NeuroEndocrinology In Gynaec. Flashcards
Functions of Fsh
Functions of FSH
The function of FSH is predominantly morphogenic, related to the growth and maturation of the Graafian follicle. It acts primarily on the granulosa cells. In conjunction with LH, it is also involved in maturation of oocyte, ovulation and steroidogenesis.
■Morphological effects
FSH rescues follicles from apoptosis
Stimulates formation of follicular vesicles (antral follicle)
Stimulates proliferation of granulosa cells
Helps full maturation of the Graafian follicle (dominant follicle) as it converts the follicular microenvironment from androgen dominated to estrogen dominated
[Biochemical effects of FSH]
Synthesizes its own receptors in the granulosa cells.
Synthesizes LH receptors in the theca cells.
Synthesizes LH receptors in the granulosa cells.
Induces aromatization to convert androgens to estrogens in granulosa cells
Enhances autocrine and paracrine function (IGF-II, IGF-I) in the follicle.
Stimulates granulosa cells to produce activin and inhibin.
Stimulates plasminogen activator_necessary for ovulation.
The FSH level tends to rise soon following the onset of menstruation and attains its peak at the twelfth day of the
cycle (preovulatory) and gradually declines to attain the
base level at about the eighteenth day
Functions of LH
The main function of LH is steroidogenic as it acts primarilly on theca cells. Along with FSH, it is responsible for full maturation of the Graafian follicle and oocyte and ovulation.
Biochemical effects (steroidogenic) of LH
■ Activation of LH receptors in the theca cells which stimulates the enzymes necessary for androgen production diffuse into the granulosa cells estrogens.
■ Luteinization of the granulosa cells progesterone. to secrete
■Synthesizes prostaglandins.
Morphological effects of LH
Stimulates resumption of meiosis with extrusion of first polar body .
■Helps in the physical act of ovulation.
Formation and maintenance of corpus luteum.
Therefore FSH receptors are present primarily on the granulosa cells. Receptors for LH are present on the theca cells at all stages of the cycle. They are also present on the granulosa cells after the follicle matures.
LH levels remain almost static throughout the cycle except at least 12 hours prior to ovulation, when it attains its peak, called LH surge
Prolactin and its role in fertility
Prolactin
Prolactin is secreted from the alpha cells and is a polypeptide.
Its role in the human reproductive physiology is not clearly understood.
Its role in the maintenance of corpus luteum in human is not well-documented,
There is high incidence of anovulation in women with elevated plasma prolactin levels (p. 486).
The mechanism of amenorrhea with hyperprolactinemia is due to the alterations of GnRH pulsatility.
Tsh function
Thyrotropic Hormone
Thyroid-stimulating hormone (TSH) is produced by the beta cells.
It acts on the thyroid gland and regulate the production of thyroxine.
Thyroid-releasing hormone (TRH) is a potent prolactin releasing factor. It may be the link between hypothyroidism and hyperprolactinemia.
TSH has got a and ẞ subunits like those of FSH and LH, with functions of ẞ subunits being different.
Abnormal TSH secretion is associated with menstrual and ovulatory dysfunction.
CRH and ACTH
Corticotropin Releasing Hormone (CRH)
CRH consists of 41 amino acids.
CRH stimulates adrenocorticotropic hormone (ACTH) biosynthesis and secretion.
CRH is under negative feedback regulation of circulating cortisol.
Increased levels of CRH inhibit GnRH secretion.
This may be the reason for hypercortisolism and menstrual abnormalities.
Adrenocorticotropic Hormone (ACTH)
ACTH is also secreted by the beta cells. It stimulates the production of corticosteroids in the adrenal cortex.
a) GHRH
b) GH or Somatotropin
c) Melanocyte Stimulating Hormone (MSH)
a) Growth Hormone-releasing Hormone (GHRH)
-Growth hormone (GH) is regulated by GHRH and inhibited by somatostatin.
-Similar to GnRH, GHRH secretion is in a pulsatile fashion.
-Exercise, stress, sleep and hypoglycemia stimulate GH release.
b) Somatotropin or Growth Producing Hormone
-It is secreted from the alpha cells of the pituitary and acts directly on the skeletal system.
-GH stimulates skeletal and muscle growth.
-GH induces insulin resistance and may precipitate diabetes mellitus.
c) Melanocyte-stimulating Hormone (MSH)
-It is clearly linked with ACTH.
-The hormone is increased during puberty and in pregnancy.
-It is probably responsible for the pigmentary changes during those periods.
Oxtocin and vasopressin (ADH) produced in which nucleus of Hypothalamus?
- Oxytocin and ADH both Nonapeptide with ADH having two amino acid composition different from that oxytocin.
Oxytocin– Paraventricular nucleus of Ht.
ADH – Supraoptic Nucleus of Ht.
FSH & LH synthesis and composition?
–pulsatile stimulation of hypothalamic GnRH is required by the pituitary for the synthesis and ovarian release of gonadotropins,
–ovarian hormones determine the cyclic pattern of FSH and LH as they occur in normal cycle.
– FSH and LH are secreted from the beta cells in a pulsatile fashion in response to pulsatile GnRH.
–These are water-soluble glycoproteins of high molecular weight.
–They have got two subunits. The amino acid composition of the a subunits of FSH, LH and human chorionic gonadotropins (hCG) are similar.
–The hormone specificity being determined by the difference between the ẞ subunits.
MOA of GnRH on Pituitary Cell
Mechanism Action of GnRH on Pituitary Cell.
GnRH binds to the specific receptors on the cell membrane of the gonadotrophs.
Within a second, there is activation of the enzyme, adenyl cyclase.
Adenyl Cyclase catalyzes the conversion of ATP to cAMP.
cAMP- receptor protein complex then activates protein kinase C.
Intracellular free Ca++ concentration increases.
Protein kinase C causes phosphorylation and activation of specific enzymes.
Ca++, protein kinase C and cAMP then interact to stimulate the release of stored FSH and LH and their subsequent biosynthesis.
However, if GnRH continues to be infused, gonadotropin secretion is inhibited, probably because the receptors are saturated and are unable to stimulate the release of second messenger.
This is k/a Desensitization or Downregulation.
Two Cell Teo Gonadotropin concept of Ovarian Steroidogenesis
Mechanism of Steroid Hormone Production (Figs. 7.5A and B)
Two cell, two gonadotropin, concept of ovarian steroidogenesis establishes the fact that two cells (theca cells and granulosa cells) produce different hormones under the influence of two gonadotropins (LH and FSH).
–During the follicular phase, under the influence of LH, androgens (androstenedione and testosterone) are produced in the theca cells. These androgens diffuse into the granulosa cells where they are aromatized under the influence of FSH to estrogens-estradiol predominantly and to lesser extent estrone.
– After ovulation, progesterone is synthesized in the luteinized granulosa cells under the influence of LH.
–The precursor-low density lipoproteins (LDL) is available to the site after vascularization of the granulosa cells following ovulation
–During luteal phase, androstenedione produced by the theca luteal cells diffuses into the granulosa luteal cells to be converted into estradiol by LH. –During follicular phase, it is the FSH that enhances aromatase activity in the granulosa cells. Whereas during the luteal phase it is the LH that enhances the aromatase activity in the luteinized granulosa cells for the conversion of androstenedione to estradiol.
–Therefore, during luteal phase, a two cell (theca luteal and granulosa luteal)-one gonadotropin (LH) system works for estradiol biosynthesis.
Amount of Estrogen production and Blood level?
Amount of Estrogen Production and Blood Level.
–Total daily production of estradiol is estimated to be about 50 µg during the early follicular phase reaching 150-300 µg at ovulation.
–The blood level rises to about 300-600 pg/mL at ovulation. After a sharp fall, it rises again to about 150-200 pg/mL in the luteal phase.
–Total quantity of estradiol production during a cycle from ovulatory ovary is estimated to be 10 mg.
Functions of Estrogen?
Physiological Action
1.Two isoforms of estrogen receptors (ERa; ERB) have been observed to be encoded by two separate genes.
They are variably expressed in tissues. Both the receptors are required for normal ovarian function.
Secondary sex characters:
1. Estrogen tends to induce feminine characteristics.
2. The hormone is responsible for feminine body configuration and feminine mental make up including shyness.
3. There is secretion in apocrine glands, change in voice and deposition of fat on the breasts, thighs and hips.
4. The growth of axillary and pubic hair is dependent predominantly on androgens of adrenal origin.
Action on the genital organs: 1. Under the action of estrogen, the genital organs not only develop into maturity but induce cyclic changes for reproduction.
2. After menopause, with the fall in the estrogen level, atrophic changes of the organs occur.
Vulva and vagina:
-All the structures are influenced by the estrogens.
- The vaginal vascularity and epithelial activity are related to estrogen. - - - Estrogen induces thickening of the lining epithelium, cornification of the superficial cells and deposition of glycogen which is converted into lactic acid by the Doderlein’s bacilli.
- As such, the vaginal flora is maintained by estrogen.
Uterus:
- There is increased vascularity with hyperplasia of the muscles.
- It changes the uterus from the infantile to adult form.
- Cyclic changes in the endometrium includes regeneration and proliferation of the endometrium.
-It produces receptors for progesterone.
- Withdrawal of estrogen causes shedding of the endometrium and menstruation.
Cervix:
-Estrogen causes hypertrophy of the cervix and increases the cervical gland secretion.
-The secretion is more watery, alkaline with less protein and more electrolytes. -These favor penetration of the sperm.
Fallopian tubes:
- There is increased vascularity with increased motility of the tubes.
Breasts:
- There is increased proliferation of the ducts and stromal tissues.
- There is also increased vascularity and pigmentation of the areola. - -Accumulation of fat also occurs.
-Breast secretion, however, cannot occur.
Blood:
-Estrogen increases the coagulability of blood by increasing many procoagulants, chiefly fibrinogen.
-The platelets become more adhesive.
Locomotor system:
-Estrogen conserves calcium and phosphorus and encourages bone formation.
General:
-Estrogen increases sodium, nitrogen and fluid retention of the body.
-It lowers the blood cholesterol and lowers the incidence of coronary heart disease in women prior to menopause. -It has got widespread capillary vasodilatation effect.
Endocrine System
■Hypothalamopituitary axis.
Negative Feedback
Estrogen exerts a negative feedback effect on the release of FSH. This is by:
■Direct action on pituitary, decreasing the sensitivity of the gonadotroph to GnRH.
■Direct action on the hypothalamus with a decrease in GnRH secretion, possibly via increased inhibitory dopaminergic activity.
Positive Feedback
-High levels of estrogen (>200 pg/mL) exert a positive feedback effect on LH (mid cycle LH surge).
-Sustained (24-48 hours) elevated levels of estrogen lead to sustained and elevated LH secretion.
It may be due to:
■Increasing pituitary responsiveness to GnRH
■Stimulating the hypothalamus in secreting GnRH. The positive feedback effect cannot occur in the post-ovulatory phase because of the presence of progesterone.
■Ovary:
The presence of E, and FSH in the antral fluid is essential for sustained proliferation of granulosa cells and continued follicular growth.
■It increases the binding globulin in circulation and raises the blood levels of protein bound iodine and protein bound cortisol.
Progesterone
-Site of secretion?
Metabolism?
Amount of production and Blood level?Physiological Action on:
.Uterus
.Vagina
.Fallopian tubes
.Breasts
.General
Endocrine System:
.HPO Axis
.GnRH secretion
.Ovary
Site of Secretion
-The progesterone is secreted from the luteinized theca granulosa cells of the corpus luteum.
-A trace amount is however, secreted from the theca granulosa cells of the follicle and also from the ovarian stroma.
Metabolism
-Progesterone is bound mainly to albumin (79%) and corticosteroid binding globulin (17.7%).
-It is metabolized in the liver and excreted as sodium pregnanediol glucuronide (pregnanediol) in the urine. -This metabolite has no progestational activity.
-Only 20% of secreted progesterone is conjugated and appears in the urine as pregnanediol. The fate of the remainder is not clear.
-17-a-hydroxyprogesterone is an important product of the ovary. It is metabolized in the liver and reduced to pregnanetriol.
Amount of Production and Blood Level
-Daily production of progesterone is 2-3 mg in follicular phase and 20-30 mg in luteal phase.
-Daily excretion of pregnanediol in the urine is less than 1 mg in follicular phase and 3-6 mg in luteal phase.
-Serum value of progesterone is less than 1 ng/mL in follicular phase and 5-15 ng/mL in midluteal phase.
Physiological Action
-PGN mediates its receptor action though multiple isoforms eneoded by a single gene.
-The PRA; PRB are almost identical. -Progesterone acts on all the organs of the genital tract and on the breasts provided they are sensitized by estrogen.
■Uterus:
-Progesterone produces myohyperplasia and diminishes the contractility of the myometrium.
-It however, increases the tone of the circular muscle fibers at the isthmus. -It produces secretory activity in the endometrium; enhances secretion of the glands rich in glycogen.
-The character of the cervical mucus is changed and become more thick and viscid preventing sperm penetration.
Vagina:
-The maturation of the vaginal epithelium is hindered.
-There is more shedding of the intermediate cells with folded edges and a tendency to clump.
■Fallopian tubes:
-The epithelial cells are stimulated to secrete clear mucus which helps in migration of the ovum.
-Tubal motility is however, decreased which may predispose to tubal pregnancy.
■Breasts:
-Along with estrogen, it produces hypertrophy and growth of the acinar structures.
■General:
-Progesterone is thermogenic, raises the basal body temperature by 0.2-0.5°C. -There may be enhanced deposition of fat in the tissues. It relaxes smooth muscles and ligaments-especially during pregnancy. It promotes the secretion of sebum by the skin. Like other steroids, it causes fluid retention.
Endocrine System
■ Hypothalamo-pituitary axis: The principal negative feedback action of progesterone is upon the midcycle gonadotropin surge and it may be responsible for its short duration.
-Progesterone by itself does not appear to exert a positive feedback effect. -However, its rise during preovulatory period is related with the FSH surge by its positive feedback action.
-The positive feedback effect of estradiol in the secretory phase is inhibited by progesterone.
■ GnRH secretion: Progesterone first (low level) stimulates, then (high level) inhibits the production of GnRH.
■ Ovary: Progesterone acts through both intraovarian and central negative feedback mechanisms to suppress new follicular growth. It is postulated that increased intraovarian progesterone concentration prevents follcular maturation in that ovary in the subsequent cycle.
1) Androgens
-measurement by?
2) Peptides and their roles:
-Inhibin
-Activin
-Follistatin
Androgens
-The androgens are produced in the ovary by all three types of cells-stroma, theca and granulosa, but mainly by the theca interna of the follicles. -The production of androgens is primarily under the control of LH. The principal androgens secreted are dehydroepiandrosterone, androstenedione and testosterone.
-The principal site of metabolism is liver.
-The androgens are reduced to androsterone and etiocholanolone. -These can be measured in the urine as 11 deoxy-17 ketosteroids.
-Total daily production of androstenedione is 3 mg and of testosterone 0.2-0.3 mg.)
-Plasma level of androstenedione is 1.3-1.5 ng/mL, that of testosterone 0.3-0.6 ng/mL and of SHBG 38-103 nmol/L.
Peptides and their Role
■ Inhibin, activin and follistatin are the polypeptides, secreted by the granulosa cells in response to FSH. -Inhibin and activin are glycoproteins. -Inhibin, inhibits FSH secretion Activin is produced by the pituitary and granulosa cells.
-(Activin stimulates FSH release from the pituitary. It also enhance FSH action in the ovary Follistatin, suppresses FSH activity by inhibiting activin.)
■Inhibin: It is secreted by the granulosa cells of the ovarian follicle in response to FSH.
-It has got a preferential negative feedback effect on FSH release.
-FSH and inhibin bear a reciprocal relationship.
-Inhibin A and inhibin B block the synthesis and secretion of FSH.
■Leptin is a peptide and is produced by adipose cells.
-It enhances the release of GnRH. Leptin level is elevated in obesity.
-It has a possible role in implantation.
- Anti-Mullerian Hormone
- Interleukin-1
ANTI-MÜLLERIAN HORMONE
■Anti-Müllerian hormone (AMH) is a peptide produced by the granulosa cells of primordial follicles (<6 mm) and by the Sertoli cells of fetal testes.
AMH belongs to transforming growth factor-ẞ super family.
It causes Müllerian duct regression during male sexual differentiation,
AMH levels reflect the number of growing follicles in the ovary.
It helps oocyte maturation and follicular development and recruitment of dominant follicle. It favours mono- follicular development.
Low levels of AMH is observed with rise of FSH and E, levels and also with increasing age of the women (as the follicle number declines).
AMH levels correlates with ovarian primordial follicle number more strongly than FSH or inhibin levels.
Estimation of serum AMH is independent of mens- tral cycle. It is used as a predictor of ovarian reserve (p. 443).
■AMH is used for assessing ovarian reserve. It suppresses
FSH stimulation. Serum levels decreases with age.
■Levels around 0.05 ng/mL indicates menopause within 4-5 years.
■Levels >2 ng/mL suggest good reserve, levels <0.5 ng/ mL suggest decreased ovarian reserve.
High levels of AMH suggest polycystic ovarian syndrome.
■Role of AMH in follicular development:
AMH inhibits initial recruitment of primordial follicles into the pool of growing follicles. It also decreases responsiveness of follicles to FSH. It prevents premature depletion of the follicular pool.
Interleukin-1 (IL-1) is a polypeptide cytokine.
It is produced by macrophages and also by the theca and granulosa cells following follicular rupture.
It has antigonadotropic activity and supresses leutinization of granulosa cells.
- Name the Glucocorticoids and androgens secretes by adrenal glands?
- Action of Glucocorticoids, androgens and adrenal steroids?
- Biosynthetic pathway in secretion of cortisol?
Adrenal gland consists of two zones-outer cortex and inner medulla. The medulla secretes adrenaline and noradrenaline.
CONTROL OF CORTICAL SECRETIONS
Zona glomerulosa: Aldosterone is secreted from this zone. The secretion is principally controlled by the renin- angiotensin mechanism and is not markedly affected by ACTH. It produces retention of sodium and increased excretion of potassium through the renal tubules.
Zona reticularis and fasciculata: They act as a single unit. The principal hormones that are secreted are cortisol, corticosterone (glucocorticoids); androstenedione, and- rosterone and dehydroepiandrosterone (collectively called androgens) and to some extent estrogen and progesterone (Table 7.1). These constitute the extraovarian sources of steroids.
The control of cortisol synthesis through ACTH is regulated by the negative feedback, diurnal rhythm and stress. Stress can override the negative feedback mechanism and diurnal rhythm. A rise of plasma cortisol causes a rapid suppression of ACTH. A fall in cortisol level leads to increased production of ACTH probably through release of CRH from the hypothalamus.
■ Action of glucocorticoids
The main action of cortisol is anabolic.
• Antagonistic to insulin and tends to raise the blood sugar.
• Suppression of inflammatory reaction.
• Lipogenic effect.
The action of androgens and adrenal steroids are anabolic to antagonize the catabolic effects of the glucocorticoids.
- Normal serum values of Thyroid profile?
Interplay of hormones in HPO axis through feedback mechanism?
