The follicle does not mature to the required size for a reason. Why doesn't he ripen? Why the follicle does not mature - reasons

Amenorrhea:

Amenorrhea can be primary or secondary. This classification does not say anything about the cause of amenorrhea, since both forms can be a consequence of the same disorders. Primary amenorrhea is defined as the absence of menstruation by age 16. In 35-40% of cases, its cause is primary ovarian failure or dysgenesis of the genitourinary organs.
Secondary amenorrhea is at least four months of absence of menstruation in women with a history of at least one spontaneous menstrual cycle.

Primary amenorrhea:

The second most common cause of primary amenorrhea is Müllerian duct dysgenesis, characterized by congenital underdevelopment of the fallopian tubes, uterus and/or vagina.
An example is Rokitansky-Küster-Hauser syndrome with vaginal aplasia, a rudimentary uterus and normal fallopian tubes. With Müllerian duct dysgenesis, ovarian function is not affected, and therefore levels of gonadotropins and sex steroids remain normal. Diagnosis is based on anatomical features, imaging studies, and hysteroscopy; Diagnostic laparoscopy is sometimes required.

Primary amenorrhea occurs when body weight lags significantly behind height. The importance of body weight for the normal development of the hypothalamic-pituitary-ovarian axis is emphasized by the hypothesis of critical body mass. According to this hypothesis, menstruation begins only at a certain ratio between body weight and height. Primary amenorrhea may also be based on a number of congenital or acquired defects of the hypothalamic-pituitary system with impaired hormonal regulation (similar to what occurs in men).

Secondary amenorrhea:

Even if there is another reason, it must be remembered that pregnancy can occur against the background of amenorrhea. This is often observed in cases of hyperprolactinemic amenorrhea.

Rarely, amenorrhea develops due to uterine adhesions(Asherman's syndrome), leading to obliteration of the uterine cavity. The cause of Asherman's syndrome is usually an infected abortion or intensive curettage, but it can also be a consequence of nonspecific or tuberculous endometriosis. Diagnosis requires careful consideration of medical history. Asherman's syndrome should be suspected if normal levels estradiol and progesterone in the luteal phase or when amenorrhea persists after hormonal stimulation.

The diagnosis is made based on the results of hysteroscopy or hysterosalpingography.

Treatment involves the elimination of uterine adhesions followed by the induction of pseudo-pregnancy with the help of estrogens and progesterone. To prevent the formation of new adhesions as the endometrium regenerates, intrauterine devices are used.

In all other cases, the cause of secondary amenorrhea is either dysfunction of the hypothalamus and pituitary gland, or ovarian failure.

Hypothalamic amenorrhea:

A common cause of lack of menstruation is hyperprolactinemia. And in these cases, amenorrhea is an extreme manifestation of pathology. Much more often there is inadequacy of the luteal phase and anovulation with normal menstrual bleeding. In case of hyperprolactinemia, pituitary adenoma or hypothyroidism should be considered.

An important cause of impaired follicular maturation and thus amenorrhea is polycystic ovary syndrome (PCOS syndrome). This is the first thing to think about when examining an obese woman with symptoms of hyperandrogenism and a typical (described above) ultrasound picture. The so-called PCOS syndrome, or Stein-Leventhal syndrome, is only the final stage in the development of a whole group of various pathological processes, manifested by a violation of the cyclic function of the ovaries, an increase in the androgen/estrogens ratio and a change in the LH/FSH balance.

In addition to the three listed common reasons There are also more rare causes of secondary amenorrhea: tumors and cysts of the hypothalamus, as well as infiltrative processes in the hypothalamus and pituitary gland (tuberculosis, sarcoidosis or histiocytosis X), however, these forms of pathology are extremely rare even in specialized centers.

Dysfunction of the hypothalamic-pituitary axis is relatively easy to treat, but primary ovarian failure with atresia of the primordial follicles and absolute loss of eggs requires the use of donor eggs. In countries where this is prohibited by law, assistance to such patients usually ends with a diagnosis. Premature ovarian failure is the loss of ovarian function before the age of 35. This may be due to chemotherapy or radiation, as well as immunological reasons.

Hyperprolactinemia:

Unlike the secretion of other pituitary hormones, the secretion of prolactin is regulated by the hypothalamus through an inhibitory factor. The main inhibitor is dopamine. In experiments on rats, infusion of dopamine against the background of preliminary blockade of its endogenous synthesis inhibits the secretion of prolactin by 70%. The second inhibitory factor, although weaker, is γ -aminobutyric acid(GABA).

A number of substances that stimulate the secretion of prolactin have also been discovered. These include thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP) and angiotensin. Serotonin precursors also enhance the secretion of prolactin, and blockade of serotonin synthesis inhibits its secretion. Endogenous opioids increase the secretion of prolactin, inhibiting the synthesis and reducing the secretion of dopamine. Histamine and substance P stimulate prolactin secretion, but the mechanism of their regulatory effects is not precisely known.

Causes of hyperprolactinemia:

Pituitary adenomas are found in approximately one third of women with secondary amenorrhea. If amenorrhea is accompanied by galactorrhea, then anomalies of the sella turcica are found in 50% of cases. Infertility in such patients is more closely related to prolactin levels than to tumor size, except, of course, in extreme cases.

Prolactinoma is accompanied by an increase in the concentration of dopamine in the hypothalamus, which inhibits the secretion of GnRH and, accordingly, gonadotropins. The latter is the basis of anovulation. In such cases, it is necessary to either remove the adenoma or reduce the concentration of prolactin using specific inhibitors.

Because the typical symptoms do not develop in all cases of hyperprolactinemia, determination of the concentration of prolactin in the serum is a mandatory diagnostic test when determining the female factor of infertility.

It is best to take a blood sample during basal metabolic conditions, in the early morning hours. Since this is not always possible, when evaluating the results obtained, it is necessary to take into account circadian rhythm hormone and the woman’s condition at the time of taking a blood sample. Detected hyperprolactinemia should be confirmed by repeat analysis. Serum prolactin levels exhibit dramatic fluctuations associated with various physiological stimuli, such as eating and sleeping patterns, stress, and physical activity. It is also necessary to consider the possibility of taking prolactin-stimulating drugs.

For mild or moderate hyperprolactinemia (less than 50 ng/ml), TSH should be determined in the same blood sample before starting treatment. Its level below 3 µU/l allows us to exclude hypothyroidism. Otherwise, treatment with thyroid hormones may be indicated. If the prolactin level is more than 50 ng/ml (in the absence of physiological stimuli for its secretion), it is necessary to x-ray check the condition of the sella turcica.

The probability of detecting a pituitary adenoma in such cases is approximately 20%. When prolactin concentration is more than 100 ng/ml, the probability of adenoma increases to 50%. With more high concentrations prolactin microadenomas are found in almost all patients, and when its levels are more than 1000 ng/ml, the presence of macroprolactinoma is very likely.

The most common pituitary tumors are prolactin-secreting adenomas. These include about 50% of all pituitary adenomas found at autopsy in men and women. Prolactinomas are found at autopsies in 9-27% of deceased people, most often between the ages of 50 and 60 years. There is no difference in the incidence of these tumors in men and women, although clinical symptoms are much more common in women. Hyperprolactinemia in women is diagnosed 5 times more often than in men.

In recent years, approaches to radiology diagnostics Pituitary adenomas have changed. X-ray of the sella turcica reveals only adenomas larger than 10 mm. CT scanning of the pituitary gland in combination with the introduction of radiopaque media can detect tumors measuring about 2 mm. MRI reveals even smaller microadenomas, and this method allows you to exclude a pituitary tumor more reliably than a CT scan. Ophthalmological examination is necessary only for adenomas with a diameter of more than 10 mm.

Empty sella syndrome:

Until recently, it was assumed that excess prolactin directly interferes with the maturation of follicles, causing their atresia and anovulation, and also inhibits the development of the corpus luteum and accelerates luteolysis. All this was shown in experiments on rats, but the possibility of transferring such data to humans remains unclear.

Later, the prevailing point of view was that these changes were caused by changes in the hypothalamus. Hyperprolactinemia appears to develop secondaryly as a result of dysregulatory processes associated mainly with impaired impulse secretion of GnRH. These disturbances affect the secretion of gonadotropins and thereby the maturation of follicles. In rhesus monkeys with hypothalamic damage, pulsed administration of exogenous GnRH normalizes postovulatory plasma progesterone concentrations independent of serum prolactin levels. In women with luteal phase inadequacy, as well as in healthy women, there is no correlation between progesterone and prolactin levels.

Regardless of whether excess prolactin affects follicle maturation directly or indirectly, hyperprolactinemia is undoubtedly a cause of infertility in women and should be eliminated.

Surgical and radiation treatment of hyperprolactinemia:

The results of radiation are even worse, and radiation therapy should be used only for recurrent large tumors that do not respond to pharmacotherapy.

Previously, it was believed that pregnancy contributes to the recurrence of pituitary adenomas, but with microadenomas this is extremely rare. Patients with microadenomas can even be allowed to breastfeed without fear of stimulating tumor growth. With large adenomas, the risk of their further growth during pregnancy increases. Previously, monthly ophthalmological examination and determination of serum prolactin concentration were recommended for microadenomas. Later, the recommendations became less strict, and relevant studies are carried out only when headaches or visual impairment occur.

Since even now neurosurgical intervention during pregnancy is resorted to only when acute symptoms, less stringent recommendations seem justified. However, both the doctor and the patient can feel more confident by adhering to the traditional approach to examinations.

Pharmacotherapy:

Bromocriptine, a lysergic acid derivative, is a dopamine agonist. It inhibits the secretion of prolactin by interacting with its receptors. Depending on the concentration of prolactin, normalization of its level is achieved by taking bromocriptine in the evening at a dose of 1.25 to 2.5 mg. For pituitary adenomas, doses of more than 10 mg per day may be required. Bromocriptine is very effective, but due to adverse reactions not tolerated by all patients. At the beginning of treatment, headaches and nausea often occur. Due to disruption of noradrenergic mechanisms, dizziness in orthostasis may occur.

Slowly increasing the dose minimizes these symptoms. Treatment should always begin with half a tablet in the evening. Every three days the dose can be increased by 1.25 mg to the maximum tolerated. Side effects of bromocriptine occur much less frequently when used transvaginally. Since bromocriptine is absorbed faster and has a weaker effect on the liver, desired effect can be achieved with less daily dose. This method is often used in the clinic.

Treatment with bromocriptine restores regular menstrual cycles in 80% of patients with hyperprolactinemic amenorrhea.

In 50-75% of patients with pituitary adenoma, treatment with dopamine agonists significantly reduces tumor size. With long-term treatment, in 25-30% of cases the tumor disappears altogether. Given this effect, pharmacotherapy for pituitary adenoma should be the method of choice. Transsphenoidal neurosurgery should only be considered when treatment with bromocriptine has not resulted in tumor shrinkage, even if prolactin levels have returned to normal. In such cases, there is apparently a non-functioning tumor that causes hyperprolactinemia simply by compressing the pituitary stalk and preventing the entry of dopamine into it.

During pregnancy, treatment with bromocriptine is usually interrupted. Three large studies have shown that continuation of therapy is not associated with any significant negative consequences for the fetus.

Currently, a number of new inhibitors of prolactin secretion have appeared. Lisuride has greater activity, a longer half-life and is better tolerated by some patients. Therefore, if it is impossible to continue taking bromocriptine, it can be replaced with lisuride.

Metagoline is an antiserotonergic substance that does not act through a dominoergic mechanism. You can try to use it as an alternative remedy.

A new inhibitor of prolactin secretion, carbegoline, has an effect when taken only 1-2 times a week. Early clinical trials show that it is better tolerated than bromocriptine.

For hyperprolactinemia due to dysfunction thyroid gland use thyroid drugs.

Polycystic ovary syndrome (PCOS):

The typical changes in the ovaries, from which the disease gets its name, are also not observed in all cases. Typically the ovaries are 2.8 times enlarged and surrounded by a smooth pearly white capsule. The number of primordial follicles does not change, but the number of maturing and atretic follicles doubles, so that each ovary contains from 20 to 100 cystic follicles visible through the capsule. The shell is approximately 50% thicker than normal. The volume of chyle cells is increased 4 times; the cortical and subcortical layers of the stroma are expanded.

Causes of PCOS:

Polycystic disease develops in the ovaries when there is no ovulation for a long time. Thus, PCOS is not a diagnosis, but only characteristic shape chronic hyperandrogenic anovulation. Recently it was shown that the cause of the syndrome is disturbances in the secretion of androgens and the regulation of their biosynthesis. Changes in ovarian morphology are completely insufficient for diagnosis. In the ovaries of many women, even in the absence of hormonal changes, more than eight cysts with a diameter of less than 10 mm are found under the capsule.

As epidemiological studies show, in approximately 25% of premenopausal women, ultrasound reveals typical signs of PCOS. Similar signs are found on ultrasound even in 14% of women using oral contraceptives. Anovulation against this background is observed in no more than 5-10% of cases.

In the pathogenesis of PCOS, the most important role is played by increased production of androgens. The biosynthesis of steroids in the ovaries and adrenal cortex in women follows the same patterns as in men. Produced by the ovaries, androstenedione serves as a precursor to both testosterone and estrogens.

Unlike men, in women androgens do not inhibit the secretion of LH and ACTH by a negative feedback mechanism, since they are only by-products synthesis of estrogen and cortisol. The main role is played by intraovarian regulation of androgen production. Androgens in the ovaries are " necessary evil"On the one hand, without them the synthesis of estrogens and the growth of small follicles is impossible, but on the other hand, their excess prevents selection dominant follicle and causes his atresia.

The nature of steroid secretion in patients with PCOS indicates a general dysregulation of androgen production, in particular at the level of 17-hydroxylase and 17,20-lyase. Dysregulation may affect androgen production in only the ovaries, only in the adrenal glands, or in both organs. PCOS syndrome may be a consequence of hyperandrogenism and purely adrenal origin.

Violation of the correct rhythm of secretion of gonadotropins and sex steroids causes constant anovulation. Serum testosterone, androstenedione, dihydroepiandrosterone sulfate, 17-hydroxyprogesterone, and estrone levels increase. Elevated levels of estrogen are not associated with their direct secretion by the ovaries. Daily estradiol production in women with PCOS does not differ from that in healthy women in the early follicular phase. The increase in serum estrogen concentration is due to increased conversion of androstenedione to estrone in adipose tissue.

In polycystic ovary disease, the LH/FSH ratio usually exceeds 3, but in 20-40% of patients there is no such shift in the ratio of gonadotropins. LH secretion remains pulsating. The amplitude of individual impulses (12.2 ± 2.7 mU/ml) is higher than at the beginning or middle of the follicular phase of the normal cycle (6.2 ± 0.8 mU/ml). This appears to be the result of changes in the frequency of GnRH pulses.

An increase in the amplitude of GnRH pulses at a constant frequency leads to a decrease in the peripheral concentration of FSH without affecting the level of LH. This causes a typical shift in the ratio of gonadotropins. Thus, the change in the LH/FSH ratio characteristic of PCOS is based on a disturbance in the frequency and amplitude of GnRH secretion, and not on a primary disturbance in LH secretion.

Hypothalamic GnRH production is influenced by endogenous opiates. In PCOS, changes in endorphin metabolism have been found. (3-endorphin and adrenocorticotropic hormone (ACTH) are formed from a single precursor, pro-opiomelanocortin (POMC). It is known that in situations accompanied by an increase in ACTH production, the level of P-endorphin also increases. In patients with PCOS, the concentrations of ACTH and cortisol are normal, which does not exclude acceleration of their metabolism.Since the level of P-endorphin increases under stress, and patients with PCOS experience psychological stress, we can assume the existence of a single cause for the violation of central regulatory mechanisms.

The effect of hyperprolactinemia described above on the central mechanisms of hormonal regulation may explain the frequent combination of PCOS with hyperprolactinemia.

High concentrations of testosterone reduce sex hormone binding globulin (SHBG) levels. Therefore, in women with polycystic ovaries, the SHBG content is usually halved due to secondary hyperandrogenism. This is accompanied by an increase in the concentration of free estrogens, which again correlates with an increase in the LH/FSH ratio. The increased concentration of free estradiol and the peripheral conversion of androstenedione to estrogens cause a decrease in FSH levels, but the residual amount of FSH is still sufficient to continue ovarian stimulation and the formation of follicles in them.

However, follicle maturation does not end with ovulation. Small follicles mature very slowly, over several months, which leads to the formation of follicular cysts measuring 2-6 mm. The hyperplastic theca, under conditions of continuous gonadotropic stimulation, constantly produces steroids. The vicious circle closes and the disease continues. After the death of the follicles and the disintegration of the granulosa, the theca layer is preserved, which (according to the two-cell theory described above) leads to an increase in the production of testosterone and androstenedione. Elevated testosterone levels further reduce SHBG levels, resulting in an increase in the concentration of free estrogens. At the same time, the fraction of free testosterone increases, affecting androgen-dependent tissues.

Insulin resistance:

Although androgens can cause mild insulin resistance, their concentrations in PCOS are insufficient to induce abnormalities in insulin metabolism. Inhibition of androgen production does not normalize insulin sensitivity. Conversely, taking androgens (for example, during a gender transition from female to male) only slightly increases the degree of insulin resistance.

In any case, with increased levels of insulin in the blood, its binding by IGF-I receptors on theca cells increases. This potentiates the stimulating effect of LH on androgen production. Thus, increased level insulin in the blood increases the production of androgens. At the same time, it reduces the production of SHBG and IGF-binding protein-I in the liver. Although there are indications of increased insulin secretion in hyperandrogenism, most evidence suggests that hyperinsulinemia precedes disturbances in androgen metabolism and not vice versa.

Obesity:

Diagnostics:

Treatment of polycystic ovary syndrome:

The following forms of treatment are used:
1) antiestrogens (for example, clomiphene),
2) glucocorticoids (dexamethasone 0.25-0.5 mg/day),
3) pulsed administration of GnRH using a special pump,
4) stimulation of MG,
5) surgical removal of part of the ovarian stroma,
6) oral antidiabetic agents.

The first three forms of therapy are designed to correct feedback in the system of regulation of follicle maturation. In contrast, MG or hCG act directly at the ovarian level, and therefore their use is associated with high risk hyperstimulation. TO surgical removal ovarian stroma, which produces androgens, should be used only if other types of treatment are ineffective.

After clomiphene therapy, ovulation appears in 63-95% of patients with PCOS. Clomiphene is a weak anti-estrogen and causes an increase in gonadotropin levels. The drug is usually prescribed at 50 mg/day. for 5 days (from 3 to 7 days of the menstrual cycle). This dosage restores ovulation in 27-50% of patients. Sometimes the dose has to be increased to 150 mg/day, which leads to ovulation in another 26-29% of women. If ovulation is not restored even with this dosage, you can additionally prescribe dexamethasone at 0.25-0.5 mg/day. depending on the concentration of DHEA sulfate in the serum.

In the case when the results of ultrasound and hormonal studies indicate maturation of the follicles, and ovulation is absent, it can be induced by hCG in a dose of 5000 to 10 thousand IU IM. Since it is normal to conceive in the first 3 months. cohabitation occurs in only 50% married couples, and a year later - in 80%, insofar as after normalization of the luteal phase (according to ultrasound and hormonal studies) treatment should be continued for at least 6 months. or cycles. Clomiphene therapy allows success in 90% of cases of infertility caused by PCOS syndrome.

MG and FSH:

"Down-regulation" of GnRH receptors:

Pulse administration of GnRH:

Wedge resection of the ovaries:

Oral antidiabetic agents:

Low body weight and follicular maturation

In such cases, it is necessary to exclude pituitary pathology. Hypothalamic regulation is disrupted not only with obvious weight deficiency, but also due to psychological stress(for example, leaving your husband or changing your partner). In this case, extremely low concentrations of gonadotropins are observed. Prolactin levels and sella turcica remain normal. A modified progesterone test (G-farlutal 5 mg twice daily for 10 days) does not cause bleeding, indicating the absence of estrogen stimulation of the endometrium.

Most shining example amenorrhea associated with low body weight - anorexia nervosa. In infertility clinics, the pure form of anorexia is extremely rare, but its “milder” forms are observed more often.

Unlike anorexia nervosa, accompanied by changes in regulatory mechanisms in the central nervous system, the maturation of follicles can be disrupted even with simple weight loss, which is not always paid attention to. Hormonal shifts in these cases are similar to those with anorexia nervosa: low concentrations of FSH and LH, increased levels of cortisol, normal levels of prolactin, TSH and thyroxine, the level of free T3 - on lower limit norms, increased content reverse T3. Abrupt loss weight is accompanied by loss of sleep-related episodes of LH secretion (similar to what is observed on early stages puberty). The condition of patients improves when body weight differs from ideal by no more than 15%.

Regulation of the cyclic function of the ovaries depends not only on body weight, but also on physical activity. It has been repeatedly shown that female athletes, especially stayers and ballerinas, have impaired menstrual function. The incidence of amenorrhea is proportional to the distance traveled per week and inversely proportional to body weight. A decrease in body weight is accompanied by an increase in anovulatory cycles and a deterioration in the quality of the luteal phase. The disruption of GnRH secretion is based on shifts in estrogen metabolism: estradiol is converted to catechol estrogens, which apparently have antiestrogenic properties.

Increased physical activity (eg, running) is accompanied by "runner's intoxication, which is believed to be due to an increase in the level of endogenous opiates. These substances increase the concentration of corticotropin-releasing hormone, which in turn reduces the secretion of gonadotropins. The production of hypothalamic GnRH appears to , falls. Naltrexone (at a dose of 25-125 mg/day) normalized the menstrual cycle in 49 of 66 women with impaired hypothalamic regulation of follicle maturation. Pregnancy occurred in almost the same percentage of cases as in healthy women in the control group. An alternative may be GnRH pulse therapy or ovarian stimulation with MG and hCG, but the risk of multiple pregnancy should be taken into account.First of all, you need to normalize body weight.

Primary ovarian failure:

1% of women under 35 years of age experience premature menopause associated with ovarian failure. The reasons generally remain unknown. Sometimes it can be chromosomal abnormalities; in other cases - autoimmune diseases, viral infections, undergone chemotherapy and/or radiation therapy.

The most common chromosomal defect in humans is Turner syndrome, which involves the loss of one of the X chromosomes. It occurs in one in 2,500 live births. In typical cases, short stature and cord-like gonads occur. The degree of ovarian pathology varies sharply. The presence of ovaries was detected by ultrasound in a third of 104 young women with Turner syndrome.

Many of these women had an incomplete deletion of the X chromosome, which explains the possibility of pregnancy and live birth (before the development of premature ovarian failure).

Hypergonadotropic hypogonadism is also characteristic of other genetic abnormalities. They are so rare in regular fertility clinics that special genetic research hardly justified.

In addition to chromosomal pathology, premature ovarian failure can also be caused by such genetic diseases like galactosemia.

Impaired ovarian function may be a consequence of chemotherapy using antimetabolites, as well as radiation, which must be taken into account when studying the patient's medical history.

The role of exogenous toxins in the genesis of premature ovarian failure remains unclear. By analogy with orchitis in men, it is assumed that mumps can lead to oophoritis, but this has been observed only in isolated cases.

Autoimmune diseases:

In the serum of patients with primary ovarian failure, autoantibodies to the ovarian stroma can be detected. It is unclear whether they are of primary or secondary origin. The same can be said about cellular autoimmune processes with lymphocytic infiltration of the ovaries.

Finally, about immunological reason Premature ovarian failure is evidenced by statistically significant correlations between this condition and certain human leukocyte antigens (HLA).

In rare cases, hypergonadotropic hypogonadism is associated with a defect in FSH receptors or with the formation of biologically inactive gonadotropins. This is extremely rare in routine clinical practice.

Treatment of ovarian failure:

Estrogen replacement therapy should also be recommended during natural menopause in order to minimize the risk of osteoporosis and cardiovascular diseases. The lowest dose is 2 mg estradiol or estradiol valeriat or 0.625 mg conjugated estrogens per day. Transdermal use of 0.05 mg estradiol optimizes the pharmacokinetics of the drug and eliminates the effect of the first passage through the liver.

In the presence of a uterus, it is necessary to additionally use progestins to prevent the risk of endometrial cancer. Progestins can be administered sequentially at a dose of 0.35 mg norethisterone, 5 mg medroxyprogesterone acetate, or 10 mg dydrogesterone per day for 10-14 days. They can also be taken continuously in the form of norethisterone acetate at 1 mg/day. With this treatment, amenorrhea usually develops after 2-6 cycles.