How does systemic lupus erythematosus (SLE) affect hormone levels in women of childbearing age?

How Lupus Affects Hormone Levels in Women

Systemic lupus erythematosus itself does not directly alter baseline hormone levels or cause hormonal dysfunction, but the disease treatments—particularly cyclophosphamide—can cause premature ovarian failure with resulting hormonal changes. 1, 2

Direct Effects of SLE on Hormones

Ovarian Reserve and Fertility Hormones

• SLE disease activity alone does not decrease fertility or significantly alter anti-Müllerian hormone (AMH) levels in most women. 1
• Multiple studies evaluating hormonal levels (including AMH) and antral follicle counts have failed to demonstrate that lupus itself impairs ovarian reserve. 1, 2
• However, women with severe disease manifestations, particularly major organ involvement, may show reduced AMH levels compared to controls, suggesting disease severity—not the disease itself—may impact ovarian reserve. 3
• SLE patients with disease damage accumulation show lower AMH levels, indicating that chronic disease burden rather than acute inflammation affects hormonal markers. 4

Sex Hormone Levels

• Estradiol levels in SLE patients are generally comparable to healthy controls, though some studies suggest associations between estradiol levels and organ-specific disease activity (particularly renal involvement). 5
• Prolactin levels remain within normal range in most SLE patients; hyperprolactinemia is not a consistent finding. 5
• Early natural menopause occurs more frequently in women who develop SLE, but this appears to be a marker of disease susceptibility rather than a consequence of the disease. 6

Treatment-Related Hormonal Effects

Cyclophosphamide-Induced Ovarian Dysfunction

• Alkylating agents, especially cyclophosphamide, are the primary cause of hormonal disruption in lupus patients, causing menstrual irregularities and premature ovarian failure (POF) in an age- and dose-dependent manner. 1, 2
• Sequential treatment with cyclophosphamide and conventional disease-modifying antirheumatic drugs (cDMARDs) significantly reduces AMH levels compared to controls, indicating substantial ovarian reserve depletion. 3
• Women treated with antimalarials only, cDMARDs only, or cyclophosphamide alone show AMH levels comparable to controls, but combination sequential therapy causes measurable hormonal impact. 3

Other Immunosuppressive Agents

• Less gonadotoxic regimens (azathioprine, mycophenolate mofetil, methotrexate) should be prioritized in non-life-threatening disease to avoid ovarian dysfunction. 1
• Active lupus nephritis may negatively impact fertility through indirect mechanisms, but this does not equate to causing direct hormonal changes. 1

Glucocorticoid Effects

• Chronic glucocorticoid use, particularly at maintenance doses ≥10-20 mg/day prednisone equivalent, affects multiple outcomes but specific direct effects on reproductive hormone levels are not well-characterized in the guidelines. 1

Exogenous Hormone Considerations

Hormonal Contraception Safety

• Combined estrogen-progestin contraceptives are safe in women with inactive or stable SLE and negative antiphospholipid antibodies, indicating that exogenous hormones do not trigger disease flares in appropriately selected patients. 1
• Progestin-only contraceptives are suitable for women with positive antiphospholipid antibodies, though thrombosis risk must be weighed. 1

Hormone Replacement Therapy

• Oestrogens may be used in SLE patients, but accompanying risks (particularly thrombosis in antiphospholipid antibody-positive patients) must be assessed. 1
• Current evidence suggests a small increased risk of mild/moderate flares with HRT, but major flare risk does not appear increased. 7

Clinical Management Implications

Fertility Preservation

• GnRH analogues should be considered for all menstruating women requiring cyclophosphamide, with excellent safety and efficacy (RR 0.12 for POF prevention). 1, 2
• GnRH analogues cause reversible menopause-like symptoms but protect ovarian function. 1, 2

Monitoring Recommendations

• In patients with multiple fertility risk factors (disease severity, cyclophosphamide exposure, advanced age), ovarian reserve assessment with AMH may be warranted at a younger age than recommended for the general population. 1, 2
• Treatment decisions involving alkylating agents must balance disease control against ovarian dysfunction risk. 1, 2

Key Pitfall to Avoid

The common misconception that lupus itself causes hormonal dysfunction leads to unnecessary anxiety and potentially inappropriate counseling. The critical distinction is that SLE disease activity does not directly alter hormone production, but treatment choices—particularly cyclophosphamide—have profound hormonal consequences that require proactive fertility preservation strategies. 1, 2