Ovarian Reserve in Systemic Lupus Erythematosus Patients with Normal Menstrual Cycles and in the Absence of Exposure to Alkylating Agents

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong predominance in young women. Early symptoms of SLE usually occur in the second and third decades of life. The disease has a wide spectrum of clinical presentations, including the cutaneous, articular, hematological, renal, and central nervous system involvement. Typical laboratory features are the presence of antinuclear antibodies (ANA) in about 99% of cases and the occurrence of serological markers, mainly anti-double stranded DNA (anti-dsDNA) and anti-Sm antibodies. Indeed, a striking feature of this disease is the production of multiple circulating autoantibodies, leading to the formation of immune complexes, which are a major cause of inflammatory tissue damage in SLE. The clinical course is characterized by periods of exacerbation (active disease) and remission. The treatment must be individualized—especially considering the severity of organ involvement—and it is based primarily on the use of antimalarial drugs, glucocorticoids, and immunosuppressive agents. ^{1 –3}

The last few decades have recorded improved rates of mortality due to SLE. Studies in the 1950s pointed out a survival rate of less than 50% at 5 years, while the most recent reviews indicate survival greater than 93% in the same time interval and above 85% in 10 years. This improved survival rate is probably related to earlier diagnosis of the disease, more conservative use of glucocorticoids, modified immunosuppressive regimens, more effective measures for the treatment of infectious complications, and better knowledge and preventive measures for the development of early atherosclerosis. ¹ Thus, currently young females affected by this disease reach adulthood and become older, but often with impaired quality of life due to comorbidities arising from the disease itself and from its treatment, such as chronic renal failure, acute myocardial infarction, diabetes mellitus, osteoporosis with fractures, osteonecrosis, and premature ovarian failure. ^1,4

In this regard, it is well known that therapy with intravenous cyclophosphamide (CYC), an important therapeutic option for the treatment of severe lupus glomerulonephritis, ⁵ may cause permanent infertility ⁶ and menstrual disorders in SLE patients. ⁷ Additionally, menstrual disturbances also may occur in SLE patients without previous and/or current alkylating therapy, ⁸ and disease activity is a major risk factor for menstrual irregularities in these patients ^8,9 prior to the treatment with high doses of glucocorticoids. ⁹ Indeed, it was reported the presence of reduced ovarian reserve assessed by serum levels of anti-Müllerian hormone (AMH) in SLE patients with ^10,11 and without ¹² previous use of cyclophosphamide. We emphasize that AMH concentration value may be the earliest marker of impaired ovarian reserve in patients undergoing chemotherapy. ¹³

On this point, it is interesting that in the recent study by Ma Wenhong and colleagues in the current issue, it was demonstrated that even in SLE patients with normal menstrual cycles, short illness duration, and with and without current and/or previous use of cyclophosphamide decreased ovarian reserve may be detected. ¹⁴ These authors recruited 42 SLE patients with normal menses and without contraceptive usage at least 3 months before enrollment in the study, 19 of them receiving current or previous CYC therapy (SLE-CYC group) and 23 of them naïve to cytotoxic agents (SLE group). Twenty-one healthy women of similar age and with regular menstrual cycles were included as a control group. The ovarian reserve was evaluated in all study subjects by determining the serum hormonal profile during the follicular phase, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂), and anti-müllerian hormone (AMH), and also by antral follicle count (AFC) assessed by transvaginal ultrasound. The mean age (28.9±5.3 vs. 30.0±4.4 vs. 29.0±6.0 years, p=0.747) were similar among the three groups, respectively, and the same result was found regarding body mass index (BMI). The basal mean levels of FSH and LH were comparable among the three groups. The mean disease duration (2.3±1.7 vs. 3.0±2.8 years, p=0.299), AMH concentration (1.2±1.3 vs. 1.7±1.3 ng/mL), and AFC (7.8±4.6 vs. 10.9±3.0) were similar in the both SLE groups (with and without use of cyclophosphamide) (p>0.05), although the mean disease activity score (systemic lupus erythematosus disease activity index, SLEDAI) ¹⁵ (5.1±3.6 vs. 2.1±1.8, p=0.039) and the mean current dose of prednisone (16.3±12.8 vs. 8.7±6.9 mg/day, p=0.020) were higher in lupus patients with CYC therapy than those without this medication. ¹⁴ Of note, AMH serum levels and AFC were significantly decreased in the SLE and SLE-CYC groups compared to health women, 3.3±1.8 ng/mL (p=0.000) and 14.6±4.9 (p=0.001). ¹⁴ These original findings suggest that ovarian dysfunction in SLE may be subclinical and may occur in patients with short disease duration and in the absence of exposure to alkylating agents.

These results warrant prospective studies to evaluate their possible long-term impact on the fertility and hormonal balance of lupus patients, since there are strategies to prevent ovarian toxicity from chemotherapeutic agents. In this regard, a recent meta-analysis showed that the adjunctive gonadotropin-releasing hormone agonist (GnRH-a) treatment attenuates depletion of ovarian reserve associated with chemotherapy. ¹⁶ However, in SLE there are few nonrandomized clinical trials suggesting that GnRH-a coadministration improves CYC-induced ovarian damage. ^17,18 However, the indications, efficacy and safety of this approach in SLE need to be further evaluated. ¹⁹