The menstrual cycle is the scientific term for the physiological changes that occur in fertile women for the purpose of sexual reproduction.The menstrual cycle is controlled by the endocrine system

1. CNS CONTROL MECHANISM
OF FEMALE
REPRODUCTION
DR NABANEETA
FEMELIFE FERTILITY FOUNDATION

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
HYPOTHALAMUS
PITUITARY
OVARY
STEROIDS and PEPTIDES
GnRH
FSH,LH

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

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

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.

19. A

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.

51. leptin
• Leptin concentrations are low in people and animals with
low body fat, and leptin appears to be a significant regulator
of reproductive function.
• These effects are probably due in part to the ability of leptin to
enhance secretion of gonadotropin-releasing hormone, and thus
luteinizing and follicle-stimulating hormones from the anterior
pituitary

52. Gonadotropin Secretion Through Fetal Life,
Childhood, and Puberty
• puberty is not a beginning, but just another stage in a
development that began at conception.
• Gonadotropin production has been documented throughout fetal
life, during childhood,
• GnRH is detectable in the hypothalamus by 10 weeks of
gestation, and by 10–13 weeks when the vascular connection is
complete, FSH and LH are being produced in the pituitary.

53.  Beginning at midgestation, there is an increasing sensitivity to inhibition by
steroids and a resultant decrease in gonadotropin secretion
 The rise in gonadotropins after birth reflects loss of the high levels of
placental steroids.
 Thus, in the first year of life there is considerable follicular activity in the
ovaries in contrast to later in childhood when gonadotropin secretion is
suppressed. Furthermore, the postnatal rise in gonadotropins is even greater
in infants born prematurely.

54.  There are higher pituitary and circulating FSH and pituitary LH levels in female
fetuses. The lower male levels are probably due to testicular testosterone and
inhibin production.
 gonadotropin levels reach a nadir during early childhood (by about 6 months of
age in males and 1–2 years in females) and then rise slightly between 4 and 10
years.
 The changes at puberty are due to a gradually increasing gonadotropin secretion
that takes place because of a decrease in the sensitivity of the hypothalamic
centers to the negative-inhibitory action of gonadal steroids

56. MENOPAUSE
 The human ovary gradually becomes unresponsive to gonadotropins with
advancing age and its function declines so that sexual cycles and menstruation
disappear (menopause).
 This unresponsiveness is associated with and probably caused by a decline in
the number of primordial follicles
 As the negative feedback effect of the estrogens and progesterone is reduced,
secretion of FSH and LH is increased, and plasma FSH and LH rise to high
levels.

57. CONCLUSION
• Pulsatile GnRH secretion must be within a critical range for
frequency and concentration (amplitude).
• GnRH has only positive actions on the anterior pituitary:
synthesis and storage, activation, and secretion of
gonadotropins. The gonadotropins are secreted in a pulsatile
fashion in response to the similar pulsatile release of GnRH.

58. CONCLUSION
 Low levels of estrogen enhance FSH and LH synthesis and storage, have little
effect on LH secretion, and inhibit FSH secretion.
High levels of estrogen induce the LH surge at midcycle, and high steady levels
of estrogen lead to sustained elevated LH secretion.
 Low levels of progesterone acting at the level of the pituitary gland enhance
the LH response to GnRH and are responsible for the FSH surge at midcycle.

59. THANK YOU