Ovarian physiology

The ovaries perform a generative function, i.e. they are the site of formation of eggs and sex hormones, which have a wide range of biological effects.

The average size is 3-4 cm in length, 2-2.5 cm in width, 1-1.5 cm in thickness. The consistency of the ovary is dense, the right ovary is usually somewhat heavier than the left. They are whitish-pink, matte in color. Without peritoneal cover, the ovaries are surrounded on the outside by one layer of cubic cells of the superficial epithelium, often called the germinal. Under it is the protein shell (t. albuginea), which is a dense connective tissue capsule. Under it is the cortex, which is the main germinal and hormone-producing part of the ovaries. In it, among the connective tissue stroma, follicles are located. Their bulk is primordial follicles, which are an egg cell surrounded by one layer of follicular epithelium.

The reproductive period of life is characterized by cyclic changes in the ovary: maturation of the follicles, their rupture with the release of a mature egg, ovulation, formation of the corpus luteum and its subsequent involution (if pregnancy does not occur).

The hormonal function of the ovary is an important link in the endocrine system of the female body, on which the normal functioning of both the reproductive organs and the entire female body depends.

A distinctive feature of the functioning of reproductive processes is their rhythm. The main content of female sexual cycles is reduced to hormone-dependent change of two processes that determine optimal conditions for reproduction: readiness of the female organism for sexual intercourse and fertilization of the egg and ensuring the development of the fertilized egg. The cyclic nature of reproductive processes in females is largely determined by sexual differentiation of the hypothalamus according to the female type. Their main meaning is the presence and active functioning of two centers of regulation of gonadotropin release (cyclic and tonic) in adult females.

The duration and nature of cycles in females of different mammal species vary greatly and are genetically determined. In humans, the cycle is most often 28 days long; it is usually divided into two phases: follicular and luteal.

In the follicular phase, the growth and maturation of the main morphofunctional unit of the ovaries - the follicle, which is the main source of estrogen formation - occurs. The process of growth and development of follicles in the first phase of the cycle is strictly determined and described in detail in the literature.

The rupture of the follicle and the release of the egg cause the transition to the next phase of the ovarian cycle - the luteal, or corpus luteum, phase. The cavity of the ruptured follicle quickly grows with granulosa cells resembling vacuoles, which are filled with a yellow pigment - lutein. An abundant capillary network and trabeculae are formed. The yellow cells of the teca interna produce mainly progestins and some estrogens. In humans, the corpus luteum phase lasts about 7 days. Progesterone secreted by the corpus luteum temporarily inactivates the positive feedback mechanism, and the secretion of gonadotropins is controlled only by the negative effect of 17beta-estradiol. This leads to a decrease in the level of gonadotropins in the middle of the corpus luteum phase to minimal values.

Regression of the corpora lutea is a very complex process, which is influenced by many factors. Researchers pay attention primarily to low levels of pituitary hormones and reduced sensitivity of luteal cells to them. An important role is given to the function of the uterus; one of its main humoral factors stimulating luteolysis are prostaglandins.

The ovarian cycle in women is associated with changes in the uterus, tubes and other tissues. At the end of the luteal phase, the mucous membrane of the uterus is rejected, accompanied by bleeding. This process is called menstruation, and the cycle itself is menstrual. Its beginning is considered to be the first day of bleeding. After 3-5 days, the rejection of the endometrium stops, the bleeding stops, and the regeneration and proliferation of new layers of endometrial tissue begins - the proliferative phase of the menstrual cycle. With the most common 28-day cycle in women, on the 16th-18th day, the proliferation of the mucous membrane stops, and it is replaced by the secretory phase. Its beginning coincides in time with the beginning of the functioning of the corpus luteum, the maximum activity of which occurs on the 21st-23rd day. If the egg is not fertilized and implanted by the 23rd-24th day, the level of progesterone secretion gradually decreases, the corpus luteum regresses, the secretory activity of the endometrium decreases, and on the 29th day from the beginning of the previous 28-day cycle, a new cycle begins.

Biosynthesis, secretion, regulation, metabolism and mechanism of action of female sex hormones. According to their chemical structure and biological function, they are not homogeneous compounds and are divided into two groups: estrogens and gestagens (progestins). The main representative of the former is 17beta-estradiol, and the latter is progesterone. The group of estrogens also includes estrone and estriol. Spatially, the hydroxyl group of 17beta-estradiol is in the beta position, while in progestins, the side chain of the molecule is in the beta position.

The starting compounds in the biosynthesis of sex steroids are acetate and cholesterol. The first stages of estrogen biosynthesis are similar to the biosynthesis of androgens and corticosteroids. In the biosynthesis of these hormones, the central place is occupied by pregnenolone, formed as a result of the cleavage of the side chain of cholesterol. Starting from pregnenolone, two biosynthetic pathways of steroid hormones are possible - these are the ∆ ⁴ - and ∆ ⁵ -pathways. The first occurs with the participation of ∆ ⁴ -3-keto compounds through progesterone, 17a-hydroxyprogesterone and androstenedione. The second includes the sequential formation of pregnenolone, 17beta-oxypregnenolone, dehydroepiandrosterone, ∆ ⁴ -androstenediol, testosterone. It is believed that the D-pathway is the main one in the formation of steroids in general. These two pathways end with testosterone biosynthesis. Six enzyme systems are involved in the process: cholesterol side chain cleavage; 17a-hydroxylase; ∆ ⁵ -3beta-hydroxysteroid dehydrogenase with ∆ ⁵ - ∆ ⁴ -isomerase; C17C20-lyase; 17beta-hydroxysteroid dehydrogenase; ∆ ^5,4 -isomerase. The reactions catalyzed by these enzymes occur mainly in microsomes, although some of them may be located in other subcellular fractions. The only difference between the microsomal enzymes of steroidogenesis in the ovaries is their localization within the microsomal subfractions.

The final and distinctive stage of estrogen synthesis is the aromatization of Cig-steroids. As a result of aromatization of testosterone or ∆ ⁴ -androstenedione, 17beta-estradiol and estrone are formed. This reaction is catalyzed by the enzyme complex (aromatase) of microsomes. It has been shown that the intermediate stage in the aromatization of neutral steroids is hydroxylation at the 19th position. It is the rate-limiting reaction of the entire aromatization process. For each of the three successive reactions - the formation of 19-oxyandrostenedione, 19-ketoandrostenedione and estrone, the need for NADPH and oxygen has been established. Aromatization involves three mixed-type oxidase reactions and depends on cytochrome P-450.

During the menstrual cycle, the secretory activity of the ovaries switches from estrogens in the follicular phase of the cycle to progesterone in the corpus luteum phase. In the first phase of the cycle, the granulosa cells have no blood supply, have weak 17-hydroxylase and C17-C20-lyase activity, and steroid synthesis in them is weak. At this time, significant secretion of estrogens is carried out by teca interna cells. It has been shown that after ovulation, the corpus luteum cells, which have a good blood supply, begin to synthesize steroids, which, due to the low activity of the indicated enzymes, stops at the progesterone stage. It is also possible that the ∆ ⁵ -pathway of synthesis with a small formation of progesterone predominates in the follicle, and in the granulosa cells and in the corpus luteum, an increase in the conversion of pregnenolone along the ∆ ⁴ -pathway, i.e. into progesterone, is observed. It should be emphasized that the synthesis of androgenic C19-steroids occurs in the interstitial cells of the stroma.

The place where estrogens are produced in the female body during pregnancy is also the placenta. The biosynthesis of progesterone and estrogens in the placenta has a number of features, the main one being that this organ cannot synthesize steroid hormones de novo. Moreover, the latest literature data indicate that the steroid-producing organ is the placenta-fetus complex.

The determining factor in the regulation of the biosynthesis of estrogens and progestins are gonadotropic hormones. In concentrated form, this looks like this: FSH determines the growth of follicles in the ovary, and LH - their steroid activity; synthesized and secreted estrogens stimulate the growth of the follicle and increase its sensitivity to gonadotropins. In the second half of the follicular phase, the secretion of estrogens by the ovaries increases, and this growth is determined by the concentration of gonadotropins in the blood and the intraovarian ratios of the resulting estrogens and androgens. Having reached a certain threshold value, estrogens, by the mechanism of positive feedback, contribute to the ovulatory surge of LH. The synthesis of progesterone in the corpus luteum is also controlled by luteinizing hormone. The inhibition of follicle growth in the postovulatory phase of the cycle is most likely explained by the high intraovarian concentration of progesterone and androstenedione. Regression of the corpus luteum is a mandatory moment of the next sexual cycle.

The content of estrogens and progesterone in the blood is determined by the stage of the sexual cycle (Fig. 72). At the beginning of the menstrual cycle in women, the concentration of estradiol is about 30 pg/ml. In the second half of the follicular phase, its concentration increases sharply and reaches 400 pg/ml. After ovulation, a drop in the estradiol level is observed with a small secondary rise in the middle of the luteal phase. The ovulatory rise in unconjugated estrone averages 40 pg/ml at the beginning of the cycle and 160 pg/ml in the middle. The concentration of the third estrogen, estriol, in the plasma of non-pregnant women is low (10-20 pg/ml) and reflects the metabolism of estradiol and estrone rather than ovarian secretion. The rate of their production at the beginning of the cycle is about 100 μg/day for each steroid; In the luteal phase, the rate of production of these estrogens increases to 250 mcg/day. The concentration of progesterone in the peripheral blood of women in the preovulatory phase of the cycle does not exceed 0.3-1 ng/ml, and its daily production is 1-3 mg. During this period, its main source is not the ovary, but the adrenal gland. After ovulation, the concentration of progesterone in the blood increases to 10-15 ng/ml. The rate of its production in the phase of the functioning corpus luteum reaches 20-30 mg/day.

Estrogen metabolism occurs differently from other steroid hormones. A characteristic feature for them is the preservation of the aromatic ring A in estrogen metabolites, and hydroxylation of the molecule is the main way of their transformation. The first stage of estradiol metabolism is its transformation into estrone. This process occurs in almost all tissues. Hydroxylation of estrogens occurs to a greater extent in the liver, resulting in the formation of 16-hydroxy derivatives. Estriol is the main estrogen in urine. Its main mass in the blood and urine is in the form of five conjugates: 3-sulfate; 3-glucuronide; 16-glucuronide; 3-sulfate, 16-glucuronide. A certain group of estrogen metabolites are their derivatives with an oxygen function in the second position: 2-oxyestrone and 2-methoxyestrone. In recent years, researchers have been paying attention to the study of 15-oxidized derivatives of estrogens, in particular 15a-hydroxy derivatives of estrone and estriol. Other estrogen metabolites are also possible - 17a-estradiol and 17-epiestriol. The main routes of excretion of estrogenic steroids and their metabolites in humans are bile and kidneys.

Progesterone is metabolized as a ∆ ⁴ -3-ketosteroid. The main pathways of its peripheral metabolism are the reduction of the A ring or the reduction of the side chain at the 20 position. The formation of 8 isomeric pregnanediols has been shown, the main one being pregnanediol.

When studying the mechanism of action of estrogens and progesterone, one should first of all proceed from the position of ensuring the reproductive function of the female organism. Specific biochemical manifestations of the controlling effect of estrogenic and gestagenic steroids are very diverse. First of all, estrogens in the follicular phase of the sexual cycle create optimal conditions that ensure the possibility of fertilization of the egg; after ovulation, the main thing is the changes in the structure of the tissues of the genital tract. Significant proliferation of the epithelium and keratinization of its outer layer, hypertrophy of the uterus with an increase in the RNA/DNA and protein/DNA ratios, and rapid growth of the uterine mucosa occur. Estrogens maintain certain biochemical parameters of the secretion released into the lumen of the genital tract.

Progesterone of the corpus luteum ensures successful implantation of the egg in the uterus in case of fertilization, development of decidual tissue, post-implantation development of the blastula. Estrogens and progestins guarantee the maintenance of pregnancy.

All the above facts indicate the anabolic effect of estrogens on protein metabolism, especially on target organs. Their cells contain special receptor proteins that cause selective capture and accumulation of hormones. The result of this process is the formation of a specific protein-ligand complex. Reaching nuclear chromatin, it can change the structure of the latter, the level of transcription and the intensity of synthesis of cellular proteins de novo. Receptor molecules are characterized by high affinity for hormones, selective binding, and limited capacity.

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