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-M€ ullerian 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 (b = 0Á001, 95% confidence interval À0Á002 to 0Á000; P = 0Á006). These results suggest that ovarian reserve is prematurely reduced in women with haemoglobin SS and raise the possibility that HC contributes to this finding.

Fertility preservation for pediatric patients with hemoglobinopathies: Multidisciplinary counseling needed to optimize outcomes

“…Three studies have demonstrated normal anti-müllerian hormone (AMH) levels in untreated adolescent and young adults with SCD ( 32 – 34 ). However, women with SCD experience a more rapid decline in ovarian reserve, with lower levels of AMH than age matched controls ( 33 , 35 , 36 ). Females with SCD develop diminished ovarian reserve (DOR) at younger ages (25-30 years) than age-matched women ( 33 , 34 ).…”

Knowledge gaps in reproductive and sexual health in girls and women with sickle cell disease

“…Preconception end‐organ assessments (retinopathy, echocardiogram, pulmonary function tests, renal function). Risk and benefit of SCD treatment in pregnancy hampered by a lack of definitive interventions to alter the trajectory of high‐risk pregnancy 52–54 Outstanding questions about whether SCD and its treatments compromise fertility 22,26 Inequitable access to fertility preservation 45 …”

“…There are limited data about whether transfusional iron overload affects oocyte quality and/or quantity 24,25 and none about SCD treatments approved over the last few years (crizanlizumab, l‐glutamine and voxelotor). Several studies raise the possibility that hydroxycarbamide accelerates the decline of ovarian reserve in some girls and women 15,22,26,27 . With limited data, clinicians are confronted by how and if to address open questions about if SCD treatment, especially hydroxycarbamide, affect future fertility.…”

Hematopoietic cell transplantation for sickle cell disease: updates and future directions

“…107,108 Fertility pres er va tion pro ce dures preHCT must also con sider that HU may cause gonadal dam age and have an adverse impact on male and female fer til ity in SCD patients. 109,110 Med ic aid cov er age of fer til ity pres er va tion is extremely lim ited both in the scope of ben e fits and the num ber of states that require such a ben e fit. 111 For exam ple, only 15 states require fer til ity pres er va tion cov er age in pri vate insur ance plans, and 5 states extend this ben e fit only to females.…”