The effects of hydroxyurea and bone marrow transplant on Anti-Müllerian hormone (AMH) levels in females with sickle cell anemia

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Abstract

Gonadal hypofunction is described in male and female patients with sickle cell anemia (SCA) after bone marrow transplant (BMT) and in males treated with hydroxyurea (HU). Anti-Müllerian hormone (AMH) is a serum marker of ovarian reserve. This study describes AMH and follicle-stimulating hormone (FSH) levels in female SCA subjects treated with supportive care (SCA-SC), HU (SCA-HU) and BMT (SCA-BMT). SCA (SS/Sβ0) subjects not on HU, on HU and status-post BMT, ages 10–21 years were recruited. SCA-HU subjects were treated with HU  20 mg/kg for ≥ 12 consecutive months. SCA-BMT subjects had received busulfan and cyclophosphamide. Serum AMH and random FSH levels were obtained. Diminished ovarian reserve (DOR) was defined as AMH level < 5th percentile for age-matched controls. Subjects also with FSH > 40 IU/L were classified as having premature ovarian insufficiency (POI). 14 SCA-SC (14.5 ± 2.7 years), 33 SCA-HU (14.4 ± 2.4 years) and 9 SCA-BMT (14.3 ± 2.7 years) females were included. AMH was undetectable in all SCA-BMT subjects and < 5th percentile in 24% of SCA-HU subjects. FSH was menopausal (> 40 IU/L) in 88.9% of SCA-BMT subjects. All SCA-BMT subjects and 24% of subjects on HU had DOR; 89% of SCA-BMT subjects had POI. AMH and FSH may be useful tools in assessing ovarian reserve and function.

Introduction

Newborn identification, prophylactic penicillin and scheduled comprehensive supportive care have improved the survival of those with sickle cell anemia (SCA), but overall life expectancy remains reduced compared with African-Americans without SCA [1], [2] There is strong and increasing evidence that hydroxyurea (HU) is beneficial for many people with SCA, but does not provide a cure [3], [4]. Currently, bone marrow transplant (BMT) is being pursued as a cure for SCA, but can be limited due to lack of an identifiable donor and has many risks, including graft failure, graft versus host disease and gonadotoxicity.

Gonadal dysfunction inherent to SCA has been described in adults; although documentation of impaired function in females is limited, reports of primary and secondary hypogonadism have been described in males [5], [6], [7]. As both treatment with HU and treatment with BMT are associated with gonadal dysfunction, they may exacerbate this risk in those with SCA. There is limited data on the effect of HU on ovarian function in patients with SCA; however, gonadotoxicity has been described in males with SCA. Decreased spermatogenesis and sperm motility in adult males on HU for SCA or myeloproliferative disease have been described, with reports of both permanent and reversible azoospermia [8], [9], [10]. Similarly, gonadotoxic effects are seen after BMT. Following BMT, studies suggest a high rate of gonadal failure in females and azoospermia in males [11], [12], [13]. Common preparatory regimen for BMT includes use of cyclophosphamide and busulfan, two alkylating agents whose use in pediatric cancer patients has been associated with infertility in males and females [14], [15], [16], [17], [18]. In a study surveying 30 adults with sickle cell disease for their perceptions of risk associated with BMT, infertility was a major concern with 50% stating that infertility was unacceptable [19]. Acknowledging the risk of infertility secondary to gonadal failure in this population is important, but of equal significance is recognizing the risk of gonadal hypofunction that precedes gonadal failure.

Chemotherapeutic agents can result in varying degrees of gonadal hypofunction, including diminished ovarian reserve (DOR) and/or premature ovarian insufficiency (POI). DOR is commonly defined in young reproductive-aged women as an AMH level < 7.14 pmol/L (1 ng/mL; multiplier for conversion from ng/mL to pmol/L is × 7.14) or an FSH > 10 IU/L on day 3 of the menstrual cycle. POI is generally defined as amenorrhea or irregular cycles with an FSH > 40 IU/L [20], [21], [22]. Women with DOR generally have no clinical symptoms and often have regular menses, or perhaps a short follicular phase, and are only detected after ovarian reserve testing with an AMH, FSH or antral follicle count by ultrasound [22]. Although POI and natural menopause are both recognized by FSH values > 40 IU/L, POI differs from natural menopause in that patients may still have intermittent menses, may ovulate and can occasionally become pregnant albeit at a lower rate than normal [23]. Assessment of ovarian reserve is a key measure used in reproductive endocrinology for the evaluation of females for infertility [24]. The most common measures of ovarian reserve are transvaginal ultrasound to determine the antral follicle count and ovarian volumes, day 3 FSH and estradiol, and AMH [25], [26]. However, transvaginal imaging is not an acceptable procedure for most pediatric- and adolescent-aged patients. Girls and women who have significant diminished ovarian reserve may still have normal FSH levels [22]. An elevated day 3 FSH generally indicates a reduced follicular pool and is a late indicator of ovarian failure, and when FSH is > 40 IU/L, fertility preservation options are typically no longer possible. AMH levels have been found to correlate well with antral follicle count and low AMH levels are used as a marker of decreased ovarian reserve [26], [27], [28]. Published normative data regarding AMH levels, although limited, exist for the pediatric and adolescent populations [29], [30].

There is limited literature to our knowledge regarding ovarian hormone profiles in patients with SCA being treated with HU or following BMT for SCA. This study was designed to characterize ovarian reserve in those with hemoglobin SS or Sβ0-thalassemia who are receiving supportive care (SCA-SC), those being treated with HU (SCA-HU), and those who have received a BMT (SCA-BMT), and to identify subgroups with: normal ovarian reserve and diminished ovarian reserve. We then subclassified those with DOR into those with and without POI. These girls and women with altered ovarian function could benefit from close longitudinal follow-up of ovarian function and additional counseling by a reproductive endocrinologist to discuss reproductive potential and treatment options in the future.

Section snippets

Subjects

Female subjects with SCA (hemoglobin SS or hemoglobin Sβ0 thalassemia) aged 10–21 years seen in the SCA clinic or the Ex-sickle-BMT clinic in the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta were eligible for this study. Subjects were grouped according to their SCA therapy: Supportive care (SCA-SC), currently receiving hydroxyurea (SCA-HU), or having received a BMT (SCA-BMT). Recruitment was conducted in a manner that enrolled SCA subjects that would best reflect a

Results

Overall, 76 subjects were asked to participate in the study and 56 subjects were enrolled. There were 14 subjects in the SCA-SC group, 33 subjects in the SCA-HU, and 9 subjects in the SCA-BMT (Table 1). The mean age at time of study was similar across the three treatment groups. Among the SCA-HU subjects, the average age at HU start was 9.7 ± 3.3 years with an average duration of 4.7 ± 2.6 years. The dose of HU ranged from 20.0 mg/kg to 31.7 mg/kg. Among the SCA-BMT subjects, the age at BMT ranged from

Discussion

This study describes markers of ovarian reserve in females aged 10–21 years with hemoglobin SS or Sβ0-thalassemia, who received supportive care, HU or a BMT. All SCA-BMT subjects had undetectable AMH levels. A majority of the SCA-BMT subjects (89%) also had a menopausal FSH level suggesting profound ovarian insufficiency. Nearly one-quarter of the SCA-HU subjects and 11% of the SCA-BMT subjects had diminished ovarian reserve but were not yet in ovarian failure as noted by an FSH < 40 IU/L. These

Conclusions

Long-term studies in females with sickle cell disease assessing ovarian function and reserve serially at frequent intervals prior to and after the initiation of HU and BMT are needed, and can show if and when diminished ovarian reserve progresses to premature ovarian insufficiency. Such studies are also required to determine if the ultimate outcome, decreased fecundity, is observed in these patients. This study emphasizes the importance of counseling patients about the impact of these

Conflicts of interest statement

All authors have no relevant conflicts of interest to disclose.

Acknowledgments

Funding Source: Grant funding for this study was received from Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta.

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