Primary ovarian – ovarian failure is a spectrum of diseases that not only affect fertility in women, but also contribute to an increased risk of mortality and the development of various conditions that are associated with a prolonged lack of sufficient estrogen levels. This spectrum of diseases was previously called premature ovarian failure. However, this term is imprecise because the degree of damage to the ovaries and their function can vary over time. Primary ovarian failure is usually seen in patients under the age of 40. The diagnosis is made in the presence of amenorrhea – absence of menstruation lasting within 4-6 months, combined with increased serum concentrations of follicle-stimulating hormone – FSH and decreased levels of estradiol, which are observed in blood tests. Primary ovarian failure differs from menopause in that variability in ovarian and primordial follicle function is preserved in the former condition. In contrast, in menopause, the primordial follicles are depleted, resulting in complete cessation of menstruation and the menstrual cycle. Other causes of secondary amenorrhea include hypothyroidism, an underactive thyroid gland, and various genetic abnormalities. These conditions must be ruled out before diagnosing primary ovarian failure. The largest number of oocytes – approximately 6-7 million are observed during intrauterine development – during the 20th week of gestation. After that, there is a substantial decline in their number, regardless of ovulation, which continues until reaching approximately 300,000-400,000 oocytes by the time reproductive age is reached. Once menstruation begins, ovulation and the constant release of mature eggs leads to a gradual depletion of the ovarian reserve until menopause. During the entire reproductive age, only 400-500 oocytes are released through ovulation. Effective regulation of ovulation and menstruation is essential for a woman’s health. For example, in the absence of normal ovarian function, which is the result of low serum concentrations of estradiol, the production of sex hormones decreases, which leads to disturbances in bone density and the development of osteoporosis. This significantly increases the risk of fractures. Primary ovarian failure is thought to result from either follicular dysfunction or depletion of ovarian follicles. However, the exact mechanisms by which this condition develops are still not fully understood. Approximately 90% of all diagnosed cases of spontaneous premature ovarian failure have no specific underlying cause. At the ovarian level, some rare mutations in the genes for follicle-stimulating-FSH and luteinizing-hormone-LH receptors can lead to altered ovarian response to the levels of these circulating gonadotropins.This leads to impaired ovarian function. Iatrogenic causes of primary ovarian dysfunction are oophorectomy – surgical removal of the ovaries, chemotherapy or radiotherapy, as well as certain diseases – such as chicken pox, malaria, shigellosis and tuberculosis. They can lead to damage to the ovarian tissue and significantly reduce the number of functional follicles. Chromosomal abnormalities, such as Turner’s syndrome, can lead to early cell death – apoptosis of oocytes as early as in utero, in addition to accelerated depletion of oocytes early in life – before the age of 10 years. This leads to a significant decrease or complete exhaustion of the ovarian reserve until reaching reproductive age. The Fragile X FMR1 premutation – presence of 59-199 CGG trinucleotide repeats significantly increases the risk of developing the condition in affected patients compared to the general population. In the presence of an FMR1 premutation of 80-100 CGG repeats, the highest risk is observed. Certain autoimmune diseases such as adrenal insufficiency – Addison’s disease, hypothyroidism due to Hashimoto’s thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, atypical congenital adrenal hyperplasia, myasthenia gravis, and inflammatory bowel disease are also associated with an increased risk of primary failure of the ovaries. Genetic mutations and autosomal recessive disorders such as galactosemia, ataxia-telangiectasia, and the blepharophimosis-ptosis-epicanthus-inversus syndrome�known as BPES, due to a mutation in the FOXL2 gene�have an undetermined effect on the risk of developing the condition. Exposure to environmental factors such as smoking and various manufactured substances is thought to contribute to depletion of the ovarian reserve due to binding of these substances to granulosa cell receptors in the ovaries. This leads to the activation of genes that affect oocyte cell death and suppresses the action of the aromatase enzyme, which is the main reason for lowering serum estradiol concentrations. References: https://www.ncbi.nlm.nih.gov/books/NBK589674/The Fragile X FMR1 premutation – presence of 59-199 CGG trinucleotide repeats significantly increases the risk of developing the condition in affected patients compared to the general population. In the presence of an FMR1 premutation of 80-100 CGG repeats, the highest risk is observed. Certain autoimmune diseases such as adrenal insufficiency – Addison’s disease, hypothyroidism due to Hashimoto’s thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, atypical congenital adrenal hyperplasia, myasthenia gravis, and inflammatory bowel disease are also associated with an increased risk of primary failure of the ovaries. Genetic mutations and autosomal recessive disorders such as galactosemia, ataxia-telangiectasia, and the blepharophimosis-ptosis-epicanthus-inversus syndrome�known as BPES, due to a mutation in the FOXL2 gene�have an undetermined effect on the risk of developing the condition. Exposure to environmental factors such as smoking and various manufactured substances is thought to contribute to depletion of the ovarian reserve due to binding of these substances to granulosa cell receptors in the ovaries. This leads to the activation of genes that affect oocyte cell death and suppresses the action of the aromatase enzyme, which is the main reason for lowering serum estradiol concentrations. References: https://www.ncbi.nlm.nih.gov/books/NBK589674/The Fragile X FMR1 premutation – presence of 59-199 CGG trinucleotide repeats significantly increases the risk of developing the condition in affected patients compared to the general population. In the presence of an FMR1 premutation of 80-100 CGG repeats, the highest risk is observed. Certain autoimmune diseases such as adrenal insufficiency – Addison’s disease, hypothyroidism due to Hashimoto’s thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, atypical congenital adrenal hyperplasia, myasthenia gravis, and inflammatory bowel disease are also associated with an increased risk of primary failure of the ovaries. Genetic mutations and autosomal recessive disorders such as galactosemia, ataxia-telangiectasia, and the blepharophimosis-ptosis-epicanthus-inversus syndrome�known as BPES, due to a mutation in the FOXL2 gene�have an undetermined effect on the risk of developing the condition. Exposure to environmental factors such as smoking and various manufactured substances is thought to contribute to depletion of the ovarian reserve due to binding of these substances to granulosa cell receptors in the ovaries. This leads to the activation of genes that affect oocyte cell death and suppresses the action of the aromatase enzyme, which is the main reason for lowering serum estradiol concentrations. References: https://www.ncbi.nlm.nih.gov/books/NBK589674/