Seminar presentation on hypothalamic ovarian axis and menstruation by year 1 obgyn resident

1. Postgraduate Seminar on Physiology Of HPO
axis and Menstrual Cycle
Presenter: Dr Endale B (R1)
Moderator: DrHusen K
(gynecologist& obstetrician)
1

2. 1/4/20231/4/2023
2
Outline
 Introduction
 Anatomy
 The hypothalamic-hypophyseal-Ovarian axis
 The menstrual cycle
 References

3. 1/4/2023
3
Introduction
 The HPO axis is essentially a complex but
necessary interplay between the hypothalamus, the
pituitary and the ovaries in such a way that they
behave like one neuroendocrine organ.
 The axis is functionally involved in the
development of primary and secondary sexual
characteristics, the control of oogenesis and by
extension reproduction.

4. 1/4/2023
4
 Menstrual cycle is a tightly coordinated cycle of
stimulatory and inhibitory effects.
 It is controlled by hormones, paracrine and
autocrine factors

5. 1/4/2023
5
 Many forms of cell-to-cell communication exist in
reproductive physiology;
1. Endocrine secretion (hormone) ; a cell product that
is secreted into the peripheral circulation and that
exerts its effects in distant target tissues
2. Paracrine communication; refers to chemical
signaling between neighboring cells.

6. 1/4/2023
6
3. Autocrine communication; occurs when a cell
releases substances that influence its own
function.
4. neuroendocrine secretion or signaling;An
action potential leads to release of NT→ enter
into and travel through the circulation to reach
their target organ. eg GnRH secretion
5. intracrine effect

7. 1/4/2023
7

8. 1/4/2023
8
Anatomy
 The hypothalamus :
 Consists of nuclei located at the base of the brain, just
superior to the optic chiasm & below 3rd ventricle
 Influence Pituitary function by neurons located within the
arcuate, ventromedial, dorsomedial, and paraventricular
nuclei
 Connection:
 synaptic connections(other CNS neurone& to
the median eminence)
 hypophyseal portal system

9. 1/4/2023
9
 In the median eminence a dense network of
capillaries arises from the superior hypophyseal
arteries.
 These capillaries drain into portal vessels that
traverse the pituitary stalk and then form a
capillary network within the anterior pituitary
gland.

10. 1/4/2023
10
 The primary direction
of this hypophyseal
portal system is from
hypothalamus to
pituitary, however,
retrograde flow also
exists.

11. 1/4/2023
11
 PITUITARY GLAND:
 Surrounded by the sphenoid bone & lies in the
sella turcica underneath the optic chiasma.
 Divided into 2 lobes:
 Adenohypophysis(80%)
 Neurohypophysis(20%)

12. 1/4/2023
12
 Anterior Pituitary Gland:
 The pituitary gland contains five hormone-
producing cell types:
1) gonadotropes ( LH and FSH)
2) lactotropes (PRL)
3) somatotropes (GH)
4) thyrotropes (TSH) and
5) adrenocorticotropes (ACTH).
 Of these gonadotropes comprise 10 to 15% of
all hormonally active cells in the anterior
pituitary

13. 1/4/2023
13
 Posterior Pituitary Gland:
 the posterior pituitary consists of the axon
terminals of magnocellular neurons from the
supraoptic and paraventricular nuclei of the
hypothalamus

14. 1/4/2023
14

15. 1/4/2023
15
Hypothalamic-Pituitary Ovarian
Axes
 The hypothalamus delivers precise signals to
the pituitary gland which then releases
hormones that influence most endocrine
systems in the body
 With the exception of PRL, which is under tonic
inhibition, pituitary hormones are stimulated by
hypothalamic neuroendocrine secretion

16. 1/4/2023
16
Hypothalamic
Neuroendocrinology
 The most significant neurotransmitters in
reproductive neuroendocrinology are the three
monoamines(DA,NE &SE)
 Clinically important neuropeptides within the
reproductive axis include;
 endogenous opiates
 kisspeptin
 neuropeptide Y
 galanin and
 pituitary adenylate cyclase-activating peptide.

17. 1/4/2023
17
1. Endogenous Opiates
 can be categorized into three classes:
endorphins,
enkephalins and
dynorphins.
 The endorphins serve a wide range of physiologic
functions that include regulation of T,cardiovascular
and respiratory systems, pain perception,mood and
reproduction.

18. 1/4/2023
18
 Opioid tone in the brain plays a central role in
menstrual cyclicity by suppressing the release of
GnRH
 Estrogen promotes endorphin secretion, and this
is increased further with the addition of
progesterone .
 Endorphin levels increase during the follicular
phase, peak during the luteal phase, and drop
markedly during menses.
 Opioid tone acts along with progesterone to
decrease GnRH pulse frequency in the luteal
phase relative to the follicular phase.

19. 1/4/2023
19
2. kisspeptin
 Play a critical role in sexual
differentiation,puberty initiation and adult
reproductive function
 Kisspeptin neurons send processes to GnRH
neurons, allowing direct control of GnRH
secretion.

20. 1/4/2023
20
3. neuropeptide Y (NPY) and galanin
 Are expressed by neurons located throughout
the hypothalamus and project to kisspeptin
neurons, to GnRH neurons, and to other areas
o the CNS that have roles in reproductive
function.
 Both of these neuropeptides alter GnRH
pulsatility and potentiate GnRH induced
gonadotrope secretion

21. 1/4/2023
21
4. Pituitary adenylate cyclase-activating peptide
(PACAP)
 is a hypothalamic peptide secreted into the
pituitary portal system.
 It binds to receptors on anterior pituitary cells
and stimulates hormone secretion including
gonadotropin secretion

22. 1/4/2023
22
 Hypothalamic-Releasing Peptides:
 Biologically active concentrations of these factors
are locally restricted to the anterior pituitary gland:
1)they are small peptides with short half-lives
2)they released in minute quantities and are
highly diluted in the peripheral circulation

23. 1/4/2023
23
 Include;
1. GnRH, which controls the secretion of LH and
FSH
2. CRH, which controls the release of ACTH
3. GHRH, which regulates the release of GH
4. TRH, which regulates the secretion of TSH

24. 1/4/2023
24
 Gonadotropin-Releasing Hormone
 GnRH is a decapeptide with a half-life of less than 10
minutes.
 Its cell bodies are primarily located within the arcuate
nucleus→ axonally transported along the
tuberoinfundibular tract to the median eminence
 Then secreted into the portal system and stimulates
gonadotropin biosynthesis and secretion

25. 1/4/2023
25
 Pharmacologic amino acid modifications
generate receptor antagonists or agonists with
a prolonged half-life

26. 1/4/2023
26

27. 1/4/2023
27
 Migration of the GnRH Neurons:
 GnRH-containing neurons originate in the medial
olfactory placode and migrate along the vomeronasal
nerve into the hypothalamus.
 A series of soluble factors regulate GnRH neuronal
migration at specific locations along their migratory
route.
 These factors are GABA, adhesion molecules, and
growth factor

28. 1/4/2023
28
 Gonadotropin-Releasing Hormone Secretion:
 Pulsatile secretion
 For proper stimulation of gonadotropin release,
GnRH neurons must secrete in a pulsatile fashion
 Continual exposure →phenomenon called
downregulation
 Intermittent exposure→ “upregulate” or“autoprime”

29. 1/4/2023
29
 The pulse secretion of GnRH has an
amplitude and frequency
 Amplitude ;signifies the amount of GnRH
delivered into portal circulation.
 Frequency ;means at what interval the GnRH
is delivered into portal circulation.
 The pulsatile secretion of GnRH varies in
frequency and amplitude throughout the
menstrual cycle and is tightly regulated

30. 1/4/2023
30
 The frequency is
rapid in the follicular
phase, about one
pulse per hour and
lower in the luteal
phase about one
pulse every 2–3
hours.
 In the follicular phase
the amplitude is low
but it is high in luteal
phase.

31. 1/4/2023
31
 Pulsatile release of
GnRH is more
frequent but of lower
amplitude during the
follicular phase
compared with that
of the luteal phase.
 More rapid pulse
frequencies
preferentially
stimulate LH
whereas slower
frequencies favor
FSH secretion .

32. 1/4/2023
32
 Tonic center;is controlled primarly by negative
feedback of sex steroid
 cyclic center;is stimulated by posetive
feedback effect of preovulatory sustained and
high rise of estradiol

33. 1/4/2023
33
 Neurohormonal contrlo of GnRH secretion is
modulated by four pathways:
1)NT and neuromodulator
2)ultrashort feedback loop
3)short feedback loop
4)long feedbackloop

34. 1/4/2023
34
 NT & neuromodulator:
 Dopamine & serotonin
inhibit but NE exert
stimulatory effect
 Endorphin,encephalin &
dynorphin inhibit GnRH
secretion
 Prostagldin E is produced
locally and increase
release
 Peptide like activin,inhibin
&follistatin

35. 1/4/2023
35
 Ultrashort feedback loop
 is autoregulation of releasing hormone of
hypothalamus on its own synthesis
 GnRH can regulate the concentration of its
own pituitary receptor

36. 1/4/2023
36
 Short feedback loop
 is negative feedback of FSH and LH on
hypothalami production of GnRH
 Long feedback loop(sex steroid)

37. HYPOTHALAMIC- PITUITARY- OVARIAN AXIS
37

38. Normal menstrual cycle physiology
38
 The “typical” menstrual cycle is 28 ± 7 days with
menstrual flow lasting 4 ± 2 days and blood loss
averaging 20 to 60 mL.
 normal menustral cycle
 length 21-35 days
 volume 10-80ml
 Flow 1-8 days (3-5 days)
 Average volume 30-50ml

39. 1/4/2023
39
 Normal menstrual cycle requires complex
interactions b/n the hypothalamus, pituitary &
end organs (uterus & ovaries).
 Hypothalamic pulsatile release of GnRH
secretion stimulates secretion of FSH & LH
from the anterior pituitary.
 FSH stimulates a cohort of ovarian follicles to
undergo growth & development.
 Androgens produced in theca cells are
converted to estrogens in granulosa cells by
the enzyme aromatase.

40. 1/4/2023
40
 ↑ing estradiol levels exert -ve feedback on FSH &
the follicle with the most FSH receptors becomes
dominant. Other follicles undergo atresia.
 ↑ing levels of estradiol exert +ve feedback on LH
secretion from the pituitary resulting in the LH
surge.
 Shortly after LH levels peak, ovulation occurs.

41. 41
 Granulosa cells produce progesterone during
the luteal phase, resulting in decidualization of
endometrial glands to their secretory form in
preparation for a pregnancy.
 If pregnancy is not established, the corpus
luteum regresses and menses ensues as the
endometrium experiences progesterone
withdrawal.

42. 1/4/2023
42
 The normal human menstrual cycle can be divided
into two segments:
 The ovarian cycle and
 The uterine cycle
 The ovarian cycle may be further divided into:
 Follicular, Ovulation and Luteal phases
 The uterine cycle is divided into ;
 proliferative and secretary phases

43. 1/4/2023
43
The ovarian cycle
 Ovary:
 Adult human ovary is oval(321)
 Composed of three part(cortical ,medullary&hilum)
 ovary develop from three major cellular source:
1. Primordial germ cell;identified in yolk sac at 3rd wk
of GA→begin migration into gonadal ridge at 6th wk
of gestation→subset of oogonia enter meiosis to
become primary oocytes starting at 12wks

44. 1/4/2023
44
2. Coelomic epithelial; wich develop into granulosa
cells
3. Mesenchymal cells; from godal ridge wich
become the ovarian stromal

45. 1/4/2023
45
 Ovaries have two interrelated functions:
A .Oocytes production ;
 Primordial germ cell identified in endoderm of the yolk sac (as
early as 3wk)
 Begin to migrate into gonadal ridge during the 6th wks of
gestation
 The germ cells undergo rapid mitotic division after reaching
gonads until 7th month of gestation

46. 1/4/2023
46
 Some enter into the prophase of first meiotic
division and are called primary oocytes (starting
from 12wks)
 Than arrested in devlt at prophase1durig 1st
meioti division
 Meiotic division resume at ovulation and complete
with fertilization
 Maximium no of oogonia achieved by 20 wk of GA
6-7 million→1-2 million at birth→400,000 at
puberty and approximately 400 ovulated

47. 1/4/2023
47
B. Ovarian steroidogenesis and peptide hormone
secretion:
 two cell theory
 inhibin and activin

48. 1/4/2023
48
 Two cell, two-gonadotropin theory;
 Explain that estrogen biosynthesis require action of
two cell & two gonadotropin
 Theca cell synthesize androge,primarily
androstenedionen in response to stimulation by LH
 Androgen secrete into exracellular fluid & diffuse
across BM

49. 1/4/2023
49
 Granulosa cell
convert androgen to
estrogen in responce
to FSH
stimulation(high
aromataze actvity)

50. 1/4/2023
50
 Peptide hormone secretion;
 Inhibin is secreted in two forms: inhibin A and
inhibin B.
 Both forms of inhibin act to inhibit FSH synthesis
and release
 Activin stimulates FSH release from the pituitary
gland and potentiates its action in the ovary

51. 1/4/2023
51
 Folliculogenesis – the cyclic recruitment of a
pool of follicles to produce a mature follicle ready
for ovulation.
 Depending on number and appearance of
granulosa cell,devt of theca cell & formation of fluid
filled structure:
1.preantral;primordial,primary and secondary
follicle
2.antral follicle;tertiary and preovulatory follicle

52. 1/4/2023
52
 Primordial follicle(0.03-0.05mm);
 is primary oocytes surrounded by single layer of flattened
granulosa cell
 Primary follicles(0.1mm);
 Granulosa cell become cuboidal $ ↑ed in number
 Intracellular gap junction develop
 Oocytes begin secretion of acellular coat called zona
pellucida
 Develop FSH receptors, without endocrine effect as a result
of the absence of follicular vascularization

53. 1/4/2023
53
 Secondary follicles(0.2 mm);
 Develop several layers of cuboidal granulosa cells
with marked expression of FSH receptors.
 Stromal cell differentiated into theca cells with LH
receptor expression.
 Neoangiogenesis occurs, vascularizing the follicle
and exposing it to circulating FSH and LH

54. 1/4/2023
54
 Tertiary follicle(antral);
 Chxd by the formation of the antral cavity or antrum
 Early tertiaryfollicles & late tertiary follicles
 Preovulatory follicles(Graafian follicles);
 Are the final stage of follicular development and
>20 mm in size
 Late in this stage and before ovulation, the primary
oocyte completes meiosis I, becoming a secondary
oocyte arrested in metaphase of meiosis II

55. 1/4/2023
55

56. 1/4/2023
56
Follicular phase
 During the end of a previous cycle, estrogen,
progesterone and inhibin levels decrease abruptly
with a corresponding increase in circulating FSH
levels
 Increase in FSH level is responsible or recruitment
of the cohort of follicles that contains the follicle
destined for ovulation.

57. 1/4/2023
57
 Each month, a group of follicles known as a cohort
begins a phase of semisynchronous growth
 The ovulatory follicle is recruited from a cohort that
began development two to three cycles prior to the
ovulatory cycle

58. 1/4/2023
58
 During the mid Follicular phase, follicles produce
increased amounts of estrogen and inhibin→ in a decline
in FSH levels through negative eedback.
 This drop in FSH levels is believed to contribute to
selection of the follicle destined to ovulate, termed the
dominant follicle.
 Nondominant follicles express decreased numbers of FSH
receptors and therefore are unable to respond adequately
to declining FSH levels.
 Thus, 95 percent of plasma estradiol produced at this time
is secreted by the dominant follicle

59. 1/4/2023
59
Ovulation
 LH surge initiates substantial changes in the ovary
and result from increasing estrogen secretion
The reentry of the oocyte into meiosis
Expansion of the cumulus oophorus
Synthesis of prostaglandins and
Luteinization of granulosa cells
 These allow release of the mature oocyte and its
surrounding cumulus cells through the surface
epithelium.
 Oocyte is released from the follicle at the surface of
the ovary approximately 34-36 hours after LH surge.

60. 1/4/2023
60
Luteal phase
 The corpus luteum develops from the remains of the
Graafian follicle in a process referred to as
luteinization
 During luteinization
The BM separating the granulosa-lutein and
theca-lutein cells breaks down
Blood vessels and capillaries invade the
granulosa cell layer(by day 2 postovulation)
Cells undergo hypertrophy and increase their
capacity to synthesize hormones.

61. 1/4/2023
61
 There is greater capacity of granulosa lutein cells
to produce progesterone as results of enhanced
access to considerably more steroidogenic
precursors through blood-borne(LDL)
 Ovarian progesterone production peaks at 25 to 50
mg/d during the midluteal phase.
 In the absence of pregnancy CL will rapidly regress
9 to 11 days after ovulation via apoptosis

62. 1/4/2023
62
The uterine cycle
 ENDOMETRIUM
 Histology across the Menstrual Cycle
 is 1-2mm after mense & 12 mm at the time of
the LH surge and does not increase significantly
there after
 consist of two layer(basalis &functionalis)
 have proliferative and secratory phase

63. 1/4/2023
63
MENSE
 An irregular breakdown of the functionalis layer in
the absence of implantation
 There is a profound spiral artery vascular spasm that
ultimately leads to endometrial ischemia(steroid
withdrawal)
 Simultaneously, there is a breakdown of lysosomes
and a release of proteolytic enzymes, which further
promote local tissue destruction.
 Shedding of functionalis layer , leaving the basalis
layer as the source of subsequent endometrial
growth.

64. 1/4/2023
64
 Prostaglandins are produced throughout the
menstrual cycle and are at their highest concentration
during menses
 This Prostaglandin F2α (PGF2α) cause;
 Arteriolar vasospasm and endometrial
ischemia(potent vasoconstrictor)
 Produces myometrial contraction

65. 1/4/2023
65
The Proliferative Phase
 Is chxd by progressive mitotic growth of the
functionalis layer in response to rising circulating
levels of estrogen
 Reepithelialization begins even before menstrual
bleeding has ceased.
 By the fifth day of the endometrial cycle the epithelial
surface of the endometrium has been restored and
revascularization has begun.

66. 1/4/2023
66
 During the early part of the proliferative phase;
the endometrium is usually less than 2 mm
thick.
The glands are narrow, tubular structures that
pursue almost a straight and parallel
Mitotic figures are identified by the fifth cycle
day (persists until day 16 to 17)
Blood vessels are numerous and prominent.

67. 1/4/2023
67
 By the late proliferative phase, the
endometrium thickens from both glandular
hyperplasia and augmented stromal ground
substance, which is edema and proteinaceous
material
 At midcycle, as ovulation nears, glandular
epithelium becomes taller and
pseudostratified.

68. 1/4/2023
68
The Secretory Phase
 Named for the clear presence of eosinophilic
protein-rich secretory products in the glandular
lumen.
 At postovulatory day 6 or 7 secretory activity of the
glands is generally maximal and the endometrium is
optimally prepared for implantation of the blastocyst.
 Is characterized by the cellular effects of
progesterone in addition to estrogen.

69. 1/4/2023
69
 Differential effects of progesterone on
endometrial epithelial and stromal cells are
thought to be due to cell type–specific
differences in PR-A and PR-B expression and
function.
 PR-A －In the stromal cell compartment
 PR-B－endometrial epithelial compartment

70. 1/4/2023
70
 Endometrial glands
 Form glycogen-containing vacuolesinitially
appear subnuclearly and progress toward the
glandular lumen ultimately undergo apocrine
secretion into the glandular lumen
 Glandular cell mitosis ceases with secretory activity
due to rising progesterone levels, which antagonize
the mitotic effects of estrogen.

71. 1/4/2023
71
 By day 17, glycogen accumulates in the basal
portion of glandular epithelium creating subnuclear
vacuoles and pseudostratification.
 On day 18, vacuoles move to the apical portion of
the secretory nonciliated cells.
 By day 19, these cells begin to secrete glycoprotein
and mucopolysaccharide contents into the gland
lumen

72. 1/4/2023
72
 stroma
 Remains unchanged histologically until the 7th
postovulatory day and mitosis began on days 22 to
25
 Than there is a progressive increase in edema (On
cycle days 21 to 24)
 vasculature
 spiral arteries become clearly visible and
progressively lengthen and coil during the remainder
of the secretory phase

73. 1/4/2023
73

74. 1/4/2023
74
Morphological and endocrinological changes during the menstrual
cycle

75. 1/4/2023
75
ABNORMALITIES IN THE
HYPOTHALAMIC-PITUITARY AXIS
 Knowledge o normal HPO axis is essential to
understand reproductive endocrine pathology
 hypogonadotropic hypogonadism
 Kallmann syndrome
 Functional disorders
 Compresive and infiltrative
 Hyperprolactinemia
 pituitary adenomas

76. 1/4/2023
76
 William’s Gynecology, 3rd ed
 Williams Obstetrics 25th ed
 Speroff’s Clinical Gynecologic
Endocrinology and Infertility, 9th Edition.
 DC duttas text book of gynecology

77. THANK YOU