Ovarian insufficiency is a functional failure of the follicular apparatus due to its underdevelopment, irreversible damage or insensitivity to gonadotropins. It is manifested by infertility, irregular menstruation or their absence, signs of hypoestrogenism. It is diagnosed by gynecological examination, analysis of sex hormone levels, ultrasound of the pelvic organs, diagnostic laparoscopy, cytogenetic examination. For the treatment of infertility, the donation method is used. In other cases, hormone replacement therapy is prescribed.
E28.3 Primary ovarian insufficiency
Ovarian insufficiency is a consequence of several diseases that have a similar clinical picture, but different etiopathogenetic mechanisms. The form of the disorder associated with gonadal dysgenesis is diagnosed in 1 girl per 10-12 thousand newborns. The depletion of the follicular apparatus and the syndrome of its resistance to follicle-stimulating hormone are noted in 10% of patients suffering from amenorrhea. In adolescence, ovarian insufficiency is usually caused by genetic factors. In women of reproductive age, menstrual function and fertility disorders may be of a primary nature or occur a second time against the background of previously normal menstrual and generative functions.
The secretion of sex hormones is disrupted with an initially insufficient number of primordial follicles, their accelerated atresia or functional failure. Specialists in the field of gynecology distinguish several groups of causes that cause primary damage to the follicular apparatus or change the sensitivity of ovarian tissue to the stimulating effect of gonadotropins:
- Genetic defects. Hypergonadotropic hypogonadism occurs with primary gonadal dysgenesis (Shereshevsky-Turner syndrome), idiopathic accelerated follicle atresia, reduced number of germ cells, X-trisomy. When the gene encoding the structure of the FSH receptor is mutated, the follicular apparatus becomes resistant to the action of gonadotropin. The secretion of hormones by the ovaries is disrupted in some congenital enzymopathies — galactosemia, deficiency of 17,20-lyase, 17-α-hydroxylase.
- Immuno-conditioned disorders. Antiovarial bodies that have a damaging effect on primordial follicles are formed in Hashimoto’s thyroiditis, thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, and some forms of myasthenia gravis. Under the action of antibodies, damage and destruction of follicles occurs, as a result of a decrease in their number, the ability of gonads to secrete sex hormones decreases, which is manifested by ovarian estrogenic insufficiency.
- Exogenous effects and extragenital pathology. The destruction of ovarian tissue can be caused by various external agents — ionizing radiation, chemotherapeutic agents, some chemical reagents, nicotine. Flu, rubella, and mumps viruses have a toxic effect on the follicles. The failure or destruction of germinal cells is possible in diabetes mellitus, sarcoidosis, Addison’s disease.
In case of tubal pregnancy, cyst rupture, malignant tumors, the ovaries are surgically removed. Functional insufficiency of the ovarian apparatus is observed in some patients with chronic inflammatory diseases of the uterine appendages — oophoritis, adnexitis. The probability of premature atresia of the primordial follicles is especially high with a specific infectious process caused by Mycobacterium tuberculosis.
The formation of ovarian insufficiency is usually based on pre- and post-pubertal destruction of germinative tissue. The mechanism of development of the disease depends on the causes that caused the disorder. With most genetic defects, the number of follicles is initially low, usually they are not enough for more than 5-15 years of reproductive life. Exogenous effects, autoimmune disorders, infectious and inflammatory diseases cause accelerated atresia of cortical layer cells. In rare cases, due to a violation of the sensitivity of the receptor apparatus, the ovarian response to the action of gonadotropins is reduced or absent.
Regardless of the etiology, the final link of the disease is common — ovulation stops, hypoestrogenism develops. Depleted ovaries look hypoplastic, have small dimensions (1.5-2.0 cm x 0.5 cm x 1.0-1.5 cm) and weight (up to 1.0-2.0 g each). After the termination of secretory activity, there are no primordial follicles in the sterile cortex, the interstitial tissue is atrophied. Against the background of low secretory activity of the gonads, the pituitary gland forms an increased amount of gonadotropins according to the feedback principle, therefore this form of ovarian insufficiency is called hypergonadotropic hypogonadism.
The systematization of the forms of ovarian insufficiency is carried out taking into account the causes that led to the development of the disease and the degree of its severity. The etiopathogenetic approach makes it possible to more accurately assess the reproductive abilities of the patient and choose the optimal treatment tactics. According to modern obstetricians and gynecologists, there are three main clinical variants of ovarian insufficiency:
- Gonadal dysgenesis. The disease is associated with an initially small supply of primordial follicles in the ovarian tissue. Usually such conditions are the result of genetic defects or dysembriogenesis. The smaller the number of follicles, the more doubtful the natural realization of reproductive function.
- Ovarian exhaustion syndrome. The cause of secretory insufficiency is premature follicle atresia caused by various external or extragenital factors. Detection and correction of the disorder in the early stages increase the likelihood of conception and gestation.
- Resistant ovarian syndrome. Congenital or secondary failure of ovarian tissue is due to the lack of its response to gonadotropins. Due to the lack of knowledge of the disorder, its therapy is extremely difficult, the restoration of generative function is possible only in isolated cases.
When assessing the severity of ovarian insufficiency, they focus on the presence of clinical symptoms and the level of FSH in the blood serum. At the latent stage of the disease, the content of FSH is normal, but a woman cannot get pregnant for no apparent reason. The biochemical stage is characterized by an increase in the basal concentration of FSH in unexplained infertility. Apparent insufficiency is accompanied by infertility, irregular menstruation and increased basal FSH levels. The early depletion of the gonads is indicated by amenorrhea, high concentration of FSH and irreversible infertility due to complete atresia of the follicular apparatus.
Symptoms of ovarian insufficiency
At the latent and biochemical stage of the disease, the only sign is often infertility, unexplained by any organic causes. The transition of the disorder into an obvious phase is indicated by a violation of the ovarian-menstrual cycle – menstruation becomes rare, irregular, and eventually stops completely. Often there are signs of estrogen deficiency — hot flashes, decreased libido, dryness and atrophy of the mucous membranes of the vagina and vulva, osteoporosis. With congenital dysgenesis in women, characteristic external signs of hereditary pathology may be revealed (dysmorphic physique, pterygoid cervical folds, arched palate, underdevelopment of secondary sexual characteristics, insufficient pubic hair, armpits).
The most serious consequence of ovarian insufficiency is infertility. Premature extinction of the secretory function of follicular tissue provokes early aging of the body with an increased risk of cardiopathology (coronary heart disease, myocardial infarction), Parkinson’s disease, dementia. Osteoporosis resulting from estrogen deficiency is accompanied by an increase in the likelihood of fractures. The patients’ working capacity decreases, the quality of life worsens, sexual relations are disrupted, depressive and even suicidal thoughts may occur.
A comprehensive examination to exclude ovarian insufficiency is prescribed to all patients with infertility of unclear genesis. The main tasks of the diagnostic search are to determine the functional capabilities of the ovaries, to assess the morphological structure of their tissues. The most valuable methods for diagnosis are considered to be such as:
- Examination on the chair. With bimanual palpation, there may be a decrease in the size of the uterus and appendages. A thorough examination, examination in mirrors and colposcopy can reveal the external symptoms of estrogen deficiency in the form of atrophic changes in the mucous membranes of the reproductive organs.
- Determination of the level of sex hormones. Markers of ovarian insufficiency are a decrease in the concentration of estradiol below 20 pg/ml and an increase in the level of FSH above 20-30 mMU/ml. The tests are carried out weekly for 2-4 weeks. The gestagen test is negative, and the cyclic hormonal test is positive.
- Ultrasound of the pelvic organs. The uterus is somewhat reduced, the endometrium is thinned. With the depletion of the germinative apparatus, the ovaries are reduced in size, compacted, with dysgenesis they are represented by cords. There are few or no follicles. In women with ovarian resistance, follicular tissue is preserved.
- Diagnostic laparoscopy. Endoscopic examination makes it possible to visually confirm the reduction of the ovaries, the absence of maturing follicles in the cortical layer and to identify their replacement with connective tissue fibers. During laparoscopy, a biopsy can be obtained for histological confirmation of the diagnosis.
If gonadal dysgenesis is suspected, a consultation with a geneticist, cytogenetic methods (karyotyping, etc.) are indicated. To determine the possible consequences of estrogen insufficiency, densitometry and a study of lipid metabolism are additionally prescribed. Primary and secondary ovarian insufficiency is differentiated with hypogonadotropic hypogonadism, polycystic and sclerocystic ovary syndrome, and other diseases that violate menstrual and reproductive functions. According to the indications, the patient is consulted by an endocrinologist, oncologist, neurologist, neurosurgeon, cardiologist.
Treatment of ovarian insufficiency
To date, no methods have been proposed to restore the follicular apparatus of ovarian tissue. The use of ovulation stimulants is usually ineffective. The choice of the patient’s management tactics is determined primarily by her age and reproductive plans. Recommended treatment regimens for ovarian insufficiency are:
- If there are plans for childbirth: IVF with a donor egg. The donor’s oocyte is fertilized in vitro, after which it is transferred to the patient’s uterus. Previously, estrogen-progestogenic stimulation is prescribed to prepare the endometrium for implantation. Hormone therapy is continued until the 15th week of the diagnosed pregnancy, after which the doses of hormones are reduced to complete withdrawal.
- In the absence of reproductive plans: estrogen/ progestin replacement therapy. In the absence of contraindications and the consent of a woman, combined hormonal drugs are prescribed until the age of 51. Their use softens the manifestations of estrogenic insufficiency — symptoms of premature menopause, osteoporosis, involution of reproductive organs.
Surgical methods of treatment are recommended for patients whose ovarian tissue pathology is associated with a genetic defect in the form of the presence of a Y chromosome. Conducting a bilateral oophorectomy reduces the risk of developing germinogenic ovarian cancer, which occurs in such women more often than the average in the population. The operation is usually performed laparoscopically.
Prognosis and prevention
In most cases, it is impossible to restore the possibility of natural fertilization in patients suffering from ovarian insufficiency, although some of these women become pregnant even without active treatment. The effectiveness of one donation attempt currently reaches 30%. The use of hormone replacement therapy can significantly improve the quality of life with premature depletion of the ovaries, their dysgenesis and resistance. Prevention involves minimizing toxic effects on ovarian tissue, timely treatment of chronic genital and extragenital pathology, the choice of organ-preserving interventions if surgical treatment is necessary.