CNS CONTROL MECHANISM OF FEMALE REPRODUCTION DR NABANEETA FEMELIFE FERTILITY FOUNDATION

1. CNS CONTROL MECHANISM OF FEMALE REPRODUCTIONDR NABANEETAFEMELIFE FERTILITY FOUNDATION www.femelife.com

2. FEMALE REPRODUCTION

3. Initial follicular development occurs independently of hormone influence. • FSH stimulation propels follicles to the preantral stage. • FSH-induced aromatization of androgen in the granulosa results in the production of estrogen. • Together, FSH and estrogen increase the FSH receptor content of the follicle.

4. The Two-Cell, Two-Gonadotropin System • In human preantral and antral follicles, LH receptors are present only on the theca cells and FSH receptors only on the granulosa cells • In response to LH, thecal tissue is stimulated to produce androgens that can then be converted, through FSH-induced aromatization, to estrogens in the granulosa cells • As the follicle develops, theca cells begin to express the genes for LH receptors

5. Selection of the Dominant Follicle • A local interaction between estrogen and FSH within the follicle • The effect of estrogen on pituitary secretion of FSH. • While estrogen exerts a positive influence on FSH action within the maturing follicle, its negative feedback relationship with FSH at the hypothalamic-pituitary level serves to withdraw gonadotropin support from the other less developed follicles

6. HYPOTHALAMO –PITUITARY- OVARIAN AXIS GnRH HYPOTHALAMUS PITUITARY OVARY STEROIDS and PEPTIDES FSH,LH

7. FEEDBACK MECHANISM Feedback effects • positive stimulatory • negative inhibitory TYPES OF FEEDBACK- • Long feedback loop • Short feedback loop • Ultra short feedback loop

8. FEEDBACK LOOPS HYPOTHALMUS GnRH STEROIDS and PEPTIDES PITUITARY FSH,LH OVARY

9. CNS CONTROL ON REPRODUCTION • Two major sites of action within the brain which are important in the regulation of reproductive function, the hypothalamus and the pituitary gland • The hypothalamus and its direction, and the pituitary, are essential for the operation of the entire mechanism, but the endocrine function that leads to ovulation is brought about by endocrine feedback on the anterior pituitary.

10. HYPOTHALAMUS • The hypothalamus is the part of the diencephalon at the base of the brain that forms the floor of the third ventricle and part of its lateral walls.

11. HYPOTHALAMUS-OLFACTION • The cells that produce GnRH originate from the olfactory area. By migration during embryogenesis, the cells move along cranial nerves connecting the nose and the forebrain to their primary location, where eventually 1000–3000 GnRH-producing cells can be found in the arcuate nucleus of the hypothalamus • This amazing journey accounts for Kallmann's syndrome, an association between an absence of GnRH and a defect in smell (a failure of both olfactory axonal and GnRH neuronal migration from the olfactory placode

12. PHEROHORMONES • The olfactory origin and the structural similarity of GnRH neurons and nasal epithelial cells suggest an evolution - reproduction controlled by pheromones. • Pheromones are airborne chemicals released by one individual that can affect other members of the same species. • Odorless compounds obtained from the axillae of women in the late follicular phase of their cycles - accelerated the LH surge and shortened the cycles of recipient women, and compounds from the luteal phase had the opposite effects.This may be one mechanism by which women who are together much of the time often exhibit a synchrony in menstrual cycle timing.

13. GnRH Secretion • The half-life of GnRH is only 2–4 minutes. • Therefore, control of the reproductive cycle depends on constant release of GnRH • This function, in turn, depends upon the complex and coordinated interrelationships among this releasing hormone, other neurohormones, the pituitary gonadotropins, and the gonadal steroids • The interplay among these substances is governed by feedback effects, both positive stimulatory and negative inhibitory.

14. Hypothalamic-Hypophyseal PortalCirculation • The hypothalamus is at the base of the brain just above the junction of the optic nerves • In order to influence the anterior pituitary gland, the brain requires a means of transmission or connection. A direct nervous connection does not exist • The blood supply of the anterior pituitary, however, originates in the capillaries that richly lace the median eminence area of the hypothalamus

15. The Neurohormone • pituitary cell proliferation and gene expression are controlled by hypothalamic peptides and their receptor • transplantation of the pituitary to ectopic sites (e.g., under the kidney capsule) results in failure of gonadal function. With retransplantation to an anatomic site under the median eminence, followed by regeneration of the portal system, normal pituitary function is regained

17. NEUROHORMONE • Neuroendocrine agents originating in the hypothalamus have positive stimulatory effects on growth hormone, thyroid-stimulating hormone (TSH), adrenocorticotropin hormone (ACTH), as well as the gonadotropins, and represent the individual neurohormones of the hypothalamus • Initially, it was believed that there were two separate releasing hormones, one for follicle-stimulating hormone (FSH) and another for luteinizing hormone (LH). It is now apparent that there is a single neurohormone (GnRH) for both gonadotropins.

18. GnRH • The divergent patterns of FSH and LH in response to a single GnRH are due to the modulating influences of the endocrine environment, specifically the feedback effects of steroids on the anterior pituitary gland. • The gene that encodes for the 92 amino acid precursor protein for GnRH is located on the short arm of chromosome 8.

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20. It is now apparent that GnRH has autocrine/paracrine functions throughout the body. It is present in both neural and nonneural tissues, and receptors are present in many extrapituitary tissues (such as the ovarian follicle and the placenta). • . A gene encoding GnRH-II is located on the human chromosome 20p13, obviously distinct from the GnRH-I gene on 8p21-p11. Both genes produce a peptide with a signal sequence, a GnRH decapeptide, a proteolytic site, and a GAP.

22. ANTERIOR PITUITARY Five different types of secretory cells coexist within the anterior pituitary gland: gonadotropes, lactotropes, thyrotropes, somatotropes, and corticotrope

23. PITUITARY • Both LH and FSH are secreted by the same cell, the gonadotrope • Responsive to the pulsatile stimulation by GnRH • These responses require a G protein receptor • The GnRH receptor, a member of the G protein family, is encoded by a gene on chromosome 4q13.—14q21 • GnRH receptors are regulated by many agents, including GnRH itself, inhibin, activin, and the sex steroids .

25. GONADOTROPHIN SECRETION • Binding of GnRH to its receptor in the pituitary immediate event is a secretory release of gonadotropins prepare for the next secretory release. self-priming action of GnRH that leads to even greater responses to subsequent GnRH pulses

26. THE BRAIN AND OVULATION • This self-priming action is important to achieve the large surge in secretion at midcycle It requires estrogen exposure, and it can be augmented by progesterone. This important action of progesterone depends upon estrogen exposure an example of cross-talk between peptide and steroid hormone receptors.

27. GnRH Agonists and Antagonists • Initial agonistic action (the so-called flare effect) is associated with an increase in the circulating levels of FSH and LH. • This response is greatest in the early follicular phase when GnRH and estradiol have combined to create a large reserve pool of gonadotropins. • After 1–3 weeks, desensitization and down-regulation of the pituitary produce a hypogonadotropic, hypo gonad state.

28. GnRH Agonists and Antagonists • The initial response is due to desensitization, while the sustained response is due to loss of receptors and the uncoupling of the receptor from its effector system. • Post receptor mechanisms lead to secretion of biologically inactive gonadotropins, which, however, can still be detected by immunoassay • This effect can be utilized for the treatment of endometriosis, uterine leiomyomas, precocious puberty, or the prevention of menstrual bleeding in special clinical situations (e.g., in thrombocytopenic patients) ,ART treatment.

29. GnRH Agonists and Antagonists • GnRH antagonists bind to the GnRH receptor and provide competitive inhibition of the naturally occurring GnRH. • Thus GnRH antagonists produce an immediate decline in gonadotropin levels with an immediate therapeutic effect • The combination of a GnRH antagonist and testosterone holds promise as a male contraceptive agent.

30. PROLACTIN • Responsible for lactogenesis • Secreted from lactotropes of anterior pituitary • Also secreted from –decidua ,myometrium • Releasing factors- TRH,VIP,EGF,GnRH • Inhibited by- dopamine • has considerable structural similarity to human growth hormone and human chorionic somatomammotropin (hCS). • The half life of prolactin, like that of growth hormone, is about 20 minutes.

31. PROLACTIN • Prolactin causes milk secretion from the breast after estrogen and progesterone priming. • Its effect on the breast is increased production of casein and lactalbumin. • Prolactin also inhibits the effects of gonadotropins, possibly by an action at the level of the ovary. Consequently, it is a "natural contraceptive" that spaces pregnancies by preventing ovulation in lactating women.

32. PROLACTIN • In humans, prolactin secretion is increased by exercise, surgical and psychological stresses, and stimulation of the nipple . The plasma prolactin level rises during sleep,the rise starting after the onset of sleep and persisting throughout the sleep period. • Secretion is increased during pregnancy, reaching a peak at the time of parturition. After delivery, the plasma concentration falls to nonpregnant levels in about 8 days. • Suckling produces a prompt increase in secretion, but the magnitude of this rise gradually declines after a woman has been nursing for more than 3 months.

33. PROLACTIN • prolactin facilitates the secretion of dopamine in the median eminence. Thus, prolactin acts in the hypothalamus in a negative feedback fashion to inhibit its own secretion. • 15–20% of women with secondary amenorrhea have elevated prolactin levels, and when prolactin secretion is reduced, normal menstrual cycles and fertility return • It appears that the prolactin may produce amenorrhea by blocking the action of gonadotropins on the ovaries, but definitive proof of this hypothesis must await further research

34. The Intrapituitary Autocrine/Paracrine System • Pituitary contains various substances encountered in organs throughout the body, including the interleukins, epidermal growth factor, fibroblast growth factors, the insulin-like growth factors, nerve growth factor, activin, inhibin, and many others

35. Activin, Inhibin, and Follistatin • These are peptide members of the transforming growth factor-b family • Inhibin consists of two dissimilar peptides (known as alpha- and beta-subunits) linked by disulfide bonds. • Two forms of inhibin (inhibin A and inhibin B) have been purified, each containing an identical alpha-subunit and distinct but related beta-subunits. • Inhibin is secreted by granulosa cells • Inhibin selectively inhibits FSH, but not LH, secretion

36. Activin, Inhibin, and Follistatin • Cells actively synthesizing LH respond to inhibin by increasing GnRH receptor number; FSH dominant cells are suppressed by inhibin • Hence while suppressing FSH synthesis, inhibin may enhance LH activity • Inhibin has little or no effect on growth hormone, ACTH, and prolactin production.

38. ACTIVIN • Activin, also derived from granulosa cells, but present as well in the pituitary gonadotropes, • It contains two subunits that are identical to the beta-subunits of inhibins A and B. • Activin augments the secretion of FSH and inhibits prolactin, ACTH, and growth hormone responses • Activin increases pituitary response to GnRH, probably by enhancing GnRH receptor formation • The effects of activin are blocked by inhibin and follistatin

39. INHIBIN • Inhibin secretion is diminished by GnRH, and enhanced by insulin-like growth factor-1 (IGF-1). • Inhibin B reaches a peak in the early- to mid-follicular phase, and a second peak at ovulation. • Inhibin A reaches its peak in the mid-luteal phase. • Inhibin is produced in the gonads, pituitary gland, placenta and other

40. CLINICAL APPLICATION • Quantification of inhibin A is part of the prenatal screen . • An elevated inhibin A (along with an increased beta-hCG, decreased AFP, and a decreased estriol) is suggestive of the presence of a fetus with Downs syndrome. • It also has been used as a marker for ovarian cancer. • Inhibin B is used as a marker of ovarian reserve, its level has been found to be elevated in PCOS.

42. The Endogenous Opiates • There are 3 classes of opiates: enkephalins, endorphin, and dynorphin. • The opioid tone is an important part of menstrual function and cyclicity • Endogenous endorphin levels, therefore, increase throughout the cycle from nadir levels during menses to highest levels during the luteal phase • Normal cyclicity thus requires sequential periods of high (luteal phase) and low (during menses) hypothalamic opioid activity.

43. The Endogenous Opiates • the endogenous opiates inhibit gonadotropin secretion by suppressing the hypothalamic release of GnRH. • Opiates have no effect on the pituitary response to GnRH. • The negative feedback of steroids on gonadotropins appears to be mediated by endogenous opiates • There is an absence of opioid effect on postmenopausal and oophorectomized levels of gonadotropins, and the response to opiates is restored with the administration of estrogen, progesterone,

44. The Endogenous Opiates • The inhibiting tone of endogenous opiates is reduced at the time of the ovulatory surge, allowing a release from suppression. • This is probably a response to estrogen, specifically an estrogen-induced decrease in opioid receptor binding and opioid release • Experiments with naloxone administration suggest that the suppression of gonadotropins during pregnancy and the recovery during the postpartum period reflect steroid-induced opioid inhibition, followed by a release from central opioid suppression.

45. Clinical Implications -OPOIDS • Responsiveness to naloxone does not develop until after puberty ---opoid inhibition does not seem to play a causal role in delayed puberty or hereditary problems such as Kallmann's syndrome. • A change in opioid tone does seem to mediate the hypogonadotropic state seen with elevated prolactin levels, exercise, and other conditions of hypothalamic amenorrhea. • Treatment of patients with hypothalamic amenorrhea (suppressed GnRH pulsatile secretion) with a drug (naltrexone) which blocks opioid receptors restores normal function (ovulation and pregnancy)

46. The Endogenous Opiates • corticotropin-releasing hormone (CRH) directly inhibits hypothalamic GnRH secretion, both directly and by augmenting endogenous opioid secretion. • Women with hypothalamic amenorrhea demonstrate hypercortisolism, suggesting that this could be the pathway by which stress interrupts reproductive function • Most studies indicate an exercise-induced increase in endogenous opiates, but a significant impact on mood remains to be substantiated

47. The Endogenous Opiates • Administration of morphine, enkephalin analogs, and b-endorphin causes release of prolactin. • The effect is mediated by inhibition of dopamine secretion in the tuberoinfundibular neurons in the median eminence. • Every pituitary hormone appears to be modulated by opiates. Physiologic effects are important with ACTH, gonadotropins, and possibly vasopressin. • Opioid compounds have no direct action on the pituitary, nor do they alter the action of releasing hormones on the pituitary

48. HYPOTHALAMO-ADIPOCYTE AXIS • Only leptin and insulin fulfill the criteria of an adiposity signal: • Leptin circulates at levels proportional to body fat. • It enters the central nervous system (CNS) in proportion to its plasma concentration. • One of the main effects on is the down-regulation of the expression of endocannabinoids, responsible—among their many other functions—for increasing appetite

49. LEPTIN • Leptin is produced by the placenta Leptin levels rise during pregnancy and fall at parturition. • Several studies have shown that fasting or a very low calorie diet lowers leptin levels . It might be that on short term leptin is an indicator of energy balance

50. LEPTIN • In addition to its endocrine action at a distance (from adipose tissue to brain) leptin also acts as a paracrine mediator. In fetal lung leptin is induced in the alveolar interstitium and induces surfactant expression • There has also been evidence that Leptin plays a role in Hyperemesis gravidarum, or Severe morning sickness of pregnancy.