Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide

Abstract

The application of modern ovarian reserve measures to women with sickle cell disease (SCD) may help answer longstanding questions about whether SCD or hydroxycarbamide (HC; also known as hydroxyurea) affect women's reproductive lifespan. Anti-Müllerian hormone (AMH), an established marker of ovarian reserve, is used to assess the ovarian follicle pool. We used a standard clinical assay to measure AMH in 285 banked samples from 93 female subjects with haemoglobin SS from the historic Multicenter Study of Hydroxyurea (MSH), which led to the United States Food and Drug Administration approval of HC for adults with SCD. No samples from the randomised portion of the MSH remain, so samples from the decade-long MSH follow-up studies were analysed. Most subjects were exposed to HC (86/93). The median AMH levels were lower in study subjects than in age- and sex-matched reference values. The median AMH levels consistent with diminished ovarian reserve, a risk factor for infertility, occurred in subjects starting at the age of 25-30 years; in healthy women, this occurs after the age of 40 years. In multivariate analysis, taking HC was independently associated with a low AMH (β = 0·001, 95% confidence interval -0·002 to 0·000; P = 0·006). These results suggest that ovarian reserve is prematurely reduced in women with haemoglobin SS and raise the possibility that HC contributes to this finding.

Keywords: anti-Müllerian hormone; fertility; hydroxyurea; ovarian reserve; sickle cell disease.

Figure 1.. Explanation of study population and sample availability.

This figure outlines the study population, sample availability by hydroxycarbamide exposure, and populations and samples used in study analyses (Figures 2 – 4 and Table 1).

Figure 2.. AMH is lower than reference values for age in women with HbSS.

Box plots of 285 AMH levels in 93 subjects by subject age at time of specimen collection. As expected, AMH decreased in an age-dependent manner. Median AMH by age as reported for this assay is indicated by a thick black line. Median AMH for age is lower than median age-dependent values in the general population. The dotted line indicates AMH less than 1.1ng/mL, a level consistent with diminished ovarian reserve, and a risk factor for infertility. (A) Most study subjects had an AMH less than 1.1ng/mL by age 30 years. (B) Box plots of AMH level by subject age and original randomization in the MSH.

Figure 3.. Low AMH is associated with age, taking hydroxycarbamide and MCV.

Box plots of univariate analysis of AMH in the first MSH follow-up visit. Fifty six subjects had a sample available at the first visit. Box plots compare subjects ≥/< 35 years of age, with BMI ≥/< 25, by randomization to placebo or hydroxycarbamide in the MSH RCT, hydroxycarbamide use at the time of sample, and MCV ≥/< 100fL. AMH is lower in older subjects, those taking hydroxycarbamide and those with an MCV greater than 100fL.

Figure 4.. AMH is normal in young women without hydroxycarbamide exposure.

Bar graphs show an age-stratified comparison of subjects never exposed to hydroxycarbamide and those exposed to hydroxycarbamide when ≦ 40 years of age. Only one sample per subject is included and the included sample for each subject was their earliest AMH level. AMH levels in subjects 35 years of age or less with no hydroxycarbamide exposure is normal for age while those with any hydroxycarbamide exposure are low. The few hydroxycarbamide unexposed subjects preclude statistical comparison.