The History of Allogeneic Ovarian Transplantation

The transplantation of endocrine organs can be regarded as the oldest form of transplantation in modern medical history. By the end of the nineteenth and beginning of the twentieth centuries, a large research focus was set on endocrine transplantations. Before the complex endocrine secretion and function was even understood, researchers attempted to cure endocrine diseases and infertility through transplantation of the endocrine glands and gonads. Hence, most endocrine organs have been transplanted in that period, including the thyroid [1], the adrenal gland [2], the testis [3] and the ovary [4]. Even though the principles of transplant rejection have not been understood at that time, researchers already noticed successful transplantations almost exclusively in experiments with autografts. The first published allogeneic ovarian transplantations in animals have been performed by Paul Bert in the sixties of the nineteenth century [5]. His experiments resulted in organ necrosis and rejection in all cases of transplanted ovaries.

In the nineties of the nineteenth century, Emil Knauer – a resident at the university women’s clinic in Vienna – performed the first systematic animal studies on ovarian transplantation (Figure 35.1). He performed autologous transplantation in ten rabbits and two dogs. Ovarian grafts were transplanted orthotopically into a peritoneal pocket, similar as it is still performed today. In addition, heterotopic transplantations were done under the fascia of the rectus muscle. With these techniques he could observe the return of several menstrual cycles in the transplanted rabbits and dogs and could achieve a healthy live-birth in one rabbit. All animals received autopsy where several of the transplanted ovaries still appeared active with mature follicles. Knauer concluded that ovaries can be transplanted into heterotopic sites and that those ovaries can return to physiologic organ function.

Figure 35.1 Emil Knauers’s publication named “Some experiments on ovarian transplantation in hares” published in 1896

Encouraged by his findings, Knauer continued the experiments and attempted allogeneic ovarian transplantation in 13 rabbits. In those, he could observe a rapid degeneration of the transplanted tissue. Despite these negative findings, due to two cases where he could still detect (non-active) ovarian tissue in autopsy, he concluded that allogeneic ovarian transplantation could be a possible future approach.

Parallel to Knauers’s animal experiments, Robert Tuttle Morris in New York performed several allogeneic ovarian transplantations in women and reported anecdotal evidence of one delivery and one miscarriage after allogeneic ovarian transplantation [6], (Figure 35.2).

Figure 35.2 Robert Tuttle Morris’s publication “A case of heteroplastic ovarian grafting, followed by pregnancy and the delivery of a living child,” published in 1906

Subsequent large animal studies could confirm aggressive rejection of allogeneic ovarian tissue while autologous tissue frequently developed endocrine activity [7]. Due to the subsequent rise of IVF and the lack of immunosuppressants to prevent organ rejection at that time, allogeneic ovarian transplantation was abandoned for many years. With the development of immunosuppressants, several groups restarted ovarian allotransplantation in animal studies. In some studies using cyclosporine to prevent immunorejection of ovarian allografts pregnancies could be achieved in tubo-ovarian transplantations in rats and rabbits, while control animals experienced aggressive rejection [8–12].

With the continuing rise of ovarian tissue preservation and autotransplantation in the mid-2000s, several ovarian allotransplantations have been made in monozygotic twins as well as genetically non-identical siblings after bone marrow transplantation. The group of Sherman Silber published several cases of ovarian transplantations in monozygotic twins followed by successful live-births [13, 14]. In Europe, Jacques Donnez’s group performed allogeneic ovarian transplantations in siblings after whole body irradiation and bone marrow transplantation for different conditions followed by one published live-birth [15–17]. It should be noted that the donor ovary came from the same donor of bone marrow transplantation, so the immune system of the recipient would recognize the ovary as immunologically compatible (because of complete HLA chimerism after bone marrow transplantation). The same group performed allogeneic ovarian transplantation in monochorionic twins with Turner Syndrome mosaic and discordant for ovarian failure and reported a live-birth [18]. Even though those mentioned cases represent allotransplantations from one individual to the other, they cannot be regarded as typical allotransplantations since no immunosuppression was required (immunologically similar to autotransplantation) in this selected patient collective.

In India, one group performed allogeneic ovarian transplantations in two women with Turner Syndrome and one woman with premature ovarian insufficiency using cyclosporine for immunosuppression. The donors of these ovaries were close relatives (mother, sister, cousin) and the authors reported recurrence of menstrual function. However, no pregnancy was achieved and long-term side effects of immunosuppression have to be acknowledged in those women [19, 20].

New discovery of immunomodulatory substances with lower side effects would make future ovarian allotransplantation more acceptable. Recently, the return of a menstrual cycle has been reported after allogeneic ovarian transplantations in a baboon model using the immunomodulator Preimplantation Factor (PIF) [21]. In this experiment, subjects were treated systemically with PIF for three months after transplantation. In addition, prepared ovarian tissue (10 × 10 × 1 mm cortical sections) was treated in vitro with PIF before grafting into the broad ligament. No additional immunosuppression has been applied. No clinical or biochemical signs of rejection were detected after transplantation throughout ten months of follow-up. Postoperatively, the return of ovarian function was monitored in both animals with FSH and estradiol levels. A steady decline of FSH levels during the whole study period was noticed. One subject demonstrated a rise in estradiol levels and the return of menstruation 229 days after ovarian transplantation (Figure 35.3).

Figure 35.3 FSH levels in two animals after ovarian allotransplantation with preimplantation factor (PIF) treatment;

adapted from Feichtinger et al. 2018 [21]

Indications for Allogeneic Ovarian Transplantation

In theory, ovarian allotransplantation could be applied to all patients suffering from primary ovarian insufficiency (POI) regardless of causes, although certain genetic conditions like Turner and fragile-X syndrome can be good indications. In addition, ovarian allotransplantation could be performed in case of iatrogenic ovarian failures caused by chemotherapy, radiotherapy and surgery. If not treated accordingly, those women suffer from not only infertility but also vasomotor symptoms, cardiovascular disease, osteoporosis and reduced quality of life [22–24]. After ovarian allotransplantation, those patients could restore spontaneous menstruation as well as ovarian and endocrine function. Furthermore, fertility can be restored after transplantation. In prepubertal girls with POI, ovarian transplantation could ensure normal development of puberty. Nowadays, several well established treatment strategies in case of POI are available. Exogenous hormone supplementation can be applied to reduce vasomotor symptoms and improve long-term cardiac and bone health [25]. Several studies underline the importance of hormonal replacement therapies mimicking physiologic hormone patterns in POI patients [25]. In women with POI who want to get pregnant, egg donation is a broadly applied and well established method [26, 27]. In the future, allogeneic ovarian transplantation may be considered as an alternative strategy which can allow spontaneous pregnancy and restore effective endogenous physiological hormone production.