Assessment Of The Endocrine Function Of Patients With Sickle Cell Disease After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Gharwan Helen , Fitzhugh Courtney , Link Mary , Coles Wynona , Citrin Deborah , Tisdale John F. , Hsieh Matthew M. 
Published: October 2019

Introduction
While medical treatment of patients with sickle cell disease (SCD) has improved, hematopoietic stem cell transplantation (HSCT) remains the only curative treatment. Standard myeloablative conditioning regimens frequently lead to endocrine abnormalities of the hypothalamus-pituitary-gonadal, -thyroid and/or -adrenal axes.

Methods
Our group performed allogeneic HSCT in 14 female (ages 20-47 years) and 17 male (ages 16-64 years) patients with SCD using a non-myeloablative regimen: lower doses of total body irradiation (300 cGy instead of 1200 cGy), alemtuzumab (anti-CD52 monoclonal antibody), and sirolimus. Additionally, the gonads of male patients were shielded with two-sided clamshells to reduce radiation exposure. Endocrine function before, and at various time points up to several years after transplantation was analyzed.

Results
Thyroid function remained within the normal range at 12 months after HSCT, although free triiodothyronine (FT3) levels rose by 18.3% in six females and 19.9% in eight males [mean before/after HSCT: females: 269.4/318 pg/dL; males: 277.8/333.2 pg/dL]. Correspondingly, thyroid stimulating hormone (TSH) levels 12 months after transplantation were decreased by 24.1% in the six females and 33.7% in the eight males [mean before/after HSCT: females: 2/1.5 mcIU/mL; males: 2.5/1.7 mcIU/mL]. One of the female patient developed Grave's disease 36 months after HSCT, while a second female patient developed post-partum thyroiditis one month after giving birth, with persistent hypothyroidism at 48 months after HSCT. One male patient developed Hashimoto's thyroiditis 36 months after HSCT.
The hypothalamus-pituitary-adrenal axes of both genders were not measurably impacted; nor was male gonadal function affected as evidenced by unaffected hormonal levels in most males at 12 months after HSCT [mean levels before/after HSCT: luteinizing hormone (LH) 6.5/6.5 U/L, follicle stimulating hormone (FSH) 9.4/6.5 U/L, total testosterone (TT) 359.9/358.3 ng/dL, calculated free testosterone (cFT) 7.6/7.6 ng/dL]. Three men have not yet reached the 12-months post transplant date. One found to have hypogonadotropic hypogonadism secondary to iron overload one year after HSCT (LH 5.4 U/L, FSH 4.2 U/L, cFT 1.9 ng/dL) and azoospermia, was successfully treated to father a child, while a second fathered two children without medical assistance. Among the remaining 14 males, the desire for fatherhood has not yet been expressed.
In contrast, this non-myeloablative HSCT regimen affected the gonadal function of the females analyzed thus far. All women had SCD-related reduced ovarian function before HSCT. At twelve months after HSCT FSH levels were increased a mean of 6.2-fold (range: 2.4- to 15.2-fold) in eight females [mean before/after HSCT: 8.9/55.5 U/L], while LH levels rose a mean of 4.2-fold (range: 1.7- to 8.7-fold) in seven of the eight females [mean before/after HSCT: 11.5/35.9 U/L]. Mean estradiol levels fell at 12 months after HSCT by 62.8% in the eight women [mean before/after HSCT: 88.2/32.8 pg/mL] consistent with reduced/diminished ovarian function. Two females less than 12 months post transplant, have not yet had their gonadal function analyzed. Three natural pregnancies occurred in two women younger than 35 years, while two women over 40 years at the time of HSCT entered menopause thereafter. One woman with hypothalamic hypogonadism was not able to conceive. She underwent infertility evaluation, but did not pursue treatment for economic reasons. Nine women have not yet had a desire to conceive.

Conclusion
While this non-myeloablative regimen appears to impact the gonadal function of females, but not males, fertility is preserved in a subset of women. Further investigation of these patients is required to understand whether the immunosuppressive drugs administered in the setting of HSCT adversely affect ovarian function, and how to better preserve gonadal function of females undergoing non-myeloablative allogeneic HSCT. In addition, long-term follow-up of patients' thyroid functions beyond three years is advisable, as in our three patients, who developed thyroid dysfunction, the changes became evident not earlier than 36 months after HSCT.

Disclosures:
No relevant conflicts of interest to declare.