Sex Hormone-Binding Globulin

Sex Hormone Binding Globulin (SHBG) plays a crucial role in regulating the bioavailability and activity of sex hormones in the body.  SHBG binds tightly to testosterone, dihydrotestosterone (DHT), and estradiol, modulating their distribution and transport throughout the bloodstream. 

This article provides a comprehensive overview of SHBG, covering its structure, production, function, laboratory testing methods, and clinical implications. Understanding SHBG is essential for comprehending the intricate interplay between hormones and their impact on various physiological processes, including reproduction, metabolism, and overall health. 

We will also explore strategies to naturally support healthy SHBG levels, offering insights into dietary, lifestyle, and supplemental interventions that may help optimize hormonal balance and well-being.

What is Sex Hormone Binding Globulin?

Definition and Overview of Sex Hormone Binding Globulin (SHBG)  

Sex hormone binding globulin (SHBG) plays a crucial role in transporting the 17β-hydroxysteroid sex steroids testosterone and estradiol in plasma.  SHBG also regulates hormone distribution between bound and free states. 

Structurally, SHBG is a homodimeric glycoprotein with a single steroid-binding site, and it has a half-life of 7 days. It is primarily expressed in the liver, although it’s also produced in other tissues. 

It is encoded by a single gene (Shbg), expressed in various tissues including the liver, testis, placenta, brain, and endometrium.  SHBG that is produced in the testes is called androgen-binding protein.  [4.]    

Its plasma concentrations are regulated by factors such as the balance of androgens and estrogens, thyroid hormones, insulin, and dietary factors.  [15.]

Biosynthesis and Regulation of SHBG Production  [15.] 

Many factors have been shown to affect SHBG levels:

Factors that Increase SHBG:

• Estrogen
• Thyroid hormones
• Growth hormone
• Somatomedin-C
• Other growth factors
• Nutritional status
• Hyperthyroidism
• Hypogonadism
• Hepatic cirrhosis

Factors that Decrease SHBG:

• Androgens
• Insulin
• Dietary lipids (high-fat diet)
• Obesity
• Myxedema
• Hyperprolactinemia
• Syndromes of excessive androgen activity
• Drugs (androgens, estrogens, thyroid hormones, anticonvulsants)

SHBG Throughout the Human Lifespan  [5.]

Throughout fetal development, plasma sex hormone-binding globulin (SHBG) production by the liver is crucial, particularly during late gestation when testosterone biosynthesis increases in male fetuses. 

In humans, SHBG is present in fetal blood early in gestation and correlates with testosterone levels, suggesting a role in male sex differentiation. Maternal plasma SHBG levels surge during mid to late pregnancy, possibly to protect the fetus from maternal sex steroids. 

During childhood and puberty, SHBG levels increase significantly and then decline progressively, influenced partly by thyroid hormone levels. Pubertal decreases in SHBG levels contribute to the maturation of the hypothalamo-pituitary-gonadal axis. 

In adults, SHBG levels vary with nutritional status and metabolic health, being lower in conditions like obesity and polycystic ovarian syndrome (PCOS). Genetic factors, including polymorphisms in the SHBG gene, also influence SHBG levels. 

During reproductive aging modest changes in SHBG levels occur, potentially related to metabolic or endocrine changes rather than declining sex hormone production.

Functions of SHBG  [5., 7., 15.]

• Dynamic Equilibrium: SHBG and albumin bind to the majority of circulating steroids, maintaining a dynamic equilibrium between bound and free fractions, governed by the Law of Mass Action.
• Steroid Distribution: Computer simulations illustrate the distribution of steroids between free and protein-bound states, affected by factors such as total plasma concentration, binding protein avidity, and competing steroids.
• Protein Binding Sites: In normal conditions, a large proportion of SHBG and albumin binding sites remain unoccupied, emphasizing the role of SHBG concentration in regulating the distribution of steroids.
• Metabolic Role: SHBG and albumin serve as buffer stores, modulating fluctuations in steroid concentration and providing a reservoir of bioavailable hormones, potentially impacting metabolic processes.  Low SHBG levels are also associated with metabolic conditions such as diabetes and metabolic syndrome.  
• Biological Activity: Although free steroids are traditionally considered metabolically active, there's evidence suggesting that protein-bound steroids may also be available for biological responses, potentially through dissociation near target tissues or direct interaction with certain cell membranes.
• Tissue Interaction: Target tissues like prostatic and decidual endometrial cells possess SHBG binding sites, suggesting direct interactions between SHBG-steroid complexes and these tissues, possibly influencing hormone transport to intracellular locations.
• Metabolic Clearance: SHBG may reduce the metabolic clearance rate of steroids with high affinity, protecting them from hepatic disposal, and modifying the conversion rate of androstenedione to testosterone.
• Estrogen Amplification: Differences in the association characteristics of testosterone and estradiol for SHBG may lead to increases in SHBG producing a more estrogenic environment, potentially impacting estrogen amplification.

Binding and Transport of Sex Hormones  [3., 9.]

SHBG serves as the primary carrier protein for sex hormones in serum, with approximately 70% of testosterone bound to SHBG with high affinity, 20-30% weakly bound to albumin, and 1-2% free.

Traditionally seen as a transporter of sex hormones to target tissues, recent studies suggest additional roles for SHBG. Evidence indicates its involvement in steroid hormone signal transduction at the plasma membrane and its uptake by cells, suggesting potential intracellular functions. 

Studies have demonstrated SHBG internalization via the Megalin receptor in various cell types, with implications for androgen- or estrogen-mediated effects. 

Furthermore, the discovery of a specific membrane receptor (SHBG-R) suggests a more intricate role for SHBG in modulating hormone effects at the cellular level, potentially inhibiting or amplifying androgen and estrogen effects through cAMP-mediated pathways. 

Notably, in estrogen-dependent breast cancer, SHBG has been shown to inhibit estradiol-induced cell proliferation through SHBG-R, cAMP, and PKA signaling pathways, presenting a potential therapeutic strategy for managing estrogen-dependent tumors.

Regulation of Free Hormone Levels: SHBG and the Free Hormone Hypothesis  [7.]

The free hormone hypothesis posits that only the unbound, or free, fraction of hormones in circulation is biologically active and able to exert physiological effects on target tissues, while hormone molecules bound to carrier proteins such as albumin or sex hormone-binding globulin (SHBG) remain inactive.

This hypothesis's validity varies depending on which step in tissue uptake, such as dissociation from plasma proteins or intracellular elimination, limits the hormone's net tissue uptake.  [10.]

As a key binding protein for androgens and estrogens, SHBG plays a crucial role in regulating the bioactivity of these hormones according to the free hormone hypothesis. 

SHBG restricts the entry of SHBG-bound testosterone (T) into target tissues, affecting its physiological functions in vivo. Contrary to the common belief that SHBG decreases free T concentrations, it appears that SHBG primarily increases total androgen and estrogen concentrations through hypothalamic-pituitary feedback and prolonged ligand half-life.  [7.]

However, despite elevating total sex steroid levels, SHBG attenuates androgen bioactivity, leading to mild hypogonadal signs in reproductive organs without major phenotypic effects on other sexually dimorphic tissues. 

Study findings support the clinical relevance of measuring free or bioavailable T and emphasize the need for careful interpretation of total sex steroid concentrations in the presence of SHBG.  [7.]

SHBG in Cardiometabolic Disease  [5.] 

In addition to its roles in maintaining levels of available sex hormones, SHBG has implications in cardiometabolic health and disease.  

Abnormally low levels of plasma SHBG are reliable biomarkers for metabolic syndrome and its associated conditions, including obesity-related pathologies like polycystic ovarian syndrome (PCOS), type 2 diabetes, and cardiovascular disease. 

The interplay between genetic variations in the human SHBG gene and metabolic disorders underscores the complex role SHBG plays in metabolic regulation and disease susceptibility. 

SHBG's function extends beyond its classical role as a hormone transporter, with evidence suggesting involvement in gene expression regulation and tissue-specific interactions. In various species, including fish, SHBG exhibits specialized functions beyond steroid transport, suggesting evolutionary conservation of its diverse roles in reproductive physiology and environmental adaptation.

Laboratory Testing for SHBG Levels

Testing Type

Blood testing for SHBG levels typically involves a blood draw.  

Before undergoing SHBG testing, it's important to follow any specific preparation instructions provided by your healthcare provider, which may include fasting for a certain period to ensure accurate results. 

Additionally, inform your healthcare provider about any medications or supplements you are taking, as certain drugs can affect SHBG levels and may need to be temporarily discontinued before testing.  For example, it is typically recommended to avoid biotin supplementation for 72 hours prior to testing.  

Interpretation of Results: Reference Ranges for SHBG

While it is important to consult with the ordering laboratory for their reference ranges, one company provides the following reference ranges:  [1.]

Male:

20-49 years: 16.5−55.9 nmol/L

>49 years: 19.3−76.4 nmol/L

Female:

20-49 years: 24.6−122.0 nmol/L

>49 years: 17.3−125.0 nmol/L

Clinical Significance of High and Low SHBG Levels

High SHBG Levels

Sex Hormone Binding Globulin levels increase in the presence of estrogen and thyroid hormones.  Often, higher levels of SHBG are associated with positive health outcomes.  

For example, elevated SHBG levels have been linked to a lower risk of type 2 diabetes and prostate cancer, although they are also linked to a higher risk of bone loss and fractures, hypogonadism in males, and hepatic cirrhosis.  [2., 15.]  It may also be caused by hyperthyroidism, as thyroid hormone stimulates SHBG production and release.  [15.]

Increased levels may also be seen in pregnancy, ostensibly as a protective mechanism to shield the fetus from higher circulating hormone levels in the mother; in women using oral contraceptives, ostensibly because of estrogenic exposure; and in prepubertal children, thought to be due to higher thyroid hormone levels.  [5., 11.]

Low SHBG Levels

Low SHBG levels have been linked to conditions such as polycystic ovary syndrome (PCOS), hirsutism, hair loss and infertility in women.  

Low SHBG levels have been associated with an increased risk of developing type 2 diabetes, cardiovascular disease, and metabolic disorders including metabolic syndrome, as well as some cancers and arthritis in both genders.  [18., 19.]

Natural Strategies to Support Healthy SHBG Levels

Dietary Factors

• Follow the Mediterranean diet, a balanced diet rich in whole grains, fruits, vegetables, and lean proteins.  The Mediterranean diet includes regular olive oil consumption, which has been shown to increase hepatic production of SHBG.  [13.]
• Include foods high in fiber, such as legumes, nuts, and seeds, to help regulate blood sugar levels.  Low SHBG levels are associated with cardiometabolic diseases including diabetes.  [8.]
• Limit intake of processed foods, sugary snacks, and high-fat meals, which may contribute to hormonal imbalances and cardiometabolic disorders 
• Incorporate omega-3 fatty acids from sources like fatty fish, flaxseeds, and walnuts, which may help improve SHBG levels

Lifestyle Modifications

• Maintain a healthy weight through regular exercise and physical activity.  Exercise has clear benefits in cardiometabolic health, and may improve SHBG levels.  [6.]
• Manage stress levels through techniques like mindfulness, meditation, or yoga.  As with exercise, stress reduction has clear benefits for cardiovascular health, which can be compromised with alterations in SHBG.  [16.]
• Get an adequate amount of quality sleep each night to support overall hormone balance.  Sleep reduction is associated with lower levels of SHBG.  [12.]
• Avoiding excessive alcohol consumption and quitting smoking, as these habits can negatively impact SHBG levels.  [14.]

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