Isogenic ovarian transplantation between identical twins discordant for ovarian follicle reserve

Abstract

This study aimed to investigate 1) the prospects for restoring spontaneous menstrual cycles and fertility by ovarian transplantation between monozygotic twin sisters, and 2) the causes of premature ovarian failure in the sterile sister A case study of monozygotic twins who were healthy and without autoimmune disease, but one of whom had had idiopathic menopause in her early teens. Sister-sister ovarian transplantation was performed and ovarian biopsies and leukocytes were analysed cytologically and cytogenetically Monozygotic twins aged 24 years old requested sister-sister ovarian transplantation following unsuccessful attempts to conceive using conventional egg donation. The fertile sister (M) had completed her target family size of three children and did not want to undergo further ART procedures for her postmenopausal sister (S). The latter sister had her last menses at 14 years of age after scanty cycles from age 11; she had a small, normal uterus and elevated serum gonadotropins (FSH 75 and LH 32). The reproductive history of sister M and her normal ovarian response to recent controlled ovarian stimulation (16 follicles >15 mm and 14 eggs) indicated that she had a normal ovarian reserve. Both sisters were taking contraceptive pills at the time of surgery. The left ovary of M was removed laparoscopically and cortical tissue was prepared and transplanted bilaterally by suturing into the resected ovary of her sister during a mini-laparotomy. Surplus tissue was cryopreserved using a slow-freezing protocol using 1,2-propanediol. Small pieces of ovarian tissue and peripheral blood from both women were consented for further analysis by cell culture for FISH and karyotype studies, by isolation of mRNA and DNA for genetic study, and by fixation in Bouin's fluid for histology Genetic fingerprinting confirmed that the women were homozygous and that immunosuppression was unnecessary for transplant survival. Investigations of transplant function are ongoing. Histology confirmed that the ovaries of S were sterile (with only one old corpus albicans). In contrast, the left (donor) ovary of M contained many primordial and small growing follicles, albeit focally distributed, confirming its pre-operative appearance by transvaginal ultrasound. The ovarian cell cultures and peripheral leukocytes of both women were karyotypically normal. The postmenopausal sister evidently had follicular ovaries as a child, but the diminutive reserve had become exhausted in her early teens. The differences in ovarian status between the sisters was especially remarkable in view of twin studies revealing high heritability of menopausal age (0.3–0.6), as well as the similarities between their life-styles and medical histories. No evidence of cytogenetic mosaicism was found. Mutation in the germ line is a plausible explanation, and candidate genes encoded on the X chromosome and autosomes are now being addressed.