Menstrual cycle, its regulation. Neurohumoral regulation of female reproductive function

Chapter 2. Neuroendocrine regulation of the menstrual cycle

Menstrual cycle - genetically determined, cyclically repeating changes in a woman's body, especially in the parts of the reproductive system, the clinical manifestation of which is blood discharge from the genital tract (menstruation).

The menstrual cycle is established after menarche (first menstruation) and persists throughout the reproductive (childbearing) period of a woman's life until menopause (last menstruation). Cyclic changes in a woman's body are aimed at the possibility of reproduction of offspring and are two-phase in nature: the 1st (follicular) phase of the cycle is determined by the growth and maturation of the follicle and egg in the ovary, after which the follicle ruptures and the egg leaves it - ovulation; The 2nd (luteal) phase is associated with the formation of the corpus luteum. At the same time, in a cyclic mode, successive changes occur in the endometrium: regeneration and proliferation of the functional layer, followed by secretory transformation of the glands. Changes in the endometrium end with desquamation of the functional layer (menstruation).

The biological significance of the changes that occur during the menstrual cycle in the ovaries and endometrium is to ensure reproductive function after the maturation of the egg, its fertilization and implantation of the embryo in the uterus. If fertilization of the egg does not occur, the functional layer of the endometrium is rejected, blood secretions appear from the genital tract, and processes aimed at ensuring the maturation of the egg occur again and in the same sequence in the reproductive system.

Menstruation - this is blood discharge from the genital tract, repeated at certain intervals, throughout the entire reproductive period, excluding pregnancy and lactation. Menstruation begins at the end of the luteal phase of the menstrual cycle as a result of shedding of the functional layer of the endometrium. First menstruation (menarhe) occurs at the age of 10-12 years. Over the next 1-1.5 years, menstruation may be irregular, and only then a regular menstrual cycle is established.

The first day of menstruation is conditionally taken as the 1st day of the menstrual cycle, and the duration of the cycle is calculated as the interval between the first days of two consecutive menstruation.

External parameters of the normal menstrual cycle:

Duration - from 21 to 35 days (60% of women have an average cycle length of 28 days);

The duration of menstrual flow is from 3 to 7 days;

The amount of blood loss on menstrual days is 40-60 ml (on average

50 ml).

The processes that ensure the normal course of the menstrual cycle are regulated by a single functionally connected neuroendocrine system, including the central (integrating) departments, peripheral (effector) structures, as well as intermediate links.

The functioning of the reproductive system is ensured by a strictly genetically programmed interaction of five main levels, each of which is regulated by overlying structures according to the principle of direct and inverse, positive and negative relationships (Fig. 2.1).

The first (highest) level of regulation reproductive system are cortex and extrahypothalamic cerebral structures

(limbic system, hippocampus, amygdala). An adequate state of the central nervous system ensures the normal functioning of all the underlying parts of the reproductive system. Various organic and functional changes in the cortex and subcortical structures can lead to menstrual irregularities. The possibility of stopping menstruation during severe stress (loss of loved ones, wartime conditions, etc.) or without obvious external influences with general mental imbalance (“false pregnancy” is a delay in menstruation with a strong desire for pregnancy or, conversely, with its fear) is well known. ).

Specific brain neurons receive information about the state of both the external and internal environment. Internal exposure is carried out using specific receptors for ovarian steroid hormones (estrogens, progesterone, androgens) located in the central nervous system. In response to the influence of environmental factors on the cerebral cortex and extrahypothalamic structures, synthesis, excretion and metabolism occur. neurotransmitters and neuropeptides. In turn, neurotransmitters and neuropeptides influence the synthesis and release of hormones by the neurosecretory nuclei of the hypothalamus.

to the most important neurotransmitters, those. Substances-transmitters of nerve impulses include norepinephrine, dopamine, γ-aminobutyric acid (GABA), acetylcholine, serotonin and melatonin. Norepinephrine, acetylcholine and GABA stimulate the release of gonadotropic releasing hormone (GnRH) by the hypothalamus. Dopamine and serotonin reduce the frequency and amplitude of GnRH production during the menstrual cycle.

Neuropeptides(endogenous opioid peptides, neuropeptide Y, galanin) are also involved in the regulation of the function of the reproductive system. Opioid peptides (endorphins, enkephalins, dynorphins), binding to opiate receptors, lead to suppression of GnRH synthesis in the hypothalamus.

Rice. 2.1. Hormonal regulation in the system hypothalamus - pituitary gland - peripheral endocrine glands - target organs (scheme): RG - releasing hormones; TSH - thyroid-stimulating hormone; ACTH - adrenococtotropic hormone; FSH - follicle-stimulating hormone; LH - luteinizing hormone; Prl - prolactin; P - progesterone; E - estrogens; A - androgens; P - relaxin; I - ingi-bin; T 4 - thyroxine, ADH - antidiuretic hormone (vasopressin)

Second level regulation of reproductive function is hypothalamus. Despite its small size, the hypothalamus is involved in the regulation of sexual behavior, controls vegetovascular reactions, body temperature and other vital body functions.

Hypophysiotropic zone of the hypothalamus represented by groups of neurons that make up the neurosecretory nuclei: ventromedial, dorsomedial, arcuate, supraoptic, paraventricular. These cells have the properties of both neurons (reproducing electrical impulses) and endocrine cells that produce specific neurosecrets with diametrically opposite effects (liberins and statins). liberins, or releasing factors, stimulate the release of appropriate tropic hormones in the anterior pituitary gland. Statins have an inhibitory effect on their release. Currently, seven liberins are known, which are decapeptides by their nature: thyreoliberin, corticoliberin, somatoliberin, melanoliberin, folliberin, luliberin, prolactoliberin, as well as three statins: melanostatin, somatostatin, prolactostatin, or prolactin inhibitory factor.

Luliberin, or luteinizing hormone-releasing hormone (LHRH), has been isolated, synthesized, and described in detail. To date, it has not been possible to isolate and synthesize follicle-stimulating releasing hormone. However, it has been established that RGHL and its synthetic analogues stimulate the release of not only LH, but also FSH by gonadotrophs. In this regard, one term has been adopted for gonadotropic liberins - "gonadotropin-releasing hormone" (GnRH), which, in fact, is a synonym for luliberin (RHRH).

The main site of GnRH secretion is the arcuate, supraoptic, and paraventricular nuclei of the hypothalamus. The arcuate nuclei reproduce a secretory signal with a frequency of approximately 1 pulse per 1-3 hours, i.e. in pulsating or circhoral mode (circhoral- around the hour). These pulses have a certain amplitude and cause a periodic flow of GnRH through the portal bloodstream to the cells of the adenohypophysis. Depending on the frequency and amplitude of GnRH pulses, the adenohypophysis predominantly secretes LH or FSH, which, in turn, causes morphological and secretory changes in the ovaries.

The hypothalamic-pituitary region has a special vascular network called portal system. A feature of this vascular network is the ability to transmit information both from the hypothalamus to the pituitary gland, and vice versa (from the pituitary gland to the hypothalamus).

The regulation of prolactin release is largely under statin influence. Dopamine, produced in the hypothalamus, inhibits the release of prolactin from the lactotrophs of the adenohypophysis. Thyreoliberin, as well as serotonin and endogenous opioid peptides, contribute to an increase in prolactin secretion.

In addition to liberins and statins, two hormones are produced in the hypothalamus (supraoptic and paraventricular nuclei): oxytocin and vasopressin (antidiuretic hormone). Granules containing these hormones migrate from the hypothalamus along the axons of large cell neurons and accumulate in the posterior pituitary gland (neurohypophysis).

Third level regulation of reproductive function is the pituitary gland, it consists of an anterior, posterior and intermediate (middle) lobe. Directly related to the regulation of reproductive function is anterior lobe (adenohypophysis) . Under the influence of the hypothalamus, gonadotropic hormones are secreted in the adenohypophysis - FSH (or follitropin), LH (or lutropin), prolactin (Prl), ACTH, somatotropic (STH) and thyroid-stimulating (TSH) hormones. The normal functioning of the reproductive system is possible only with a balanced selection of each of them.

Gonadotropic hormones (FSH, LH) of the anterior pituitary gland are under the control of GnRH, which stimulates their secretion and release into the bloodstream. The pulsating nature of the secretion of FSH, LH is the result of "direct signals" from the hypothalamus. The frequency and amplitude of GnRH secretion impulses varies depending on the phases of the menstrual cycle and affects the concentration and ratio of FSH/LH in blood plasma.

FSH stimulates the growth of follicles in the ovary and the maturation of the egg, the proliferation of granulosa cells, the formation of FSH and LH receptors on the surface of granulosa cells, the activity of aromatase in the maturing follicle (this enhances the conversion of androgens to estrogens), the production of inhibin, activin and insulin-like growth factors.

LH promotes the formation of androgens in theca cells, provides ovulation (together with FSH), stimulates the synthesis of progesterone in luteinized granulosa cells (yellow body) after ovulation.

Prolactin has a variety of effects on the body of a woman. Its main biological role is to stimulate the growth of the mammary glands, regulate lactation; it also has a fat-mobilizing and hypotensive effect, controls the secretion of progesterone by the corpus luteum by activating the formation of LH receptors in it. During pregnancy and lactation, the level of prolactin in the blood increases. Hyperprolactinemia leads to impaired growth and maturation of follicles in the ovary (anovulation).

Posterior pituitary gland (neurohypophysis) is not an endocrine gland, but only deposits the hormones of the hypothalamus (oxytocin and vasopressin), which are in the body in the form of a protein complex.

ovaries relate to the fourth level regulation of the reproductive system and perform two main functions. In the ovaries, cyclic growth and maturation of follicles, maturation of the egg, i.e. a generative function is carried out, as well as the synthesis of sex steroids (estrogens, androgens, progesterone) - a hormonal function.

The main morphofunctional unit of the ovary is follicle. At birth, a girl's ovaries contain approximately 2 million primordial follicles. Most of them (99%) undergo atresia (reverse development of follicles) during their lifetime. Only a very small part of them (300-400) goes through a full development cycle - from primordial to preovulatory with the subsequent formation of the corpus luteum. By the time of menarche, the ovaries contain 200-400 thousand primordial follicles.

The ovarian cycle consists of two phases: follicular and luteal. Follicular phase begins after menstruation, associated with growth

and maturation of follicles and ends with ovulation. luteal phase occupies the interval after ovulation until the onset of menstruation and is associated with the formation, development and regression of the corpus luteum, the cells of which secrete progesterone.

Depending on the degree of maturity, four types of follicles are distinguished: primordial, primary (preantral), secondary (antral) and mature (preovulatory, dominant) (Fig. 2.2).

Rice. 2.2. The structure of the ovary (diagram). Stages of development of the dominant follicle and corpus luteum: 1 - ligament of the ovary; 2 - protein coat; 3 - vessels of the ovary (the final branch of the ovarian artery and vein); 4 - primordial follicle; 5 - preantral follicle; 6 - antral follicle; 7 - preovulatory follicle; 8 - ovulation; 9 - corpus luteum; 10 - white body; 11 - egg (oocyte); 12 - basement membrane; 13 - follicular fluid; 14 - egg tubercle; 15 - theca-shell; 16 - shiny shell; 17 - granulosa cells

Primordial follicle consists of an immature egg (oocyte) in the prophase of the 2nd meiotic division, which is surrounded by a single layer of granulosa cells.

AT preantral (primary) follicle the oocyte increases in size. The cells of the granular epithelium proliferate and round, forming a granular layer of the follicle. From the surrounding stroma, a connective-nonwoven sheath is formed - theca (theca).

Antral (secondary) follicle characterized by further growth: the proliferation of cells of the granulosa layer continues, which produce follicular fluid. The resulting fluid pushes the egg to the periphery, where the cells of the granular layer form an egg tubercle (cumulus oophorus). The connective tissue membrane of the follicle is clearly differentiated into external and internal. Inner shell (the-ca interna) consists of 2-4 layers of cells. outer shell (theca externa) is located above the internal and is represented by a differentiated connective tissue stroma.

AT preovulatory (dominant) follicle the ovum located on the egg tubercle is covered with a membrane called the zona pellucida (zona pellucida). In the oocyte of the dominant follicle, the process of meiosis resumes. During maturation, a hundredfold increase in the volume of follicular fluid occurs in the preovulatory follicle (the diameter of the follicle reaches 20 mm) (Fig. 2.3).

During each menstrual cycle, 3 to 30 primordial follicles begin to grow, transforming into preantral (primary) follicles. In the subsequent menstrual cycle, follicle-logogenesis continues and only one follicle develops from preantral to preovulatory. During the growth of the follicle from preantral to antral

Rice. 2.3. Dominant follicle in the ovary. Laparoscopy

granulosa cells synthesize anti-Mullerian hormone, which contributes to its development. The remaining follicles that initially entered into growth undergo atresia (degeneration).

Ovulation - rupture of the preovulatory (dominant) follicle and the release of the egg from it into the abdominal cavity. Ovulation is accompanied by bleeding from the destroyed capillaries surrounding the theca cells (Fig. 2.4).

After the release of the egg, the resulting capillaries quickly grow into the remaining cavity of the follicle. Granulosa cells undergo luteinization, morphologically manifested in an increase in their volume and the formation of lipid inclusions - a corpus luteum(Fig. 2.5).

Rice. 2.4. Ovarian follicle after ovulation. Laparoscopy

Rice. 2.5. The corpus luteum of the ovary. Laparoscopy

Yellow body - transient hormonally active formation, functioning for 14 days, regardless of the total duration of the menstrual cycle. If pregnancy does not occur, the corpus luteum regresses, but if fertilization occurs, it functions until the formation of the placenta (12th week of pregnancy).

Hormonal function of the ovaries

Growth, maturation of follicles in the ovaries and the formation of the corpus luteum are accompanied by the production of sex hormones by both the granulosa cells of the follicle and the cells of the internal theca and, to a lesser extent, the external theca. The sex steroid hormones include estrogens, progesterone, and androgens. The starting material for the formation of all steroid hormones is cholesterol. Up to 90% of steroid hormones are in a bound state, and only 10% of unbound hormones have their biological effect.

Estrogens are divided into three fractions with different activity: estradiol, estriol, estrone. Estrone - the least active fraction, is secreted by the ovaries mainly during aging - in postmenopause; the most active fraction is estradiol, it is significant in the onset and maintenance of pregnancy.

The amount of sex hormones changes throughout the menstrual cycle. As the follicle grows, the synthesis of all sex hormones increases, but mainly estrogen. In the period after ovulation and before the onset of menstruation, progesterone is predominantly synthesized in the ovaries, secreted by the cells of the corpus luteum.

Androgens (androstenedione and testosterone) are produced by the thecal cells of the follicle and interstitial cells. Their level during the menstrual cycle does not change. Getting into granulosa cells, androgens actively undergo aromatization, leading to their conversion into estrogens.

In addition to steroid hormones, the ovaries also secrete other biologically active compounds: prostaglandins, oxytocin, vasopressin, relaxin, epidermal growth factor (EGF), insulin-like growth factors (IPFR-1 and IPFR-2). It is believed that growth factors contribute to the proliferation of granulosa cells, the growth and maturation of the follicle, and the selection of the dominant follicle.

In the process of ovulation, prostaglandins (F 2a and E 2) play a certain role, as well as proteolytic enzymes contained in the follicular fluid, collagenase, oxytocin, relaxin.

The cyclical activity of the reproductive system is determined by the principles of direct and feedback, which is provided by specific hormone receptors in each of the links. A direct link is the stimulating effect of the hypothalamus on the pituitary gland and the subsequent formation of sex steroids in the ovary. Feedback is determined by the influence of an increased concentration of sex steroids on the overlying levels, blocking their activity.

In the interaction of the links of the reproductive system, "long", "short" and "ultra-short" loops are distinguished. "Long" loop - impact through the receptors of the hypothalamic-pituitary system on the production of sex hormones. The "short" loop determines the connection between the pituitary gland and the hypothalamus, the "ultrashort" loop determines the connection between the hypothalamus and nerve cells, which, under the influence of electrical stimuli, carry out local regulation with the help of neurotransmitters, neuropeptides, and neuromodulators.

Follicular phase

The pulsatile secretion and release of GnRH leads to the release of FSH and LH from the anterior pituitary gland. LH promotes the synthesis of androgens by theca cells of the follicle. FSH acts on the ovaries and leads to follicle growth and oocyte maturation. At the same time, an increasing level of FSH stimulates the production of estrogens in granulosa cells by aromatization of androgens formed in the thecal cells of the follicle, and also promotes the secretion of inhibin and IPFR-1-2. Before ovulation, the number of receptors for FSH and LH in theca and granulosa cells increases (Fig. 2.6).

Ovulation occurs in the middle of the menstrual cycle, 12-24 hours after reaching the peak of estradiol, causing an increase in the frequency and amplitude of GnRH secretion and a sharp preovulatory rise in LH secretion by the type of "positive feedback". Against this background, proteolytic enzymes are activated - collagenase and plasmin, which destroy the collagen of the follicle wall and thus reduce its strength. At the same time, the observed increase in the concentration of prostaglandin F 2a, as well as oxytocin, induces rupture of the follicle as a result of their stimulation of smooth muscle contraction and the expulsion of the oocyte with the oviparous tubercle from the cavity of the follicle. Rupture of the follicle is also facilitated by an increase in the concentration of prostaglandin E 2 and relaxin in it, which reduce the rigidity of its walls.

luteal phase

After ovulation, the level of LH decreases in relation to the "ovulatory peak". However, this amount of LH stimulates the process of luteinization of granulosa cells remaining in the follicle, as well as the predominant secretion of progesterone by the corpus luteum formed. The maximum secretion of progesterone occurs on the 6-8th day of the existence of the corpus luteum, which corresponds to the 20-22nd day of the menstrual cycle. Gradually, by the 28-30th day of the menstrual cycle, the level of progesterone, estrogen, LH and FSH decreases, the corpus luteum regresses and is replaced by connective tissue (white body).

Fifth level regulation of reproductive function are target organs sensitive to fluctuations in the level of sex steroids: uterus, fallopian tubes, vaginal mucosa, as well as mammary glands, hair follicles, bones, adipose tissue, central nervous system.

Ovarian steroid hormones affect metabolic processes in organs and tissues that have specific receptors. These receptors can be

Rice. 2.6. Hormonal regulation of the menstrual cycle (scheme): a - changes in the level of hormones; b - changes in the ovary; c - changes in the endometrium

both cytoplasmic and nuclear. Cytoplasmic receptors are highly specific for estrogen, progesterone, and testosterone. Steroids penetrate into target cells by binding to specific receptors - respectively, to estrogen, progesterone, testosterone. The resulting complex enters the cell nucleus, where, by combining with chromatin, it provides the synthesis of specific tissue proteins through the transcription of messenger RNA.

Uterus consists of the outer (serous) cover, myometrium and endometrium. Endometrium morphologically consists of two layers: basal and functional. The basal layer during the menstrual cycle does not change significantly. The functional layer of the endometrium undergoes structural and morphological changes, manifested by a successive change of stages proliferation, secretion, desquamation followed by

regeneration. Cyclic secretion of sex hormones (estrogens, progesterone) leads to biphasic changes in the endometrium, aimed at the perception of a fertilized egg.

Cyclic changes in the endometrium concern its functional (superficial) layer, consisting of compact epithelial cells that are rejected during menstruation. The basal layer, which is not rejected during this period, ensures the restoration of the functional layer.

The following changes occur in the endometrium during the menstrual cycle: desquamation and rejection of the functional layer, regeneration, proliferation phase and secretion phase.

The transformation of the endometrium occurs under the influence of steroid hormones: the proliferation phase - under the predominant action of estrogens, the secretion phase - under the influence of progesterone and estrogens.

Proliferation phase(corresponds to the follicular phase in the ovaries) lasts an average of 12-14 days, starting from the 5th day of the cycle. During this period, a new surface layer is formed with elongated tubular glands lined with a cylindrical epithelium with increased mitotic activity. The thickness of the functional layer of the endometrium is 8 mm (Fig. 2.7).

Secretion phase (luteal phase in the ovaries) associated with the activity of the corpus luteum, lasts 14±1 days. During this period, the epithelium of the endometrial glands begins to produce a secret containing acidic glycosaminoglycans, glycoproteins, glycogen (Fig. 2.8).

Rice. 2.7. Endometrium in the proliferation phase (middle stage). Stained with hematoxylin and eosin, × 200. Photo by O.V. Zayratyan

Rice. 2.8. Endometrium in the secretion phase (middle stage). Stained with hematoxylin and eosin, ×200. Photo by O.V. Zayratyan

Secretion activity becomes highest on the 20-21st day of the menstrual cycle. By this time, the maximum amount of proteolytic enzymes is found in the endometrium, and decidual transformations occur in the stroma. There is a sharp vascularization of the stroma - the spiral arteries of the functional layer are tortuous, form "tangles", the veins are dilated. Such changes in the endometrium, observed on the 20-22nd day (6-8th day after ovulation) of the 28-day menstrual cycle, provide the best conditions for the implantation of a fertilized egg.

By the 24-27th day, due to the beginning of the regression of the corpus luteum and a decrease in the concentration of the progesterone produced by it, the endometrial trophism is disturbed, and degenerative changes gradually increase in it. From the granular cells of the endometrial stroma, granules containing relaxin are released, which prepares the menstrual rejection of the mucous membrane. In the superficial areas of the compact layer, lacunar expansion of capillaries and hemorrhages in the stroma are noted, which can be detected 1 day before the onset of menstruation.

Menstruation includes desquamation, rejection and regeneration of the functional layer of the endometrium. Due to the regression of the corpus luteum and a sharp decrease in the content of sex steroids in the endometrium, hypoxia increases. The onset of menstruation is facilitated by a prolonged spasm of the arteries, leading to blood stasis and the formation of blood clots. Tissue hypoxia (tissue acidosis) is exacerbated by increased permeability of the endothelium, fragility of vessel walls, numerous small hemorrhages, and massive leukemia.

cytic infiltration. Lysosomal proteolytic enzymes released from leukocytes enhance the melting of tissue elements. Following a prolonged spasm of the vessels, their paretic expansion occurs with increased blood flow. At the same time, there is an increase in hydrostatic pressure in the microvasculature and a rupture of the walls of the vessels, which by this time have largely lost their mechanical strength. Against this background, active desquamation of necrotic areas of the functional layer of the endometrium occurs. By the end of the 1st day of menstruation, 2/3 of the functional layer is rejected, and its complete desquamation usually ends on the 3rd day of the menstrual cycle.

Regeneration of the endometrium begins immediately after the rejection of the necrotic functional layer. The basis for regeneration is the epithelial cells of the stroma of the basal layer. Under physiological conditions, already on the 4th day of the cycle, the entire wound surface of the mucous membrane is epithelialized. This is again followed by cyclic changes in the endometrium - the phases of proliferation and secretion.

Successive changes throughout the cycle in the endometrium - proliferation, secretion and menstruation - depend not only on cyclic fluctuations in the level of sex steroids in the blood, but also on the state of tissue receptors for these hormones.

The concentration of nuclear estradiol receptors increases until the middle of the cycle, reaching a peak by the late period of the endometrial proliferation phase. After ovulation, a rapid decrease in the concentration of nuclear estradiol receptors occurs, continuing until the late secretory phase, when their expression becomes significantly lower than at the beginning of the cycle.

Functional state fallopian tubes varies depending on the phase of the menstrual cycle. So, in the luteal phase of the cycle, the ciliated apparatus of the ciliated epithelium and the contractile activity of the muscle layer are activated, aimed at optimal transport of the sex gametes into the uterine cavity.

Changes in extragenital target organs

All sex hormones not only determine functional changes in the reproductive system itself, but also actively influence metabolic processes in other organs and tissues that have receptors for sex steroids.

In the skin, under the influence of estradiol and testosterone, collagen synthesis is activated, which helps to maintain its elasticity. Increased sebum, acne, folliculitis, skin porosity and excessive hairiness occur with an increase in androgen levels.

In bones, estrogens, progesterone, and androgens support normal remodeling by preventing bone resorption. The balance of sex steroids affects the metabolism and distribution of adipose tissue in the female body.

The effect of sex hormones on receptors in the central nervous system and hippocampal structures is associated with changes in the emotional sphere and

reactions in a woman in the days preceding menstruation - the phenomenon of "menstrual wave". This phenomenon is manifested by an imbalance in the processes of activation and inhibition in the cerebral cortex, fluctuations in the sympathetic and parasympathetic nervous system (especially affecting the cardiovascular system). External manifestations of these fluctuations are mood changes and irritability. In healthy women, these changes do not go beyond the physiological boundaries.

Influence of the thyroid gland and adrenal glands on reproductive function

Thyroid produces two iodamine acid hormones - triiodothyronine (T 3) and thyroxine (T 4), which are the most important regulators of metabolism, development and differentiation of all body tissues, especially thyroxine. Thyroid hormones have a certain effect on the protein-synthetic function of the liver, stimulating the formation of globulin that binds sex steroids. This is reflected in the balance of free (active) and bound ovarian steroids (estrogens, androgens).

With a lack of T 3 and T 4, the secretion of thyreoliberin increases, which activates not only thyrotrophs, but also pituitary lactotrophs, which often causes hyperprolactinemia. In parallel, the secretion of LH and FSH decreases with inhibition of follicle and steroidogenesis in the ovaries.

An increase in the level of T 3 and T 4 is accompanied by a significant increase in the concentration of globulin that binds sex hormones in the liver and leads to a decrease in the free fraction of estrogens. Hypoestrogenism, in turn, leads to a violation of the maturation of the follicles.

Adrenals. Normally, the production of androgens - androstenedione and testosterone - in the adrenal glands is the same as in the ovaries. In the adrenal glands, the formation of DHEA and DHEA-S occurs, while these androgens are practically not synthesized in the ovaries. DHEA-S, which is secreted in the largest amount (compared to other adrenal androgens), has a relatively low androgenic activity and serves as a kind of reserve form of androgens. Suprarenal androgens, along with androgens of ovarian origin, are the substrate for extragonadal estrogen production.

Assessment of the state of the reproductive system according to tests of functional diagnostics

For many years, so-called tests of functional diagnostics of the state of the reproductive system have been used in gynecological practice. The value of these rather simple studies has been preserved to the present day. The most commonly used is the measurement of basal temperature, the assessment of the "pupil" phenomenon and the state of the cervical mucus (its crystallization, extensibility), as well as the calculation of the karyopyknotic index (KPI,%) of the vaginal epithelium (Fig. 2.9).

Rice. 2.9. Functional diagnostic tests for a two-phase menstrual cycle

Basal temperature test is based on the ability of progesterone (in increased concentration) to directly affect the thermoregulatory center in the hypothalamus. Under the influence of progesterone in the 2nd (luteal-new) phase of the menstrual cycle, a transient hyperthermic reaction occurs.

The patient daily measures the temperature in the rectum in the morning without getting out of bed. The results are displayed graphically. With a normal two-phase menstrual cycle, the basal temperature in the 1st (follicular) phase of the menstrual cycle does not exceed 37 ° C, in the 2nd (luteal) phase there is an increase in rectal temperature by 0.4-0.8 ° C compared to the initial value . On the day of menstruation or 1 day before it begins, the corpus luteum in the ovary regresses, the level of progesterone decreases, and therefore the basal temperature decreases to its original values.

A persistent two-phase cycle (basal temperature should be measured over 2-3 menstrual cycles) indicates that ovulation has occurred and the functional usefulness of the corpus luteum. The absence of a temperature rise in the 2nd phase of the cycle indicates the absence of ovulation (anovulation); rise delay, its short duration (temperature increase by 2-7 days) or insufficient rise (by 0.2-0.3 ° C) - for an inferior function of the corpus luteum, i.e. insufficient production of progesterone. A false positive result (an increase in basal temperature in the absence of a corpus luteum) is possible with acute and chronic infections, with some changes in the central nervous system, accompanied by increased excitability.

Symptom "pupil" reflects the amount and condition of the mucous secretion in the cervical canal, which depend on the estrogen saturation of the body. The "pupil" phenomenon is based on the expansion of the external os of the cervical canal due to the accumulation of transparent vitreous mucus in it and is assessed when examining the cervix using vaginal mirrors. Depending on the severity of the symptom of the "pupil" is evaluated in three degrees: +, ++, +++.

The synthesis of cervical mucus during the 1st phase of the menstrual cycle increases and becomes maximum immediately before ovulation, which is associated with a progressive increase in estrogen levels during this period. On preovulatory days, the dilated external opening of the cervical canal resembles a pupil (+++). In the 2nd phase of the menstrual cycle, the amount of estrogen decreases, progesterone is predominantly produced in the ovaries, so the amount of mucus decreases (+), and before menstruation it is completely absent (-). The test cannot be used for pathological changes in the cervix.

Symptom of crystallization of cervical mucus(the phenomenon of "fern") When drying, it is most pronounced during ovulation, then crystallization gradually decreases, and is completely absent before menstruation. Crystallization of air-dried mucus is also evaluated in points (from 1 to 3).

Symptom of cervical mucus tension is directly proportional to the level of estrogen in the female body. To conduct a test, mucus is removed from the cervical canal with a forceps, the jaws of the instrument are slowly moved apart, determining the degree of tension (the distance at which the mucus "breaks"). The maximum stretching of the cervical mucus (up to 10-12 cm) occurs during the period of the highest concentration of estrogens - in the middle of the menstrual cycle, which corresponds to ovulation.

Mucus can be negatively affected by inflammatory processes in the genital organs, as well as hormonal imbalances.

Karyopyknotic index(KPI). Under the influence of estrogens, cells of the basal layer of the stratified squamous epithelium of the vagina proliferate, and therefore the number of keratinizing (exfoliating, dying) cells increases in the surface layer. The first stage of cell death is changes in their nucleus (karyopyknosis). CPI is the ratio of the number of cells with a pycnotic nucleus (i.e., keratinizing) to the total number of epithelial cells in a smear, expressed as a percentage. At the beginning of the follicular phase of the menstrual cycle, CPI is 20-40%, on preovulatory days it rises to 80-88%, which is associated with a progressive increase in estrogen levels. In the luteal phase of the cycle, the level of estrogen decreases, therefore, the CPI decreases to 20-25%. Thus, the quantitative ratios of cellular elements in smears of the vaginal mucosa make it possible to judge the saturation of the body with estrogens.

Currently, especially in the in vitro fertilization (IVF) program, follicle maturation, ovulation and corpus luteum formation are determined by dynamic ultrasound.

test questions

1. Describe the normal menstrual cycle.

2. Specify the levels of regulation of the menstrual cycle.

3. List the principles of direct and feedback.

4. What changes occur in the ovaries during a normal menstrual cycle?

5. What changes occur in the uterus during a normal menstrual cycle?

6. Name the tests of functional diagnostics.

Gynecology: textbook / B. I. Baisova and others; ed. G. M. Savelyeva, V. G. Breusenko. - 4th ed., revised. and additional - 2011. - 432 p. : ill.

List of abbreviations:

ADH - antidiuretic hormone
ACTH - corticoliberin
aRG-GN - gonadotropin releasing hormone agonist
LH - luteinizing hormone
OP - oxyprogesterone
RG-GN - gonadotropin releasing hormone
STH - somatoliberin
VEGF - vascular endothelial growth factor
TSH - thyrotropic hormone (thyroliberin)
FSH - follicle stimulating hormone
FGF - fibroplastic growth factor

Normal menstrual cycle

Menses- this is bloody discharge from the genital tract of a woman, periodically occurring as a result of rejection of the functional layer of the endometrium at the end of a two-phase menstrual cycle.

The complex of cyclic processes that occur in the female body and are externally manifested by menstruation is called the menstrual cycle. Menstruation begins as a response to a change in the level of steroids produced by the ovaries.

Clinical signs of a normal menstrual cycle

The duration of the menstrual cycle in the active reproductive period of a woman is an average of 28 days. A cycle length of 21 to 35 days is considered normal. Large intervals are observed during puberty and menopause, which may be a manifestation of anovulation, which may occur most often at this time.

Usually menstruation lasts from 3 to 7 days, the amount of blood lost is negligible. Shortening or lengthening of menstrual bleeding, as well as the appearance of scanty or heavy menstruation, can serve as a manifestation of a number of gynecological diseases.

Characteristics of a normal menstrual cycle:

Duration: 28±7 days;

Duration of menstrual bleeding: 4±2 days;

Volume of blood loss during menstruation: 20-60 ml * ;

Average iron loss: 16 mg

* 95 percent of healthy women lose less than 60 ml of blood with each menstruation. Blood loss of more than 60-80 ml is combined with a decrease in hemoglobin, hematocrit and serum iron.

Physiology of menstrual bleeding:

Immediately before menstruation, a pronounced spasm of the spiral arterioles develops. After dilatation of the spiral arterioles, menstrual bleeding begins. At first, platelet adhesion in the endometrial vessels is suppressed, but then, as blood transudation progresses, the damaged ends of the vessels are sealed with intravascular thrombi, consisting of platelets and fibrin. 20 hours after the onset of menstruation, when most of the endometrium has already been torn away, a pronounced spasm of spiral arterioles develops, due to which hemostasis is achieved. Regeneration of the endometrium begins 36 hours after the onset of menstruation, despite the fact that the rejection of the endometrium is not yet fully completed.

The regulation of the menstrual cycle is a complex neurohumoral mechanism, which is carried out with the participation of 5 main links of regulation. These include: the cerebral cortex, subcortical centers (hypothalamus), pituitary gland, sex glands, peripheral organs and tissues (uterus, fallopian tubes, vagina, mammary glands, hair follicles, bones, adipose tissue). The latter are called target organs, due to the presence of receptors that are sensitive to the action of hormones that the ovary produces during the menstrual cycle. Cytosol receptors - receptors of the cytoplasm, have a strict specificity for estradiol, progesterone, testosterone, while nuclear receptors can be acceptors of molecules such as insulin, glucagon, aminopeptides.

Receptors for sex hormones are found in all structures of the reproductive system, as well as in the central nervous system, skin, adipose and bone tissue, and the mammary gland. A free steroid hormone molecule is captured by a specific cytosol receptor of a protein nature, the resulting complex is translocated to the cell nucleus. A new complex with a nuclear protein receptor appears in the nucleus; this complex binds to chromatin, which regulates mRNA transcription and is involved in the synthesis of a specific tissue protein. The intracellular mediator - cyclic adenosine monophosphoric acid (cAMP) regulates the metabolism in the cells of the target tissue in accordance with the needs of the body in response to the effects of hormones. The bulk of steroid hormones (about 80% is in the blood and is transported in a bound form. Their transport is carried out by special proteins - steroid-binding globulins and non-specific transport systems (albumins and erythrocytes). In a bound form, steroids are inactive, therefore globulins, albumins and erythrocytes can be considered as a kind of buffer system that controls the access of steroids to the receptors of target cells.

Cyclic functional changes occurring in a woman's body can be conditionally divided into changes in the hypothalamus-pituitary-ovaries system (ovarian cycle) and the uterus, primarily in its mucous membrane (uterine cycle).

Along with this, as a rule, cyclic shifts occur in all organs and systems of a woman, in particular, in the central nervous system, cardiovascular system, thermoregulation system, metabolic processes, etc.

Hypothalamus

The hypothalamus is the part of the brain located above the optic chiasm and forming the bottom of the third ventricle. It is an old and stable component of the central nervous system, the general organization of which has changed little during human evolution. Structurally and functionally, the hypothalamus is related to the pituitary gland. There are three hypothalamic regions: anterior, posterior, and intermediate. Each area is formed by nuclei - accumulations of bodies of neurons of a certain type.

In addition to the pituitary gland, the hypothalamus affects the limbic system (amygdala, hippocampus), thalamus, and pons. These departments also directly or indirectly affect the hypothalamus.

The hypothalamus secretes liberins and statins. This process is regulated by hormones that close three feedback loops: long, short and ultrashort. A long feedback loop is provided by circulating sex hormones that bind to the corresponding receptors in the hypothalamus, a short one: adenohypophysis hormones, an ultrashort one: liberins and statins. Liberins and statins regulate the activity of the adenohypophysis. Gonadoliberin stimulates the secretion of LH and FSH, corticoliberin - ACTH, somatoliberin (STG), thyroliberin (TSH). In addition to liberins and statins, antidiuretic hormone and oxytocin are synthesized in the hypothalamus. These hormones are transported to the neurohypophysis, from where they enter the bloodstream.

Unlike the capillaries of other areas of the brain, the capillaries of the funnel of the hypothalamus are fenestrated. They form the primary capillary network of the portal system.

In the 70-80s. a series of experimental studies was performed on monkeys, which made it possible to identify differences in the function of the neurosecretory structures of the hypothalamus of primates and rodents. In primates and humans, the arcuate nuclei of the mediobasal hypothalamus are the only site for the formation and release of RG-LH, which is responsible for the gonadotropic function of the pituitary gland. The secretion of RG-LH is genetically programmed and occurs in a certain pulsating rhythm with a frequency of approximately once per hour. This rhythm is called circhoral (hour-th). The region of the arcuate nuclei of the hypothalamus is called the arcuate oscillator. The circoral nature of RG-LH secretion was confirmed by direct determination of it in the blood of the portal system of the pituitary stalk and jugular vein in monkeys and in the blood of women with an ovulatory cycle.

Hormones of the hypothalamus

The releasing hormone LH has been isolated, synthesized and described in detail. To date, it has not been possible to isolate and synthesize folliberin. RG-LH and its synthetic analogues have the ability to stimulate the release of LH and FSH from the anterior pituitary gland, therefore, one term for hypothalamic gonadotropic liberins is currently accepted - gonadotropin-releasing hormone (RG-GN).

Gonadoliberin stimulates the secretion of FSH and LH. It is a decapeptide secreted by the infundibulum nucleus neurons. Gonadoliberin is secreted not constantly, but in a pulsed mode. It is very rapidly destroyed by proteases (the half-life is 2–4 min), so its impulsation must be regular. The frequency and amplitude of GnRH emissions change throughout the menstrual cycle. The follicular phase is characterized by frequent fluctuations in the small amplitude of the level of gonadoliberin in the blood serum. Towards the end of the follicular phase, the frequency and amplitude of oscillations increase, and then decrease during the luteal phase.

Pituitary

There are two lobes in the pituitary gland: anterior - adenohypophysis and posterior - neurohypophysis. The neurohypophysis is of neurogenic origin and represents a continuation of the funnel of the hypothalamus. The neurohypophysis receives its blood supply from the inferior pituitary arteries. The adenohypophysis develops from the ectoderm of Rathke's pouch, therefore it consists of a glandular epithelium and has no direct connection with the hypothalamus. Synthesized in the hypothalamus, liberins and statins enter the adenohypophysis through a special portal system. It is the main source of blood supply to the adenohypophysis. Blood enters the portal system mainly through the superior pituitary arteries. In the region of the funnel of the hypothalamus, they form the primary capillary network of the portal system, from which the portal veins are formed, which enter the adenohypophysis and give rise to a secondary capillary network. Reverse flow of blood through the portal system is possible. Features of the blood supply and the absence of the blood-brain barrier in the funnel of the hypothalamus provide a two-way connection between the hypothalamus and the pituitary gland. Depending on staining with hematoxylin and eosin, the secretory cells of the adenohypophysis are divided into chromophilic (acidophilic) and basophilic (chromophobic). Acidophilic cells secrete growth hormone and prolactin, basophilic cells - FSH, LH, TSH, ACTH

pituitary hormones

The adenohypophysis produces GH, prolactin, FSH, LH, TSH, and ACTH. FSH and LH regulate the secretion of sex hormones, TSH - the secretion of thyroid hormones, ACTH - the secretion of hormones of the adrenal cortex. STH stimulates growth, has an anabolic effect. Prolactin stimulates the growth of the mammary glands during pregnancy and lactation after childbirth.

LH and FSH are synthesized by gonadotropic cells of the adenohypophysis and play an important role in the development of ovarian follicles. Structurally, they are classified as glycoproteins. FSH stimulates follicle growth, proliferation of granulosa cells, induces the formation of LH receptors on the surface of granulosa cells. Under the influence of FSH, the content of aromatase in the maturing follicle increases. LH stimulates the formation of androgens (estrogen precursors) in theca cells, together with FSH promotes ovulation and stimulates the synthesis of progesterone in the luteinized granulosa cells of the ovulated follicle.

Secretion of LH and FSH is variable and modulated by ovarian hormones, especially estrogen and progesterone.

Thus, a low level of estrogen has a suppressive effect on LH, while a high level stimulates its production by the pituitary gland. In the late follicular phase, serum estrogen levels are quite high, the positive feedback effect is tripled, which contributes to the formation of a preovulatory LH peak. And, conversely, during therapy with combined contraceptives, the level of estrogen in the blood serum is within the limits that determine negative feedback, which leads to a decrease in the content of gonadotropins.

The positive feedback mechanism leads to an increase in the concentration and production of RG-GN in the receptors.

In contrast to the effect of estrogens, low progesterone levels have a positive feedback on the secretion of LH and FSH by the pituitary gland. These conditions exist just before ovulation and lead to the release of FSH. The high level of progesterone, which is noted in the luteal phase, reduces the pituitary production of gonadotropins. A small amount of progesterone stimulates the release of gonadotropins at the level of the pituitary gland. The negative feedback effect of progesterone is manifested by a decrease in the production of RG-GN and a decrease in sensitivity to RG-GN at the level of the pituitary gland. The positive feedback effect of progesterone occurs on the pituitary gland and includes increased sensitivity to RH-GN. Estrogens and progesterone are not the only hormones that affect the secretion of gonadotropins by the pituitary gland. The hormones inhibin and activin have the same effect. Inhibin suppresses pituitary FSH secretion, while activin stimulates it.

Prolactin is a polypeptide consisting of 198 amino acid residues, synthesized by lactotropic cells of the adenohypophysis. Prolactin secretion is controlled by dopamine. It is synthesized in the hypothalamus and inhibits the secretion of prolactin. Prolactin has a variety of effects on the body of a woman. Its main biological role is the growth of the mammary glands and the regulation of lactation. It also has a fat-mobilizing effect and has a hypotensive effect. An increase in the secretion of prolactin is one of the common causes of infertility, since an increase in its level in the blood inhibits steroidogenesis in the ovaries and the development of follicles.

Oxytocin- a peptide consisting of 9 amino acid residues. It is formed in the neurons of the large cell part of the paraventricular nuclei of the hypothalamus. The main targets of oxytocin in humans are smooth muscle fibers of the uterus and myoepithelial cells of the mammary glands.

Antidiuretic hormone(ADH) is a peptide consisting of 9 amino acid residues. Synthesized in the neurons of the supraoptic nucleus of the hypothalamus. The main function of ADH is the regulation of BCC, blood pressure, and plasma osmolality.

Ovarian cycle

The ovaries go through three phases of the menstrual cycle:

follicular phase;
ovulation;
luteal phase.

Follicular phase:

One of the highlights of the follicular phase of the menstrual cycle is the development of the egg. The ovary of a woman is a complex organ consisting of many components, as a result of the interaction of which sex steroid hormones are secreted and an egg ready for fertilization is formed in response to the cyclic secretion of gonadotropins.

Steroidogenesis

Hormonal activity from the preantral to periovulatory follicle has been described as the "two cells, two gonadotropins" theory. Steroidogenesis occurs in two cells of the follicle: the theca and granulosa cells. In theca cells, LH stimulates the production of androgens from cholesterol. In granulosa cells, FSH stimulates the conversion of the resulting androgens into estrogens (aromatization). In addition to the aromatization effect, FSH is also responsible for the proliferation of granulosa cells. Although other mediators in the development of ovarian follicles are known, this theory is the main one for understanding the processes occurring in the ovarian follicle. It was revealed that both hormones are necessary for a normal cycle with a sufficient level of estrogen.

The production of androgens in the follicles can also regulate the development of the preantral follicle. A low level of androgens enhances the process of aromatization, therefore, increases the production of estrogen, and vice versa, a high level inhibits the process of aromatization and causes atresia of the follicle. The balance of FSH and LH is essential for early follicle development. The optimal condition for the initial stage of follicle development is a low level of LH and high FSH, which occurs at the beginning of the menstrual cycle. If the LH level is high, the theca cells produce large amounts of androgens, causing follicular atresia.

Dominant follicle selection

The growth of the follicle is accompanied by the secretion of sex steroid hormones under the influence of LH and FSH. These gonadotropins protect the preantral follicle group from atresia. However, normally only one of these follicles develops to the preovulatory follicle, which is then released and becomes dominant.

The dominant follicle in the middle follicular phase is the largest and most developed in the ovary. Already in the first days of the menstrual cycle, it has a diameter of 2 mm and within 14 days by the time of ovulation increases to an average of 21 mm. During this time, there is a 100-fold increase in the volume of the follicular fluid, the number of granulosa cells lining the basement membrane increases from 0.5x10 6 to 50x10 6 . This follicle has the highest aromatizing activity and the highest concentration of FSH-induced LH receptors, so the dominant follicle secretes the highest amount of estradiol and inhibin. Further, inhibin enhances the synthesis of androgens under the influence of LH, which is a substrate for the synthesis of estradiol.

Unlike the level of FSH, which decreases as the concentration of estradiol increases, the level of LH continues to rise (at low concentrations, estradiol inhibits the secretion of LH). It is long-term estrogen stimulation that prepares the ovulatory peak of LH. At the same time, the dominant follicle is preparing for ovulation: under the local action of estrogens and FSH, the number of LH receptors on granulosa cells increases. The release of LH leads to ovulation, the formation of a corpus luteum and an increase in the secretion of progesterone. Ovulation occurs 10-12 hours after the LH peak or 32-35 hours after the start of the rise in its level. Usually only one follicle ovulates.

During follicle selection, FSH levels decrease in response to the negative effects of estrogen, so the dominant follicle is the only one that continues to develop with falling FSH levels.

The ovarian-pituitary connection is decisive in the choice of the dominant follicle and in the development of atresia of the remaining follicles.

inhibin and activin

The growth and development of the egg, the functioning of the corpus luteum occurs through the interaction of autocrine and paracrine mechanisms. It should be noted two follicular hormones that play a significant role in steroidogenesis - inhibin and activin.

Inhibin is a peptide hormone produced by granulosa cells of growing follicles that reduces FSH production. In addition, it affects the synthesis of androgens in the ovary. Inhibin affects folliculogenesis in the following way: by reducing FSH to a level at which only a dominant follicle develops.

Activin is a peptide hormone produced in the granulosa cells of the follicles and the pituitary gland. According to some authors, activin is also produced by the placenta. Activin increases the production of FSH by the pituitary gland, enhances the binding of FSH to granulosa cells.

Insulin-like growth factors

Insulin-like growth factors (IGF-1 and IGF-2) are synthesized in the liver under the influence of growth hormone and, possibly, in the granulosa cells of the follicles, they act as paracrine regulators. Before ovulation, the content of IGF-1 and IGF-2 in the follicular fluid increases due to an increase in the amount of fluid itself in the dominant follicle. IGF-1 is involved in the synthesis of estradiol. IGF-2 (epidermal) inhibits the synthesis of steroids in the ovaries.

Ovulation:

The ovulatory peak of LH leads to an increase in the concentration of prostaglandins and protease activity in the follicle. The process of ovulation itself is a rupture of the basal membrane of the dominant follicle and bleeding from the destroyed capillaries surrounding the theca cells. Changes in the wall of the preovulatory follicle, which ensure its thinning and rupture, occur under the influence of the collagenase enzyme; a certain role is also played by prostaglandins contained in the follicular fluid, proteolytic enzymes formed in granulosa cells, oxytopin and relaxin. As a result of this, a small hole is formed in the wall of the follicle, through which the egg is slowly released. Direct measurements have shown that the pressure inside the follicle does not increase during ovulation.

At the end of the follicular phase, FSH acts on LH receptors in granulosa cells. Estrogens are an obligatory cofactor in this effect. As the dominant follicle develops, estrogen production increases. As a result, the production of estrogens is sufficient to achieve secretion of LH by the pituitary gland, which leads to an increase in its level. The increase occurs very slowly at first (from the 8th to the 12th day of the cycle), then quickly (after the 12th day of the cycle). During this time, LH activates luteinization of granulosa cells in the dominant follicle. Thus, progesterone is released. Further, progesterone enhances the effect of estrogens on the secretion of pituitary LH, leading to an increase in its level.

Ovulation occurs within 36 hours of the start of the LH surge. Determination of the LH surge is one of the best methods that determines ovulation and is carried out using the "ovulation detector" device.

The periovulatory peak in FSH probably occurs as a result of the positive effect of progesterone. In addition to the increase in LH, FSH, and estrogens, there is also an increase in serum androgen levels during ovulation. These androgens are released as a result of the stimulatory effect of LH on theca cells, especially in the non-dominant follicle.

The increase in androgens has an effect on increased libido, confirming that this period is the most fertile in women.

LH levels stimulate meiosis after the sperm enters the egg. When an oocyte is released from the ovary during ovulation, the wall of the follicle is destroyed. This is regulated by LH, FSH, and progesterone, which stimulate the activity of proteolytic enzymes such as plasminogen activators (which release plasmin, which stimulates collagenase activity) and prostaglandins. Prostaglandins not only increase the activity of proteolytic enzymes, but also contribute to the appearance of an inflammatory-like reaction in the follicle wall and stimulate the activity of smooth muscles, which contributes to the release of the oocyte.

The importance of prostaglandins in the ovulation process has been proven by studies that indicate that a decrease in prostaglandin release can lead to a delay in the release of the oocyte from the ovary during normal steroidogenesis (non-developing luteinized follicle syndrome - SNLF). Since SNLF is often the cause of infertility, women who wish to become pregnant are advised to avoid taking synthesized prostaglandin inhibitors.

luteal phase:

The structure of the corpus luteum

After the release of the egg from the ovary, the forming capillaries quickly grow into the cavity of the follicle; granulosa cells undergo luteinization: an increase in the cytoplasm in them and the formation of lipid inclusions. Granulosa cells and thecocytes form the corpus luteum, the main regulator of the luteal phase of the menstrual cycle. The cells that formed the wall of the follicle accumulate lipids and the yellow pigment lutein and begin to secrete progesterone, estradiol-2, and inhibin. A powerful vascular network contributes to the entry of corpus luteum hormones into the systemic circulation. A full-fledged corpus luteum develops only when an adequate number of granulosa cells with a high content of LH receptors is formed in the preovulatory follicle. The increase in the size of the corpus luteum after ovulation occurs mainly due to an increase in the size of granulosa cells, while their number does not increase due to the absence of mitoses. In humans, the corpus luteum secretes not only progesterone, but also estradiol and androgens. The mechanisms of regression of the corpus luteum are not well understood. It is known that prostaglandins have a luteolytic effect.

Rice. Ultrasound picture of the "blooming" corpus luteum during pregnancy 6 weeks. 4 days. Energy mapping mode.

Hormonal regulation of the luteal phase

If pregnancy does not occur, involution of the corpus luteum occurs. This process is regulated by a negative feedback mechanism: hormones (progesterone and estradiol) secreted by the corpus luteum act on the gonadotropic cells of the pituitary gland, suppressing the secretion of FSH and LH. Inhibin also inhibits FSH secretion. The decrease in FSH levels, as well as the local action of progesterone, prevents the development of a group of primordial follicles.

The existence of the corpus luteum depends on the level of LH secretion. When it decreases, usually 12-16 days after ovulation, the corpus luteum involution occurs. A white body forms in its place. The mechanism of involution is unknown. Most likely, it is due to paracrine influences. As the corpus luteum involutes, estrogen and progesterone levels fall, leading to increased secretion of gonadotropic hormones. As the content of FSH and LH increases, a new group of follicles begins to develop.

If fertilization has occurred, the existence of the corpus luteum and the secretion of progesterone is supported by chorionic gonadotropin. Thus, embryo implantation leads to hormonal changes that preserve the corpus luteum.

The duration of the luteal phase in most women is constant and is approximately 14 days.

Ovarian hormones

The complex process of steroid biosynthesis ends with the formation of estradiol, testosterone and progesterone. The steroid-producing tissues of the ovaries are granulosa cells lining the cavity of the follicle, cells of the internal theca and, to a much lesser extent, the stroma. Granulosa cells and theca cells are synergistically involved in the synthesis of estrogens, the cells of the thecal membrane are the main source of androgens, which are also formed in small amounts in the stroma; progesterone is synthesized in theca cells and granulosa cells.

In the ovary, 60-100 mcg of estradiol (E2) is secreted in the early follicular phase of the menstrual cycle, 270 mcg in the luteal phase, and 400-900 mcg per day by the time of ovulation. About 10% of E2 is aromatized in the ovary from testosterone. The amount of estrone formed in the early follicular phase is 60-100 mcg, by the time of ovulation its synthesis increases to 600 mcg per day. Only half of the amount of estrone is produced in the ovary. The other half is aromatized at E2. Estriol is an inactive metabolite of estradiol and estrone.

Progesterone is produced in the ovary at 2 mg/day during the follicular phase and 25 mg/day during the luteal phase of the menstrual cycle. In the process of metabolism, progesterone in the ovary turns into 20-dehydroprogesterone, which has a relatively low biological activity.

The following androgens are synthesized in the ovary: androstenedione (a precursor of testosterone) in an amount of 1.5 mg / day (the same amount of androstenedione is formed in the adrenal glands). About 0.15 mg of testosterone is formed from androstenedione, approximately the same amount is formed in the adrenal glands.

A brief overview of the processes occurring in the ovaries

Follicular phase:

LH stimulates androgen production in theca cells.

FSH stimulates estrogen production in granulosa cells.

The most developed follicle in the middle of the follicular phase becomes dominant.

Increasing production of estrogens and inhibin in the dominant follicle suppresses the release of FSH by the pituitary gland.

A decrease in FSH levels causes atresia of all follicles except the dominant one.

Ovulation:

FSH induces LH receptors.

Proteolytic enzymes in the follicle lead to the destruction of its wall and the release of the oocyte.

luteal phase:

The corpus luteum is formed from granulosa and theca cells preserved after ovulation.

Progesterone, secreted by the corpus luteum, is the dominant hormone. In the absence of pregnancy, luteolysis occurs 14 days after ovulation.

uterine cycle

The endometrium consists of two layers: functional and basal. The functional layer changes its structure under the action of sex hormones and, if pregnancy does not occur, is rejected during menstruation.

Proliferative phase:

The beginning of the menstrual cycle is considered the 1st day of menstruation. At the end of menstruation, the thickness of the endometrium is 1-2 mm. The endometrium consists almost exclusively of the basal layer. The glands are narrow, straight and short, lined with low cylindrical epithelium, the cytoplasm of stromal cells is almost the same. As the level of estradiol increases, a functional layer is formed: the endometrium is preparing for the implantation of the embryo. The glands elongate and become tortuous. The number of mitoses increases. With proliferation, the height of epithelial cells increases, and the epithelium itself from a single-row becomes multi-row by the time of ovulation. The stroma is edematous and loosened, the nuclei of cells and the volume of the cytoplasm increase in it. The vessels are moderately tortuous.

secretory phase:

Normally, ovulation occurs on the 14th day of the menstrual cycle. The secretory phase is characterized by high levels of estrogen and progesterone. However, after ovulation, the number of estrogen receptors in endometrial cells decreases. Proliferation of the endometrium is gradually inhibited, DNA synthesis decreases, and the number of mitoses decreases. Thus, progesterone has a predominant effect on the endometrium in the secretory phase.

Glycogen-containing vacuoles appear in the glands of the endometrium, which are detected using the PAS reaction. On the 16th day of the cycle, these vacuoles are quite large, present in all cells and located under the nuclei. On the 17th day, the nuclei, pushed aside by vacuoles, are located in the central part of the cell. On the 18th day, the vacuoles are in the apical part, and the nuclei are in the basal part of the cells, glycogen begins to be released into the lumen of the glands by apocrine secretion. The best conditions for implantation are created on the 6-7th day after ovulation, i.e. on the 20-21st day of the cycle, when the secretory activity of the glands is maximum.

On the 21st day of the cycle, the decidual reaction of the endometrial stroma begins. The spiral arteries are sharply tortuous; later, due to a decrease in edema of the stroma, they are clearly visible. First, decidual cells appear, which gradually form clusters. On the 24th day of the cycle, these accumulations form perivascular eosinophilic muffs. On the 25th day, islands of decidual cells are formed. By the 26th day of the cycle, the decidual reaction becomes the number of neutrophils that migrate there from the blood. Neutrophilic infiltration is replaced by necrosis of the functional layer of the endometrium.

Menstruation:

If implantation does not occur, the glands cease to produce a secret, and degenerative changes begin in the functional layer of the endometrium. The immediate reason for its rejection is a sharp decline in the content of estradiol and progesterone as a result of the involution of the corpus luteum. In the endometrium, venous outflow decreases and vasodilation occurs. Narrowing of the arteries then occurs, leading to ischemia and tissue damage and functional loss of the endometrium. Then bleeding occurs from fragments of arterioles remaining in the basal layer of the endometrium. Menstruation stops with narrowing of the arteries, the endometrium is restored. Thus, the cessation of bleeding in the vessels of the endometrium is different from hemostasis in other parts of the body.

As a rule, bleeding stops as a result of platelet accumulation and fibrin deposition, which leads to scarring. In the endometrium, scarring can lead to the loss of its functional activity (Asherman's syndrome). To avoid these consequences, an alternative system of hemostasis is needed. Vascular contraction is a mechanism for stopping bleeding in the endometrium. At the same time, scarring is minimized by fibrinolysis, which destroys blood clots. Later, the restoration of the endometrium and the formation of new blood vessels (angiogenesis) leads to the completion of bleeding within 5-7 days from the start of the menstrual cycle.

The effect of estrogen and progesterone withdrawal on menstruation is well defined, but the role of paracrine mediators remains unclear. Vasoconstrictors: prostaglandin F2a, endothelial-1, and platelet-activating factor (TAF) may be produced within the endometrium and participate in vasoconstriction. They also contribute to the onset of menstruation and further control over it. These mediators can be regulated by the action of vasodilators such as prostaglandin E2, prostacyclin, nitric oxide, which are produced by the endometrium. Prostaglandin F2a has a pronounced vasoconstrictive effect, increases arterial spasm and endometrial ischemia, causes contractions of the myometrium, which, on the one hand, reduces blood flow, and on the other hand, helps to remove the rejected endometrium.

Endometrial repair includes glandular and stromal regeneration and angiogenesis. Vascular endothelial growth factor (VEGF) and fibroplastic growth factor (FGF) are found in the endometrium and are strong angiogenesis agents. It was found that estrogen-produced glandular and stromal regeneration is enhanced under the influence of epidermal growth factors (EGF). Growth factors such as transforming growth factor (TGF) and interleukins, especially interleukin-1 (IL-1), are of great importance.

A brief overview of the processes occurring in the endometrium

Menstruation:

The main role in the beginning of menstruation is played by spasm of arterioles.

The functional layer of the endometrium (upper, constituting 75% of the thickness) is rejected.

Menstruation stops due to vasospasm and restoration of the endometrium. Fibrinolysis prevents the formation of adhesions.

Proliferative phase:

It is characterized by estrogen-induced proliferation of glands and stroma.

secretory phase:

It is characterized by progesterone-induced secretion of glands.

In the late secretory phase, decidualization is induced.

Decidualization is an irreversible process. In the absence of pregnancy, apoptosis occurs in the endometrium, followed by the appearance of menstruation.

So, the reproductive system is a supersystem, the functional state of which is determined by the reverse afferentation of its constituent subsystems. Allocate: a long feedback loop between the hormones of the ovary and the nuclei of the hypothalamus; between ovarian hormones and the pituitary gland; a short loop between the anterior pituitary and hypothalamus; ultrashort between RG-LH and neurocytes (nerve cells) of the hypothalamus.

Feedback from a sexually mature woman is both negative and positive. An example of a negative association is an increase in LH release from the anterior pituitary gland in response to low levels of estradiol in the early follicular phase of the cycle. An example of positive feedback is the release of LH and FSH in response to the ovulatory maximum of estradiol in the blood. According to the mechanism of negative feedback, the formation of RG-LH increases with a decrease in the level of LH in the cells of the anterior pituitary gland.

Summary

GnRH is synthesized by the neurons of the infundibulum nucleus, then enters the portal system of the pituitary gland and enters through it into the adenohypophysis. GnRH secretion occurs impulsively.

The early stage of development of the primordial follicle group is independent of FSH.

As the corpus luteum involutes, secretion of progesterone and inhibin decreases and FSH levels rise.

FSH stimulates the growth and development of a group of primordial follicles and their secretion of estrogens.

Estrogens prepare the uterus for implantation by stimulating the proliferation and differentiation of the functional layer of the endometrium and, together with FSH, promote the development of follicles.

According to the two-cell theory of sex hormone synthesis, LH stimulates the synthesis of androgens in thecocytes, which are then converted to estrogens in granulosa cells under the influence of FSH.

An increase in the concentration of estradiol by a negative feedback mechanism, a loop

which closes in the pituitary and hypothalamus, suppresses the secretion of FSH.

The follicle that will ovulate in a given menstrual cycle is called the dominant follicle. Unlike other follicles that have begun to grow, it carries a greater number of FSH receptors and synthesizes more estrogen. This allows it to develop despite the decrease in FSH levels.

Sufficient estrogenic stimulation provides an ovulatory LH peak. It, in turn, causes ovulation, the formation of the corpus luteum and the secretion of progesterone.

The functioning of the corpus luteum depends on the level of LH. With its decrease, the corpus luteum undergoes involution. This usually occurs on the 12-16th day after ovulation.

If fertilization has occurred, the existence of the corpus luteum is supported by chorionic gonadotropin. The corpus luteum continues to secrete progesterone, which is necessary to maintain pregnancy in the early stages.

The regulation of the menstrual cycle occurs at five different levels.: from the cerebral cortex to the main organ - the uterus.

To understand how it goes imagine a clock with a pendulum:

a small weight on the pendulum corresponds to uterus;
the pendulum itself is ovaries, paired sex glands of a woman;
the conducting axis on which the pendulum is attached is hypothalamus, the main "clockwork" of the menstrual cycle;
an anchor fork that transmits the movements of the pendulum to the gears is part of the subcortical structure of the brain;
mechanism that moves the hands of the dial - part of the cerebral cortex that regulates the hormonal cycle.

And weights, or a watch winder spring, is a genetic code, as far as it is programmed, so much time and the whole mechanism will work.

By analogy with a cuckoo clock or a fight - this is, the absence of which indicates a malfunction of the clock, that is, the irregularity of the menstrual cycle.

Pendulum, as you know, moves alternately: first in one direction, then in the other direction, which corresponds to two phases of the menstrual cycle.

It is not necessary to have the profession of a watchmaker - any person will be able to notice a malfunction of a watch by violating its work: they are in a hurry, they are lagging behind, they have stopped, they do not call.

So women can determine the state of their health by simple signs:

The regularity of menstruation has disappeared - malfunction. No ovulation - accident! Absence of menstruation during an uncommon pregnancy - catastrophe.

Features of the female body during different phases of the menstrual cycle

First phase The hormonal cycle aims to prepare a woman for the conception of a child. This requires absolutely healthy cells in all organs and systems.

Therefore, the body is dominated by the sympathetic nervous system, which is regulated by adrenaline and norepinephrine - the hormones of "flight and fight".

All organs and systems of the female body during this period work in exactly the same way. like in a stressful situation.

After ovulation the picture is changing. Hormonal background set gestagens are conservation hormones. Now the growth of cells is replaced by their maturation.

In the regulation of the work of organs, the parasympathetic nervous system predominates, the action of which is aimed at eliminating the consequences of stressful situations.

The practical significance of knowledge about the characteristics of the hormonal background in different phases of the cycle

In the first phase of the cycle taking stimulant drugs will be ineffective. This applies not only to drugs that improve memory and attention, but also to immunomodulators.

The body already works on the verge of its capabilities, and spurring it on in the first phase is not only useless, but also not safe.

Vice versa, the means used to combat stress will have the best effect in the first phase of the cycle, while in the second - they will be useless.

In the second phase- everything is exactly the opposite. Any stimulants are shown, and sedative drugs, including tranquilizers, do not have the desired effect.

Why is it necessary to regulate the menstrual cycle?

When the female body is cyclically rejuvenated, it is protected from all diseases of old age, any cardiologist will say that all diseases of the cardiovascular system lie in wait for women after the completion of the cyclic function, and before this age, heart attacks and hypertension are a “male privilege”.

Why is the whole human body rejuvenated? To ensure normal life, there is a constant process of replacing some cells with others, including in men. But in the male body there is no clear "clock" organization.

Proven that the replacement of some cells by others in women occurs everywhere and every month. So, the layer that is rejected during menstruation is replaced in the next phase of the cycle, not only in the uterus.

Analysis of cell scrapings from the buccal mucosa shows the same phenomenon. This discovery was made back in the fifties of the 20th century.

That is once a month, with a normal cycle, there is a complete replacement of cells throughout the body: from skin to bone marrow. That is why it is necessary to correct the menstrual cycle at the slightest deviation.

Correction of the menstrual cycle

Debugging a biphasic hormonal cycle now presents no difficulty.

Known hormones, which are produced in the first and second phases. Synthesized combination drugs that maintain the correct balance of hormones.

These are regular birth control pills. When they are prescribed to normalize the cycle, the contraceptive effect is considered a side effect.

The selection of a hormonal agent is prescribed only by a doctor. The following parameters must be taken into account:

cause, which caused a violation of the cycle;
constitution(individual features of the body structure) women;
presence or absence manifestations of male sexual characteristics (hair growth of the skin, temperament);
condition of the mammary glands and venous circulatory system.

normal cycle is the key to a woman's health. The slightest changes in the menstrual cycle are subject to immediate correction. Only under such conditions is it possible for a woman's body to fully function.

Menstrual cycle- cyclically repeating changes in a woman's body, especially in the parts of the reproductive system, the external manifestation of which is blood discharge from the genital tract - menstruation. The menstrual cycle is established after menarche (first menstruation) and persists throughout the reproductive, or childbearing, period of a woman's life with the ability to reproduce offspring. Cyclic changes in a woman's body are biphasic. The first (folliculin) phase of the cycle is determined by the maturation of the follicle and the egg in the ovary, after which it ruptures and the egg leaves it - ovulation. The second (luteal) phase is associated with the formation of the corpus luteum.

At the same time, in a cyclic mode, regeneration and proliferation of the functional layer sequentially occur in the endometrium, which is replaced by the secretory activity of its glands. Changes in the endometrium end with desquamation of the functional layer (menstruation). The biological significance of the changes that occur during the menstrual cycle in the ovaries and endometrium is to ensure reproductive function at the stages of egg maturation, its fertilization and implantation of the embryo in the uterus. If the fertilization of the egg does not occur, the functional layer of the endometrium is rejected, bloody discharge appears from the genital tract, and processes aimed at ensuring the maturation of the egg occur again and in the same sequence in the reproductive system.

Menses- this is bloody discharge from the genital tract that repeats at certain intervals during the entire reproductive period of a woman's life outside of pregnancy and lactation. Menstruation is the culmination of the menstrual cycle and occurs at the end of its luteal phase as a result of rejection of the functional layer of the endometrium. The first menstruation (menarhe) occurs at the age of 10-12 years. Over the next 1 - 1.5 years, menstruation may be irregular, and only then a regular menstrual cycle is established. The first day of menstruation is conditionally taken as the first day of the cycle, and the duration of the cycle is calculated as the interval between the first days of two subsequent menstruations.

menstrual reproductive ovulation gynecology

Rice. one. Hormonal regulation of the menstrual cycle (scheme): a - the brain; b - changes in the ovary; c - change in the level of hormones; d - changes in the endometrium

External parameters of the normal menstrual cycle: duration from 21 to 35 days (for 60% of women, the average cycle length is 28 days); duration of menstrual flow from 2 to 7 days; the amount of blood loss on menstrual days 40-60 ml (average 50 ml).

The processes that ensure the normal course of the menstrual cycle are regulated by a single functional neuroendocrine system, which includes central (integrating) departments and peripheral (effector) structures with a certain number of intermediate links. In accordance with their hierarchy (from higher regulatory structures to direct executive organs), neuroendocrine regulation can be divided into 5 levels interacting according to the principle of direct and inverse positive and negative relationships (Fig.

The first (highest) level of regulation functioning of the reproductive system are the structures that make up the acceptor of all external and internal (from the subordinate departments) influences - the cerebral cortex of the central nervous system and extrahypothalamic cerebral structures (limbic system, hippocampus, amygdala). The adequacy of the CNS perception of external influences and, as a result, its influence on the subordinate departments that regulate processes in the reproductive system, depend on the nature of external stimuli (strength, frequency and duration of their action), as well as on the initial state of the CNS, which affects its resistance to stress loads.

It is well known about the possibility of stopping menstruation under severe stress (loss of loved ones, wartime conditions, etc.), as well as without obvious external influences with general mental imbalance (“false pregnancy” - delay in menstruation with a strong desire or with a strong fear get pregnant). The higher regulatory departments of the reproductive system perceive internal influences through specific receptors for the main sex hormones: estrogens, progesterone and androgens. In response to external and internal stimuli in the cerebral cortex and extrahypothalamic structures, the synthesis, release and metabolism of neuropeptides, neurotransmitters, as well as the formation of specific receptors occur, which in turn selectively affect the synthesis and release of the releasing hormone of the hypothalamus. To the most important neurotransmitters, i.e. Transmitters include norepinephrine, dopamine, gamma-aminobutyric acid (GABA), acetylcholine, serotonin, and melatonin. Cerebral neurotransmitters regulate the production of gonadotropin-releasing hormone (GnRH): norepinephrine, acetylcholine and GABA stimulate their release, while dopamine and serotonin have the opposite effect.

Neuropeptides(endogenous opioid peptides - EOP, corticotropin-releasing factor and galanin) also affect the function of the hypothalamus and the balance of the functioning of all parts of the reproductive system. Currently, there are 3 groups of EOP: enkephalins, endorphins and dynorphins. These substances are found not only in various structures of the brain and the autonomic nervous system, but also in the liver, lungs, pancreas and other organs, as well as in some biological fluids (blood plasma, follicle contents). According to modern concepts, EOP are involved in the regulation of GnRH formation. An increase in the level of EOP suppresses the secretion of GnRH, and hence the release of LH and FSH, which may be the cause of anovulation, and in more severe cases, amenorrhea. It is with an increase in EOP that the occurrence of various forms of amenorrhea of central genesis is associated with stress, as well as with excessive physical exertion, for example, in athletes. The appointment of opioid receptor inhibitors (drugs such as naloxone) normalizes the formation of GnRH, which contributes to the normalization of ovulatory function and other processes in the reproductive system in patients with central amenorrhea. With a decrease in the level of sex steroids (with age-related or surgical shutdown of ovarian function), EOP does not have an inhibitory effect on the release of GnRH, which probably causes increased production of gonadotropins in postmenopausal women. Thus, the balance of synthesis and subsequent metabolic transformations of neurotransmitters, neuropeptides and neuromodulators in brain neurons and suprahypothalamic structures ensures the normal course of processes associated with ovulatory and menstrual function.

The second level of regulation reproductive function is the hypothalamus, in particular its pituitary zone, consisting of neurons of the ventro- and dorsomedial arcuate nuclei, which have neurosecretory activity. These cells have the properties of both neurons (reproducing regulatory electrical impulses) and endocrine cells, which have either a stimulating (liberin) or blocking (statin) effect. The activity of neurosecretion in the hypothalamus is regulated both by sex hormones that come from the bloodstream and by neurotransmitters and neuropeptides formed in the cerebral cortex and suprahypothalamic structures. The hypothalamus secretes GnRH, which contain follicle-stimulating (RGFSH - folliberin) and luteinizing (RGLG - luliberin) hormones, which act on the pituitary gland. The releasing hormone LH (RGLG - luliberin) has been isolated, synthesized and described in detail. To date, it has not been possible to isolate and synthesize releasing-follicle-stimulating hormone. However, it has been established that decapeptide RGLG and its synthetic analogues stimulate the release of gonads by otrophs not only of LH, but also of FSH. In this regard, one term has been adopted for gonadotropic liberins - gonadotropin-releasing hormone (GnRH), which is essentially a synonym for RHLH. Hypothalamic liberin, which stimulates the formation of prolactin, has also not been identified, although it has been established that its synthesis is activated by TSH-releasing hormone (thyroliberin). The formation of prolactin is also activated by serotonin and endogenous opioid peptides that stimulate the serotonergic systems. Dopamine, on the contrary, inhibits the release of prolactin from the lactotrophs of the adenohypophysis. The use of dopaminergic drugs such as parlodel (bromkriptin) can successfully treat functional and organic hyperprolactinemia, which is a very common cause of menstrual and ovulatory disorders. GnRH secretion is genetically programmed and has a pulsatile (circhoral) character: peaks of increased hormone secretion lasting several minutes are replaced by 1-3-hour intervals of relatively low secretory activity. The frequency and amplitude of GnRH secretion regulates the level of estradiol - GnRH emissions in the preovulatory period against the background of maximum estradiol release are significantly greater than in the early follicular and luteal phases.

The third level of regulation reproductive function is the anterior pituitary gland, in which gonadotropic hormones are secreted - follicle-stimulating, or follitropin (FSH), and luteinizing, or lutropin (LH), prolactin, adrenocorticotropic hormone (ACTH), somatotropic hormone (STH) and thyroid-stimulating hormone ( TSH). The normal functioning of the reproductive system is possible only with a balanced selection of each of them. FSH stimulates the growth and maturation of follicles in the ovary, the proliferation of granulosa cells; the formation of FSH and LH receptors on granulosa cells; aromatase activity in the maturing follicle (this enhances the conversion of androgens to estrogens); production of inhibin, activin and insulin-like growth factors. LH promotes the formation of androgens in theca cells; ovulation (together with FSH); remodeling of granulosa cells during luteinization; synthesis of progesterone in the corpus luteum. Prolactin has a variety of effects on the body of a woman. Its main biological role is to stimulate the growth of the mammary glands, regulate lactation, and also control the secretion of progesterone by the corpus luteum by activating the formation of receptors for LH in it. During pregnancy and lactation, inhibition of prolactin synthesis ceases and, as a result, an increase in its level in the blood .

To the fourth level regulation of reproductive function include peripheral endocrine organs (ovaries, adrenal glands, thyroid gland). The main role belongs to the ovaries, and other glands perform their own specific functions, while maintaining the normal functioning of the reproductive system. In the ovaries, the growth and maturation of follicles, ovulation, the formation of the corpus luteum, and the synthesis of sex steroids occur. At birth, a girl's ovaries contain approximately 2 million primordial follicles. Most of them undergo atretic changes throughout life, and only a very small part goes through a full development cycle from primordial to mature with the subsequent formation of the corpus luteum. By the time of menarche, the ovaries contain 200-400 thousand primordial follicles. During one menstrual cycle, as a rule, only one follicle develops with an egg inside. In case of maturation of a larger number, multiple pregnancy is possible.

Folliculogenesis begins under the influence of FSH in the late part of the luteal phase of the cycle and ends at the beginning of the peak of gonadotropin release. Approximately 1 day before the onset of menstruation, the level of FSH rises again, which ensures the entry into growth, or recruitment, of follicles (1--4th day of the cycle), selection of the follicle from a cohort of homogeneous - quasi-synchronized (5--7th day), maturation of the dominant follicle (8-12th day) and ovulation (13-15th day). This process, which constitutes the follicular phase, lasts about 14 days. As a result, a preovulatory follicle is formed, and the rest of the cohort of follicles that have entered into growth undergo atresia. The selection of a single follicle destined for ovulation is inseparable from the synthesis of estrogen in it. The stability of estrogen production depends on the interaction between theca and granulosa cells, the activity of which, in turn, is modulated by numerous endocrine, paracrine and autocrine mechanisms that regulate the growth and maturation of follicles. Depending on the stage of development and morphological features, primordial, preantral, antral and preovulatory, or dominant, follicles are distinguished. The primordial follicle consists of an immature ovum, which is located in the follicular and granular (granular) epithelium. Outside, the follicle is surrounded by a connective tissue membrane (theca cells). During each menstrual cycle, 3 to 30 primordial follicles begin to grow, transforming into preantral (primary) follicles. preantral follicle. In the preantral follicle, the oocyte increases in size and is surrounded by a membrane called the zona pellucida. The granulosa epithelial cells proliferate and round, forming a granular layer of the follicle (stratum granulosum), and the theca layer is formed from the surrounding stroma. This stage is characterized by activation of the production of estrogens formed in the granulosa layer.

Preovulatory (dominant) follicle(Fig. 2.2) stands out among the growing follicles by the largest size (diameter by the time of ovulation reaches 20 mm). The dominant follicle has a richly vascularized layer of theca cells and granulosa cells with a large number of receptors for FSH and LH. Along with the growth and development of the dominant preovulatory follicle in the ovaries, atresia of the remaining (recruited) follicles that initially entered the growth occurs in parallel, and atresia of the primordial follicles also continues. During maturation, a 100-fold increase in the volume of follicular fluid occurs in the preovulatory follicle. In the process of maturation of antral follicles, the composition of the follicular fluid changes.

Antral (secondary) follicle undergoes an increase in the cavity formed by the accumulating follicular fluid produced by the cells of the granulosa layer. The activity of the formation of sex steroids also increases. Theca cells synthesize androgens (androstenedione and testosterone). Once in the granulosa cells, androgens actively undergo aromatization, which determines their conversion into estrogens. At all stages of follicle development, except for preovulatory, the progesterone content is at a constant and relatively low level. Gonadotropins and prolactin in the follicular fluid is always less than in the blood plasma, and the level of prolactin tends to decrease as the follicle matures. FSH is determined from the beginning of cavity formation, and LH can only be detected in a mature preovulatory follicle along with progesterone. The follicular fluid also contains oxytocin and vasopressin, and in concentrations 30 times higher than in the blood, which may indicate the local formation of these neuropeptides. Prostaglandins of classes E and F are detected only in the preovulatory follicle and only after the start of the LH level rise, which indicates their directed involvement in the ovulation process.

Ovulation- rupture of the preovulatory (dominant) follicle and the release of the egg from it. Ovulation is accompanied by bleeding from the destroyed capillaries surrounding the theca cells (Fig. 2.3). It is believed that ovulation occurs 24-36 hours after the preovulatory peak of estradiol, which causes a sharp rise in LH secretion. Against this background, proteolytic enzymes are activated - collagenase and plasmin, which destroy the collagen of the follicle wall and thus reduce its strength. At the same time, the observed increase in the concentration of prostaglandin F2a, as well as oxytocin, induces rupture of the follicle as a result of their stimulation of smooth muscle contraction and expulsion of the oocyte with the ovipositous mound from the cavity of the follicle. The rupture of the follicle is also facilitated by an increase in the concentration of prostaglandin E2 and relaxin in it, which reduce the rigidity of its walls. After the release of the egg, the resulting capillaries quickly grow into the cavity of the ovulated follicle. Granulosa cells undergo luteinization, morphologically manifested in an increase in their volume and the formation of lipid inclusions. This process, leading to the formation of the corpus luteum, is stimulated by LH, which actively interacts with specific granulosa cell receptors.

corpus luteum- a transient hormonally active formation, functioning for 14 days, regardless of the total duration of the menstrual cycle. If pregnancy does not occur, the corpus luteum regresses. A full corpus luteum develops only in the phase when an adequate amount of granulosa cells with a high content of LH receptors is formed in the preovulatory follicle. In the reproductive period, the ovaries are the main source of estrogens (estradiol, estriol and estrone), of which estradiol is the most active. In addition to estrogens, progesterone and a certain amount of androgens are produced in the ovaries. In addition to steroid hormones and inhibins that enter the bloodstream and affect target organs, biologically active compounds with a predominantly local hormone-like effect are also synthesized in the ovaries. Thus, the formed prostaglandins, oxytocin and vasopressin play an important role as ovulation triggers. Oxytocin also has a luteolytic effect, providing regression of the corpus luteum. Relaxin promotes ovulation and has a tocolytic effect on the myometrium. Growth factors - epidermal growth factor (EGF) and insulin-like growth factors 1 and 2 (IPGF-1 and IPFR-2) activate the proliferation of granulosa cells and the maturation of follicles. The same factors are involved together with gonadotropins in the fine regulation of the processes of selection of the dominant follicle, atresia of degenerating follicles of all stages, as well as in the termination of the functioning of the corpus luteum. The formation of androgens in the ovaries remains stable throughout the cycle. The main biological purpose of the cyclic secretion of sex steroids in the ovary is the regulation of physiological cyclic changes in the endometrium. Ovarian hormones not only determine the functional changes in the reproductive system itself. They also actively influence the metabolic processes in other organs and tissues that have receptors for sex steroids. These receptors can be either cytoplasmic (cytosol receptors) or nuclear.

Cytoplasmic receptors are strictly specific for estrogen, progesterone, and testosterone, while nuclear receptors can accept not only steroid hormones, but also aminopeptides, insulin, and glucagon. For progesterone receptor binding, glucocorticoids are considered antagonists. In the skin, under the influence of estradiol and testosterone, collagen synthesis is activated, which helps to maintain its elasticity. Increased sebum, acne, folliculitis, porosity, and excess hair are associated with increased exposure to androgens. In bones, estrogens, progesterone, and androgens support normal remodeling by preventing bone resorption. In adipose tissue, the balance of estrogens and androgens predetermines both the activity of its metabolism and distribution in the body. Sex steroids (progesterone) significantly modulate the work of the hypothalamic thermoregulatory center. With receptors for sex steroids in the central nervous system, in the structures of the hippocampus that regulate the emotional sphere, as well as in the centers that control autonomic functions, the phenomenon of the "menstrual wave" in the days preceding menstruation is associated. This phenomenon is manifested by an imbalance in the processes of activation and inhibition in the cortex, fluctuations in the tone of the sympathetic and parasympathetic systems (especially noticeably affecting the functioning of the cardiovascular system), as well as mood changes and some irritability. In healthy women, these changes, however, do not go beyond the physiological boundaries.

Fifth level regulation of reproductive function are sensitive to fluctuations in the levels of sex steroids internal and external parts of the reproductive system (uterus, fallopian tubes, vaginal mucosa), as well as the mammary glands. The most pronounced cyclic changes occur in the endometrium.

Cyclic changes in the endometrium touch its surface layer, consisting of compact epithelial cells, and the intermediate, which are rejected during menstruation. The basal layer, which is not rejected during menstruation, ensures the restoration of desquamated layers. According to changes in the endometrium during the cycle, the proliferation phase, the secretion phase and the bleeding phase (menstruation) are distinguished.

Proliferation phase("follicular") lasts an average of 12-14 days, starting from the 5th day of the cycle. During this period, a new surface layer is formed with elongated tubular glands lined with a cylindrical epithelium with increased mitotic activity. The thickness of the functional layer of the endometrium is 8 mm.

Secretion phase (luteal) associated with the activity of the corpus luteum, lasts 14 days (+ 1 day). During this period, the epithelium of the endometrial glands begins to produce a secret containing acidic glycosaminoglycans, glycoproteins, and glycogen. The activity of secretion becomes the highest on the 20-21st day. By this time, the maximum amount of proteolytic enzymes is found in the endometrium, and decidual transformations occur in the stroma (the cells of the compact layer become larger, acquiring a rounded or polygonal shape, glycogen accumulates in their cytoplasm). There is a sharp vascularization of the stroma - the spiral arteries are sharply tortuous, form "tangles" found in the entire functional layer. The veins are dilated. Such changes in the endometrium, observed on the 20-22nd day (6-8th day after ovulation) of the 28-day menstrual cycle, provide the best conditions for the implantation of a fertilized egg. By the 24th-27th day, due to the beginning of the regression of the corpus luteum and a decrease in the concentration of hormones produced by it, the trophism of the endometrium is disturbed with a gradual increase in degenerative changes in it. From the granular cells of the endometrial stroma, granules containing relaxin are released, which prepares the menstrual rejection of the mucous membrane. In the superficial areas of the compact layer, lacunar expansion of capillaries and hemorrhages in the stroma are noted, which can be detected in 1 day. before the onset of menstruation.

Menstruation includes desquamation and regeneration of the functional layer of the endometrium. Due to the regression of the corpus luteum and a sharp decrease in the content of sex steroids in the endometrium, hypoxia increases. The onset of menstruation is facilitated by a prolonged spasm of the arteries, leading to blood stasis and the formation of blood clots. Tissue hypoxia (tissue acidosis) is exacerbated by increased permeability of the endothelium, fragility of vessel walls, numerous small hemorrhages, and massive leukocyte infiltration. Lysosomal proteolytic enzymes released from leukocytes enhance the melting of tissue elements. Following a prolonged spasm of the vessels, their paretic expansion occurs with increased blood flow. At the same time, an increase in hydrostatic pressure in the microvasculature and a rupture of the walls of the vessels are noted, which by this time have largely lost their mechanical strength. Against this background, active desquamation of necrotic areas of the functional layer occurs. By the end of the 1st day of menstruation, 2/3 of the functional layer is rejected, and its complete desquamation usually ends on the 3rd day. Regeneration of the endometrium begins immediately after the rejection of the necrotic functional layer.

The basis for regeneration is the epithelial cells of the stroma of the basal layer. Under physiological conditions, already on the 4th day of the cycle, the entire wound surface of the mucous membrane is epithelialized. This is followed again by cyclic changes in the endometrium - the phases of proliferation and secretion. Successive changes throughout the cycle in the endometrium: proliferation, secretion and menstruation depend not only on cyclic fluctuations in the levels of sex steroids in the blood, but also on the state of tissue receptors for these hormones. The concentration of nuclear estradiol receptors increases until the middle of the cycle, reaching a peak by the late period of the endometrial proliferation phase. After ovulation, a rapid decrease in the concentration of nuclear estradiol receptors occurs, continuing until the late secretory phase, when their expression becomes significantly lower than at the beginning of the cycle. It has been established that the induction of the formation of receptors for both estradiol and progesterone depends on the concentration of estradiol in the tissues. In the early proliferative phase, the content of progesterone receptors is lower than that of estradiol, but then a preovulatory rise in the level of progesterone receptors occurs.

After ovulation, the level of nuclear receptors for progesterone reaches a maximum for the entire cycle. In the proliferative phase, estradiol directly stimulates the formation of progesterone receptors, which explains the lack of relationship between plasma progesterone levels and the content of its receptors in the endometrium. Regulation of the local concentration of estradiol and progesterone is mediated to a large extent by the appearance of various enzymes during the menstrual cycle. The content of estrogen in the endometrium depends not only on their level in the blood, but also on education. The endometrium of a woman is able to synthesize estrogens by converting androstenedione and testosterone with the participation of aromatase (aromatization). This local source of estrogen enhances the estrogenization of endometrial cells that characterizes the proliferative phase. During this phase, the highest aromatization of androgens and the lowest activity of estrogen-metabolizing enzymes are noted. Recently, it has been established that the endometrium is able to secrete prolactin, which is completely identical to the pituitary. Synthesis of prolactin by the endometrium begins in the second half of the luteal phase (activated by progesterone) and coincides with the decidualization of stromal cells. The cyclic activity of the reproductive system is determined by the principles of direct and feedback, which is provided by specific hormone receptors in each of the links. A direct link is the stimulating effect of the hypothalamus on the pituitary gland and the subsequent formation of sex steroids in the ovary. The feedback is determined by the influence of the increased concentration of sex steroids on the overlying levels. In the interaction of the links of the reproductive system, “long”, “short” and “ultra-short” loops are distinguished. The "long" loop is the effect through the receptors of the hypothalamic-pituitary system on the production of sex hormones. The "short" loop defines the connection between the pituitary gland and the hypothalamus. The "ultra-short" loop is the connection between the hypothalamus and nerve cells, which carry out local regulation with the help of neurotransmitters, neuropeptides, neuromodulators and electrical stimuli.

Assessment of the state of the reproductive system according to tests of functional diagnostics. For many years, so-called tests of functional diagnostics of the state of the reproductive system have been used in gynecological practice. The value of these rather simple studies has been preserved to the present day. The most commonly used are the measurement of basal temperature, the assessment of the "pupil" phenomenon and cervical mucus (crystallization, distensibility), as well as the calculation of the karyopyknotic index (KPI, %) of the vaginal epithelium.

Basal temperature test is based on the ability of progesterone (in increased concentration) to cause a restructuring of the work of the hypothalamic thermoregulation center, which leads to a transient hyperthermic reaction. The temperature is measured daily in the rectum in the morning without getting out of bed. The results are shown graphically. With a normal two-phase menstrual cycle, the basal temperature rises in the progesterone phase by 0.4--0.8 ° C. On the day of menstruation or 1 day before it begins, the basal temperature decreases. A persistent two-phase cycle (basal temperature should be measured over 2-3 menstrual cycles) indicates that ovulation has occurred and a functionally active corpus luteum. The absence of a rise in temperature in the second phase of the cycle indicates anovulation, a delay in the rise and / or its short duration (an increase in temperature by 2--7 days) - a shortening of the luteal phase, insufficient rise (by 0.2-0.3 ° C) - - for insufficiency of the function of the corpus luteum. A false-positive result (an increase in basal temperature in the absence of a corpus luteum) can be with acute and chronic infections, with some changes in the central nervous system, accompanied by increased excitability. Symptom "pupil" reflects the amount and condition of the mucous secretion in the cervical canal, which depend on the estrogen saturation of the body. The largest amount of cervical mucus is formed during ovulation, the smallest - before menstruation. The "pupil" phenomenon is based on the expansion of the external os of the cervical canal due to the accumulation of transparent vitreous mucus in the cervix. On preovulatory days, the dilated external opening of the cervical canal resembles a pupil. The “pupil” phenomenon, depending on its severity, is estimated by 1-3 pluses. The test cannot be used for pathological changes in the cervix.

Assessment of the quality of cervical mucus reflects its crystallization and degree of tension. Crystallization (the “fern” phenomenon) of cervical mucus during drying is most pronounced during ovulation, then it gradually decreases, and is completely absent before menstruation. Crystallization of air-dried mucus is also evaluated in points (from 1 to 3). The tension of cervical mucus depends on estrogen saturation. Mucus is removed from the cervical canal with a forceps, the jaws of the instrument are moved apart, determining the degree of tension. Before menstruation, the length of the thread is maximum (12 cm). Mucus can be negatively affected by inflammatory processes in the genital organs, as well as hormonal imbalances.

Karyopyknotic index. Cyclic fluctuations in ovarian hormones are associated with changes in the cellular composition of the endometrial mucosa. In a smear from the vagina, according to morphological features, 4 types of squamous stratified epithelium cells are distinguished:

a) keratinizing;
b) intermediate;
c) parabasal;
d) basal. The karyopyknotic index (KPI) is the ratio of the number of cells with a pycnotic nucleus (i.e., keratinizing cells) to the total number of epithelial cells in a smear, expressed as a percentage.

In the follicular phase of the menstrual cycle, CPI is 20–40%, on preovulatory days it rises to 80–88%, and in the luteal phase of the cycle it decreases to 20–25%. Thus, the quantitative ratios of cellular elements in smears of the vaginal mucosa make it possible to judge the saturation of the body with estrogens.