Can high testosterone serum and high Sex Hormone-Binding Globulin (SHBG) raise Follicle-Stimulating Hormone (FSH) levels?

Effect of High Testosterone and High SHBG on FSH Levels

High testosterone and high SHBG do not typically raise FSH levels; in fact, high testosterone generally suppresses FSH through negative feedback mechanisms, while high SHBG may indirectly lead to increased FSH only when it reduces free testosterone significantly. 1

Relationship Between Testosterone, SHBG, and FSH

Testosterone's Effect on FSH

• Testosterone exerts negative feedback on the hypothalamic-pituitary axis, typically suppressing FSH production 2
• When testosterone levels rise, this normally leads to decreased FSH secretion through this feedback loop
• Studies show that testosterone replacement in men with hypogonadotropic hypogonadism leads to suppression of FSH levels from baseline values 2

SHBG's Indirect Effect on FSH

• SHBG binds to testosterone, reducing the amount of free (biologically active) testosterone 1
• When SHBG is elevated:
  • Total testosterone may appear high, but free testosterone can be low
  • This reduced free testosterone may weaken the negative feedback on the pituitary
  • In some cases, this could potentially allow FSH levels to rise 3

Clinical Scenarios Where This Relationship Is Observed

Functional Hypothalamic Amenorrhea with PCOM

• In women with functional hypothalamic amenorrhea (FHA) with polycystic ovarian morphology (PCOM), those without PCOM actually have:
  • Higher FSH levels
  • Higher SHBG levels
  • Lower testosterone levels 4
• This suggests an inverse relationship where higher SHBG and lower testosterone correlate with higher FSH levels

Testosterone/SHBG Ratio and Gonadal Function

• The ratio of total testosterone to SHBG (free testosterone index) is more clinically relevant than either value alone 1
• A ratio ≥0.3 indicates normal gonadal function
• A ratio <0.3 suggests hypogonadism, which may be associated with altered FSH levels 1

Mechanisms and Physiological Considerations

Feedback Regulation

• FSH production is primarily regulated by:
  • Negative feedback from gonadal steroids (testosterone, estradiol)
  • Inhibin B from Sertoli cells
• High testosterone typically suppresses FSH through this negative feedback loop 5
• However, when SHBG is also high, the bioavailable testosterone decreases, potentially weakening this negative feedback 3

Experimental Evidence

• Studies have shown that when SHBG increases (e.g., during ethinylestradiol administration), there can be a biphasic response in LH and testosterone, though FSH may not show significant changes 3
• In cases where SHBG rises rapidly, the resulting decrease in free testosterone may alter the feedback regulation of gonadotropins 3

Clinical Implications

Diagnostic Considerations

• When evaluating hormone levels, both total and free testosterone should be measured 1
• Relying solely on total testosterone can miss clinically significant hormone deficiencies when SHBG is elevated 1
• Free testosterone index (ratio of total testosterone to SHBG) provides more accurate information about androgen status 1

Common Pitfalls

• Overlooking the role of SHBG when interpreting testosterone levels
• Failing to consider free testosterone when total testosterone is high
• Not recognizing that changes in SHBG can indirectly affect the hypothalamic-pituitary-gonadal axis 1

In summary, while high testosterone typically suppresses FSH, high SHBG can bind testosterone and reduce free testosterone levels, potentially weakening the negative feedback on FSH. However, this indirect effect would only raise FSH if the reduction in free testosterone is significant enough to alter the feedback mechanism.