Normal menstrual cycle

Menstrual cycle - regularly repeated individual cyclic changes in the reproductive system and the body as a whole.

The menstrual cycle is an extremely complex process, regulated by the neuroendocrine system. The most pronounced changes occur at five levels of the reproductive system: in the uterus, in the ovaries, in the anterior pituitary, in the hypothalamus (mainly in the arcuate nuclei of the mediobasal hypothalamus) and in the extrapyptalamic structures of the central nervous system. The function of each level by the mechanism of positive or negative feedback is regulated by the superior.

Uterine tissues are target tissues for sex steroid hormones. Uterine tissue cells contain nuclear and cytoplasmic hormone receptors, the latter possess strict specificity for estradiol, progesterone or testosterone.

In the first half of the menstrual cycle, which, depending on the total duration of the period (14 ± 3) days, the endometrium is under the predominant effect of estrogens, which provide normal proliferative changes in the glands, stroma and vessels of the functional layer. The second half of the mother cycle passes under gestagenic influence and continues (14 ± 2) days. The phase of desquamation, or rejection, of the functional layer of the endometrium occurs due to a drop in the titer of both sex hormones and lasts from 3 to 6 days.

Biosynthesis of sex steroids occurs in the ovaries. It has now been established that estradiol is produced mainly in granulosa cells; progesterone - in the cells of the yellow body; androgens - in teka-cells and stroma of the ovaries. The sexual organs affect not only the target organ - the uterus, but also the central parts of the reproductive system: the pituitary gland, the hypothalamus, other parts of the central nervous system.

In turn, the function of the ovaries is under the regulating influence of the anterior lobe of the pituitary gland, which produces gonadotropic hormones: foliotropin (follicle stimulating hormone, FSH), lutropine (luteinizing hormone, LH) and prolactin (luteotropic hormone, LTG). FSH and LH are glucoprots, prolactin is a polypeptide. The functions of these hormones are extremely wide and complex. In particular, FSH stimulates the growth and maturation of the follicle, increases the number of LH receptors in granulosa, together with LH stimulates the synthesis of estrogens and induces ovulation. The formation of the yellow body is carried out under the influence of LH. Prolactin takes part in the synthesis of progesterone in a yellow body. Recent studies have shown that secretion of LH and FSH occurs in a pulsating mode, the rhythm of which depends on the functional activity of the hypothalamic zone of the hypothalamus. Nerve cells of the arteriate nuclei of the mediobasal hypothalamus secrete the gonadotropy-releasing hormone (Gn-RG) in the cirrchoral regime, which provides the corresponding rhythm of LH surge: more frequent in the I phase of the menstrual cycle and more rare in the II phase. Amplitude of gonadotropic hormones is mainly determined by the level of estradiol.

The function of arcuate nuclei is not autonomous, in many respects it is determined by the action of neurotransmitters (biogenic amines and endogenous opiates), through which the higher structures of the central nervous system exercise their influence.

Thus, the menstrual cycle is a complex multi-link process, the external manifestation of which are regularly occurring bleeding associated with the rejection of the functional layer of the endometrium, and the essence is ovulation of the follicle and the release of a mature egg ready for fertilization. Violation of the function of any level of the reproductive system can be accompanied by uterine bleeding against anovulation background (more often) or with preserved ovulation (less often).

Age limits of menstrual functions are menarche and menopause. The latter, along with the onset of sexual activity and any pregnancy, normally resolved or interrupted, refer to the so-called critical periods of development of the female body. In connection with the increased burden on the body of a woman at these moments, frequent failures, breakdown of the mechanisms of regulation of the most important organs and systems, leading to the emergence or aggravation of previously hidden disturbances of their work, the development of severe somatic, endocrine, gynecological, mental, infectious diseases.

Cyclical changes in the endometrium during the menstrual cycle

The first day of menstrual bleeding is considered the first day of the menstrual cycle. After menstruation, the basal layer of the endometrium contains the premordial glands and a very thin layer of stromal cells - 1-2 mm. Under the influence of estrogens, rapid growth of glands and stroma begins due to mitotic division of cells. By the end of the proliferative stage, before ovulation, the thickness of the endometrium is 12-14 mm. With ultrasound, the linearity of the endometrium is clearly visible and blood flow is often determined by the method of Doppler.

After 48-72 hours after ovulation an increased level of progesterone turns the proliferative phase of the development of the endometrium into a secretory one.

In the secretory phase of the cycle, endometrial glands form characteristic glycogen-containing vacuoles. At 6-7 days after ovulation, the secretory activity of endometrial glands is maximal. This activity continues until 10-12 days after ovulation and then sharply decreases. Knowing the exact time of ovulation, by means of endometrial biopsy, it is possible to determine whether the development of the secretory phase of the endometrium is normal or not, which is of great importance in the diagnosis of certain forms of infertility and miscarriage.

Traditionally, this study was done 10-12 days after ovulation (25-26 day menstrual cycle). In order to diagnose - luteal phase failure - an endometrial biopsy can be performed during these days of the cycle. Studies of recent years have shown that it is more informative to conduct a biopsy on the 6-8th day after ovulation - the time of implantation. At the time of implantation, very large changes occur in the endometrium compared to other days of the cycle. This is due to the emergence of the so-called "implantation window". Changes include: the expression of specific glycoproteins, adhesion molecules, various cytokines and enzymes.

Extremely interesting data were obtained by G. Nikas (2000) when studying the surface morphology of the endometrium by the method of scanning electron microscopy. The author made consecutive endometrial biopsies with a 48-hour interval in the same patients in the natural cycle, after superovulation and in the cycle of cyclic hormone therapy. In the proliferative phase of the cycle, the surface of the endometrial cells varies, it is either elongated or polygonal with minimal stretches, the intercellular clefts are barely discernible and the microvilli of the ciliated cells are rare. By the end of the proliferative phase, the number of villi increases. In the secretory phase, changes in the surface of cells occur literally by the hour. On the 15-16th day of the cycle, the surface of the cells protrudes in the central part, on day 17 these protrusions capture the entire apex of the cell and the microvilli grows, becomes long, thick. On the 18-19 day of the cycle, microvilli are reduced by fusion or disappearance, cells are as if covered with a thin membrane rising above the apices of the cell. On the 20th day of the cycle the villi practically disappear, the apexes of the cells reach their maximum protrusion, the gaps between the cells increase (a phenomenon called in the English literature "pinopod") - the culmination point of the development of the secretory endometrium. This period is called the "implantation window". On day 21, protrusions decrease, and small villi appear on the cell surface. The membranes wrinkle, the cells begin to decrease. On day 22 the number of villi increases. By day 24 the cells look dome, with a lot of short villi. On the 26th day, degenerative changes begin that end with menstrual bleeding on day 28 of the cycle.

It is believed that the appearance and development of the "implantation window" in time is synchronous with the development of the embryo in the conception cycle in the normal menstrual cycle. With infertility and miscarriage of early terms, the development of the "implantation window" may "outrun" or "lag" behind the development of the embryo, in connection with this, there may be abnormalities in implantation and termination of pregnancy.

The role of prostaglandins in the reproductive system

According to many researchers, prostaglandins play a fundamental role in human reproductive function. Prostaglandins are formed from free arachidonic acid by hydrolysis, and there are two ways of their formation-lipoxygenase (leukotriene formation) and cyclooxygenase pathway-the formation of prostaglandins proper.

The first true prostaglandins PgG2 and PgH "with their half-life of about 5 minutes are, as it were, maternal, of which the whole family of prostaglandins subsequently forms. The greatest value of all prostaglandins in the reproductive system is given to prostaglandins E and F20tn possibly PgD2.

According to Moncada S. Thromboxane is not a true prostaglandin, unlike prostacyclin, but they are antagonists: the actions of one are directed against the action of another, but normally there must be a balance between them.

Thromboxane A2 is a potent vasoconstrictor, Pd12-vasodilator. In thrombocytes, in the lungs, spleen, thromboxane is synthesized, while in the heart, stomach, in the vessels prostacyclin is synthesized. The lung is also synthesized in the norm of prostacyclin, and under the influence of stimulation and thromboxane.

Thromboxane A2-stimulator of adhesion and aggregation of platelets. In the endothelium, the synthesized prostacyclin inhibits the adhesion and aggregation of platelets, preventing the formation of thrombi. If the vessels are damaged, the balance is broken and thrombosis of the affected area takes place, but a certain level of prostacyclin is recorded. Metabolism of prostaglandins occurs in the lungs, kidneys and liver. Metabolism of prostaglandins E and FM mainly occurs in the lungs. Due to the short half-life of prostaglandins, they act autocrine / paracrine in the place of formation.

According to Olson DM, the inhibitor of prostaglandin synthesis is glucocorticoids. They cause the synthesis of proteins of lipocortins (or annexins), which block the action of phospholipases.

The inhibitor of prostaglandin synthesis is aspirin, indomethacin. Inhibition is carried out through cyclooxygenase enzymes. A feature of the action of aspirin is its long-lasting effect on platelets, on their life span (8-10 days). In small doses, aspirin blocks the synthesis of thromboxane only in platelets, and in large doses the production of prostacyclin in the wall of the vessels.

Prostaglandin F2alfa takes part in the regression of the yellow body in the event that no pregnancy has occurred. The mechanism of luteolysis occurs in two ways: the first way is a fast action against LH due to the loss of LH receptors in the yellow body of the ovary, this occurs only in intact cells and is the result of the action of mediators that block LH receptors and activate adenylate cyclase. A slow response is due to the indirect action of prolactin on the LH receptors.

There is evidence of the role of estrogens - increasing estrogens leads to a decrease in progesterone and an increase in prostaglandin F.

Out of pregnancy in the endometrium, there is a certain level of prostaglandins taking part in the rejection of the endometrium during menstruation. In pregnancy, due to the increased content of progesterone, endometrial cells produce a secretory component that reduces the synthesis of prostaglandin after implantation, and thus contributes to the preservation of pregnancy.

Prostaglandins play an important role in maintaining the fetal circulation, supporting the vasodilatation of the ductus arteriosus. After birth, there are mechanisms, apparently in the lungs, which after birth lead to the closure of the ductus arteriosus. If there is no closure of the duct, the use of an inhibitor of prostaglandin synthesis - indomethacin helps close the duct more than 40% of premature newborns. Prostaglandins play a key role in softening the cervix and causing labor.

What are the characteristics of a normal menstrual cycle?

First of all:

• timing menarche (timely, premature, belated);
• regularity (the cycle count goes from the 1st day of the next monthly until the beginning of the next);
• duration of the cycle, which in most healthy women is 21-35 days;
• duration of bleeding, normally ranged from 3 to 7 days;
• the volume of menstrual blood loss - 60-150 ml;
• morbidity of menstruation;
• date of the last menstruation.

Any deviation in either direction of each of the parameters may indicate a developing violation. At the same time, these parameters are only the external, quantitative side of the menstrual cycle and do not always characterize the qualitative one - the ability to attack and preserve pregnancy. Similar parameters of the menstrual cycle can have both women capable of pregnancy, and infertile. Internal, hidden parameters of the menstrual cycle, reflecting the qualitative side of it, and detected, primarily by means of special examination methods, are: the presence of ovulation and, consequently, the 2nd phase of the cycle and the usefulness of the latter.

Thus, the normal menstrual cycle is regular, ovulatory and, therefore, biphasic with a full-fledged 2-nd phase.

[1], [2]

Investigation of menstrual function

When examining gynecological patients, especially those having various forms of menstrual cycle disorders, it is necessary to pay attention to those factors that can influence the formation and manifestation of menstrual function disorder.

1. Age.
2. General anamnesis: working conditions, occupational hazards. Heredity, somatic and mental development, the transferred diseases and operations.
3. Gynecological anamnesis. Menstrual function: menarche, duration of establishment, regularity, duration of cycle and menstruation, volume of blood loss, pain syndrome, date of last menstruation. Reproductive function: the number of pregnancies (childbirth, abortions, miscarriages, ectopic pregnancy), complications during and after them. Gynecological diseases and operations.
4. Anamnesis of the disease: when the cycle began to break down, in what way they are expressed, whether the examination and treatment were carried out.
5. О objective examination: growth, body weight, physique, genetic stigma (congenital malformations, pterygopalatine folds on the neck, birthmarks, etc.), cardiovascular and respiratory systems, palpation of the abdomen. The nature of hair. Palpation of the thyroid gland, mammary glands (size, shape, consistency, presence and nature of discharge from the nipples).
6. Gynecological examination: the structure of the genital organs, clitoris; measurement of vaginal length by the uterine probe and rectal examination; vaginal examination (condition of the mucous membrane and the nature of the discharge, the shape of the cervix, the symptom of the "pupil", the size and condition of the uterus, appendages and ovaries).

Tests of functional diagnostics of the ovaries

Basal (rectal) thermometry (RT). In a two-phase cycle, the temperature rises above 37.0 ° C in the second half of the cycle, while in a single-phase cycle, the temperature is monotonically low.

Criteria for a normal menstrual cycle:

• Two-phase character throughout the menstrual cycle.
• In the 1st phase, the rectal temperature is below 37.0 ° C.
• In terms of ovulation, its level may decrease by 0.2-0.3 ° C.
• The timing of ovulation is strictly in the middle of the cycle or 1-2 days later.
• Rapid elevation of rectal temperature after ovulation is higher than 37.0 ° C (for 1-3 days).
• The temperature difference in the phases of the cycle is up to 0.4-0.6 ° C.
• The duration of the second phase is no more than 14 days (in the 28-30-day cycle).
• The duration of rectal temperature rise above 37.0 ° C in the 2 nd phase is not less than 9 days (in the 28-30-day cycle).
• Rapid drop in rectal temperature below 37.0 ° C on the eve of menstruation.

If the primary analysis of rectal temperature makes it possible to assess the degree of menstrual cycle irregularity (complete cycle - failure of the 2nd phase - deficiency of the 1 st and 2 nd phases - anovulatory cycle), then the picture of the rectal temperature change in the course of hormonal therapy can serve the purposes of the Dynamic monitoring the effectiveness of treatment and selecting the optimal dose and timing of the drug.

Examination of cervical mucus. In the dynamics of the menstrual cycle, such parameters as the character of the "fern" symptom, the phenomenon of tension of cervical mucus, the symptom of "pupil", quantified in the form of a cervical index (cervical number) are investigated . These symptoms are maximum expressed in the middle of the cycle, on the eve of the timing of ovulation.

Colpositodiagnostics - cytological examination of vaginal smears. The dynamics of changes in the colpocytolo- gical parameters reflects the total fluctuation of the level of ovarian hormones in the body throughout the cycle. The method allows to estimate the level of estrogenic, gestagenic, and in some cases, androgenic saturation of the organism.

Histological examination of the endometrium (obtained by endometrial biopsy, separate diagnostic curettage of the cervical canal and uterine cavity) is performed with the saved cycle on the 1st day of menstruation; with amenorrhea - any day, dysfunctional bleeding - better at the beginning of bleeding (the endometrium is preserved).

Determination of serum levels of hormones. Blood is taken from the vein in the morning, on an empty stomach. Determination of levels of luteinizing (LH) and follicle-stimulating (FSH) hormones is necessary for amenorrhea or long-term delay of the monthly for differential diagnosis of central and ovarian forms of cycle disturbance. With the saved cycle, this examination is performed on the 3rd-6th day of the menstrual cycle.

Determination of the level of prolactin (PRL) is necessary to eliminate the often occurring hyperprolactinemic insufficiency of the ovaries. With the saved cycle, the blood sampling is expedient at the time of its maximum rise, after the phase of the heyday of the yellow body, on the 25-27th day of the cycle (at the end of the rise of the rectal temperature in the 2 nd phase); at oligo- and amenorrhea - against a background of a long delay. In detecting hyperprolactinaemia to exclude hypothyroid genesis, the next step is to determine the hormonal parameters of the thyroid gland - TSH (thyroid stimulating hormone), T3 (triiodothyronine), T4 (thyroxine), antibodies to thyroglobulin (AT to TG) and thyroid peroxidase (AT to TPO). The blood for these hormones is taken on any day of the cycle.

Estradiol levels (E1) are determined in both the first and second phases of the cycle, to assess the degree of estrogen saturation before treatment with ovulation stimulants or the elimination of hyperestrogenism. The evaluation of the usefulness of the 2nd phase of the cycle requires a repeated measurement of the level of progesterone on the 19th-21st and 24-26th day of the cycle.

Levels of testosterone (T), cortisol (K), adrenocorticotropic hormone (ACTH), DEA (dehydroepiandrosterone), Al (androstenedione) are studied in the differential diagnostics of various forms of hyperandrogenism on the 5th-7th day of the cycle.

Additional hormonal tests to assess the level of damage in the system of regulation of the sexual function are functional tests with hormones (gestagens, estrogens and gestagens, stimulants of ovulation, LH-RG, TRH, dexamethasone, etc.).

As modern methods of additional laboratory study of patients with various disorders of the menstrual cycle, the following are used:

X-ray examination of the skull - with a broken menstrual cycle in order to exclude a pituitary tumor.

Computer and magnetic resonance imaging - for diagnosis of the microadenomas of the pituitary gland, detection of tumors of the ovaries and adrenals.

Investigation of visual fields (in two colors) - to exclude suprasellar growth of the pituitary tumor.

Definition of karyotype - with primary amenorrhea to exclude genetic abnormalities.

Instrumental Research Methods

The ultrasound of the pelvic organs on the 5th-7th day of the cycle allows to establish the size and structure of the uterus, the size of the ovaries, to reveal the initial stages of development of the uterine myoma, to differentiate the true ovarian tumors and their cystic enlargement. The method allows to monitor the growth of the follicle, the presence and timing of ovulation. The study at the end of the cycle makes it possible to diagnose hyperplastic changes in the endometrium (thickness more than 10-12 mm).

Ultrasound of the thyroid gland allows to estimate the size of the latter, the presence of nodular and cystic formations, to reveal the signs characteristic of chronic thyroiditis. The presence of nodes and cysts serves as an indication for a puncture biopsy. The question of the further tactics of reference is solved together with the endocrinologist.

Breast examination is a mandatory method of examining patients with menstrual cycle disorders. Clinical examination includes examination and palpation of glands, regional lymph nodes, lactor control, and ultrasound. Mammography is performed for women over 35 years old, younger only on indications, if there are nodular or cystic gland changes with ultrasound. The examination is carried out on the 5th-7th day with the saved cycle, with amenorrhea - any days. Lactoreal activity is more pronounced at the end of the cycle.

Hysterosalpingography (GAS) is indicated for the elimination of malformations of the uterus, uterine synechia, tumor nodes, and uterine hypoplasia. Conduct it in the first half of the saved cycle, with no signs of infection, changes in blood, urine, vaginal smears.

Endoscopic examination methods

Laparoscopy is indicated for violations of the menstrual cycle, especially when combined with infertility, when there is a suspicion of organic changes in the pelvic organs, or in the case of ineffective long-term hormone therapy, and also when it is necessary to produce an ovarian biopsy.

Hysteroscopy is indicated for violations of the menstrual cycle, infertility, meno- and metrorrhagia, suspected intrauterine pathology according to ultrasound and hysterosalpingography (GHA).

[3], [4], [5], [6], [7]