What is the interpretation of abnormal Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) lab results?

Interpretation of Abnormal LH and FSH Laboratory Results

Abnormal LH and FSH results must be interpreted in the context of testosterone/estradiol levels, clinical presentation, and testicular/ovarian examination to distinguish between primary gonadal failure (elevated LH/FSH with low sex hormones) and secondary hypogonadism (low or inappropriately normal LH/FSH with low sex hormones).

Primary Diagnostic Framework

The interpretation of gonadotropin abnormalities follows a hierarchical algorithm based on the pattern of hormone elevation or suppression:

Pattern 1: Elevated FSH and/or LH with Low Testosterone/Estradiol

This pattern indicates primary gonadal failure (hypergonadotropic hypogonadism):

• In males: FSH >7.6 IU/L strongly suggests primary testicular dysfunction, particularly when accompanied by testicular atrophy on physical examination 1, 2
• Testosterone levels below normal range with elevated LH and FSH confirm primary testicular failure 2
• Physical examination reveals small, soft testes (typically <15 mL volume) in primary testicular failure 1
• In females: Elevated FSH with low estradiol indicates primary ovarian insufficiency, particularly when FSH is persistently elevated on repeat testing 1

Critical threshold: FSH >7.6 IU/L in males with azoospermia indicates non-obstructive azoospermia with approximately 70% sensitivity, though up to 50% may still have retrievable sperm with testicular extraction 2

Pattern 2: Low or Inappropriately Normal LH/FSH with Low Testosterone/Estradiol

This pattern indicates secondary (central) hypogonadism:

• Measure serum prolactin in all patients with this pattern, as hyperprolactinemia is a common reversible cause 1
• If prolactin is elevated, repeat measurement to exclude spurious elevation; persistently elevated prolactin warrants pituitary MRI and endocrinology referral 1
• Men with total testosterone <150 ng/dL combined with low or low-normal LH should undergo pituitary MRI regardless of prolactin levels to exclude non-secreting adenomas 1
• Evaluate for pituitary mass lesions, infiltrative diseases (sarcoidosis, hemochromatosis, histiocytosis), or medication effects 1

Pattern 3: Elevated LH with Normal or Low FSH

This pattern suggests:

• In women: Polycystic ovary syndrome (PCOS) when LH/FSH ratio >2, though this ratio has poor sensitivity (only 41-44% of PCOS patients demonstrate this pattern) and should not be used as a sole diagnostic criterion 3
• Total testosterone is a superior biochemical marker for PCOS, with 70% sensitivity 3
• In men: Consider partial androgen insensitivity or androgen receptor abnormalities 1

Pattern 4: Isolated FSH Elevation with Normal LH and Sex Hormones

This pattern indicates:

• In males: Selective impairment of spermatogenesis with preserved Leydig cell function; FSH levels are negatively correlated with spermatogonia number 2
• Testicular volume may be normal despite severe spermatogenic dysfunction in cases of maturation arrest 2
• In females: Diminished ovarian reserve, particularly when anti-Müllerian hormone (AMH) is also low 1

Age-Specific Interpretation

Prepubertal Children

• Normal prepubertal LH: 0.04 ± 0.04 IU/L 4
• FSH levels are measurably higher than LH in prepubertal children, with mean FSH excretion of 2.2 U/L versus LH of 0.44 U/L 5
• GnRH-stimulated LH >5 IU/L suggests maturing gonadotropin secretion and onset of puberty 4
• Failure to initiate puberty by age 11 years in girls (absence of Tanner stage 2 breast development) warrants FSH and estradiol measurement 1

Reproductive-Age Adults

• Normal follicular phase (women): FSH and LH show characteristic patterns with FSH initially higher than LH in early follicular phase, followed by mid-cycle LH surge 6
• Mid-cycle LH peak is essential laboratory criterion for normal ovulatory cycle 6
• Men: LH and FSH should be measured in morning samples due to diurnal variation 1
• In men with chronic liver disease or conditions affecting sex hormone-binding globulin (SHBG), calculate free testosterone index (total testosterone/SHBG ratio; <0.3 indicates hypogonadism) 1

Essential Adjunctive Testing

When abnormal LH/FSH patterns are identified, the following tests are mandatory:

For Elevated FSH/LH (Primary Gonadal Failure)

• Karyotype analysis: Essential to identify Klinefelter syndrome (47,XXY) and other chromosomal abnormalities 2
• Y-chromosome microdeletion testing in males with non-obstructive azoospermia: Complete AZFa or AZFb deletions have near-zero sperm retrieval likelihood 2
• Semen analysis (at least two samples after centrifugation) to confirm azoospermia versus oligospermia 2
• Testicular examination for volume, consistency, and presence of varicocele 1

For Low/Normal FSH/LH (Secondary Hypogonadism)

• Prolactin measurement is mandatory; if elevated, repeat to confirm 1
• Pituitary MRI when testosterone <150 ng/dL with low/normal LH, or when prolactin persistently elevated 1
• Evaluate for symptoms of pituitary mass: headache (85% of hypophysitis cases), visual field defects (bitemporal hemianopsia), fatigue (66%) 1
• Morning cortisol and ACTH to exclude secondary adrenal insufficiency, which occurs in >75% of hypophysitis cases 1
• Free T4 and TSH to identify central hypothyroidism (present in >90% of hypophysitis) 1

For All Patterns

• Measure estradiol in males presenting with gynecomastia or breast symptoms prior to any testosterone therapy 1
• Thyroid function testing, as thyroid disorders commonly disrupt the hypothalamic-pituitary-gonadal axis 2

Critical Clinical Pitfalls

Assay Variability

• Absolute gonadotropin values differ significantly between assay methods despite using identical reference preparations 3
• Older radioimmunoassays diverge markedly from modern immunochemiluminometric assays at lower concentrations 4
• Always repeat abnormal values to exclude laboratory error and account for pulsatile secretion 2

FSH Cannot Predict Fertility Definitively

• FSH levels alone have variable correlation with sperm retrieval outcomes in non-obstructive azoospermia 2
• Up to 50% of men with elevated FSH and non-obstructive azoospermia have retrievable sperm with microdissection testicular sperm extraction 2
• Men with maturation arrest can have normal FSH despite severe spermatogenic dysfunction 2

Reversible Causes Must Be Excluded

• Exogenous testosterone suppresses FSH and LH through negative feedback, causing iatrogenic hypogonadism; never prescribe testosterone to men desiring fertility 2
• Chronic opioid use, glucocorticoids, and anabolic steroids suppress gonadotropin secretion 1
• Metabolic stress, obesity, and thyroid dysfunction can transiently elevate FSH 2
• Hyperprolactinemia from medications (antipsychotics, metoclopramide) is reversible 1

Normal Sex Hormone Levels Do Not Exclude Gonadotropin Abnormalities

• Normal estradiol and progesterone secretion can occur despite grossly abnormal FSH and LH patterns in women with unexplained infertility 7
• Persistently elevated LH relative to FSH (LH/FSH ratio >2) with normal ovarian steroid production may indicate subtle gonadotropin dysregulation contributing to infertility 7

Treatment Implications

Primary Gonadal Failure

• Lifelong hormone replacement therapy is required for most cases 1
• In males desiring fertility with secondary hypogonadism, human chorionic gonadotropin (hCG) followed by FSH analogues can initiate spermatogenesis 2
• Assisted reproductive technology (IVF/ICSI) offers superior pregnancy rates compared to empiric hormonal therapy 2

Secondary Hypogonadism

• Treat underlying cause (prolactinoma, pituitary mass, medication adjustment) 1
• Selective estrogen receptor modulators preserve fertility potential in men with low/normal LH who wish to conceive 1
• Adrenal insufficiency must be treated before initiating thyroid hormone replacement to avoid precipitating adrenal crisis 1