From the Guidelines
Premature ovarian failure is most commonly caused by iatrogenic factors, including chemotherapy and radiation therapy, with pelvic irradiation and alkylating agents playing a pivotal role in the onset of ovarian insufficiency. The causes of premature ovarian failure can be categorized into several groups, including:
- Iatrogenic causes: chemotherapy, radiation therapy, and ovarian surgery, with alkylating agents such as cyclophosphamide and procarbazine being particularly gonadotoxic 1
- Genetic disorders: Turner syndrome and Fragile X premutations
- Autoimmune conditions: where the body attacks its own ovarian tissue
- Viral infections: although the evidence is limited
- Environmental toxins: and metabolic disorders like galactosemia It is essential to note that in many cases (up to 50-75%), the exact cause remains unknown despite thorough investigation 1. The risk of developing premature ovarian insufficiency (POI) is dose-dependent, with higher doses of chemotherapy and radiation increasing the likelihood of POI 1. The cyclophosphamide equivalent dose (CED) method can be used to estimate the risk of POI, with CED lower than 4000 mg/sm associated with a low risk of POI 1. Radiation-induced ovarian damage is also dose-dependent, with abdominal radiation doses above 20.3 Gy in infants, 18.4 Gy at the age of 10 years, and 16.5 Gy at the age of 20 years associated with a high risk of developing POI 1. Some patients may experience hypogonadotropic hypogonadism due to cranial or cranio-spinal radiotherapy, neurosurgery involving the hypothalamic-pituitary area, or tumors infiltrating sellar or supra-sellar regions 1. Younger age at the time of exposure to chemo- and/or radiotherapy may be protective against POI, probably due to the natural decline of primordial follicles with aging 1. Women with premature ovarian failure should seek medical evaluation as they face increased risks of osteoporosis, cardiovascular disease, and psychological impacts, and treatment typically focuses on hormone replacement therapy until the natural age of menopause to manage symptoms and prevent long-term health complications 1.
From the Research
Causes of Premature Ovarian Failure
The causes of premature ovarian failure (POF) can be divided into several categories, including:
- Genetic factors: such as X chromosome abnormalities (e.g. Turner syndrome) 2, 3, 4, 5
- Autoimmune factors: including alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells 3, 4, 5
- Environmental factors: such as exposure to toxins, chemotherapy, radiotherapy, and infections 2, 3, 6, 5
- Iatrogenic causes: including pelvic surgery, chemotherapy, and radiotherapy 3, 5
- Lifestyle factors: such as cigarette smoking 6, 5
- Idiopathic causes: in most cases, no identifiable etiology can be recognized after complete evaluation 4, 5
Genetic Causes
Genetic causes of POF can involve the X chromosome (monosomy, trisomy, translocations, deletions) or autosomes 4, 5. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation 4.
Autoimmune Causes
Autoimmune causes of POF are characterized by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells 4. Antiovarian antibodies are reported in POF, but their specificity and pathogenic role are obscure 5.
Environmental and Lifestyle Factors
Environmental and lifestyle factors, such as exposure to toxins, chemotherapy, radiotherapy, infections, and cigarette smoking, can also contribute to the development of POF 2, 3, 6, 5. These factors can affect female ovarian function via epigenetic regulations 6.