WASHINGTON (FRONTLINE MEDICAL NEWS) – Low-dose pulsed cyclophosphamide doesn’t appear to affect ovarian reserve when used to treat women with systemic lupus erythematosus, according to an analysis of patients’ anti-Mullerian hormone levels.

The protocol – known as the Euro-Lupus regimen – may be the best choice for younger patients with systemic lupus erythematosus (SLE) who wish to preserve their fertility, Farah Tamirou, MD, said at the annual meeting of the American College of Rheumatology.

“I think we can say that the Euro-Lupus regimen can be safely proposed to patients with future pregnancy plans,” said Dr. Tamirou of the University Clinic Saint-Luc, Brussels.

The protocol was first reported in the Euro-Lupus Nephritis Trial, published in 2002. The study randomized 90 lupus patients with proliferative glomerulonephritis to high-dose intravenous cyclophosphamide (six monthly pulses and two quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose regimen (six pulses at a fixed dose of 500 mg), each of which was followed by azathioprine ( Arthritis Rheum. 2002;46[8]:2121-31 ).

Patients actually did better on the low-dose regimen: 16% experienced treatment failure, compared to 20% of those in the high-dose group. Renal remission occurred in 71% of the low-dose group and 54% of the high-dose group.

High-dose cyclophosphamide has proven to be gonadotoxic, but no studies have assessed whether the low-dose regimen may be gonadoprotective, Dr. Tamirou said. Nevertheless, she said there have been no reports of sustained amenorrhea associated with it.

“However, sustained amenorrhea is a poor endpoint for fertility. It doesn’t quantify the full effect of cyclophosphamide on ovarian reserve, especially in young women with more reserve, who may experience cytotoxic damage that is not enough to cause full cessation of ovarian function.”

Anti-Müllerian hormone (AMH) seems to be a better marker of subclinical ovarian damage. AMH is produced by granulosa cells in growing ovarian follicles. The level of AMH is highest in primordial follicles and decreases as the follicles mature. Since it’s only made in these immature ova, AMH is considered to be a fairly accurate measure of ovarian reserve, Dr. Tamirou said. AMH naturally decreases with advancing age, increasing body mass index, pregnancy, and menopause, but it’s not influenced by the menstrual cycle or by any hormonal contraceptive.

Given this utility, Dr. Tamirou and her colleagues used AMH levels to assess cyclophosphamide-induced ovarian damage in 155 patients with SLE. They measured AMH in the frozen sera of patients who had received different cumulative cyclophosphamide doses: up to 3 grams, 3-6 grams, and more than 6 grams. They compared AMH levels at those cumulative dose ranges with AMH levels in patients who had not been treated with cyclophosphamide.

Since the patients were of widely varied ages, Dr. Tamirou and her associates created an age-adjusted slope for normal AMH levels in the nontreated group, which were normalized for 30 years – the mean age of the entire cohort.

There were 101 patients in the nontreated group, and their mean age-adjusted AMH level was 2.8 ng/mL. There were 11 patients in the 3- to 6-gram cyclophosphamide group, and they had a mean AMH of 2.5 ng/mL – not significantly different from the nontreated group. The group of 30 patients who received up to 3 grams of cyclophosphamide had a similar mean age-adjusted AMH level of 3 ng/mL.

However, for 13 patients who received more than 6 grams of cyclophosphamide, the mean age-adjusted AMH level was 1.4 ng/mL, which was significantly lower than any of the other treatment groups.

The investigators conducted several subanalyses to see if there were any clinical characteristics that could have contributed to the AMH level differences. Cumulative cyclophosphamide dose was, as expected, directly related to disease duration. Untreated women and those in the lowest dose group had a mean disease duration of 9 years, while those who took 3-6 grams had a mean duration of 11 years. The disease duration was 15 years among those who received 6 or more grams.

There were no associations with any organ involvement or related immunosuppressive disorders. AMH was not associated with body mass index or the use of hormonal contraception. Nor were there any significant associations with prednisone use or dosage, or disease severity, she added.

Finally, the investigators conducted a subanalysis of 10 patients who had blood drawn before and after entering the Euro-Lupus regimen. None of these women showed any significant change in AMH levels after being on the treatment.

Dr. Tamirou and her colleagues had no financial disclosures.

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