Ovarian Reserve in SLE: Low AMH Common, Stable Over 24 Months

Key Takeaways

• Nearly half of premenopausal women with systemic lupus erythematosus (SLE) at a Ferrara, Italy, lupus clinic had low anti-Müllerian hormone (AMH) at enrollment.
• Cohort AMH did not progressively decline during follow-up.
• Lupus anticoagulant positivity was more common with diminished ovarian reserve and was associated with lower AMH in adjusted analysis.
• Hydroxychloroquine use was more common without diminished reserve at baseline, but AMH trajectories did not differ significantly by exposure.
• AMH trajectories did not differ significantly by belimumab exposure, while a small cytomegalovirus (CMV) serology subgroup showed an exploratory time interaction.

For women living with systemic lupus erythematosus (SLE), whether anti-Müllerian hormone (AMH)-defined ovarian reserve changes over time remains a reproductive-health question. Ovarian reserve may relate to disease features and treatment exposure, but a reserve marker and the ability to conceive are distinct questions. These questions prompted enrollment and repeated AMH measurements at a lupus clinic.

Investigators prospectively enrolled 80 premenopausal women aged 18–45 at the University Hospital of Ferrara lupus clinic in Italy during 2019–2023. All were receiving immunomodulating or immunosuppressive therapy; current cyclophosphamide treatment was excluded, and prior exposure was recorded. Twenty-two women with active disease started belimumab at entry as an observed exposure group, not an assigned intervention. Investigators recorded reproductive history, disease activity, accumulated damage, treatment history, and lupus anticoagulant status.

Serum AMH was measured by enzyme-linked immunosorbent assay (ELISA), with diminished reserve defined as AMH <1 ng/mL. Sampling occurred at baseline and every six months through month 24. Immunoglobulin G (IgG) and immunoglobulin M (IgM) serologies were measured for Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human herpesviruses 6, 7, and 8. Baseline comparisons, repeated measures, and covariate-adjusted mixed-effects analyses distinguished baseline characteristics from AMH change.

At enrollment, 36 of 80 women (45%) had AMH below the study cutoff. Those with diminished reserve tended to be older, have longer SLE duration, and have greater accumulated damage; disease activity measures were comparable. Lupus anticoagulant positivity was significantly more common with diminished reserve, at 39% versus 14% without it. Hydroxychloroquine use was significantly less common with diminished reserve, at 69% versus 89% without it. These baseline associations did not establish effects on subsequent AMH trajectories.

Aggregate AMH and the proportion below the cutoff showed no progressive decline during follow-up. In the adjusted mixed-effects analysis, lupus anticoagulant positivity was associated with lower AMH: β = -0.582 (95% CI -1.159 to -0.006; p = 0.048). Age had a significant interaction with time, whereas disease activity, duration, and accumulated damage were not independently associated with AMH in that model. Neither hydroxychloroquine nor belimumab had a significant time-by-treatment interaction; belimumab recipients had higher disease activity at baseline. Longitudinal EBV and human herpesvirus findings were largely null, and investigators considered an isolated baseline EBV IgG difference possibly due to chance. A significant positive time interaction in the CMV IgG-positive/IgM-negative subgroup was exploratory because the subgroup was small.

Ovarian reserve was classified mainly by AMH, without antral follicle counts or a comprehensive follicle-stimulating hormone and luteinizing hormone profile. The small, predominantly Caucasian, single-center Italian cohort and some pandemic-era missed visits limited interpretation. Observational therapy comparisons, baseline differences between treatment groups, few women unexposed to hydroxychloroquine, and small viral subgroups precluded causal conclusions about drug protection, reproductive drug safety, or CMV effects.

The authors concluded that diminished AMH was frequent at enrollment while cohort AMH remained broadly stable, with clinical and treatment associations requiring confirmation.

Clinician Questions

Does low AMH in women with systemic lupus erythematosus establish infertility or premature ovarian insufficiency?

AMH below the investigators’ cutoff classified diminished ovarian reserve in premenopausal women with systemic lupus erythematosus. The biomarker alone did not establish infertility or premature ovarian insufficiency, and the AMH trajectory did not determine fertility outcomes.

Was prior cyclophosphamide exposure significantly associated with diminished ovarian reserve in women with lupus?

Among premenopausal women with systemic lupus erythematosus, previous cyclophosphamide exposure was more common in the low-AMH group at enrollment, but the difference did not meet the investigators’ statistical significance threshold. Current cyclophosphamide therapy was excluded, and the baseline comparison does not establish whether earlier exposure caused a change in ovarian reserve.