Allogeneic ovarian transplantation using immunomodulator preimplantation factor (PIF) as monotherapy restored ovarian function in olive baboon.

PURPOSE: Allogeneic ovarian transplantation may be an alternative in the future to oocyte donation in women with premature ovarian failure. The objectives of this study were to (a) evaluate allotransplantation feasibility for restoration of ovarian function and (b) assess efficacy of synthetic preimplantation factor (PIF) monotherapy as sole immune-acceptance regimen. METHODS: This is an experimental animal study using non-human primates (Papio anubis). Allogeneic orthotopic ovarian tissue transplantation was performed in two female olive baboons. PIF was administered as a monotherapy to prevent immune rejection and achieve transplant maintenance and function. Subjects underwent bilateral oophorectomy followed by cross-transplantation of prepared ovarian cortex. Postoperatively, subjects were monitored for clinical and biochemical signs of graft rejection and return of function. Weekly blood samples were obtained to monitor graft acceptance and endocrine function restoration. RESULTS: Postoperatively, there were no clinical signs of rejection. Laboratory parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine) did not indicate organ rejection at any stage of the experiment. Initially, significant loss of follicles was noticed after grafting and serum follicle-stimulating hormone (FSH) and E2 levels were consistent with ovarian failure. Seven months after transplantation, one animal exhibited recurrence of ovarian endocrine function (perineal swelling, E2 rise, FSH decrease, and return of menstruation). CONCLUSIONS: Organ rejection after allogeneic ovarian transplantation was prevented using PIF as monotherapy for the first time and no side effects were recorded. The study suggests the clinical feasibility of ovarian allotransplantation to obtain ovarian function.

Three Faces of Fragile X.

Fragile X syndrome (FXS) is the first of 3 syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other 2 syndromes are fragile X-associated primary ovarian insufficiency syndrome (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which together are referred to as fragile X-associated disorders (FXDs). Collectively, this group comprises the 3 faces of fragile X. Even though the 3 conditions share a common genetic defect, each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains, and, for FXTAS, a late-onset neurodegeneration. Although each FXD condition may benefit from physical therapy intervention, available evidence as to the efficacy of intervention appropriate to FXDs is lacking. This perspective article will discuss the genetic basis of FMR1 gene dysfunction and describe health conditions related to this mutation, which have a range of expressions within a family. Physical therapy concerns and possible assessment and intervention strategies will be introduced. Understanding the intergenerational effect of the FMR1 mutation with potential life-span expression is a key component to identifying and treating the health conditions related to this specific genetic condition.

From victim to survivor to thriver: helping women with primary ovarian insufficiency integrate recovery, self-management, and wellness.

Most women discover that they are infertile in a gradual manner after many failed attempts at conception. By contrast, most women with primary ovarian insufficiency (POI) uncover their infertility as part of an evaluation of other presenting complaints, frequently before attempts at conception have even been contemplated. The most common words women use to describe how they feel in the hours after getting the diagnosis of POI are "devastated," "shocked," and "confused." Clearly, the news propels some patients onto a difficult journey. POI is a serious and incurable chronic disease. The diagnosis is more than infertility and affects a woman's physical and emotional well-being. Management of the condition must address both. Patients face the acute shock of the diagnosis, associated stigma of infertility, grief from the death of dreams, anxiety from the disruption of life plans, confusion around the cause, symptoms of estrogen deficiency, worry over the associated potential medical sequelae such as reduced bone density and cardiovascular risk, and the uncertain future that all of these factors create. There is a need for an evidenced-based integrated program to assist women with POI in navigating the transition to acceptance of the diagnosis, ongoing management of the condition, and ongoing maintenance of wellness in the presence of the disorder. A health-centered approach can gradually replace the disease-centered approach and put patients in partnerships with professional health-care providers. Ideally, the journey transitions each patient from seeing herself as a victim, to a survivor, to a woman who is thriving.

Limited value of ovarian function markers following orthotopic transplantation of ovarian tissue after gonadotoxic treatment.

CONTEXT: In young women, some treatments for cancer or other conditions (such as sickle cell anemia) may give rise to primary ovarian insufficiency. Ovarian transplantation is one of the available options for fertility preservation, with highly variable pregnancy rates. OBJECTIVE: The objective of the study was to investigate markers of ovarian reserve and ovarian function in women up to 7 yr after orthotopic ovarian transplantation. Secondary objectives were to assess the relationship between markers of ovarian reserve and pregnancy rate along with the duration of ovarian function. DESIGN: This was a prospective cohort study in 10 women, with a mean follow-up of 2.5 yr. SETTING: The study was conducted at a university hospital in Brussels, Belgium. PATIENTS: Patients included 10 women who were about to receive or had previously received gonadotoxic treatment. In seven women cryopreservation of ovarian tissue was performed before starting treatment. Subsequently autografts were orthotopically transplanted in these women. Three women, who had already developed primary ovarian insufficiency due to treatment, underwent orthotopic transplantation of ovarian allograft tissue originating from their human leukocyte antigen-compatible sisters. MAIN OUTCOME MEASURES: Serum concentrations of FSH, LH, estradiol, inhibin B, and anti-Müllerian hormone (AMH) were measured. RESULTS: On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. FSH concentrations remained elevated, whereas estradiol levels normalized and AMH was low to undetectable. Inhibin B varied among women and was not associated with the duration of ovarian function (hazard ratio 0.966, 95% confidence interval 0.881-1.059). Two spontaneous pregnancies occurred. Endocrine characteristics were not significantly different in these women. CONCLUSIONS: Low AMH and inhibin B concentrations may suggest decreased ovarian reserve in women after ovarian transplantation. AMH and inhibin B levels may not be associated with the duration of ovarian graft function or probability to achieve a pregnancy.

Autotransplantation of cryopreserved ovarian tissue in 12 women with chemotherapy-induced premature ovarian failure: the Danish experience.

OBJECTIVE: To describe a cohort of 12 Danish women who received autotransplantation of frozen-thawed cryopreserved ovarian tissue because of premature ovarian failure after cancer treatment. DESIGN: Retrospective study. SETTING: University hospitals. PATIENT(S): Twelve women with autotransplanted frozen-thawed ovarian tissue. INTERVENTION(S): Monitoring of hormonal parameters and results of 56 IVF cycles in 10 women. MAIN OUTCOME MEASURE(S): Levels of gonadotropins and sex steroids, functional life span of the grafts, and results of IVF. RESULT(S): All 12 women regained ovarian function between 8 and 26 weeks (mean 19 weeks) after transplantation. Ten women underwent a total of 56 IVF cycles, 76 follicles developed, 49 oocytes were aspirated, 18 were fertilized, and 16 embryos were transferred resulting in six pregnancies: two biochemical, one clinical that miscarried in week 7, and two ongoing resulting in the delivery of two healthy infants born at term to two women. One of these women subsequently conceived spontaneously and delivered another healthy infant. The life span of the transplanted tissue has been between 6 months and still functioning after 54 months. CONCLUSION(S): Autotransplantation consistently leads to recovery of ovarian function after treatment-induced ovarian failure. Four women became pregnant, after IVF or spontaneously, resulting in the delivery of three healthy infants.

Live birth after ovarian tissue autograft in a patient with sickle cell disease treated by allogeneic bone marrow transplantation.

OBJECTIVE: To report the first case of restoration of ovarian activity and live birth after cryopreserved ovarian tissue autograft in a patient without cancer treated by allogeneic bone marrow transplantation. DESIGN: Case report. SETTING: University hospital. PATIENT(S): One woman with homozygous sickle cell anemia. INTERVENTION(S): An orthotopic autotransplantation of ovarian cortical strips was performed after freeze-thawing. MAIN OUTCOME MEASURE(S): Cryopreservation of ovarian tissue, bone marrow transplantation, ovarian autograft, and restoration of ovarian function. RESULT(S): In autumn 2005, biopsy samples of ovarian tissue were cryopreserved before chemotherapy followed by bone marrow transplantation. In spring 2008, because the patient had been menopausal for 2.5 years as a result of the conditioning therapy, an orthotopic autotransplantation of thawed ovarian cortex was performed. The patient conceived spontaneously in a natural cycle in autumn 2008, and delivered a healthy female child in June 2009. CONCLUSION(S): Cryopreservation of ovarian tissue with subsequent autotransplantation is an emerging procedure for preserving the fertility of young patients with a high risk of premature ovarian failure (POF) resulting from gonadotoxic treatment. This case opens up new perspectives in cases of nonmalignant diseases.