What is the role of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), in reproductive health and treatment?

Gonadotropins in Reproductive Health and Treatment

Overview of Gonadotropin Function

Gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—are essential glycoprotein hormones that regulate gametogenesis and gonadal steroid production in both males and females, with their deficiency or dysfunction directly compromising fertility and requiring targeted replacement therapy. 1

Physiological Roles

In Females:

• FSH stimulates ovarian follicular growth and development in women without primary ovarian failure 2
• LH triggers ovulation and maintains corpus luteum function 1
• Premature pulsatile GnRH secretion induces release of LH and FSH, activating the hypothalamic-pituitary-gonadal (HPG) axis 1
• Human chorionic gonadotropin (hCG) must be administered following FSH therapy to achieve final follicular maturation and ovulation in the absence of an endogenous LH surge 2

In Males:

• FSH stimulates spermatogenesis when administered with hCG in men with hypogonadotropic hypogonadism 2
• LH stimulates Leydig cells to produce testosterone, which is essential for spermatogenesis 1
• In the absence of LH and FSH stimulation, testosterone secretion ceases and spermatogenesis is disrupted 1

Clinical Assessment of Gonadotropin Status

Female Assessment Protocol

For women at risk of hypogonadism (post-chemotherapy, radiation, or surgery):

• Assess LH, FSH, and estradiol levels at age 13 years in prepubertal survivors 1
• Monitor menstrual history, Tanner stage, and sexual maturity annually until full development 1
• Screen LH, FSH, and estradiol in patients with delayed puberty, irregular menses, amenorrhea, or estrogen deficiency symptoms 1
• Consider bone mineral density testing for hypogonadal patients 1
• Anti-Müllerian hormone (AMH) correlates better with ovarian reserve than age, basal FSH, estradiol, or inhibin B 1

For precocious puberty evaluation:

• Assay LH, FSH, and estradiol levels when Tanner stage 2 breast development occurs before age 8 years 1
• Assess bone age in rapidly growing children 1
• Perform pelvic ultrasound to evaluate ovarian volume and uterine stimulation 1
• Elevated basal LH, advanced bone age, and ultrasonic evidence of uterine stimulation indicate premature HPG axis activation 1

Male Assessment Protocol

For men with suspected hypogonadotropic hypogonadism:

• Measure serum FSH, LH, and testosterone levels 1
• Men with decreased libido, impotence, and testosterone deficiency with low/low-normal LH require serum prolactin measurement 1
• Persistently elevated prolactin without exogenous etiology warrants MRI evaluation 1
• FSH levels >7.6 IU/L suggest impaired spermatogenesis but do not indicate complete absence of sperm production 3
• Complete semen analysis is essential to distinguish between oligospermia and azoospermia 3

Treatment Approaches

Hypogonadotropic Hypogonadism Treatment

In males with confirmed hypogonadotropic hypogonadism:

• Initiate hCG injections first, monitoring serum testosterone response 1
• After testosterone normalization, add FSH or FSH analogues to optimize sperm production 1
• Spermatogenesis can be initiated and pregnancies achieved in many men with idiopathic hypogonadotropic hypogonadism when treated with exogenous gonadotropins or pulsatile GnRH 1
• Up to 75% of non-obstructive azoospermia patients with hypogonadotropic hypogonadism achieve sperm production in ejaculate with hCG with or without FSH 1

Critical warning: Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary, inhibiting gonadotropin secretion and potentially causing azoospermia—avoid testosterone monotherapy in men seeking fertility 1, 3

Idiopathic Infertility Treatment

For women with idiopathic infertility:

• FSH administration significantly increases sperm production (concentration and total count) in a dose-dependent manner 1
• FSH treatment significantly increased both spontaneous and ART pregnancy rates 1
• Selective estrogen receptor modulators (SERMs) significantly increased pregnancy rates and sperm/hormonal parameters in 16 studies, though study quality was low 1
• Aromatase inhibitors increase endogenous testosterone production and improve spermatogenesis by inhibiting estrogen's negative feedback on the hypothalamus 1

For men with idiopathic infertility:

• FSH analogues may be considered to improve sperm concentration, pregnancy rate, and live birth rate, though benefits are limited compared to ART 1
• SERMs have measurable but small fertility benefits, outweighed by advantages of IVF with higher pregnancy rates and earlier conception timeframes 1
• FSH is not FDA-approved for use in idiopathic infertile men without hypogonadotropic hypogonadism 1
• Treatment typically requires 3+ months to affect spermatogenesis, with questionable cost-to-benefit ratio 1

Non-Obstructive Azoospermia

Patients with non-obstructive azoospermia should be informed of limited data supporting pharmacologic manipulation with SERMs, aromatase inhibitors, and gonadotropins prior to surgical intervention. 1

• Positive sperm retrieval after testicular sperm extraction (TESE) occurs in up to 50% of non-obstructive azoospermia patients 1, 3
• Even with elevated FSH levels, retrievable sperm may be present 3

Precocious Puberty Treatment

GnRH analogs are the treatment of choice for precocious puberty to:

• Preserve final adult height 1
• Delay menarche 1
• Optimize development of secondary sex characteristics 1
• Through continuous stimulation, these analogs desensitize gonadotrophs and reduce LH release, halting ovarian stimulation 1
• Treatment continues until normal age of puberty 1

Assisted Reproductive Technology Considerations

For couples requiring ART:

• Intracytoplasmic sperm injection (ICSI) during IVF abrogates adverse effects of sperm quality (concentration, motility, morphology) as long as adequate viable sperm are present 1
• Intrauterine insemination (IUI) requires total motile sperm count >5 million after processing for reasonable pregnancy chances 1, 3
• IVF with ICSI is highly effective even with poor sperm parameters when viable sperm are available 1, 3

Monitoring During Gonadotropin Therapy

Essential monitoring parameters:

• Ultrasound monitoring of ovarian response and/or serum estradiol measurement minimizes risk of ovarian stimulation 2
• If ovaries are abnormally enlarged on the last day of FSH therapy, withhold hCG to reduce ovarian hyperstimulation syndrome (OHSS) risk 2
• Serum inhibin levels respond with least delay and decline rapidly after FSH discontinuation 2
• Maximum follicular volume correlates better with inhibin and estradiol peak levels than with FSH concentration 2
• Spermatogenesis requires approximately 74 days, so treatment effects need at least this timeframe for observation 3

Critical Safety Considerations

Major risks with gonadotropin therapy:

• Multi-fetal gestation occurred in 20% of live births with ovulation induction and 35.1% with ART 2
• OHSS risk increases with abnormal ovarian enlargement—prohibit intercourse with significant ovarian enlargement after ovulation due to rupture risk 2
• Ectopic pregnancy incidence may increase in women with tubal abnormalities undergoing ART 2
• Spontaneous abortion risk increases with gonadotropin products, though causality not established 2