NEUROENDOCRINAL REGULATION OFMENSTRUAL CYCLE AMAN BALOCH
NEUROENDOCRINAL REGULATION OF MENSTRUAL CYCLE – is a complex, genetically determined system of inter-regulation of genitals, central nervous system and target organs. Formation of reproductive system starts antenatally and finishes at the age of 18-21.
5 LEVELS OF MENSTRUAL CYCLE REGULATION. 1 Target organs. These include external and internal genital organs, mammary glands, bone tissue and skin. Target organs have receptors for steroid hormones. Influence of sex hormones on these organs leads to formation of secondary sexual character, cyclical processes in endometrium and vagina.
2. Ovaries. Steroid hormones in the ovary are synthesized due to the action pituitary hormones. The hormones synthesis process inside the ovary is called steroidogenesis. Adrenal glands and adipose tissue synthesize steroid hormones too. Steroid hormones are synthesized from cholesterol and have the same nature. Schematically this process can be represented in the following way: cholesterol – pregnenolone – androgens – estrogens.
Ovaries synthesize 3 types of hormones: estrogens, gestogens, androgens. Female organism produces 3 fractions of estrogens. Estradiol - is the most active estrogen and is produced by ovaries. Estrone – less active, mainly produced by adipose tissue. Estriol – is a result of transformation of estradiol, estrone and androgens of epinephroses. Estriol is produced only during pregnancy and has minimal hormonal activity.
Progesterone – is the hormone of yellow body of ovary and is a gestogen. Major androgen of ovary is testosterone , which is produced by cells of internal theca. Testosterone is not very active. Under the influence of enzyme 5-α- reductase, it is transformed into a more active hormone – dehydrotestosterone.
Most estrogens and androgens merge with sex steroid-binding globulin (SSBG). Smaller amount of estrogens merge with albumin and erythrocytes. Only one per cent of estrogens remains free and influences the target organs. SSBG is synthesized by liver, its quantity is proportional to estrogen level, and decreases under the influence of androgens. Today have been discovered 2 progesterone-binding proteins.
PHYSIOLOGIC EFFECTS OF ESTROGEN ON FEMALE ORGANISM Uterus. Estrogens determine the proliferation processes in endometrium, growth of myometrium and uterine tubes. Mammary glands. Stimulate growth. Bone tissue. Estrogens are parathormone antagonists. They hinder development of osteoporosis and condense growth zones in bones. Cardiovascular system - i ncrease the arterial pressure and vascular tone.
Circulatory system. Increase the amount of fibrin. Mineral metabolism. Estrogens influence the natrium metabolism they attract sodium from tissues and can cause oedemas. Lipidic metabolism. Increases quantity of high-density β-lipoproteins; this has anti- atherosclerotic effect. Central nervous system. Estrogens form optimal neuropsychic condition. They change synthesis of pituitary and hypothalamus hormone.
PHYSIOLOGIC EFFECTS OF PROGESTERONE. Uterus. In case of sufficient concentration of estrogens, progesterone exerts influence upon tissues. Progesterone creates the evident anti- proliferative effect and conditions the secretion processes in endometrium. Besides, progesterone furthers myometrium growth. Mammary gland. Along with estrogens and prolactin, progesterone conditions tissue development. Progesterone also furthers lactation.
Cardiovascular system. Progesterone decreases vessels tone and arterial pressure. Circulatory system. Progesterone does not influence the amount of fibrin. Mineral metabolism. Progesterone has diuretic effect. Central nervous system. Progesterone may cause depressions. It shows evident anti-gonadotrophic action.
EFFECTS OF ANDROGENS. - Androgens in normal concentration are synergists of estrogens. - In high concentrations androgens show evident anti-gonadotrophic action and further the development of secondary male sexual characters. - During antenatal and postnatal periods increase of their level causes change of central nervous system.
3. Hypophysis. Hypophysis is divided into 2 lobes: anterior – adenohypophysis and posterior – neurohypophysis. Adenohypophysis consists of groups of cells, these groups of cells are responsible for the synthesis of the following hormones: growth hormone (somatotropic hormone – STH);
LH, FSH, PRL are major hormones which regulate menstrual cycle. But it is only possible under the condition of optimal concentrations of other pituitary hormones. Synthesis of pituitary hormones is realized due to stimulating impact of hypothalamus. PRL synthesis depends on dopamine concentration. PRL concentration increases when dopamine level decreases.
Hormones are not synthesized in the posterior lobe of hypophysis. Oxytocin and vasopressin are synthesized in hypothalamus, but are accumulated in the posterior lobe of hypophysis.
4. Hypothalamus. Nucleuses of hypothalamus synthesize the following neurohormones: libertines and statines. The libertines stimulate adenohypophysis, statines inhibit it. These hormones are called releasing hormones.
Libertines include the following hormones: adrenocorticotropin-releasing hormone (ACTH-RG); thyrotropin-releasing hormone (TRG); gonadotropin-releasing hormone (GN- RG); growth hormone-releasing hormone (somatoliberin GH-RG); melanoliberin (M-RG)/
Statines include the following hormones: somatostatin; dopamine (major prolactin- inhibiting factor).
Neurohormones are synthesized not only in hypothalamus. Somatostatin is synthesized in tissues of thyroid gland, bowels. Other hypothalamus peptides – gastrin, cholecystokinin, enkephaline are synthesized by other tissues also. They create a regulation system called “diffused neuroendocrinal system of organism”.
5. Extra-hypothalamic structures. Epiphysis, limbic system, celebrum tonsil and hippocampus influence the reproductive function. They are related to extra-hypothalamic structures. Function of hypothalamus can be stimulated or inhibited by enkephalins, endorphins, neuropeptides.
NEUROENDOCRINAL REGULATION OF MENSTRUAL CYCLE. At the age of 10-12 years the reproductive system starts its development.There are several theories, which explain activation of hypothalamo-pituitary-ovarian system. 1.Theory of late-pubescence. According to this theory sensitivity of hypothalamus to the steroid hormones changes with the age. Besides, sensitivity of ovaries to gonadotropin increases also.
2.Theory of resonance. According to this theory the increase in electrical activity of hypothalamus nucleuses stimulates an increase of GN-RG level. 3.Theory of block release. According to this theory at the start of pubescence epiphysial function decreases and hypothalamic function increases.
The activation of hypothalamus makes it oversensitive to decrease in estrogen concentration. Next, it synthesizes GN-RG, which stimulates production of FSH and LH. Gonadotropins influence the process of growth and development of follicle (“folliculogenesis”) in ovaries. This descending process is called direct relationship.
The ovary of a newborn girl contains from 400.000 to 500.000 primary ovarian follicles. Only 400 follicles ripen and reach the ovulation. Under the influence of FSH the development of several primari ovarian follicles starts in the ovary. In the beginning they grow independently.
Later on, their growth depends on the FSH level and the sensitivity of follicle to the FSH. Therefore, only one follicle reaches the size of pre-ovulatory, others atrophy. The wall of antrum-containing follicle has 3 sheaths: interstitial, internal theca and granulosis. These sheaths have different sensitivity to gonadotrophic hormones. Intersticium and theca are more sensitive to LH; granulosis is more sensitive to FSH.
Follicle synthesizes steroid hormones. This process is called steroidogenesis. Theca and intersticium synthesize steroids up to androgen fraction; granulosis produces estrogens. Increase in estrogen concentration depresses the function of hypophysis. This process is called negative inverse relationship.
It takes place in the early pubertal period when menstrual cycles are monophase. Positive inverse relationship is characterized by maximum estrogen concentration. Consequently honadotropines and libertines increase dramatically. Ovulation follows this process. The ovulation process is a histochemical process. Estrogens, prostaglandins and histamine influence the sheath of the follicle and cause its rupture.
Granulosis cells are transformed into the yellow body under the influence of LH after ovulation. The yellow body synthesizes progesterone. Increase of progesterone inhibits the synthesis of LH. This causes the death of the yellow body.
The ovarian cycle is a consistent process of growth and development of follicle, ovulation, development and death of the yellow body. Ovarian cycle is divided into 3 phases: Follicular phase is characterized by growth and development of follicle. It lasts 12-14 days. Ovulatory phase – lasts several hours. Lutein phase is characterized by development and functioning of the yellow body.
Uterine cycle is a cyclic process in the ovary, which causes cyclic changes in the endometrium. It has 4 phases: Desquamation. Decrease of steroid hormones causes spasm, ischemia and rejection spiroid artery of decidual sphere of endometrium. First day of desquamation corresponds to the first day of menstruation and menstrual cycle. Regeneration. It corresponds to the early period of follicular phase in the ovary. Regeneration lasts 4-5 days. It starts with epithelization of endometrium.
Proliferation. It lasts 5-7 days and results in ovulation. It corresponds to the late period of follicular phase in the ovary. Is characterized by proliferation of epithelium and development of spiroid arteries. Secretion. It corresponds to lutein phase in the ovary. It lasts 10-12 days. The process of proliferation is superseded by secretion. If pregnancy did not take place, cyclic processes in the system uterus-ovaries-hypothalamic- pituitary system repeat.
MENSTRUAL DISORDERS ETIOLOGY Nervous diseases. Mental diseases. Malnutrition. Some occupational hazards. Systemic and gynecologic inflammatory diseases. Illness of the haemopoiesis, cardiovascular and other systems. Gynecologic operations. Puberty disorders. Age-specific reconstruction of the functional state in hypothalamic-pituitary-ovarian axis in the menopause.
AMENORRHOEA Pathological primary amenorrhoea – when the patient has never menstruated. Pathological secondary amenorrhoea – when the periods are absent for more than 6 months. Physiological amenorrhoea – before puberty, during pregnancy and lactation, and after the menopause. False amenorrhoea – when the flow does not escape because of some obstruction. True amenorrhoea – when the endometrial cycle is absent.
TRUE PATHOLOGICAL AMENORRHOEA 1.Uterine disorders. the uterus may be congenitally defective; the endometrium atrophies after irradiation with X-ray or radium, and hysterectomy.
2. Ovarian disorders. failure of ovarian development occurs in cases of gonadal dysgenesis; Stein-Leventhal syndrome is a disorder of unknown cause. After some years of normal menstruation amenorrhoea occurs with hirsuties. Both ovaries are enlarged and contain multiple small follicular cysts. There is a block in the normal conversion of progesterone to estrogen so that an intermediate androgen substance androstendione appears in excess. The urinary excretion of estrogens is normal or low, while that of pregnantriol (a metabolic product of certain androgens) is raised; arrhenoblastoma is a very rare cause of amenorrhoea; ovarian infections or new growths as processes destroying all ovarian tissue.
3. Pituitary disorders. There is of production of gonadotrophic hormones. Amenorrhoea is one aspect of general disorders and the gynecologist is seldom responsible for treatment. Pituitary infantilism (Levi-Loraine syndrome). The adult resembles a child. No effective treatment is known. Pituitary cachexia (Simmond’s disease). This is usually due to ischemic necrosis of the pituitary glands (hypophysis) due to thrombosis of pituitary vessels after postpartum hemorrhage and collapse. Failure of lactation is followed by genital atrophy, loss of pubic hair, weakness, anorexia.
Treatment with cortisone, thyroxin and anabolic steroids may cause some improvement. Adipogenital dystrophy is characterized by dwarfing, adiposity and genital infantilism, and is usually caused by a craniopharyngioma that involves the pituitary gland and hypothalamus. The treatment is surgical. In acromegaly the eosinophilic adenoma of the pituitary gland may destroy the gonadotrophic cells, and the same may happen with other pituitary tumors. Small pituitary adenoma may secrete prolactin and cause amenorrhoea with galactorrhoea.
4.Other endocrine disorders. Amenorrhoea occurs: in severe cases of hyperthyreoidism, myxoedema and cretinism; in some cases of diabetes; in Addison’s disease; with adrenocortical tumors or hyperplasia.
5. Nervous disorders (stress or hypothalamic amenorrhoea). This is the commonest type of secondary amenorrhoea, and may be the result of emotional disturbances.
6.Disorders of general health and nutrition. Any chronic or severe illness (including nutritional deficiency) will cause amenorrhoea. 7.Oral contraception. A delayed first period is common after stopping oral contraception. More prolonged amenorrhoea sometimes occurs.
DIAGNOSIS General examination; Special gynecologic examination; Ultrasonic; X-ray; Hormonal tests.
TREATMENT Sedative therapy; Vitamin therapy; Adequate nutrition, a special diet intended to decrease the body weight; Physiotherapy (endonasal electrophoresis with 2% solution of vitamin B1, 0.25% solution of dyphenhydramine hydrochloride). Drugs suppressing prolactin secretion (bromocriptine, parlodel, dostineks). Hormonal therapy of the cyclic hormones (estrogens followed by progesterone).
DISFUNCTIONAL UTERINE BLEEDING Disfunctional,or anovulatory uterine bleeding is associated with anovulation caused by impaired or unestablished functional relationships in the hypothalamic-pituitary-ovarian axis.
Classification In juvenile age; In reproductive age; In the premenopausal period.
Dysfunctionaluterine bleedings may be divided into anovulatory and ovulatory ones.
Anovulatory bleedings are induced by the absence of ovulation and luteal phase of the cycle. Anovulatory uterine bleeding develops in patients with: persistence of an ovarian follicle; persistent follicles release a large number of estrogens; atresia of a few follicles; atresia of some small follicles is associated with hypoestrogenism.
Both account for continuous, monotonous secretion of estrogens. Ovulation does not occur and the corpus luteum fails to form. Excessive proliferation of the endometrium occurs as a result of prolonged exposure to estrogens in both processes. Persistent and atretic follicles undergo involution. The level of hormones (estrogens) is decreased in the blood, and bleeding develops.
Circulation in the endometrium is impaired, the capillary permeability is decreased, and the sites of dystrophy and necrosis are manifested. The necrotic mucosa is rejected slowly, which causes prolonged bleeding. Dysfunctional uterine bleedings are not attended with pain.
CLINICAL PICTURE Amenorrhoea: in 4-8 weeks in persistent follicle; 3-4 months in atretic follicles; Bleedings are more abundant in persistent follicles, being occasionally profuse; Anemia; Decrease the patient’s working capacity; General fatigue; Headache; Poor appetite; Sleep; Pale skin; Tachycardia; Decreased blood pressure.
DIAGNOSIS Diagnosis is based on general and gynecologic examination. At general examination one should pay attention to the typical sings: bleedings that follow the suppression of menses; monophase basal body temperature; high or low karyopycnotic index.
Dysfunctional uterine bleedings should be differentiated from many disease forms that are attended with bleedings: abortions; interrupted fallopian pregnancy; tumors of the uterus.
TREATMENT Thedoctor’s tactics largely depend on the patient’s age.
Juvenile bleedings. Conservative treatment (use coagulants, hemostatic agents, stimulants of uterine contractility). Hormonal haemostasis (“medicamentous curettage” synthetic estrogen-progesteron drugs (logest, yrina, dgaz, ganin) are prescribed in a dose of 5-6 tablets daily is gradually decreased to 1 tablet per day ( the total couse of drug administration is 21 days). Diagnostic curettage of the uterine mucosa. When bleeding has been arrested, cyclic hormone therapy is administered for 6 or 9 cycles.
In the child-bearing age. Diagnostic curettage of the uterine mucosa. Conservative treatment. Hormonal haemostasis (“medicamen-tous curettage” synthetic progestins (norcolut, orgametril, utrogestan, dyphaston) are prescribed in a dose of 5-6 tablets daily is gradually decreased to 1 tablet per day ( the total couse of drug administration is 21 days). When bleeding has been arrested, cyclic hormone therapy is administered for 6 or 9 cycles.
Premenopausal and menopausal age Diagnostic curettage of the uterine mucosa. Conservative treatment. Hormonal haemostasis (“medicamen-tous curettage” synthetic progestins (norcolut, orgametril, utrogestan, dyphaston) are prescribed in a dose of 5-6 tablets daily is gradually decreased to 1 tablet per day ( the total couse of drug administration is 21 days). The therapy is directed at regulating the menstrual function ( in women under 45 years) or its suppression ( in women over 45 years).
DYSMENORRHOEA (ALGOMENORRHOEA) This term is used to painful menstruation. Pain may develop before the onset of menstruation and continue throughout the period of menstrual flow.
Sometimes, pain is severe and attended by nausea, vomiting and other disturbances, which reduce the patient’s working capacity. In many cases dysmenorrhoea is just a manifestation of systemic diseases. It may be attributed to retroflexion or anteflexion of the uterus, cicatricial changes, and narrowing of the cervical canal.
Primary and secondary forms of dysmenorrhoea are distinguished. The formes does not appear to be linked to any organic disease and is congenital. The latter develops in women with previously normal menstruations. Secondary dysmenorrhoea may be related to inflammatory processes, endometriosis, and genital tumors.