The FSH reset hypothesis: optimizing spermatogenesis in azoospermia

Area of Science:

• Reproductive Endocrinology
• Hormone Therapy
• Male Infertility

Background:

• Elevated follicle-stimulating hormone (FSH) in primary hypogonadism is typically interpreted as maximal testicular stimulation failure.
• Men with high FSH are often deemed unsuitable candidates for hormonal therapy.
• This review challenges the assumption that high FSH concentration directly correlates with testicular response.

Purpose of the Study:

• To re-examine the interpretation of elevated FSH in hypogonadism.
• To investigate whether FSH bioactivity, not just concentration, influences testicular response.
• To propose a new hypothesis regarding FSH function in male hypogonadism.

Main Methods:

• Narrative review of existing literature.
• Analysis of FSH isoforms and their receptor-binding efficiency.
• Examination of mechanisms of FSH receptor downregulation and desensitization.
• Review of clinical observations and criteria (e.g., APHRODITE).

Main Results:

• Circulating FSH exists as glycosylation-dependent isoforms with varying receptor-binding efficiencies.
• Chronic gonadotropin excess can lead to FSH receptor downregulation and desensitization, causing functional FSH resistance.
• High immunoreactive FSH may coexist with a weaker effective testicular signal.
• FSH suppression is associated with rises in inhibin B, suggesting potential for improved testicular function.

Conclusions:

• The 'FSH reset hypothesis' proposes that a period of pituitary suppression can reduce inefficient endogenous FSH and potentially restore receptor sensitivity.
• This may allow for improved testicular response to controlled recombinant FSH therapy.
• A stepwise treatment algorithm is proposed for investigation in men with spermatogenic failure.
• The hypothesis is speculative and requires validation through prospective clinical trials.