PHYSIOLOGY OF OVULATION

MODERATOR: DR.L.KRISHNA
PRESENTER: DR.N.ANUSHA
• HPO AXIS
• STAGES OF FOLLICULAR DEVELOPMENT
• PHYSIOLOGY OF OVULATION
HPO AXIS
HYPOTHALAMUS
• Located at the base of the brain
• Connected to
Pituitary gland
Other parts of the brain
• Secretes
Releasing hormones
Dopamine
• Controlled by
Hormonal feedback
Neurotransmitters
Impulses from other parts of the brain
PITUITARY GLAND
• Connected to the hypothalamus by a stalk
• Divided into
Anterior: Adenohypophysis
Posterior: Neurohypophysis
Adenohypophysis Neurohypophysis

Secretes Gonadotrophins Secretes Oxytocin

Prolactin Arginine-vasopressin
Other trophic hormones
Supplied by portal system Supplied by hypophyseal arteries
GONADOTROPHIN-RELEASING HORMONE
• Peptide hormone
• Secreted by the hypothalamus
• Half-life 2-4 minutes
• Stimulates secretion of FSH and LH by pituitary.
• Released in pulsatile fashion
Follicular phase
Once in 60 minutes
Low amplitude
Luteal phase
Once in 90-120 minutes
High amplitude
FOLLICLE-STIMULATING HORMONE
• Glycoprotein consisting of alpha and beta sub units
• Stimulated by GnRH production
• Suppressed by oestrogen and inhibin
• Two peak levels during menstrual cycle
Follicular phase (sixth day)
Preovulatory phase (twelfth day)
The biological half life of FSH is 3-4 hrs.
• Functions
Recruitment of follicles
Follicular growth
Acts on granulosa cells
Increase in number
Increase in LH receptors
Increase in aromatase activity
 LUTEINISING HORMONE
• Glycoprotein made up of alpha and beta subunits.The alpha subunits of
LH,FSH &HCG are identical containing 92 amino acids
• Stimulated by GnRH and high level of estrogen
• Suppressed by moderate level of estrogen
• Present in low levels throughout menstrual cycle
• Peak level 24-36 hours before ovulation
• The biological half life of LH is 20 mins
• Functions
Triggers ovulation
Stimulates androgen production by theca cells
Stimulates synthesis of progesterone by corpus luteum
INHIBINS

• Inhibins are heterodimeric protein hormones secreted bt granulosa cells of

the ovary.They consist of a dimer of 2 homologous subunits,an alpha
subunit and either a beta A subunit(Inhibin A)or a beta B subunit(Inhibin
B).
• Inhibin A is primarily produced by the dominant follicle and corpus
luteam(ie., in the late follicular phase and luteal phase)
• Inhibin B is is predominantly produced by the small developing follicles(ie.,
in the early follicular phase)
• Post menopause,both Inhibin A and B levels are very low to undetectable
• They are also used in the detection of some ovarian cancers.
ACTIVINS

• Activin is a dimer composed of

two identical or very similar
beta sub units.
• Activin is produced by the
gonads,pituitary gland,placenta
etc.In the ovarian follicle,Activin
increases FSH binding and FSH-
induced aromatization.It also
helps in androgen synthesis
enhancing the LH action in the
ovary.
STAGES OF FOLLICULAR DEVELOPMENT
STAGES OF FOLLICULAR DEVELOPMENT
• Primordial follicle
Single layer of flattened granulosa cells
• Primary follicle
Cuboidal granulosa cells
Increase in number of granulosa cells
Pseudostratification
Formation of zona pellucida
• Secondary follicle
Preantral follicle
Increase in number of granulosa cells
Stromal differentiation into theca cells
Formation of theca externa and theca interna
• Tertiary follicle
Antral follicle
Collection of fluid in the follicle
Rapid increase in follicular size
Formation of cumulus oophorus
Formation of corona radiate
Formation of Graafian follicle
STAGES OF FOLLICULAR
DEVELOPMENT

• Follicular development begins with primordial follicles that were generated

during fetal life
• These follicles consist of an oocyte arrested in the first meiotic division
surrounded by a single layer of flattened granulosa cells.
• These follicles are separated from the stroma by a thin basement
membrane.
• Pre ovulatory follicles are avascular. As a result, they are critically
dependent on diffusion and on the later development of gap junctions for
obtaining nutrients and clearing metabolic waste.
• Diffusion also allows passage of steroid precursors from the thecal to the
granulosa cell layer.
Primary Follicle
• Granulosa cells become cuboidal and increase in number to form a
pseudostratified layer.
• Intercellular gap junctions develop between adjacent granulosa cells
and between granulosa cells and the developing oocyte .
• These connections allow the passage of nutrients, ions, and
regulatory factors between cells.
• Gap junctions also allow cells without gonadotropin receptors to
receive signals from cells with receptor expression, as a result,
hormone mediated effects can be transmitted throughout the follicle.
• During this stage, the oocyte begins secretion of an acellular coat
known as the zona pellucida.
• The human zona pellucida contains at least three proteins, named
ZP1, ZP2, and ZP3.
• In current physiologic models, receptors on the acrosome head of
the sperm recognize ZP3.
• This interaction results in release of acrosomal contents, penetration
of the zona pellucida, and fertilization of the egg.
Secondary Follicle/ Pre antral Follicle
• Development of a secondary, or preantral, follicle includes final
growth of the oocyte and a further increase in granulosa cell number.
• The stroma differentiates into the theca interna and the theca
externa, which abuts the surrounding stroma
Tertiary Follicle/ Antral
Follicle
• With ongoing development, follicular fluid begins to collect between
the granulosa cells, ultimately producing a fluid-filled space known as
the antrum.
• The follicle is now termed a tertiary, or antral, follicle.
• Further accumulation of antral fluid results in a rapid increase in
follicular size and development of a preovulatory, or Graafian, follicle.
• Granulosa cells in the antral follicle are histologically and functionally
divided into two groups.
• The granulosa cells surrounding the oocyte form the cumulus
oophorus, whereas the granulosa cells surrounding the antrum are
known as mural granulosa cells.
OVULATION
• Triggered by LH surge .
• LH surge causes
Completion of first meiotic division
Extrusion of first polar body
Inflammatory reaction in the follicle
Release of PG and cytokines
Perforation of follicular wall
Ovulation
Pickup of oocyte by fimbriae
 OOGONIA
IN INTRA
(46 XX)
UTERINE
LIFE MITOSIS

PRIMARY OOCYTE

( 46 XX)
MEOSIS I
BUT ARRESTED IN
DIPLOTENE STAGE
OF PROPHASE
PRIMARY OOCYTE

( 46 XX)
 AT PRIMARY OOCYTE
PUBERTY (46 XX)

LH IS RELEASED
FROM PITUITARY,
MEOSIS I WILL BE
RESUMED

SECONDARY OOCYTE + 1ST POLAR BODY

(23 X) (23X)

OVULATION: RELEASE OF SECONDARY

OOCYTE FROM PRIMARY OOCYTE
 SECONDARY OOCYTE
( 23 X) MEOSIS II
DIVISION GETS
ARRESTED IN
METAPHASE

COMPLETED ONLY
AT THE TIME
FERTILISATION

FEMALE PRONUCLEUS + 2ND POLAR BODY

( 23 X ) ( 23 X)
• HPO AXIS BEOMES FUNCTIONAL
AT
PUBERTY
HYPOTHALAMUS
GnRH IS
RELEASED IN
PULSATILE
MANNER

ANTERIOR PITUITARY

FSH is released
It prevents apoptosis of
follicles and stimulate them
 • FSH acts on granulosa cells of follicle

ESTROGEN INHIBIN B

-VE FEED PROLIFERATION -VE FEED

OF UTERINE + VE FEED
BACK ON FSH BACK ON LH BACK ON FSH
ENDOMETRIUM

LEVELS OF FSH DECREASE

CAUSING DEGENERATION OF LEVELS OF LH
ALL FOLLICLES EXCEPT THE SUDDENLY
DOMINANT FOLLICLE INCREASE
 LEVELS OF LH INCREASE

THIS SUDDEN INCREASE IN LH

IS K/A LH SURGE ACTS ON THECA CELLS ACTS ON GRANULOSA CELLS
IT CAUSES RESUMPTION OF TO PRODUCE AND LUTEINIZES THEM TO
MEOSIS I THUS CAUSING ANDROGENS PRODUCE PROGESTERONE
OVULATION
 Following ovulation, the remaining follicular cells
differentiate into the corpus luteum, it secretes

PROGESTERONE ESTROGEN INHIBIN A

SUPPORT TO UTERINE - VE FEED BACK ON LH

ENDOMETRIUM
-VE FEED BACK ON FSH

LEVELS OF LH DECREASE
CAUSING DEGENERATION OF
CORPUS LUTEUM
 CORPUS LUTEUM DEGENERATES

PROGESTERON ESTROGEN INHIBIN

-VE FEED BACK ON FSH IS LOST

SUPPORT TO THUS, FHS

ENDOMETRIUM IS LOST
CAUSING MENSTRUATION
Gonadotropins and Follicular Development
• Early stages of development (up to the secondary follicle) do not
require gonadotropin stimulation and thus are said to be
“gonadotropin-independent.”
• Final follicular maturation requires the presence of adequate
amounts of circulating LH and FSH and is therefore said to be
“gonadotropin-dependent”
Concept of a Selection Window
• During the luteal-follicular transition, a small increase in FSH levels is
responsible for selection of the single dominant follicle that will
ultimately ovulate
• Theca cells produce androgens and granulosa cells generate
estrogens. Estrogen levels increase with increased follicular size,
enhance the effects of FSH on granulosa cells, and create a feed-
forward action on follicles that produce estrogens.
• Granulosa cells also produce inhibin B, which passes from the follicle
into the plasma and specifically inhibits the release of FSH, but not of
LH, by the anterior pituitary.
• The combined production of estradiol and inhibin B by the dominant
follicle results in the decline of follicular-phase FSH levels and may be
responsible at least in part for the failure of the other follicles to
reach pre ovulatory status during any one cycle.
Follicular Phase
• During the end of a previous cycle, estrogen, progesterone,
and inhibin levels decrease abruptly with a corresponding
increase in circulating FSH levels
• This increase in FSH level is responsible for recruitment of
the cohort of follicles that contains the follicle destined for
ovulation.
• During the midfollicular phase, follicles produce increased
amounts of estrogen and inhibin, resulting in a decline in
FSH levels through negative feedback.
• This drop in FSH levels is believed to contribute to selection
of the follicle destined to ovulate, termed the dominant
follicle
• During the late follicular phase, development of LH-receptor
expression occurs and granulosa cells begin to produce small
amounts of progesterone.
• This progesterone decreases granulosa cell proliferation, thereby
slowing follicular growth
• Progesterone also augments the positive feedback on estrogen
• Clinical Significance: This effect may explain the occasional induction
of ovulation in anovulatory amenorrheic women when given
progesterone to induce menses.
L H SURGE

• Toward the end of the follicular phase, estradiol levels increase

dramatically, this rapid increase, estradiol is no longer inhibitory and
instead develops positive feedback effects at both the hypothalamus
and anterior pituitary gland to generate the LH surge.
• Estradiol concentrations of 200 pg/mL for 50 hours are necessary to
initiate a gonadotropin surge .
• LH surge initiates the reentry of the oocyte into meiosis, expansion of
the cumulus oophorus, synthesis of prostaglandins, and luteinization
of granulosa cells
• The mean duration of the LH surge is 48 hours, and ovulation occurs
approximately 36 to 40 hours after the onset of the LH surge
• Prostaglandins also reach a peak concentration in follicular fluid
during the preovulatory gonadotropin surge. Prostaglandins may
stimulate smooth muscle contraction in the ovary, thereby
contributing to ovulation
• Women undergoing infertility treatment are advised to avoid
prostaglandin synthetase inhibitors in the preovulatory period to
avoid luteinized unruptured follicle syndrome (LUFS)
 Following ovulation, the remaining follicular cells
differentiate into the corpus luteum, literally yellow
body.

This process, which requires LH stimulation, includes

both morphologic and functional changes known as
luteinization

Luteal Phase Maximal levels of progesterone production are

observed in the midluteal phase and have been
estimated at an impressive 40 mg of progesterone
per day.

Ovulation can be safely assumed to have occurred if

the progesterone level exceeds 3 ng/mL on cycle day
21.
• The corpus luteum also produces large quantities of the polypeptide
inhibin A.
• This coincides with a decrease in circulating FSH levels in the luteal
phase.
• If inhibin A levels decline at the end of the luteal phase, FSH levels
rise once more to begin selection of a oocyte cohort for the next
menstrual cycle.
Luteolysis
• If pregnancy does not occur, the corpus luteum regresses through a
process called luteolysis.
• Following luteolysis, the blood supply to the corpus luteum
diminishes, progesterone and estrogen secretion drop precipitously,
and the luteal cells undergo apoptosis and become fibrotic. This
creates the corpus albicans (white body).
TWO CELL – TWO GONADOTROPIN THEORY
1) 1ST POLAR BODY RELEASED
(A) AT OVULATION (B) AT FERTILIZATION (C) AT PUBERTY (D) AT MENARCHE

2) 2ND POLAR BODY RELEASE AT FERTILIZATION

(A) AT OVULATION (B) AT FERTILIZATION (C) AT PUBERTY (D) AT MENARCHE

3) WHICH HORMONE PREVENTS APOPTOSIS OF FOLLICLES

(A) LH (B) TSH (C) FSH (D) GnRH

4)LH SURGE IS INITIATED BY

(A) PROGESTERONE (B) ESTROGEN (C) INHIBIN (D) A + B