Role of FSH and LH in Male Fertility
Both FSH and LH are essential for achieving quantitatively normal sperm production in men, though neither hormone alone is absolutely required for qualitative spermatogenesis—FSH primarily drives Sertoli cell function and spermatogonial proliferation, while LH stimulates testosterone production by Leydig cells, which is critical for supporting all phases of spermatogenesis. 1, 2
Physiological Mechanisms
FSH Function in Spermatogenesis
FSH acts exclusively through Sertoli cells since germ cells lack FSH receptors, making Sertoli cells the critical mediators of FSH action on spermatogenesis 2
FSH determines Sertoli cell number during development and is required for induction and maintenance of normal sperm production 2
FSH is the prime inducer of spermatogonial proliferation, particularly stimulating mitotic division of A-pale spermatogonia, though successive maturation can proceed with reduced FSH levels 2
FSH stimulates cAMP-dependent activation of protein kinase A in Sertoli cells, though the complete molecular mechanism remains incompletely understood 2
LH and Testosterone Function
LH acts on Leydig cells to produce testosterone, which is the primary mediator of LH's effects on spermatogenesis 2
Intratesticular testosterone concentrations are 50-100 times higher than serum levels and are essential for normal spermatogenesis 3
Both FSH and testosterone can stimulate all phases of spermatogenesis, though their combined action is required for quantitatively normal sperm production 2
Clinical Evidence from Experimental Studies
Selective Hormone Deficiency Studies
When normal men were made gonadotropin-deficient with high-dose testosterone, selective replacement of either LH (via hCG) or FSH alone increased sperm counts to 20-50 million/mL, but quantitatively normal spermatogenesis was not achieved 1
When selective FSH deficiency was induced with hCG administration (providing high LH-like activity), sperm production was partially suppressed to the 20-50 million/mL range 1
Replacement of both FSH and LH together restored sperm production to the normal control range in all subjects, demonstrating that both hormones are required for quantitatively normal spermatogenesis 1
Genetic Evidence from FSH Receptor Mutations
A patient with an activating FSH receptor mutation maintained fertility and fathered three children despite being hypophysectomized with undetectable gonadotropins, demonstrating that FSH signaling alone can maintain spermatogenesis in the presence of adequate testosterone replacement 2
Men with inactivating FSH receptor mutations show variable spermatogenic impairment—among five men studied, only one was infertile, though all had some degree of reduced sperm production 2, 4
These inactivating mutation cases had incompletely suppressed inhibin B and only moderately elevated FSH, suggesting residual FSH receptor function, which explains the variable phenotype 2
Clinical Implications for Subfertility Evaluation
Diagnostic Interpretation of Hormone Levels
FSH levels >7.6 IU/L strongly suggest non-obstructive azoospermia or impaired spermatogenesis, with higher FSH reflecting the pituitary's compensatory response to reduced testicular function 3, 5
FSH is negatively correlated with spermatogonia numbers—elevated FSH indicates decreased sperm production capacity 3
FSH levels alone cannot definitively predict fertility status—up to 50% of men with non-obstructive azoospermia and elevated FSH still have retrievable sperm via testicular sperm extraction 3, 5
Normal LH with elevated FSH suggests primary seminiferous tubule dysfunction with preserved Leydig cell function 3
Essential Diagnostic Workup
Obtain at least two semen analyses separated by 2-3 months after 2-7 days abstinence to confirm actual sperm production, as hormone levels alone are insufficient 3, 6
Measure complete hormonal panel including FSH, LH, total testosterone, and SHBG to calculate free testosterone and fully characterize the hypothalamic-pituitary-gonadal axis 3, 6
Perform physical examination focusing on testicular volume (normal >12 mL), consistency, and presence of varicocele 3, 6
If semen analysis shows severe oligospermia (<5 million/mL) or azoospermia with elevated FSH, obtain karyotype analysis and Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) 3, 6
Treatment Considerations
Critical Pitfall to Avoid
- Never prescribe exogenous testosterone therapy if fertility is desired—it completely suppresses FSH and LH through negative feedback, causing azoospermia that can take months to years to recover 3, 6, 5
Therapeutic Options for Impaired Spermatogenesis
For hypogonadotropic hypogonadism, treatment with hCG (providing LH activity) followed by FSH analogues successfully initiates spermatogenesis, with 75% of men achieving sperm in ejaculate 3
FSH analogue treatment may improve sperm concentration, pregnancy rate, and live birth rate in men with idiopathic infertility and FSH <12 IU/L, though benefits are modest 6, 5, 7
Selective estrogen receptor modulators (SERMs) or aromatase inhibitors may be used for low testosterone with elevated FSH, though benefits are limited compared to assisted reproductive technology 3, 6
Assisted reproductive technology (IVF/ICSI) offers superior pregnancy rates compared to empiric hormonal therapy and should be discussed early, particularly given female partner age considerations 3, 6
Addressing Reversible Factors
Weight loss and metabolic optimization can normalize gonadotropins and improve testosterone levels in functional hypogonadism associated with obesity 3, 6
Correct thyroid dysfunction, as it disrupts the hypothalamic-pituitary-gonadal axis and can artificially elevate FSH 3, 6
Varicocele repair should be considered in men with palpable varicoceles and impaired semen parameters, as it may improve testosterone levels, reduce FSH, and stabilize testicular volume 3
Emerging Research Insights
Recent animal studies challenge traditional paradigms by demonstrating that very low intratesticular testosterone levels (1.4% of normal) can support full spermatogenesis, and strong FSH signaling can maintain near-normal spermatogenesis even with minimal testosterone 8
These findings suggest potential for developing hormonal male contraception targeting FSH/LH suppression and novel treatments for idiopathic oligozoospermia using FSH stimulation 8
However, clinical translation requires caution, as human studies consistently demonstrate that both FSH and LH together are required for quantitatively normal sperm production in men 1, 2