Autologous Stem Cell Therapy for Premature Ovarian Insufficiency and Low Ovarian Reserve

Premature ovarian insufficiency (POI), formerly referred to as premature ovarian failure (POF), is defined as hypergonadotropic ovarian insufficiency occurring prior to age 40 (1). It is surprisingly common and affects approximately 1% of women below the age of 40 (2, 3). The incidence is 10% to 28% in women with primary amenorrhea and 4% to 18% in women with secondary amenorrhea (2). The clinical manifestations include amenorrhea and abnormally high levels of luteinizing (LH) and follicle stimulating hormone (FSH) and low levels of Anti Mullerian Hormone (AMH). The etiology of POI is unknown in most cases. It can be caused by a combination of inherited conditions such as immune disorders, environmental toxins and iatrogenic injury (2, 3). The majority of patients with POI are considered to have idiopathic premature ovarian insufficiency because usually no cause can be identified (3). POI has been shown to be associated with an increased incidence of other conditions, including Alzheimer's, cardiovascular and immune system diseases, metabolic syndrome, osteoporosis, diabetes and cancer of reproductive organs. POI is characterized by loss of secondary follicles, arrested folliculogenesis, decreased estrogen production, and infertility (3). The mechanism of ovarian insufficiency is most likely accelerated follicular atresia but detailed pathogenesis is yet to be fully understood (2).

In women younger than 40, at least two menopausal FSH levels (≥40 IU/L) will be sufficient for the diagnosis of POI. It is not essential to have amenorrhea for the diagnosis of POI. Subjects with oligomenorrhea or low ovarian reserve and elevated FSH, referred to as transitional ovarian insufficiency (TOI), or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter, and are included in this category. Spontaneous menstrual cycles can sometimes be seen after the diagnosis of POI as well. Resumption of normal ovarian function, albeit temporary, in patients with normal karyotypes has been documented in 10 to 20% of patients; thus, spontaneous resumption of fertility is possible (1).

No therapeutic intervention has proven effective in restoring fertility in patients with POI. Currently, egg donation remains the only reliable method to establish a pregnancy in women with POI (2, 3). Even though this approach is attainable, resulting children will not be genetically related to the recipient mother. Furthermore, egg donation is not ethically acceptable to many couples. Various attempts at ovarian stimulation patients with POI are usually unsuccessful because they are poor responders. Therefore, the diagnosis of POI can cause great physical and mental suffering among these patients. Thus, there is critical need to develop novel effective approaches for the treatment of POI.

Throughout life, there is an ongoing physiological level of atresia of oocytes. A decreased germ cell endowment combined with an increased rate of germ cell destruction can explain POI (1). The current concept that the ovary has a static ovarian reserve is entirely at odds with the germ cell dynamics. Current research supports the concept that the ovary continues to produce new germ cells into adult life, however, whether this occurs in humans is not universally accepted. Recent research suggests that diminished ovarian reserve is a result of the aging of the niche rather than a defect in the germ cells (4-6). Anti-mullerian hormone has been used as a reliable biomarker for ovarian reserve in humans and the circulating AMH levels change with age as follows:

20-25: 1.23-11.51 ng/mL 26-30: 1.03-11.10 ng/mL 31-35: 0.66-8.75 ng/mL 36-40: 0.42-8.34 ng/mL 41-46: 0.26-5.81 ng/mL 47-54: <0.82 ng/mL Emerging evidence suggests that bone marrow-derived mesenchymal stem cells (BMSCs) could restore the structure and function of injured tissues (7). During embryologic development, cells of the mesodermal layer give rise to multiple mesenchymal tissue types including bone, cartilage, tendon, muscle, and fat and marrow stroma (8). These precursor cells, also present in the postnatal organism, are referred to as mesenchymal stem cells. These stem cells have been shown to retain their developmental potential following extensive sub-cultivation in vitro. Implantation of culture-expanded mesenchymal stem cells has been demonstrated to effect tissue regeneration in a variety of animal models and depends on local factors to stimulate differentiation into the appropriate phenotype (8).