The diagnosis and management of patients with primary ovarian insufficiency, also known as premature menopause, premature ovarian failure, ovarian dysgenesis, hypergonadotropic hypogonadism, requires the doctor to be especially careful and competent, since the establishment of such a diagnosis significantly affects the emotional sphere of a woman. Doctors are advised to be more attentive to such patients, devote more time to them, provide all the necessary information regarding the disease.
Primary ovarian failure (POI) was first described by the American endocrinologist Fuller Albright in 1942 in a young patient with amenorrhea syndrome, estrogen deficiency and menopausal follicle-stimulating hormone (FSH). He used this term to more clearly show that ovarian function is inherently abnormal, as evidenced by high levels of FSH - even higher than with insufficient secretion of gonadotropins. Amenorrhea is associated with inadequate release of gonadotropins, and low FSH levels can be regarded as secondary ovarian failure - inadequate ovarian function is a secondary cause of pituitary or hypothalamic disorders. The scientist described a case with Turner's syndrome (i.e. POI) in a woman who did not have physical manifestations of stigmas.
Later, researchers began to use the term "premature menopause" or "premature ovarian wasting" to describe processes similar to menopause - the complete depletion of potentially functional primordial follicles, the final cessation of menstruation and the irreversible end of fertility. However, the term proposed by F. Albright is more accurate.
More than half of women with POF have intermittent ovarian function, and approximately 5-10% of them can eventually become pregnant without medical intervention, often many years after diagnosis. Moreover, most POI patients find the term less embarrassing than "premature ovarian failure" or "premature menopause."
In the US, the incidence of POI among 20-year-old patients is approximately one case per 10,000, among 30-year-olds - per 1000, and among 40-year-olds - per 100 women. Most cases of POI are sporadic. However, approximately 10-15% of patients with POI have a positive family history.
Etiology of primary ovarian failure and symptoms of the disease
As you know, at birth, a girl's ovaries have a certain number of primordial follicles, which are consumed over time. The bud of primordial cells proliferates in the female fetus until the 4th month of gestation. It has been established that the maximum reserve of primordial follicles is 7 million. When this level is reached, their number decreases to 1-2 million at the time of birth and to 0.5 million by the period of puberty. With the depletion of potentially functional primordial follicles, menopause occurs.
In the etiology of POI, two main mechanisms can be distinguished: a decrease in the number (depletion of the pool) of follicles and their dysfunction. Typical causes of depletion of the follicular pool are Turner's syndrome, chemotherapy and radiotherapy, while FSH receptor mutation and autoimmune oophoritis can be causes of follicular dysfunction.
Clinical manifestations of primary ovarian failure
In patients with Turner's syndrome, POI manifests itself as primary amenorrhea. If POI develops after radiation or chemotherapy, the disease has an acute onset. In women with an FMR1 gene premutation, autoimmune oophoritis, or idiopathic POI, the history of the menstrual cycle (MC) does not have any features. However, in many patients the disease may be preceded by oligomenorrhea or dysfunctional uterine bleeding. Most idiopathic cases of POI develop after menarche and the establishment of regular menses. In some patients, menarche may occur, but later, when POI is already diagnosed, it is retrospectively revealed that there was poly- or oligomenorrhea. Often in such cases, girls are unreasonably prescribed oral contraceptives (OC) for “cycle regulation” (without first determining the mechanism underlying the wrong MC). In some women with POI, menstruation does not resume after childbirth or after stopping OCs. Overall, approximately 10% of patients with POI have primary amenorrhea.
Many (but not all) women with POF develop symptoms of estrogen deficiency (hot flashes, vaginal dryness, sleep disturbances). The absence of evidence of estrogen deficiency may be indicative of ongoing intermittent ovarian function, which is known to occur in many women with POF. A number of individuals experience hot flashes even when menstruating regularly.
It should be noted that patients with POI are less satisfied with their sexual life than healthy women, although most of them have normal sexual function.
The diagnostic criteria for POI are:
- age < 40 years;
- abnormal MC lasting 4 months or more (oligo-, polymenorrhea, menometrorrhagia, dysfunctional uterine bleeding);
- FSH levels are consistent with menopausal levels on two tests conducted 1 month or more apart.
Individuals with POI have an increased risk of developing hypothyroidism and adrenal insufficiency. Therefore, they are shown to determine the level of thyroid-stimulating hormone, antibodies to thyroid peroxidase and to the tissue of the adrenal glands. Determination of the level of ovarian antibodies is not recommended due to the low specificity of this test. Women who have adrenal antibodies should be tested annually for the presence of adrenal insufficiency. If thyroid antibodies are detected, it is necessary to examine the function of the thyroid gland annually.
Hypogonadism is a recognized risk factor for osteoporosis. Therefore, during the diagnosis of POI, women should perform basic studies to determine the BMD. Ultrasonography is also indicated to identify possible causes that may lead to ovarian enlargement and/or increase the risk of their over
This cause is 17,20-desmolase deficiency or autoimmune oophoritis [2].
Treatment of patients with primary ovarian failure
Treatment of patients with POI should be aimed at correcting endocrine, genetic, emotional and reproductive status.
POI is associated with a number of endocrine disorders that can be corrected with HT. Thus, when using transdermal estradiol, the normal level of this hormone in the woman's body is restored, vasomotor symptoms decrease, the vaginal epithelium is preserved and an acceptable level of BMD is maintained.
Medroxyprogesterone acetate is used as first-line therapy. This progestin has been shown to be effective in preventing endometrial hyperplasia in women receiving total estrogen replacement therapy, which is indicated in young patients with POF. Other progestins do not have this effect, but in combination with low doses of estrogen are recommended for the treatment of people of menopausal age. This treatment regimen stabilizes their MC.
The use of OCs as a HT in POI is not recommended, as it leads to an excessive intake of steroid hormones, i.e. more than what is required for replacement therapy. In addition, oral estrogens increase the risk of thromboembolism. The use of continuous combination HT regimens to induce amenorrhea in patients with POI is not recommended as it may result in an unintended pregnancy. It is important to remember that HT in patients with POI does not have a contraceptive effect.
There are some suggestions that even high doses of hormones contained in steroidal contraceptives may not be effective enough to prevent pregnancy in patients with POF. The risk of spontaneous pregnancy in such women is 5-10%, and they should keep a calendar of menstrual bleeding and take a pregnancy test if they miss one period. With a positive pregnancy test result, it is recommended to stop HT. Women with POI who are not planning pregnancy should consider using non-hormonal contraception, such as barrier methods or intrauterine devices.
Because of the increased risk of osteoporosis in patients with POF, it is important to optimize factors that support BMD, such as adequate dietary calcium and vitamin D intake, and exercise to reduce excess weight. Approximately half of patients with POF have insufficient daily calcium intake (<1200 mg of elemental calcium per day) and blood vitamin D levels of < 30 ng/ml. Therefore, supplemental calcium and vitamin D intakes are indicated for these women. The usual recommendation is 1,500 mg/day of calcium carbonate (corresponding to 600 mg of elemental calcium, which is half the body's daily requirement) and 1,000 IU/day of cholecalciferol.
Women who are not getting the remaining 600mg of elemental calcium from their daily diet should be given total trace element replacement therapy at a dose of 1200mg of elemental calcium per day.
Bisphosphonates are not indicated for patients with POI due to their long half-life from bone tissue and unexplored effects on the fetus.
Unfortunately, there is no controlled-study evidence-based therapy that improves ovarian function and restores fertility, and is safe and effective.
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