Normal menstrual cycle

The menstrual cycle is a regularly recurring individual cyclical change in the reproductive system and the body as a whole.

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

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

In the first half of the menstrual cycle, which, depending on its total duration, lasts (14±3) days, the endometrium is under the predominant influence of estrogens, which ensure normal proliferative changes in the glands, stroma and vessels of the functional layer. The second half of the uterine cycle is under the gestagenic influence and lasts (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 corpus luteum cells; androgens - in theca cells and ovarian stroma. The genitals affect not only the target organ - the uterus, but also the central parts of the reproductive system: the pituitary gland, hypothalamus, and other parts of the central nervous system.

In turn, the function of the ovaries is under the regulatory influence of the anterior pituitary gland, which produces gonadotropic hormones: follicle-stimulating hormone (FSH), lutropin (luteinizing hormone, LH) and prolactin (luteotropic hormone, LTH). FSH and LH are glucoproteins, prolactin is a polypeptide. The functions of these hormones are extremely broad and complex. In particular, FSH stimulates the growth and maturation of the follicle, increases the number of LH receptors in the granulosa, and together with LH stimulates the synthesis of estrogens and induces ovulation. The formation of the corpus luteum is carried out under the influence of LH. Prolactin takes part in the synthesis of progesterone by the corpus luteum. Research in recent years has shown that the secretion of LH and FSH occurs in a pulsating mode, the rhythm of which depends on the functional activity of the pituitary zone of the hypothalamus. The nerve cells of the arcuate nuclei of the mediobasal hypothalamus secrete gonadotropin-releasing hormone (GnRH) in a circulatory mode, which ensures the corresponding rhythm of LH release: more frequent - in the first phase of the menstrual cycle and less frequent - in the second phase. The amplitude of gonadotropic hormone releases is mainly determined by the level of estradiol.

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

Thus, the menstrual cycle is a complex multi-link process, the external manifestation of which is 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. Dysfunction of any level of the reproductive system can be accompanied by uterine bleeding against the background of anovulation (more often) or with preserved ovulation (less often).

The age boundaries of menstrual functions are menarche and menopause. The latter, along with the onset of sexual activity and any pregnancy, normally resolved or interrupted, are related to the so-called critical periods of development of the female body. Due to the increased load on the female body at these moments, breakdowns and failures of the mechanisms of regulation of the most important organs and systems are frequent, leading to the emergence or exacerbation of previously hidden disorders in their work, the development of severe somatic, endocrine, gynecological, mental, infectious diseases.

Cyclic 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 primordial 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 cell division. By the end of the proliferative stage, before ovulation, the thickness of the endometrium is 12-14 mm. Ultrasound clearly shows the linearity of the endometrium and often determines blood flow using Doppler.

48-72 hours after ovulation, increased progesterone levels transform the proliferative phase of endometrial development into a secretory phase.

In the secretory phase of the cycle, the endometrial glands form characteristic glycogen-containing vacuoles. On the 6th-7th day after ovulation, the secretory activity of the endometrial glands is maximal. This activity continues until the 10th-12th day after ovulation and then decreases sharply. Knowing the exact time of ovulation, by means of an 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 diagnosing some forms of infertility and miscarriage.

Traditionally, this study was done on the 10th-12th day after ovulation (25th-26th day of the menstrual cycle). In order to make a diagnosis - luteal phase insufficiency - endometrial biopsy can be done on these days of the cycle. Research in recent years has shown that it is more informative to do a biopsy on the 6th-8th day after ovulation - the time of implantation. By 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: expression of specific glycoproteins, adhesion molecules, various cytokines and enzymes.

Extremely interesting data were obtained by G. Nikas (2000) in a study of the surface morphology of the endometrium using scanning electron microscopy. The author made successive endometrial biopsies at 48-hour intervals in the same patients in a natural cycle, after superovulation and in a cycle of cyclic hormonal therapy. In the proliferative phase of the cycle, the surface of the endometrial cells varies, it is either elongated or polygonal with minimal stretching, intercellular gaps are barely distinguishable and microvilli of ciliated cells are rare. By the end of the proliferative phase, the number of villi increases. In the secretory phase, changes in the cell surface occur literally by the hour. On the 15-16th day of the cycle, the cell surface protrudes in the central part, on the 17th day these protrusions capture the entire top of the cell and the microvilli increase, become long and thick. On the 18th-19th day of the cycle, the microvilli decrease by merging or disappearing, the cells seem to be covered with a thin membrane rising above the cell tops. On the 20th day of the cycle, the villi practically disappear, the cell tops reach their maximum protrusion, the spaces between the cells increase (a phenomenon called "pinopod" in English literature) - the culmination point of the development of the secretory endometrium. This period is called the "implantation window". On the 21st day, the protrusions decrease, and small villi appear on the cell surface. The membranes wrinkle, the cells begin to decrease. On the 22nd day, the number of villi increases. By the 24th day, the cells look dome-shaped, with many short villi. On the 26th day, degenerative changes begin, which end with menstrual bleeding on the 28th day of the cycle.

It is believed that the emergence and development of the "implantation window" is synchronous in time with the development of the embryo in the conception cycle during a normal menstrual cycle. In case of infertility and early pregnancy loss, the development of the "implantation window" may "ahead" or "lag" behind the development of the embryo, which may lead to implantation disorders 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 (formation of leukotrienes) and cyclooxygenase pathway - formation of prostaglandins themselves.

The first true prostaglandins PgG2 and PgH„ their half-life period is about 5 minutes are like mothers, from which the entire family of prostaglandins is subsequently formed. The greatest significance of all prostaglandins in the reproductive system is given to prostaglandins E and F20, possibly PgD2.

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

Thromboxane A2 is a powerful vasoconstrictor, Rd12 is a vasodilator. Thromboxane is synthesized in platelets, lungs, spleen, while prostacyclin is synthesized in the heart, stomach, and vessels. Prostacyclin is also synthesized in the lungs normally, and under the influence of stimulation, thromboxane.

Thromboxane A2 is a stimulator of platelet adhesion and aggregation. Prostacyclin synthesized in the endothelium inhibits platelet adhesion and aggregation, preventing thrombus formation. When blood vessels are damaged, the balance is disturbed and thrombosis of the damaged area occurs, but a certain level of prostacyclin is recorded. Prostaglandins are metabolized in the lungs, kidneys and liver. Prostaglandins E and FM are metabolized mainly in the lungs. Due to the short half-life of prostaglandins, they act in an autocrine/paracrine manner at the site of formation.

According to Olson DM, glucocorticoids are inhibitors of prostaglandin synthesis. They cause the synthesis of lipocortin proteins (or annexins), which block the action of phospholipases.

Aspirin and indomethacin are inhibitors of prostaglandin synthesis. Inhibition is carried out through cyclooxygenase enzymes. A special feature of aspirin is its long-term effect on platelets, on their lifespan (8-10 days). In small doses, aspirin blocks thromboxane synthesis only in platelets, and in large doses, prostacyclin production in the vascular wall.

Prostaglandin F2alpha is involved in the regression of the corpus luteum if pregnancy has not occurred. The mechanism of luteolysis occurs in two ways: the first way is fast - action against LH due to the loss of LH receptors in the corpus luteum of the ovary, this occurs only in intact cells and is the result of the action of mediators that block LH receptors and the activation of adenylate cyclase. Slow response - due to the indirect action of prolactin on LH receptors.

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

Outside of pregnancy, the endometrium contains a certain level of prostaglandins that participate in the rejection of the endometrium during menstruation. During pregnancy, due to the increased content of progesterone, the endometrial cells produce a secretory component that reduces the synthesis of prostaglandin after implantation, and thus helps maintain pregnancy.

Prostaglandins play an important role in maintaining fetal circulation by maintaining vasodilation of the ductus arteriosus. After birth, there are mechanisms, presumably in the lungs, that lead to closure of the ductus arteriosus after birth. If closure does not occur, the use of the prostaglandin synthesis inhibitor indomethacin promotes closure of the ductus in more than 40% of premature infants. Prostaglandins play a key role in softening the cervix and inducing labor.

What parameters characterize a normal menstrual cycle?

First of all:

• timing of menarche (timely, premature, late);
• regularity (the cycle is counted from the 1st day of the next period until the beginning of the next);
• the duration of the cycle, which in most healthy women is 21-35 days;
• duration of bleeding, which normally ranges from 3 to 7 days;
• volume of menstrual blood loss - 60-150 ml;
• painful periods;
• date of last menstrual period.

Any deviation in one direction or another of each of the parameters may indicate a developing disorder. At the same time, these parameters are only the external, quantitative side of the menstrual cycle and do not always characterize the qualitative side - the ability to achieve and maintain pregnancy. Similar parameters of the menstrual cycle can be found in both women capable of pregnancy and infertile ones. Internal, hidden parameters of the menstrual cycle, reflecting its qualitative side and revealed primarily with the help of special examination methods, are: the presence of ovulation and, consequently, the 2nd phase of the cycle and the completeness of the latter.

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

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Research of menstrual function

When examining gynecological patients, especially those with various forms of menstrual cycle disorders, it is necessary to pay attention to those factors that can influence the development and manifestation of menstrual dysfunction.

1. Age.
2. General anamnesis: working conditions, occupational hazards, heredity, somatic and mental development, past illnesses and surgeries.
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: number of pregnancies (deliveries, abortions, miscarriages, ectopic pregnancy), complications during and after them. Gynecological diseases and surgeries.
4. Medical history: when the menstrual irregularities began, what they are, whether examination and treatment were carried out.
5. Objective examination: height, body weight, build, genetic stigmas (congenital malformations, pterygoid folds on the neck, birthmarks, etc.), condition of the cardiovascular and respiratory systems, abdominal palpation. Character of hairiness. Palpation of the thyroid gland, mammary glands (size, shape, consistency, presence and character of discharge from the nipples).
6. Gynecological examination: structure of the genitals, clitoris; in virgins, measurement of the length of the vagina with a uterine probe and rectal examination; vaginal examination (condition of the mucous membrane and nature of the discharge, shape of the cervix, "pupil" symptom, size and condition of the uterus, appendages and ovaries).

Functional diagnostic tests of ovarian activity

Basal (rectal) thermometry (RT). In a two-phase cycle, the temperature rises above 37.0° C in the 2nd half of the cycle, while in a single-phase cycle, it is monotonously low.

Criteria for a normal menstrual cycle:

• Biphasic nature throughout the menstrual cycle.
• In the 1st phase, the rectal temperature level is below 37.0° C.
• During ovulation, its level can decrease by 0.2-0.3° C.
• Ovulation times are strictly in the middle of the cycle or 1-2 days later.
• Rapid rise in rectal temperature after ovulation above 37.0° C (within 1-3 days).
• The difference in temperature between the phases of the cycle is up to 0.4-0.6° C.
• The duration of the 2nd phase is no more than 14 days (in a 28-30-day cycle).
• The duration of the rise in rectal temperature above 37.0° C in the 2nd phase is at least 9 days (in a 28-30-day cycle).
• A rapid drop in rectal temperature below 37.0°C on the eve of menstruation.

If the primary analysis of rectal temperature allows us to assess the degree of menstrual cycle disorder (full cycle - insufficiency of the 2nd phase - insufficiency of the 1st and 2nd phases - anovulatory cycle), then the pattern of changes in the rectal temperature chart during hormonal therapy can serve the purposes of dynamic monitoring of treatment effectiveness and selection of the optimal dose and timing of drug use.

Cervical mucus examination. In the dynamics of the menstrual cycle, such parameters as the nature of the "fern" symptom, the phenomenon of cervical mucus tension, the "pupil" symptom are examined, assessed quantitatively in the form of the cervical index (cervical number). These symptoms are most pronounced in the middle of the cycle, on the eve of ovulation.

Colpocytodiagnostics is a cytological examination of vaginal smears. The dynamics of changes in colpocytolotic indices reflects the total fluctuation in the level of ovarian hormones in the body during the cycle. The method allows assessing the level of estrogen, gestagen, and in some cases, androgen saturation of the body.

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

Determination of hormone levels in the blood serum. Blood is taken from a vein in the morning, on an empty stomach. Determination of the levels of luteinizing (LH) and follicle-stimulating (FSH) hormones is necessary in case of amenorrhea or a long delay in menstruation for the differential diagnosis of central and ovarian forms of cycle disorders. If the cycle is preserved, this study is performed on the 3rd-6th day of the menstrual cycle.

Determination of prolactin (PRL) level is necessary to exclude frequently occurring hyperprolactinemic ovarian insufficiency. If the cycle is preserved, blood sampling is advisable at the time of its greatest rise, after the corpus luteum bloom phase, - on the 25th-27th day of the cycle (at the end of the rise in rectal temperature in the 2nd phase); in oligo- and amenorrhea - against the background of a long delay. If hyperprolactinemia is detected, to exclude hypothyroid genesis, its 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). Blood for these hormones is taken on any day of the cycle.

Estradiol (E1) levels are determined both in the 1st and 2nd phases of the cycle to assess the degree of estrogen saturation before treatment with ovulation stimulants or to exclude hyperestrogenism. To assess the adequacy of the 2nd phase of the cycle, it is necessary to re-measure the progesterone level on days 19-21 and 24-26 of the cycle.

The levels of testosterone (T), cortisol (K), adrenocorticotropic hormone (ACTH), DHEA (dehydroepiandrosterone), and Al (androstenedione) are usually examined on the 5th-7th day of the cycle as part of the differential diagnosis of various forms of hyperandrogenism.

Additional hormonal tests for assessing the level of damage in the sexual function regulation system include functional tests with hormones (gestagens, estrogens and gestagens, ovulation stimulants, LH-RH, TRH, dexamethasone, etc.).

Modern methods of additional laboratory testing of patients with various menstrual cycle disorders include:

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

Computer and magnetic resonance imaging - for the diagnosis of pituitary microadenomas, detection of ovarian and adrenal tumors.

Visual field examination (in two colors) - to exclude suprasellar growth of the pituitary tumor.

Determination of the karyotype - in case of primary amenorrhea to exclude genetic abnormalities.

Instrumental research methods

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 identify the initial stages of the development of uterine fibroids, to differentiate true ovarian tumors and their cystic enlargement. The method allows monitoring 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).

Thyroid ultrasound allows you to assess the size of the thyroid gland, the presence of nodular and cystic formations, and identify signs characteristic of chronic thyroiditis. The presence of nodules and cysts is an indication for a puncture biopsy. The question of further management tactics is decided jointly with an endocrinologist.

Examination of the mammary glands is a mandatory method of examination of patients with menstrual cycle disorders. Clinical examination includes inspection and palpation of the glands, regional lymph nodes, lactorea control, and ultrasound. Mammography is performed on women over 35 years old, younger women - only according to indications, when nodular or cystic changes in the glands are detected during ultrasound. The examination is performed on the 5th-7th day with a preserved cycle, with amenorrhea - on any day. The activity of lactorea is more pronounced towards the end of the cycle.

Hysterosalpingography (HSG) is indicated to exclude uterine malformations, uterine adhesions, tumor nodes, uterine hypoplasia. It is performed in the first half of the saved cycle in the absence of signs of infection, changes in blood tests, urine, vaginal smears.

Endoscopic examination methods

Laparoscopy is indicated for menstrual cycle disorders, especially in combination with infertility, when there is a suspicion of organic changes in the pelvic organs or in the case of ineffectiveness of long-term hormonal therapy, as well as when it is necessary to perform an ovarian biopsy.

Hysteroscopy is indicated for menstrual cycle disorders, infertility, menorrhagia and metrorrhagia, and suspected intrauterine pathology based on ultrasound and hysterosalpingography (HSG).

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