What are the causes of elevated Follicle-Stimulating Hormone (FSH) levels in individuals?

Causes of Elevated FSH Levels

Elevated FSH levels primarily indicate ovarian failure or diminished ovarian reserve in women, and testicular dysfunction in men, but can also result from physiological variations, premature ovarian insufficiency, gonadotoxic treatments, and specific genetic mutations.

Primary Pathophysiological Mechanisms

In Women

• Primary ovarian insufficiency (POI) is the most common cause of persistently elevated FSH in women under 40 years, defined by amenorrhea for ≥4 months with two FSH measurements in the menopausal range 1
• Diminished ovarian reserve due to reproductive aging causes characteristic FSH elevation during the early follicular phase, reflecting declining oocyte quantity and quality 2, 3
• The mechanism involves loss of negative feedback from the ovaries (reduced inhibin B and estradiol production), leading to compensatory FSH elevation by the pituitary 3

In Men

• Primary testicular failure results in elevated FSH due to impaired spermatogenesis and loss of negative feedback from the testes 4
• FSH >7.5 IU/L in men is associated with 5-13 fold higher risk of abnormal sperm concentration and morphology compared to FSH <2.8 IU/L 4

Specific Causes of Elevated FSH

Gonadotoxic Treatments

• Alkylating chemotherapy agents (cyclophosphamide, procarbazine) cause dose-dependent ovarian damage leading to POI and elevated FSH 1
• Radiotherapy exposing the ovaries causes POI with a dose-dependent relationship, though no clear safe threshold exists 1
• Cancer survivors treated with these modalities require FSH surveillance, particularly those ≥25 years presenting with menstrual dysfunction 1

Genetic and Congenital Causes

• FSHR inactivating mutations cause ovarian dysgenesis with amenorrhea, infertility, and markedly elevated FSH in females 5
• Males with severe FSHR mutations exhibit varying spermatogenic defects but typically not complete azoospermia 5

Premature Ovarian Insufficiency

• Young women (<40 years) with elevated FSH may have autoimmune-mediated premature ovarian failure, with significantly higher prevalence of autoimmune antibodies 3
• These women show slower follicular growth, smaller follicle diameter, and lower luteal progesterone despite regular cycles 3

Physiological and Transient Elevations

• Post-unilateral ovariectomy causes compensatory FSH elevation 2
• Recovery phase from hypothalamic amenorrhea may show transiently elevated FSH 2
• Heavy smoking is associated with significantly elevated FSH levels 2
• Puberty, hereditary dizygotic twinning, post-oral contraceptive use, and lactation can all show physiologically elevated FSH 2

Important Clinical Distinctions

FSH Patterns in Different Conditions

• Primary gonadal failure: FSH and LH both elevated due to loss of negative feedback 6
• Secondary (hypogonadotropic) hypogonadism: FSH and LH are low or inappropriately normal despite low sex steroids 6
• PCOS: LH/FSH ratio typically >2, contrasting with other conditions 1
• Functional hypothalamic amenorrhea (FHA): LH/FSH ratio <1 in approximately 82% of cases, with both gonadotropins typically low 1

Spontaneous Recovery Potential

• In young women (<35 years) with oligomenorrhea or secondary amenorrhea and FSH >20 U/L, approximately 25% (17/67) subsequently ovulated spontaneously and 9% (6/67) conceived 7
• Lower coincident LH concentrations and higher urinary estrogen levels predict better likelihood of spontaneous ovulation recovery 7
• The degree of FSH elevation does not correlate well with future ovarian function 7

Critical Diagnostic Considerations

Assay and Temporal Variability

• FSH concentrations vary considerably due to intra-assay, inter-assay, hourly, cycle-day dependent, intercycle, and lifetime variations 2
• Serial measurements are essential: POI diagnosis requires two elevated FSH measurements, not a single value 1
• Timing matters: in women with regular cycles, FSH should be measured during early follicular phase (days 2-5); if amenorrheic, random measurement is acceptable 1

Common Pitfalls

• A single elevated FSH should not be over-interpreted without considering the clinical context and obtaining confirmatory testing 2
• In regularly menstruating women with elevated basal FSH, this may represent early perimenopause despite apparently normal ovulatory cycles 3
• Treatment with estrogens, clomiphene, or gonadotropins provides no benefit in inducing ovarian response while FSH remains elevated 7