Fresh and cryopreserved ovary transplantation and resting follicle recruitment

Abstract

Ovary cryopreservation and transplantation has garnered increasing interest as a possible method to preserve fertility for cancer patients and to study ovarian resting follicle recruitment. Eleven consecutive women underwent fresh donor ovary transplantation, and 11 underwent cryopreserved ovary auto-transplantation in the same centre, with the same surgeon. Of the 11 fresh transplant recipients, who were all young but menopausal, nine women had normal ovarian cortex transplanted from an identical twin sister, and two had a fresh allograft from a non-identical sister. In the second group, 11 women with cancer had ovarian tissue cryopreserved before bone marrow transplant, and then after years of therapeutically induced menopause, underwent cryopreserved ovarian cortex autotransplantation. Recovery of ovarian function and follicle recruitment was assessed in all 22 recipients, and the potential for pregnancy was further investigated in 19 (11 fresh and 8 cryopreserved) with over 1-year follow-up. In all recipients, normal FSH levels and menstruation returned by about 150 days, and anti-Müllerian hormone reached much greater than normal concentrations by about 170 days. Anti-Müllerian hormone levels then fell below normal by about 240 days and remained at that lower level. Seventeen babies have been born to these 11 fresh and eight cryopreserved ovary transplant recipients.

Unifying theory of adult resting follicle recruitment and fetal oocyte arrest

“…The sudden massive recruitment of primordial follicles and increased anti-Müllerian hormone (AMH) levels after human ovarian transplantation, with eventual loss of huge numbers of follicles but continued ovarian function, would support a theory that ovarian follicle recruitment with resumption of meiosis in adults and meiotic arrest in the early fetal ovary may be related events (Silber et al, 2015). For example, the early clinical event of massive resting follicle recruitment after frozen as well as fresh ovarian cortex grafting, with massive AMH elevation (following FSH decline) from about 140 to 280 days indicates a rapid 'escape' of massive numbers of adult primordial follicles from their 'resting phase' in the transplanted ovarian cortex, a phenomenon that is never seen in the normal ovarian state (Figure 1).…”

“…By about 280 days, the AMH of the recipient descends to well below baseline levels, and then remains steady at this level usually for many years. Therefore, follicle loss comes later, not from ischaemia but apparently from over-recruitment (Silber et al, 2015).…”

“…The tunica albuginea of the testes is the most dense fibrous (Silber et al, 2015). tissue in the body, and the ovarian cortex is its female homologue (Morris Textbook of Anatomy; Morris, 1966).…”

“…In all cases of ovarian development in mammals, the first meiotic germ cells are situated towards the medulla, and the oogonia in the cortical periphery are the last to enter meiosis (Byskov and Andersen, 2013); only the oocytes that arrive to the cortex are arrested and thus salvaged. In the ovarian cortex, a gradient of stromal density exists, with the most tissue pressure and density being near the surface, gradually decreasing towards the centre, with the least dense tissue in the ovarian medulla (Figure 2) (Shikanov et al, 2011;Silber et al, 2015;Woodruff and Shea, 2011). With the use of in-vitro follicle culture, it has already been postulated that pressure may hugely affect resting follicle development (Shikanov et al, 2011;Woodruff and Shea, 2011).…”

Novel use of the ovarian follicular pool to postpone menopause and delay osteoporosis

“…The tissue is still active and the patient has an opportunity to undergo one additional transplantation. Others also report on a prolonged period of function from transplanted ovarian tissue (Silber et al, 2015).…”