Sexual Medicine (BSSM), suggests that SHBG measurement can be particularly useful when interpreting testosterone levels in men with conditions that affect SHBG production, such as obesity, type 2 diabetes, liver disease, or thyroid disorders.

Initial assessment should include baseline SHBG measurement alongside total testosterone, ideally taken in a morning sample (between 08:00 and 11:00) before commencing treatment. This establishes a reference point and helps calculate baseline free testosterone using validated equations. Other essential baseline tests include full blood count, PSA, and digital rectal examination in men over 40 years. Follow-up measurements are typically performed at 3–6 months after starting treatment, once steady-state hormone levels have been achieved, and then annually thereafter unless clinical concerns arise.

When SHBG levels fall significantly during treatment, clinicians should consider several factors:

• Calculate free or bioavailable testosterone to assess true androgen exposure

• Review for signs of excessive androgenic effects, including haematocrit elevation (pause/reduce treatment if >0.54), mood changes, or accelerated hair loss

• Assess metabolic parameters, as worsening insulin resistance can further suppress SHBG

• Consider dose adjustment or formulation change if free testosterone appears excessive

Blood sampling timing varies by formulation. For long-acting injectable testosterone undecanoate (Nebido), the SmPC recommends measuring levels immediately before the next injection (at the end of the dosing interval). For shorter-acting injectables, mid-cycle sampling (halfway between injections) is appropriate. For transdermal preparations, sampling can occur at any time once steady state is achieved, typically after 2–4 weeks of consistent use.

Patients should be advised to attend regular monitoring appointments as recommended by their prescribing clinician, typically every 3–6 months initially, then annually once stable. Monitoring should include haematocrit, PSA (in men >40 years), and assessment of symptoms and side effects. If concerning symptoms develop between scheduled appointments, such as significant mood changes, excessive fatigue, marked fluid retention, or symptoms of polycythaemia (headaches, visual disturbances, dizziness), patients should contact their GP promptly rather than waiting for routine review. These symptoms may indicate that hormone levels require adjustment, and earlier reassessment including SHBG measurement may be appropriate.

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