Ovarian Transplantation In A Series Of Identical Twins Discordant For Ovarian Failure

Abstract

To investigate the prospects for restoring spontaneous menstrual cycles and fertility by ovarian isotransplantation between monozygotic twin sisters. A series of 4 otherwise healthy monozygotic twins, where 1 had idiopathic premature menopause & the other had normal ovarian function. 4 pairs of monozygotic twins (aged 24, 25 and 38[n=2] years of age) requested ovarian transplantation from the fertile sister to their sibling who had premature ovarian failure (POF). 3 of the donor sisters had normal menstrual cycles and had completed their target family sizes of 2 or 3 children; a 25 y.o. twin donor had no children and was on oral contraception. All 4 prospective recipients had FSH levels > 90 mIU/ml, no menses for ≥10 years, and complete absence of ovarian follicles in ovarian biopsies. They were menopausal from ages 14, 15, 16, and 22 years. 2 of the twins underwent transplantation at age 24 and 38, and 2 are awaiting. One ovary was removed from the donor and cortical tissue was dissected ex vivo in Leibovitz-L15 medium at 4°C. Donor ovarian cortex was then sutured microsurgically into the recipient’s medulla via a mini-laparotomy. This procedure was outpatient, with prompt & uneventful recovery. Surplus tissue from the youngest twin-pair was cryopreserved for future use with a slow-freezing protocol using 1,2-propanediol & sucrose as cryoprotective agents. Ovarian tissues & peripheral blood from both women was cultured for analysis by karyotyping and analyzed by FISH for sex chromosome mosaicism. All twin-pairs were genetically fingerprinted, and DNA from the sterile sisters was tested for fragile X mutation. All the twin-pairs were confirmed by genetic fingerprinting to be homozygous, implying that immunosuppression was unnecessary for transplant survival. Histology confirmed that the recipient ovaries were sterile, whereas the donor ovaries contained numerous primordial and small growing follicles, consistent with the antral follicle counts obtained preoperatively by transvaginal ultrasound. Karyotypes were normal 46,XX and there was no expansion of CCG repeats in the FMR-1 gene. The first of the ovary transplant recipients menstruated lightly at 12 weeks postoperatively and conceived naturally with an intrauterine pregnancy at the next cycle (∼20 weeks postoperatively). At 22 weeks of pregnancy, ultrasound revealed a normal girl and, at the time of writing, the pregnancy is proceeding uneventfully at the 33rd week. The 2nd twin-pair has also undergone transplantation with similar genetic and histologic findings, and 2 additional pairs are awaiting the same procedure. Evidence we present elsewhere indicates that POF within discordant twin-pairs is less rare than expected. These first cases of ovarian tissue transplantation between women are made possible by virtue of a genetically identical twin willing to be a donor. There is a latent period of several months before ovulation is restored & the endocrine profile is normalized, but in our first case, conception occurred promptly thereafter & pregnancy was normal. If this success can be repeated, ovarian transplantation may provide an alternative to conventional egg donation for comparable patients, and it confirms the feasibility of natural conception after transplanting thawed ovarian tissue in cancer patients. Finally, ongoing molecular study of such twin-pairs may eventually shed light on the causes of premature ovarian failure.%3:45 p.m.