Several factors such as lifestyle changes, social causes, work, and economic scenarios have led to the trend of delayed motherhood despite the biological clock that keeps ticking. Females in their 20s have the best reproductive potential but not many women choose to be mothers during this age. The quality of oocytes produced in 20s is the best which increases the chances of a safe pregnancy that will result in a healthy baby. However, it has been estimated that premature ovarian failure (POF) or early menopause affects 10% of the female population, who despite the young age, will have problems to conceive. [1, 14]
Primary ovarian insufficiency (POI) of premature ovarian failure (POF) is a condition marked b the loss of normal function of ovaries before the age of 40. Ovarian failure implies that the eggs are not regularly released which results in infertility (2,3). Many women naturally experience reduced fertility by 40 years of age. This age may mark the start of irregular menstrual cycle that signals the onset of menopause. Women with POI experience early menopause which is denoted by irregular periods and reduced fertility before 40 years old, sometimes as early as the teenage years (4,5)
The first sign of POI is usually menstrual irregularities (6), also called amenorrhea. The other symptoms may include occurrence of hot flashes, night sweats, poor concentration, irritability, decreased sex drive, vaginal dryness, and pain during sex which are consistent with the symptoms of naturally occurring menopause (7,8). For most of the women with POI, trouble getting pregnant is the first symptom they experience which leads them to visit their health care provider. This is sometimes called “occult” (hidden) or early POI (9), which is usually characterized by amenorrhea, low Anti-Mullerian Hormone (AMH) and estradiol levels, oligomenorrhea, hypoestrogenism, and elevated gonadotrophin and follicular stimulating hormone (FSH) levels in women under the age of 40 (10,11,14).
The cause of POI can be natural or it can result after surgery, disease, chemotherapy, and/or radiation. With POI, some women may still have occasional periods and they may even get pregnant. Evaluation of ovarian reserve and personalisation of the therapeutic approach are crucial for optimizing the success rate for its treatment.
Various study groups have tried to restore fertility in women with POI; however, very few randomized therapeutic trials registered show significant improvement in ovulation and pregnancy rates. In a systematic review about various therapeutic interventions with a purpose to restore ovarian function in women with POI, the authors concluded that most of the interventions were equally ineffective and unlikely to project an improvement in the prevailing scenario.
Nevertheless, it was shown that stem cells derived from varied sources may rescue the ovarian functions, such as recovery of ovarian sex hormone function, reduction in apoptosis of germ cells, and increment in the number of follicles. However, the improved ovary function after stem cell transplantation is a complex mix of many unclear factors requiring further investigation. [13, 14].
According to earlier reports, spontaneous pregnancies were successfully achieved after bone marrow transplantation in oncologic women with POI. Stem cells derived from varied origins promote follicular development, increase follicle and stromal cell proliferation, increase ovarian local vascularization, and reduce cell apoptosis and follicular atresia, while keeping the embryo quality intact (14). Hence, if the ovarian environment is adequate, residual quiescent follicles of damaged or aged ovaries can potentially produce competent oocytes. Nevertheless, further research is required to properly evaluate underlying mechanisms, identify best cell sources and design less/ minimally invasive infusion techniques. This study shows that stem cell therapy can potentially be used as a relevant therapeutic alternative for ovary regeneration and follicular development in patients with impaired ovaries (14).
Overview Of POF:
A normal healthy woman menstruates regularly from menarche – her first period- (usually occurring at 10–14 years old) until menopause (usually that was taking place at 50–55 years old). Nowadays, women have their menarche much sooner (7–9 years old) and the ovaries stop functioning before the age of 40, pathology known as premature ovarian failure (POF)– also called Primary ovarian insufficiency (POI). (15)
POI affects approximately one in 1,000 women under the age of 30 and one in 100 women under the age of 40.and is characterized by menstrual disturbance (amenorrhea or oligomenorrhea) with raised gonadotropins, low anti-Mullerian hormone (AMH), the ovaries do not produce normal amounts of the hormone estrogen and do not release eggs regularly. This condition leads to infertility.(16)
Signs and Symptoms
Women with POF were found to have a wide variety of signs and symptoms affecting many body systems due to hypoestrogenism and hypoandrogenemia, that may lead to serious diseases. Main symptoms include hot flushes – that especially appear prior to the onset of amenorrhea, vasomotor symptoms associated with sleep problems which may affect social and work performance, urogenital symptoms as vaginal dryness, vaginal irritation, and itching, cardiovascular disease due to abnormal lipid profile, insulin action disturbances as patients with POI have a higher risk of developing type 2 diabetes mellitus as compared to women with normal menopause. In addition to these, peak bone mass (PBM) formation and bone mineral density (BMD) status were found to be affected at younger age and with more severity. (17)
According to pathogenesis, there are two types of POF: one has an abundant number of follicles but with maturation defects and the other type has limited number of remaining follicles. The POF pathophysiology is believed to differ from normal menopause. The declined ovarian function in the first type of POF is reversible, whereas in the latter one the changes are permanent.
However, the pathogenesis of premature ovarian failure is not entirely clear and it requires further investigation, but until now, there have been described three major causes for POF.
The first cause for POF is based on X chromosome-linked genetic defects, which include X monosomy (also called Turner’s syndrome), trisomy X7, mosaicism and X chromosome deletions. Most of the genetic studies in POI were conducted on genes already known to play a role in folliculogenesis (NR5A1, NOBOX, FIGLA, and FOXL2), as folliculogenesis growth factors (inhibin A, GDF9, and BMP15), or in ovarian steroid genesis (FSHR, FSH, LHR, and LH). (17)
Karyotype testing should be always recommended, as it was shown that approximately 5–10% of women with a diagnosis of POI that have a normal karyotype, can achieve a spontaneous pregnancy even if the recovery of ovarian function is temporary and poorly predictable (18)
The second cause for POF is represented by autoimmune disorders, associated with humoral and cellular immunity modifications, resulting in antibody creation and T-cell mediated injury of ovarian granulosa cells (GCs), oocytes and the zona pellucida. Based on the data from the St. Marianna University School of Medicine and the Rose Ladies Clinic, 45% of the patients with idiopathic, normal karyotypic POI, tested for 16 autoantibody tests (Mentioned in paper). were found to have positive results. From these, forty-one patients (15% of patients with positive autoantibodies) were diagnosed with clinical autoimmune diseases. The autoimmune disorder most frequently associated with POI, as mentioned in the paper, was hypothyroidism, followed by hyperparathyroidism.
The third most important cause for POF is iatrogenic, due to ovarian surgery, chemotherapy and radiotherapy (cancer survivors). (17)
In addition to this, it is worth mentioning that the Chemotherapy-induced premature ovarian failure may be reversible and the patient may gain back her fertility. One report suggests that the younger females who suffered from chemotherapy- induced POF still retain enough ovarian function with good quality oocytes to support a successful pregnancy (18).
In addition to these 3 major causes, it has been shown in case reports that viral infections can be followed by ovarian failure. However, only mumps oophoritis has been considered to be a cause of POI, accounting for 3–7% of POI cases (17)
Overview Of Stem cells:
Stem cells are a population of undifferentiated cells characterized by the pliability to extensively proliferate and differentiate into differing types of cells and tissues. Stem cells have many sorts, that differ from each other by their origins and derivatives.(19) Pluripotent cells which are derived from the inner cell mass of the embryo and induced pluripotent cells can differentiate into tissue from all three germ layers.(20) Multipotent stem cells may become multiple specialized cells in an exceedingly specific tissue like hematopoietic stem cells (HSC) and mesenchymal stem cells which form tissue, bone, and cartilage. Unipotent or oligopotent stem cells will only differentiate into one cell type, since they will form terminally differentiated cells of a selected tissue. (21)
There are many applications of stem cells nowadays, starting from cellular therapy that aims to exchange damaged cells and regenerate organs. (22) Also, stem cells have expanded our understanding of development and the pathogenesis of diseases. (23) Nowadays, there is a big development within the field of somatic cell and regenerative medicine that have driven basic, translational, and clinical advances.
Mesenchymal stem cells (MSCs) are considered to be a relevant therapeutic alternative for ovary regeneration and follicular development in patients with impaired ovaries, like women diagnosed with primary ovarian insufficiency.(24) Although adult stem cell treatments do not modify the embryo quality, they have achieved a golden role in this field, by promoting follicular development, increasing ovarian local vascularization, enhancing follicle and stromal cell proliferation and reducing cell apoptosis and follicular atresia.(25) Following transplantation of stem cells, clinical trials have shown that menstrual cycle and even pregnancy may occur in POF patients.(26, 27) Nevertheless, we should have in mind also the restrictions, including inadequate number of cases reported, and the need for the development of transplantation methodology. In addition to this, we should remind that immunogenicity, heterogeneity and stem cells inherent properties of tumorigenicity are all considered challenges that may encounter in this promising field.