Premature ovarian failure

G.S.Conway

Br. MedBull, 2000; 56, No3, pp 643-649.

Menopause usually occurs around age 50; in 1% of women it continues until the age of 60, in 1% it stops before the age of 40. Officially, menopause that occurs before the age of 40 is considered premature.

Premature ovarian failure (POF) can be caused by various factors that reduce the number of oocytes in the ovary. In the embryo, the first gamete precursors appear in the urogenital sinus. These cells then migrate to the ovary. There they multiply, producing 3.4 million potential oocytes in each ovary (Fig. 1). From this time, the oocytes are in an inhibited process of meiosis until they enter ovulation - for some only after 40 years. If a woman ovulates every month throughout her reproductive life, she may use fewer than 500 eggs—a tiny fraction of the original 7 million (0.007%). If a woman prevents ovulation, for example, by constantly using combination pills, the age of menopause is still not delayed. When natural menopause occurs is genetically programmed, daughters get it from their mothers, and it also depends on environmental factors such as smoking.

Most germ cells die due to apoptosis. Before birth, 2/3 of the 7 million had already died due to the mechanisms of natural selection. Between childhood and age 40, the number of eggs gradually decreases from approximately 1 million to 10 thousand in each ovary. At about 40 years of age, the process of egg death intensifies, and by the age of 50, only single cells remain. With anomalies of the X chromosome, for example, with Turner syndrome, when one X chromosome is missing, the production of germ cells is not impaired, but the first phase of their death is sharply enhanced, so that only a few remain at birth.

Etiology of premature ovarian failure

For most women, the causes of this condition are unknown. The psychological trauma that occurs when faced with such a diagnosis can be reduced by clearly defining the mechanism of its development. Known causes of PMN can be divided into genetic and environmental factors (Table 1).

Table 1. Causes of PYN in 352 women who applied to Middlesex Hospital, London, UK

Idiopathic (including autoimmune) - 204 (58%)

Turner syndrome - 82 (23%)

Chemotherapy - 24 (7%)

Family history - 15 (4%)

Surgery on the pelvic organs - 8 (2%)

Gonadal dysgenesis 46, XY - 7 (2%)

Galactosemia - 6 (2%)

Pelvic irradiation - 6 (2%)

Genetic causes

Any defect in the female sex X chromosome can cause POI. The most common form is Turner syndrome. Women with Turner syndrome have a single X chromosome, the karyotype is 45, X0. Phenotype of Turner syndrome: short stature, absence of spontaneous puberty. Early ovarian development in Turner syndrome is normal, but all germ cells die before birth, creating a picture of gonadal dysgenesis.

Turner syndrome demonstrates the requirement for two intact X chromosomes for normal ovarian function. Studies of women with partial deletions of the X chromosome revealed that at least three loci are responsible for ovarian development. On the short arm of the X chromosome there are genes responsible for the development of stigmata of Turner syndrome and primary amenorrhea. Of particular interest is the Xp22 locus, where the genes responsible for inactivation of the X chromosome in humans are located. The minimal deletion of the X chromosome that can cause PMN was identified in the Xq26-Xq28 loci - the PMN gene. The third locus responsible for ovarian development is Xq 13-22.

Familial cases of PMN are observed in the absence of any cytogenetic defects. It is likely that genetic markers will be found that will predict the development of PMN in future generations in such families. From this perspective, when determining the possible cause of PMN in a patient, a thorough examination of the family history is very important. Of the known types of inheritance of familial PMN, autosomal dominant, autosomal recessive and X-linked types of inheritance are noted.

PMN also occurs in families with rare hereditary pathologies - such as galactosemia, blepharophimosis. In these cases, the mechanism of damage to oogenesis is unclear. With galactosemia, it is primary amenorrhea that develops in women, while the genital area of ​​men remains intact. With blepharophimosis, only half of the families have ovarian failure, with a clinical picture of resistant ovaries. In Finland, the Ala189Val mutation, affecting the extracellular domain of the FSH receptor, was described in 22 women with premature menopause from 6 families with primary amenorrhea.

Environmental factors

Any surgical intervention on the pelvic organs - removal of ovarian cysts, hysterectomy - can damage the ovaries, probably affecting their blood supply or causing inflammation in the surrounding tissues. The risk of developing ovarian failure for most routine operations is low. Surgeries on more distant organs, such as the appendix, do not damage the ovaries - although the associated infection can cause infertility by forming adhesions between the fallopian tubes and surrounding organs.

As more and more women survive childhood cancers and leukemias, we believe that chemotherapy and radiation therapy may be a cause of POF. This group of women is offered cryopreservation of ovarian tissue before chemotherapy.

Autoimmune reactions

Examples of endocrine and autoimmune disorders combined with ovarian failure are hypothyroidism, adrenal insufficiency (Addison's disease), and type 1 diabetes. Autoimmune damage to the ovaries can also be isolated, with the remaining glands intact.

It is of interest to search for autoimmune markers that predict the development of ovarian failure. With timely initiation of immunosuppressive therapy, the development of complete ovarian failure can be prevented. A few pilot studies suggest that treatment with prednisone may reverse the development of ovarian failure in some women.

Toxins and viruses

Most women with premature ovarian failure have no family history, chromosomal abnormalities, or signs of autoimmune disorders. We can assume that there are environmental factors at play that may have acted in the past. It is known that in men, some viruses, in particular, can cause inflammation of the gonads, causing infertility. There is a popular point of view about the general population deterioration of spermogram parameters due to the recent increased impact on the testicles of harmful environmental factors, toxins and medications. It is likely that the ovaries are also susceptible to the adverse effects of toxins or viruses.

Diagnosis of ovarian failure

The diagnosis of ovarian failure is made by measuring and, the level of which in the blood increases, and estrogen, whose level, on the contrary, decreases. The most sensitive of these indicators is the rise in FSH, which is the best early marker of ovarian failure. Pregnancy is extremely unlikely if FSH is 2 times higher than normal (20 U/L in sryu with 10 U/L). In reality, FSH increases in the second half of reproductive life in parallel with a decrease in fertility - after 30 years.

The first subjective symptom of ovarian failure is amenorrhea. There are many reasons for the cessation of menstruation: weight loss, many hormonal disorders, but ovarian failure is the only cause of amenorrhea, accompanied by an increase in LH and FSH levels and a decrease. In addition to amenorrhea, a decrease in estrogen levels in the blood leads to symptoms such as hot flashes, mood changes, and vaginal dryness - these symptoms are not specific to premature menopause.

In most cases, the hormonal status characteristic of menopause means a clear and irreversible diagnosis. Sometimes, however, the phase of decreased ovarian activity is temporary and they return to their original functional activity. For this reason, repeat hormone measurements after a few weeks are necessary to make a diagnosis of premature menopause. Next, it is useful to monitor FSH levels at 1-month intervals to determine the degree of ovarian activity. Any attempts to achieve pregnancy should be made during those time intervals when FSH levels drop to normal values. Over time, the likelihood of the ovaries returning to a normal level of functional activity decreases, although spontaneous pregnancies rarely occur against the background of long-term PMN. The mechanisms of this reversion are unknown, and it is not known how to increase their likelihood with drugs.

The usefulness of ovarian biopsy is debated. Some clinics prefer a biopsy to an ultrasound. Ultrasound is able to identify the ovaries in 2/3 of women with POF, and during biopsy only 10-15% of women can detect ovarian tissue. The appearance of the ovaries today is not given much importance - the best looking ovaries will not allow the egg to mature if they do not respond to FSH stimulation and if its level is constantly high.

Prognosis for PYN

The process of menopause - natural or premature - varies over time. For some women, the regular menstrual cycle suddenly stops abruptly; for others, the transition from normal menstrual function to full menopause lasts for years with fluctuations in ovarian activity. Rarely, partial suppression of ovarian function occurs - partial, but permanent, without progression to full menopause - this condition is accompanied by a rise in FSH levels and infertility and is characterized as resistant ovarian syndrome.

After no menses for 6 months and a diagnosis of premature ovarian failure, less than 1% of women can achieve pregnancy in our experience. Spontaneous pregnancy is never impossible, but it is extremely unlikely. Certain criteria increase the chances of spontaneous pregnancy: fluctuations in FSH levels, detection of ovaries on ultrasound, association with autoimmune disorders or chemotherapy.

For young women with ovarian failure, not only the problem of infertility is relevant, but also years of life with HRT. Women with long-term estrogen deficiency have an increased risk of cardiovascular disease, but a lower risk of thrombosis. A comparative analysis still leans towards greater benefit and lower risk of long-term HRT. However, in each case the issue is resolved individually.

Translation by Malyarskaya M.M.

The ovaries are important organs of the reproductive system; in women, they regulate the menstrual cycle and also influence the process of conception.

This organ is a pair, located in the upper part of the uterus at the head of the fallopian tubes. There are two types of pathology: primary and secondary.

In the first case, the cause of the disease lies in deviations and dysfunction of the ovaries themselves. In the second case, the deficiency is a consequence of hormonal dysfunction. The causes of primary ovarian failure, symptoms, diagnosis and treatment will be discussed further.

Primary failure is determined by the cessation of menstruation, as well as its irregular cycle.

This is a huge problem for women of reproductive age, since the exhaustion of the ovaries does not allow the production of eggs, which prevents conception.

Most often, pathology occurs in those women who experience constant stress and also lead an unhealthy lifestyle.

However, recently cases have become more frequent when a completely healthy woman develops primary ovarian failure.

Depending on the initial cause of the pathology, there are several types of ovarian failure:

1. Gonadal dysgenesis– pathology assumes the presence of aggressive factors, under the long-term influence of which the structure of the ovarian body is modified, which affects its functionality. These can be protracted inflammatory processes that have a chronic course.
2. Early gonadal wasting syndrome– the diagnosis involves the impact of several aggressive factors on the genitals at once (trauma, frequent surgical interventions, hormonal dysfunction, radiation). As the pathology progresses, the woman gradually loses the ability to become pregnant, as the cycle becomes anovulatory.
3. Gonadal resistance– a completely healthy ovary produces the required number of follicles from which eggs could ovulate, but the hormonal system does not perceive this process, so eggs cannot be fully produced. Gradually, reproductive function fades away, and after 2-3 years menopause begins, which is characterized by the complete cessation of menstruation, as well as a decrease in ovarian activity.

Ovarian insufficiency can occur not only in mature women. There are more and more cases when girls aged 18-25 are faced with this problem, when they are unable to conceive a child for more than a year.

Causes of pathology

Among the most common causes that provoke the development of ovarian failure are:

1. Autoimmune diseases – a malfunction occurs in the body when the body’s immune cells perceive hormones as foreign and threatening cells, destroying them. The result is a hormonal imbalance that prevents the ovaries from working properly.
2. Injuries to the ovaries and pelvic organs as a result of falls, impacts, compression, and surgical operations.
3. Inflammatory processes of the genital organs, which occur in a chronic form, causing damage to the integrity of the ovarian tissue, which deprives it of normal functioning.
4. Abuse of medications that affect the hormonal system, especially the genitals.
5. Genetic abnormalities that arise at the stage of formation of the gonads during intrauterine development.

The disease takes on a particularly rapid course in cases where not one factor, but several at once, has a detrimental effect. In just 3-4 months, a woman can lose her ability to reproduce, although no complaints about her own health appear.

Germ cell tumor of the ovary is a dangerous malignant neoplasm. Follow the link for information on methods of diagnosing and treating this insidious disease.

Symptoms of ovarian failure

For different stages of ovarian failure, the diseases and underlying causes have distinct symptoms.

However, the following generalized clinical picture can be identified:

1. Change in the nature of vaginal discharge - the discharge is more scanty and does not change in consistency throughout the entire cycle.
2. Itching and dryness of the vagina, which is explained by a change in the composition of the secretion produced.
3. Decreased sex drive, which is explained by sudden changes in emotional state (due to problems with hormones).
4. Frequent migraine-type headaches that occur after experiencing stress.
5. Poor health in the absence of illnesses. Poor sleep, constant feeling of anxiety for any situation.
6. Increased sweating, as well as a feeling of hot flashes, which increases in the genital area and spreads throughout the body.
7. Failure of the menstrual cycle, in which menstruation does not come constantly.
8. Amenorrhea is the premature cessation of menstruation caused by dysfunction of the ovaries and the entire hormonal system.
9. Oligomenorrhea - menstruation comes more than twice a month, while the cycle is noticeably shortened to 10-15 days.
10. Uncharacteristic behavior with attacks of aggression.
11. Changes in the skin of the body, its dryness and lethargy.

It is not necessary for everyone to experience these symptoms. It is enough that the cycle is disrupted, due to which the woman is not able to get pregnant.

Even small deviations from the schedule, delays or shortening of the cycle should serve as a reason for consultation with a specialist.

Diagnostics

After an initial examination by a gynecologist, as well as a medical history, the woman is offered to undergo a series of studies that will help make a correct diagnosis, as well as determine the cause of the pathology.

Diagnostic measures include laboratory and instrumental studies.

To do this, resort to the following manipulations:

1. Ultrasound of the genital organs - intravaginal ultrasound is most often used, which allows you to examine the ovaries in more detail, assess their performance on a specific day of the cycle, and also identify changes in their shape and structure.
2. Determination of autoimmune disorders in the body by identifying antibodies that can suppress hormones.
3. Laboratory examination of blood for hormones, including the reproductive system.
4. Determination of karyotype, which allows diagnosing the presence of genetic abnormalities.

Typically, diagnosis takes from a month to six months, so it is better to undergo it with one specific doctor who can evaluate and monitor the dynamics. In some cases, ovarian puncture may be required, through which the qualitative composition of the organ tissues is assessed.

Treatment of the disease

Before deciding on treatment, it is important to fully examine the woman, as well as identify the root cause of the deficiency. The main goal of treatment is to normalize hormonal levels, as well as stimulate the ovaries. Treatment involves a whole range of measures, so it may take more than one month.

They use drugs such as:

1. Hormones that replenish the deficiency. Selected in accordance with test results. Blood levels are constantly monitored through weekly blood donations.
2. Vitamin and mineral complexes are designed to strengthen the body, as well as normalize the functioning of all organs and systems.
3. Secondary treatment is aimed at eliminating the inflammatory process in the genital organs, which can also contribute to the development of the anovulatory cycle and amenorrhea.

It is important to begin treatment of ovarian insufficiency as early as possible, since delaying the problem for a long time reduces the chances of restoring reproductive function.

The absence of menstruation precedes the absence of ovulation, but the problem is not only the inability to conceive a child. When hormones don't work properly, the entire body suffers. The woman feels bad, and the aging process accelerates significantly.

The appearance of deep wrinkles by the age of 30, weakness, and depression are only the first manifestations of ovarian failure, which modern medicine has learned to combat.

Ovarian hypofunction and IVF

Since ovaries that are not working properly do not contribute to the maturation of follicles with eggs, the only way out if you want to get pregnant is in vitro fertilization (IVF).

This procedure can help a woman become pregnant and bear a healthy child.

It is produced in several stages:

1. Preparatory – the woman is fully examined, and the chances of a favorable pregnancy are assessed.
2. Hormone therapy - hormones are artificially introduced into the body, which stimulate the ovaries to produce as many follicles with eggs as possible.
3. Collection of donor material - germ cells are collected from the couple: eggs and sperm, examining them for the presence of pathologies at the DNA level.
4. Artificial insemination - under artificial conditions, the sex cells of a man and a woman are combined and then placed in a special chamber where active cell division occurs.
5. Examination of the embryo - the resulting zygote is examined for pathologies, after which only the strongest and healthiest embryos are isolated.
6. Transfer - an embryo is introduced into the uterine cavity, after which they wait 2 weeks, during which it will be decided whether the embryo will take root or not.

But even with IVF there is not always a chance of getting pregnant. Therefore, with such a pathology, you should not despair, but try to conceive a child again and again. The world knows miracles that science cannot explain. Infertile couples who were treated for years gave birth to healthy children, contrary to all the laws of medicine. In this case, you need to hope only for the best, and also not ignore the doctor’s recommendations.

Video on the topic

Ovarian insufficiency is a pathological condition that occurs in women of childbearing age.

The disease is characterized by the fact that the ovaries do not produce the required amount of estrogens, resulting in a disruption in the production of eggs and ovulatory function. Under such conditions, conception and pregnancy are impossible, which is why ovarian failure is considered one of the most common causes.

Ovarian failure may be physiological in origin. This means that the decline of ovarian function occurs due to natural age-related changes and the onset of menopause. In other cases, we will be talking about pathological ovarian failure, when disorders occur in women of childbearing age. In this case, ovarian failure can occur in the following forms:

• resistant ovarian syndrome- a pathology in which the ovaries contain an adequate number of follicles, but they do not develop fully due to their immunity to the effects of hormones. As a result, ovulation does not occur in the woman’s body;
• exhausted ovarian syndrome- sometimes in fairly young women, ovarian function may fade prematurely. This usually occurs due to hereditary predisposition, various diseases, as well as previous surgical operations in the ovarian area.

Causes of ovarian failure

You should know that ovarian failure can develop under the influence of quite a number of factors, although it may not be easy to pinpoint the exact cause. Often this pathological condition is a consequence of radiation or chemotherapy. Primary ovarian failure can develop due to:

• when the fetus was exposed to various negative factors;
• hormonal imbalance in the body of a woman carrying a girl;
• infectious diseases of the mother during pregnancy;
• genetic diseases.

Secondary ovarian failure can occur for even more reasons:

• anorexia, in which menstruation stops completely;
• deficiency of vitamins and nutrients;
• nervous tension, frequent stress;
• tuberculosis of the genital organs;
• chronic inflammatory diseases of the uterine appendages;
• head injuries in which damage to the pituitary gland or hypothalamus occurred;
• disturbance of blood flow in the cerebral arteries.

Manifestations of the disease

If you have ovarian failure, you may experience typical symptoms that accompany the onset of menopause:

• or lack thereof;
• hot flashes;
• increased sweating, especially at night;
• vaginal dryness;
• increased irritability;
• mood swings;
• decreased libido.

We recommend that you do not delay your visit to our clinic if you have been observing similar clinical manifestations for several weeks. Our specialist will prescribe a series of studies that will determine the cause of the pathology and prescribe adequate treatment.

Possible complications

Timely treatment of ovarian failure is indeed very important, because such a condition is fraught with a number of serious complications, one of which is infertility. In addition, women with this disease have an increased risk of developing osteoporosis due to decreased levels of estrogen in the body. A lack of this hormone also contributes to depression, constant feelings of anxiety and bad mood.

Diagnostics and treatment in our clinic

After the initial examination and collection of your detailed medical history, the doctor will ask you to undergo a series of tests that will identify ovarian failure and its possible causes. The list of necessary studies may vary depending on individual indications, but, as a rule, it includes the following diagnostic procedures:

• measuring basal temperature and charting it;
• hormonal blood tests;
• diagnostic laparoscopy.

Since the main cause of ovarian failure is usually a deficiency of estrogen in your body, the pathology is treated with hormonal therapy. Additionally, as a preventative measure for osteoporosis, our doctor may prescribe calcium and vitamin D supplements. In most cases, timely treatment can eliminate disorders and completely restore reproductive function.

Primary ovarian failure

Primary Ovarian Insufficiency

L.M. Nelson

N Engl J Med 2009;360:606-612

Abstract. A 30-year-old woman presented with absence of menstruation for 6 months after she stopped taking combined oral contraceptives (COCs) to become pregnant. Puberty was normal, menarche began at 12 years of age. Since the age of 18, she has been using COCs to regulate the menstrual cycle. Notes high stress loads at work. Weight 59 kg, height 1.66 m, body mass index - 21.3. She had no manifestations of galactorrhea, hirsutism or acne. Ultrasound of the pelvic organs is unremarkable, pregnancy test is negative, prolactin level is normal, FSH level is in the menopausal range. How to manage such a patient and what treatment to prescribe?

The ovary is a unique endocrine system in which a new secretory structure, the graafian follicle, appears monthly, which develops from a microscopic primordial follicle. Menopause is the cessation of menstruation as a result of the natural depletion of potentially functional primordial follicles. The average age of menopause is 50+4 years. Menopause occurring before age 40 is considered premature.
The term “premature ovarian failure” (POI) is currently used to define a condition that was previously characterized as premature menopause, premature ovarian failure, secondary hypogonadal gonadism, etc. The clinical characteristics of this condition are amenorrhea  4 months in women under 40 years of age, infertility and an increase in FSH levels to menopausal values ​​(twice with an interval of at least 1 month). POI differs from premature menopause in the “unpredictability” of ovarian function, since in approximately 50% of cases its resumption is possible, and in 5-10% of women pregnancy and childbirth may occur after this diagnosis. Thus, this term, proposed back in 1942 by F. Albright., characterizes the dysfunction of the ovaries “in dynamics” (continuum), and not the “final” state, which was assumed when using previously proposed terms.
The frequency of spontaneous ovarian failure in women with chromosome 46 XX is about 1%, while epidemiological studies indicate a close connection of this disorder with age. Thus, in women under the age of 20, POI occurs with a frequency of 1:10,000, and in women between the ages of 30 and 40 - 1:1000.
The reasons leading to the development of POI are very heterogeneous: genetic, enzymatic, autoimmune, infectious-toxic, iatrogenic, psychogenic, as well as defects in the structure of gonadotropins. In recent years, much attention has been paid by researchers to the molecular genetic aspects of this ovarian pathology, since a certain set of genes has been identified that may be responsible for the development of POI. The formation of a complete or partial (pre) mutation in them contributes to the development of clinical symptoms of ovarian failure, an example of which is the premutation of the FMR1 gene (located in the Xq26-28 region), which promotes accelerated apoptosis of the follicular pool. In women with sporadic forms of POF, the frequency of FMR1 gene premutation ranges from 0.8 to 7.5%, while in familial forms of the disease it can reach 13%. It has been shown that women carriers of the FMR1 gene premutation suffer from oligomenorrhea much more often (38%) compared to population data (6%). Syndromes, one of the clinical manifestations of which is POF, include
autoimmune polyglandular syndrome (AIRE - autoimmune regulator), hereditary adrenal hyperplasia as a result of 17α-hydroxylase deficiency (CYP 17A1), aromatase deficiency (CYP 19A1), etc.
The presence of two possible pathogenetic mechanisms of POI is assumed:
dysfunction of the follicles means that they are present in the ovaries, but some pathological process disrupts their normal functioning (extremely rare signaling defects - mutations of the FSH or LH receptors; isolated deficiency of enzymes (17,19-hydroxylase or aromatase); autoimmune oophoritis; luteinization of the antrum follicles.
depletion of the pool of primordial follicles, for example, in Turner syndrome (a child is born with a normal chromosomal complement and number of follicles, but which are almost completely depleted by puberty due to accelerated apoptosis; the only gene responsible for the development of this syndrome has not been identified).

Clinic.
In most cases, POI develops in women with normal puberty and timely menarche. More often, a harbinger of the onset of amenorrhea is oligomenorrhea, polymenorrhea or dysfunctional uterine bleeding. Less commonly, menstruation stops suddenly, for example, does not return after childbirth or after stopping hormonal contraceptives. Characteristics of menstrual function include amenorrhea for 4 months or more, possibly alternating with an irregular menstrual cycle (oligo-, poly- and metrorrhagia) against the background of menopausal FSH values. Many women develop symptoms of estrogen deficiency (hot flashes, hyperhidrosis, sleep disturbances, dyspareunia due to vaginal dryness), but not all. In some patients, estrogen production is sufficient to ensure that there are no clinical manifestations, and vaginal examination does not reveal changes characteristic of estrogen deficiency.

Diagnostics.
Clear diagnostic criteria for POI have not been defined. The doctor is faced with the question of the cause of secondary amenorrhea. There can be many such reasons: severe diabetes mellitus, stressful events, excessive physical activity, chemotherapy, galactorrhea due to hyperprolactinemia, hyperandrogenism, etc. The most common causes of secondary amenorrhea are polycystic ovary syndrome, hypogonadotropic amenorrhea, hyperprolactinemia and primary ovarian failure.
Although POI occurs mostly sporadically, an unfavorable family history is identified in 10-15% of cases. Therefore, when collecting a family history, it is necessary to pay special attention to the age of switching off ovarian function in representatives of the 1st and 2nd degree of kinship, both on the maternal and paternal side (mother, grandmother, aunt, cousin). Due to the importance of the premorbid background in the genesis of the development of POI, it is necessary to clarify viral infections suffered during puberty (mumps and rubella), as well as autoimmune diseases of endocrine and non-endocrine origin (thyroiditis, rheumatoid arthritis, collagenosis, myasthenia, etc.), which can indicate autoimmune polyglandular syndrome.
Physical examination may reveal hyperpigmentation or vitiligo, indicating possible autoimmune adrenal insufficiency, enlarged thyroid gland, and the well-known stigmata of Turner syndrome (short stature, short neck, pterygoid folds, etc.). If menstruation has not resumed after pregnancy, it is necessary to study the levels of prolactin, FSH and TSH. If amenorrhea occurs after stress, so-called “hypothalamic” amenorrhea, FSH levels will be low or normal. If FSH levels correspond to menopausal values, the study should be repeated after a month, along with measuring estrogen levels. The so-called “progesterone” test, which is recommended for the differential diagnosis of amenorrhea, should not be performed. Up to 50% of women with POI will “respond” with menstrual-like bleeding due to sufficient estrogen saturation despite menopausal FSH levels, and this testing will only delay diagnosis.
Necessary genetic testing includes karyotyping, testing for FMR1 premutation in first-degree relatives, and 21-hydroxylase immunoprecipitation (CYP21) testing for adrenal disorders. Antibodies to the adrenal glands are detected in 4% of cases. In such women, as a rule, autoimmune disorders are detected in relation to cells that produce steroid hormones, including autoimmune oophoritis, which is the cause of ovarian failure. Ovarian antibodies have low specificity, so their determination is not recommended.
Densitometry is necessary given the high risk of osteoporosis.
When performing an ultrasound, the ovaries are large in size with multiple follicles, and partial ovarian torsion may be observed. A biopsy of ovarian tissue is also not recommended, since this study does not provide anything for diagnosis and prognosis: even the complete absence of follicles does not guarantee subsequent pregnancy.

Recommendations.
The announcement of the diagnosis to the patient is usually accompanied by severe emotional distress, and even in the absence of hot flashes, anxiety disorders and depression, as a consequence of estrogen deficiency, these symptoms can occur, especially if the woman has not achieved reproductive function.
It is known that early menopause is accompanied by an increased risk of fractures due to osteoporosis, cardiovascular diseases and overall mortality/mortality from coronary artery disease. According to the updated recommendations of the International Menopause Society (2008), to prevent these diseases, patients should be offered HRT at least until the age of natural menopause (51 years). While there is no consensus on the most appropriate type of HRT for these women, in the absence of better data, these patients should be offered drugs tailored to their individual risk factors that are well tolerated as long-term use is expected.
As is known, the level of estrogen in women of reproductive age is, on average, 100 pg/ml; the administration of transdermal estradiol at a dose of 100 g per day creates approximately the same concentration of estrogen and at the same time effectively relieves the symptoms of estrogen deficiency; progestogen is necessary to protect the endometrium, is selected individually and prescribed for at least 12-14 days a month (dydrogesterone, utrozhestan in standard dosages or progesterone gel 100-200 mcg/day

.). There is evidence that the effect on the endometrium of micronized progesterone in combination with the dose of estrogen required for complete replacement in young women may be insufficient. If the clinical picture is dominated by an estrogen-deficient state (weakness, asthenia, hypotension, decreased libido, pain in bones and joints, osteoporosis), preference should be given to drugs with a gestagenic component - derivatives of 19-nortestosterone, which have a weak androgenic effect.
Elimination of psychoasthenic syndrome, depression, and sexual dysfunction caused by androgen deficiency significantly improves the quality of life and also serves as an effective prevention of osteoporosis.
One should remember about the possibility of pregnancy, so patients must keep a menstrual calendar and conduct a pregnancy test in case of delayed MPR due to HRT. The use of COCs is not advisable for a number of reasons: firstly, these drugs contain more hormones than these women need for the purpose of hormonal replacement; secondly, the treatment is long-term, so drugs with natural estrogens are preferable.
Due to the high risk of osteoprorosis, densitometry should be performed and the patient should be given recommendations necessary to maintain bone health. Calcium intake with food 1,200 mg per day and vit. D from 800 to 1,000 units, especially in case of insufficient insolation. Recommended physical exercises: brisk walking, running (in the absence of osteoporosis). Use of bisphosphonates in young women with POF. for the prevention of osteoporosis is inappropriate for a number of reasons: they can not only reduce the processes of bone tissue destruction, but also slow down the processes of bone formation; we must not forget about the importance of the beneficial effects of estrogens on the cardiovascular system; these women may become pregnant, and these drugs have a long period of elimination from the bones, so the effect on the fetal skeleton has not been studied. If osteoporosis is diagnosed, there is a wide range of drugs that can be used in combination with HRT. A balanced diet is also recommended, as the risk of developing obesity increases, annual screening for CVD risk factors (levels, lipid profiles, fasting glucose levels, etc.)
Associated disorders. According to various sources, autoimmune thyroiditis is detected in 14-27% of women (usually Hashimoto’s goiter), so it is necessary to conduct a study of thyroid function and a test for thyroid peroxidase antibodies. If the test for adrenal antibodies and 21-hydroxyldase immunoprecipitation is negative, there is no need to repeat them, but it is necessary to monitor the condition and repeat the test if symptoms of adrenal insufficiency appear.
Forecast. There are no markers that would make it possible to judge the chance of remission and restoration of fertility, just as there are no sufficiently effective methods for restoring ovarian function and fertility. If pregnancy is not necessary, use barrier methods of contraception or an IUD. If pregnancy is necessary - ART (donor egg donation).

Premature ovarian insufficiency (POI), also known as primary ovarian failure, premature menopause, hypergonadotropic hypogonadism, is the loss of ovarian function before the age of 40. At presentation, the diagnosis is usually characterized by the presence of amenorrhea, hypergonadotropism and hypoestrogenemia. If the cause of the disease is a genetic factor, then the disorder may be called gonadal dysgenesis.

Story

In 1942, Fuller Albright and colleagues first reported a syndrome in young women characterized by follicle-stimulating hormone (FSH) levels that correspond to menopausal levels, low estrogen levels, and amenorrhea. They called this condition "primary ovarian insufficiency" in order to differentiate this condition from secondary ovarian insufficiency, which develops when the pituitary gland fails to produce FSH. Chapter 28 of a work on gynecology written at the beginning of the Qing dynasty describes the cause and appropriate treatment of premature menopause.

Incidence/prevalence

Manifestation

On average, the ovaries supply a woman's body with ovaries until she is 51 years old; This age is considered the average age of menopause. POI is not the same as natural menopause, as ovarian dysfunction, loss of eggs, or removal of ovaries at a young age is not a normal physiological phenomenon. Infertility is a result of this condition and is the most discussed problem caused by this disease, but there are also other health consequences; Research in this regard is ongoing. For example, almost all women in POI have osteoporosis or low bone density caused by estrogen deficiency. There is also an increased risk of developing cardiovascular disease, hypothyroidism in the form of Hashimoto's thyroiditis, Addimon's disease and other autoimmune disorders. In hormonal terms, POI is defined as abnormally low estrogen levels and high FSH levels, demonstrating the fact that the ovaries are no longer responding by producing estrogen and fertile eggs from circulating FSH. The ovaries appear to become shriveled. The onset of the disorder may occur during adolescence, and sometimes signs are detected at birth, but the onset rate of the disorder varies greatly. If a girl has never started menstruating, the condition is called primary ovarian failure. 40 years of age is considered to be the so-called cut-off point for diagnosing POI. This age was chosen somewhat arbitrarily because all women experience a decline in ovarian function over time. However, age had to be selected in order to differentiate normal menopause from the abnormal condition of premature menopause. Premature ovarian failure has a number of characteristics that help differentiate it from normal menopause. By age 40, approximately one percent of women suffer from POI. These women typically experience menopausal symptoms that are more severe than those experienced by older menopausal women.

Reasons

The cause of POI is usually idiopathic. Some cases of POI are related to autoimmune disorders, such as Turner syndrome or Martin-Bell syndrome. A study conducted in India showed a clear correlation between the incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation therapy for cancer can sometimes lead to ovarian failure. During natural menopause, the ovaries usually continue to produce low levels of hormones, but during POI caused by chemotherapy or radiation therapy, the ovaries usually stop producing hormones completely, so in such cases, women's hormone levels are comparable to those with the ovaries removed. Women who have a hysterectomy typically experience menopause several years earlier than middle age, which is likely due to decreased blood flow to the ovaries. Family history as well as ovarian or pelvic surgery are risk factors for POI. There are two main types of premature ovarian failure. First case: there is little or no remaining follicles; second case: there is an excess number of follicles. In the first situation, causes include genetic disorders, autoimmune disorders, chemotherapy, radiation therapy to the pelvis, surgery, endometriosis and various infections. In most cases, the specific cause is not known. In the second situation, the most common cause is an autoimmune ovarian disease that affects the maturation of follicles, leaving the primordial follicles intact. In addition, in some women, FSH may bind to the FSH receptor site while remaining inactive. By reducing endogenous FSH levels with ethinyl estradiol (EE) or GnRH analogues, the receptor sites become unoccupied, and treatment with exogenous recombinant FSH activates the receptors and normal follicular growth, which promotes ovulation. (Because serum anti-Mullerian hormone (AMH) levels correlate with the number of remaining primordial follicles, some researchers believe that more than two phenotypes can be distinguished by measuring serum AMH levels.)

Genetic disorders;

Autoimmune diseases;

Tuberculosis of the genital tract;

• Radiation therapy or chemotherapy;

  Ovarian disorders followed by hysterectomy;

  Long-term therapy with GnRH (gonadotropin-releasing hormone);

  Enzyme disorders;

  Ovarian resistance;

  Induction of multiple ovulation in infertility.

Notes

Mutations in FOXL2 cause blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). Premature weakening of the ovaries refers to BPES type I, and if there is no weakening of the ovaries, then we are talking about BPES type II.

Laboratory

Measurements of serum follicle-stimulating hormone (FSH) alone can be used to diagnose the disease. Two FSH measurements one month apart are common practice. The anterior pituitary gland releases FSH and LH at high levels due to ovarian dysfunction, then causing low estrogen levels. Typical FSH levels in patients with POI are greater than 40 mIU/mL (similar to postmenopausal levels).

Fertility

About 5-10 percent of women with POI can become pregnant spontaneously. To date, no effective treatment for infertility in women with POF has been studied; The use of eggs as part of in vitro fertilization (IVF) has become quite popular; in addition, child adoption has become popular among women with POF. Some women with POI prefer to live without children. Currently, fertility researchers in New York are studying the use of the mild hormone dehydroepiandrosterone (DHEA) in women with POI to increase the likelihood of spontaneous pregnancy. Published research on DHEA has shown that DHEA may increase the likelihood of spontaneous pregnancy, reduce the likelihood of spontaneous miscarriage, and increase the success rate of IVF in women with POI. Additionally, over the past five years, a Greek research group has successfully introduced the use of dehydroepiandrosterone (DHEA) to treat infertility in women suffering from POI. Most patients sought donor eggs or surrogacy, however, after a few months of using DHEA, some managed to become pregnant through IVF, IUI, VMTPO or natural conception. Many children have been born after treatment with DHEA. Cryopreservation of ovarian tissue can be performed in prepubertal girls who are at risk of premature ovarian failure; The procedure is considered to be as safe as other comparable procedures in children.

Hormone replacement therapy

It is important to initiate hormone replacement therapy after diagnosis of POI, as untreated patients are at high risk of bone loss due to increased osteoclast activity, leading to osteopenia and osteoporosis. In addition, most patients develop symptoms of estrogen deficiency, including vasomotor hot flashes and vaginal dryness, which are effectively treated with estrogen therapy. There are several contraindications to estrogen use, including smoking after age 35, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of thromboembolism. If the patient's family members have a history of thromboembolism, hormone replacement therapy should be initiated with caution. A transdermal estradiol patch (usually 100 mcg) is recommended for use. It provides replacement through sustained delivery rather than through single dosages of daily pill use. This also avoids the first pass effect in the liver.

In culture