Evaluation and Management of Low FSH and LH
When you encounter low FSH and LH, immediately distinguish between secondary (hypothalamic-pituitary) hypogonadism and functional suppression by measuring sex steroids (testosterone in men, estradiol in women) and conducting a targeted workup for central causes. 1
Initial Diagnostic Approach
Confirm the Diagnosis with Proper Timing
In men: Draw morning total testosterone (8-10 AM), free testosterone by equilibrium dialysis, and sex hormone-binding globulin on at least two separate occasions before proceeding with further evaluation. 1
In women: Measure FSH and LH during the early follicular phase (cycle days 3-6), averaging three samples taken 20 minutes apart for accuracy. 2 Simultaneously measure estradiol, testosterone, and progesterone (mid-luteal phase for the latter). 2
Distinguish Secondary Hypogonadism from Functional Suppression
Low FSH/LH with low sex steroids indicates secondary (central) hypogonadism, which requires investigation of hypothalamic-pituitary dysfunction. 1 This differs fundamentally from primary gonadal failure, where FSH/LH are characteristically elevated. 3
Common functional causes to exclude first:
Obesity: Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback, suppressing LH secretion. 1 Free testosterone measurement is essential in obese men, as low total testosterone may reflect only low SHBG. 1
Acute illness: Avoid testosterone testing during acute illness, as transient suppression occurs. 1
Medications: Identify drugs interfering with the HPG axis (opioids, glucocorticoids, anabolic steroids). 1
Workup for Central Hypogonadism
When secondary hypogonadism is confirmed (low FSH/LH with low sex steroids), proceed systematically:
Essential Laboratory Tests
Serum prolactin: Hyperprolactinemia suppresses gonadotropin secretion. 1 Men with low/low-normal LH accompanied by decreased libido, impotence, or testosterone deficiency warrant prolactin measurement. 1
Iron saturation: Screen for hemochromatosis, which can cause pituitary dysfunction. 1
Pituitary function testing: Assess other pituitary axes (thyroid, adrenal, growth hormone). 1
Imaging
MRI of the sella turcica: Indicated when prolactin is persistently elevated above normal without exogenous cause, or when other pituitary hormone deficiencies are present. 1
For cancer survivors: Those who received cranial irradiation ≥30 Gy are at highest risk for central hypogonadism. 1 Even lower doses (18-24 Gy) decrease fertility rates. 1
Management Strategy
Address Reversible Causes First
Weight loss and lifestyle modification are mandatory initial steps for obesity-related hypogonadism:
Low-calorie diets reverse obesity-associated secondary hypogonadism by improving testosterone levels and normalizing gonadotropins. 1
Physical activity provides similar benefits, with results correlating to exercise duration and weight loss. 1
However, testosterone increases are modest (1-2 nmol/L), and combining lifestyle changes with hormone therapy yields better outcomes in symptomatic patients. 1
Hormone Replacement Depends on Fertility Goals
For Men NOT Seeking Fertility
Testosterone replacement therapy is the treatment of choice:
Transdermal preparations (gel or patch) are preferred for most men because they produce stable serum testosterone concentrations and are most convenient. 1
Monitor testosterone levels 2-3 months after initiation to confirm normal serum concentrations are achieved. 1
Critical caveat: Exogenous testosterone provides negative feedback to the hypothalamus and pituitary, inhibiting gonadotropin secretion and potentially causing azoospermia. 1 TTh is absolutely contraindicated in men seeking fertility. 1
For Men Seeking Fertility
Gonadotropin therapy is standard for secondary hypogonadism:
Initiate human chorionic gonadotropin (hCG) injections first, monitoring serum testosterone response. 1
After testosterone normalization, add FSH or FSH analogues to optimize sperm production. 1
Combined hCG and FSH therapy provides optimal outcomes. 1
Alternative: Pulsatile GnRH therapy (4-16 mcg subcutaneous pulses via portable pump) is highly effective, inducing spermatogenesis in 3-15 months in men with idiopathic hypogonadotropic hypogonadism. 4
Pulse frequency matters: Slower LHRH pulse frequencies (every 2-3 hours vs. every 1 hour) preferentially increase FSH over LH, which may be therapeutically useful. 5
For Women
Estrogen replacement (oral, micronized, or transdermal) normalizes ovarian hormone levels. 1
Progesterone therapy is mandatory in women with a uterus to avoid unopposed estrogen effects and maintain endometrial health. 1
For fertility: Gonadotropin therapy is required for secondary hypogonadism. 1
Special Populations
Cancer survivors with central hypogonadism from cranial irradiation:
Screen annually for gonadotropin deficiency, delayed/arrested puberty, or premature ovarian failure. 1
In prepubertal survivors, assess onset and tempo of puberty, menstrual history, and Tanner stage annually until sexual maturity, with baseline LH, FSH, and estradiol at age 13 years. 1
Bone mineral density testing should be considered for all hypogonadal patients due to increased fracture risk. 1
Common Pitfalls to Avoid
Do not use SERMs (clomiphene, tamoxifen) for idiopathic infertility: Benefits are limited relative to ART results. 1 While exogenous FSH may be used as adjunct for hypogonadotropic hypogonadism, its use in idiopathic infertile men without HH has measurable but limited fertility benefits. 1
Do not prescribe testosterone to men seeking fertility: This will worsen their condition by suppressing spermatogenesis. 1
Do not assume low total testosterone equals true hypogonadism in obese men: Always measure free testosterone, as low SHBG alone can cause low total testosterone with normal free levels. 1
Do not forget to repeat abnormal hormone levels: Confirm low testosterone on at least two separate morning samples before diagnosing hypogonadism. 1