GYNECOLOGY
1.2 Reproductive Endocrinology (Julie del Rosario-Lim, MD, FPOGS, FPSREI)
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The HPO Axis
→ Hypothalamus > secrete GnRh > stimulate Ant. Pit > release
gonadotropins (LH and FSH) > stimulate ovaries > to have a
dominant follicle > this follicle will produce your estradiol and
progesterone > estradiol will send a negative feedback to the
hypothalamus to stop secreting GnRH (if no negative feedback
is happening, then estradiol is continuously produced)
→ Estradiol will also send positive feedback to your Ant. Pit. for → Corpus luteum will now start producing estrogen and
ovulation to occur (estradiol peak followed by LH peak)
→ Ovaries produce activin and inhibin to both stimulate and
inhibit the production of FSH consecutively
GnRH: Pulsatile Secretion
→ Released in pulsatile secretion
→ During Follicular Phase, it is secreted very frequent but very
small amplitude
→ During Luteal Phase, less frequent but more amplitude
Key Events
Date: December 14, 2015
FEU-NRMF MEDICINE BATCH 2017
→ Ovarian cycle divided into follicular and luteal phase
→ Endometrial cycle divided into proliferative and secretive phase
→ FSH will be the one responsible in recruitment of follicles (start
of cycle)
→ Recruited follicle will have one dominant follicle, enlarging, and
is the one responsible for secreting large amounts of estrogen
(the one with the largest amount of estrogen receptors)
→ Dominant follicle will secrete a certain amount of estrogen
which is called estradiol peak
→ This estradiol peak will be followed by the LH peak before
ovulation
→ Inhibin hormone rises together with estrogen
→ At the start of the cycle there will be a lot of pre-antral follicles,
Inhibin will help the dominant follicle by inhibiting FSH and
other pre-antral follicles will not grow anymore (Inhibin can also
be secreted by the dominant follicle)
→ After ovulation, this follicle will become the corpus luteum
progesterone
→ Lifespan of corpus luteum is 14 days (that’s why secretory phase
is constant which depends on the lifespan of the corpus luteum,
unlike the proliferative phase, it is variable. When you give
ovulating drugs, the phase would be shorter depending on the
dominant follicle, when will it reach the estradiol and LH peak)
→ After corpus luteum, there would be a production of
progesterone which is the one responsible in the shift of body
temperature and bi-basal temperature
→ Estrogen will be the one responsible for the proliferation of
endometrial glands
→ After regression of corpus luteum, hormones Estrogen and
Progesterone diminish, will send a stimulatory feedback to
hypothalamus to secrete GnRH and another cycle begins
→ Preadolescent girls having menarche will have anovulatory
cycles due to immaturity of the HPO axis (menarche then no
mens for 3 months, assure them that it is normal)
THE HYPOTHALAMUS AND GNRH
Gonadotropin-releasing hormone (GnRH molecule)
→ Modulate the release of FSH and LH
→ Secreted in pulsatile manner to be effective
→ Released from the neurons within the Anterior
hypothalamus (Arcuate nucleus in the median basal
hypothalamus)
JOSE TORRES III, RN, EMT 1
GnRH: Route of secretion: MAJOR (CYCLIC)
o Hypothalamus, Anterior hypothalamus, Medial basal /
tuberal hypothalamus, Arcuate Nucleus →
Tuberoinfundibular Tract → Median eminence* (part of
the neurohypophysis) → Portal circulation → Anterior
Lobe of Pituitary

GnRH: Route of secretion: ALTERNATIVE (TONIC)

o Almost same with the major route but this time, from
Tubuloinfundibular tract, it can go to the Tanacytes and
straight to the portal circulation bypassing the Median
eminence

The GnRH Pulse Generator

→ There is a link between environmental factor and internal
hormonal milieu (both should be coordinated to have a normal
menstrual cycle)
The Anterior Pituitary and the Gonadotropins

Estrogen and the GnRH Receptor

(GnRH-R)
o GnRH-receptor numbers
*Pulsatile Release of GnRH increase when estrogen levels
are high
Mechanism for GnRH Pulsatility o There is a greater or amplified
response of the gonadotropes
to GnRH pulses when estrogen
levels are high
o More GnRH receptors are
found in the late follicular and
luteal phase compared with
early follicular phase)

GnRH Pulse Frequency and Gonadotropin Release

o Inherent pace-making activity of the GnRH neuron
o Binds with Kisspeptin (KISS1) and Kisspeptin receptor

Modulatory Influences on GnRH Pulsatility

o Ovarian steroids (feedback loop actions)
§ Estrogenà decreases pulse amplitude
§ Progesteroneà decreases pulse frequency
Stimulatory Inputs Inhibitory Inputs
NE GABA GnRH receptor (GNRH-R) desensitization
Glutamate Dopamine o Sustained exposure of the GnRH-R to constant GnRH
Peptide neuropeptide Y Β-Endorphin concentrations which reduces the response of the
CRH (Stress hormone) gonadatropes to subsequent stimulation with GnRH
INFLUENCE MAYBE TONAL OR CONDITIONAL o Desensitization signifies a reduced ability of GnRH to elicit
*During stress, women experience periods of amenorrhea due to inhibitory gonadotropin release after prior continuous exposure to
feedback to GnRH GnRH
*Too much dopamine, having hyperprolactinemia, will be having o GnRH, when given continuously, results in down-
amenorrhea regulation by desensitization mechanism (GnRH
analogues given to patients who do not want to
Metabolic Influences and GnRH Release menstruate, heavy bleeding, precocious puberty, or those
Energy homeostasis is related to human reproductive function: with pelvic endometriosis)
→ An accurate integration of energy balance is required for
a functional reproductive system and a significant GnRH Analogues and the GnRH-R
imbalance leads to reproductive dysfunction and
amenorrhea

Nutritional deprivation and abnormal eating habits

ANOREXIA
OBESITY
• Complex integrated physiologic mechanisms connect the
reproductive axis to the person’s metabolic state.

JOSE TORRES III, RN, EMT 2

GnRH Analogues → Before puberty, meiosis arrested at diplotene stage
GnRH AGONISTS GnRH ANTAGONISTS → After puberty, meiosis II resumes
Acts by desensitization Acts by competitive → In folliculogenesis, granulosa cells are produced in which FSH
INITIAL FLARE inhibitIon is responsible, and theca cells produced by LH
Rapid action with NO FLARE → This will eventually become a mature follicle with zona
*both end result is down regulation of gonadal hormones pellucida which is the barrier for sperm to penetrate

Clinical Applications of GnRH Analogues

o Activation of pituitary-gonadal function
o Delayed puberty
o Cryptochordism
o Functional hypothalamic amenorrhea
o Hypogonadotropic hypogonadism
o Precocious puberty
o Hormone-dependent tumors
o Suppression of ovarian function in PCOS and IVF
o PMS
o DUB
o Contraception
o Suppression of spermatogenesis
o Ovulation inhibition → At birth, there would be millions of follicles while others will
undergo atresia
Gonadotropins: FSH and LH → At puberty, there would only be 400,000 follicles
→ High molecular weight glycoproteins → Only 400 will only be used during the ovulating life
→ Same structural similarity → It is the physicians role to explain the reproductive capacity of
o Identical Alpha subunits a woman especially those in the age of menopause
o Different Beta subunits
→ Biological half-life The Gonadotropin receptors
o FSH – 3-4 hours
o LH – 20 minutes
→ FSH acts on the granulosa cells of the ovarian follicles to
stimulate follicular growth and when this follicle enlarges, it
will produce LH
→ LH acts on theca cells to stimulate ovarian hormone
production
→ FSH and LH act synergistically together
The OVARIES
Biosynthesis of the Ovarian Steroids
Following binding of the gonadotropins to their receptors, steroid
production begins in the ovary
Three principal sex steroids of the ovary:
→ Estradiol
→ Progesterone
→ Androstenedione
(The chief secretory products of the maturing follicle, the corpus
luteum and ovarian stroma)

Ovarian Gametogenesis and Folliculogenesis

JOSE TORRES III, RN, EMT 3

The Aromatase Enzyme COMMUNICATION WITHIN HYPOTHALAMIC- PITUITARY-OVARIAN
o Converts androgens into Estradiol or Estrone ENDOCRINE AXIS
o Found in gonads, endometrium, brain, placenta, bone,
skin, adipose → There would
o Ovaryà From ovarian testosterone, it is converted to be an increase in
Estrone using this enzyme FSH production,
o Fatsà From adrenal adrostenedione, also converted to leading to an
Estrone using the same enzyme
increase in
estrogen
production and
this will send a
negative
feedback to your
FSH because
there is enough
estradiol and at
the same time
this estradiol will send a positive feedback (estrogen peak)
Aromatase
that will lead to LH surge and will cause luteinization of the
Deficiency
follicle. There would be ovulation, then secretion of
Syndrome
progesterone by the corpus luteum then will demise in 14 days,
(testosterone
and then there would be a decrease in both estrogen and
dominates the
progesterone sending a stimulatory feedback to Ant. Pit. and
estrogen
the cycle begins again.
production)
Steroid Receptor Activation Process
Aromatase Inhibitors
o Aromatase inhibition leads to profound hypoestrogenism
o These agents have been useful in the treatment of
estrogen dependent receptor positive tumors (e.g. breast
cancer)
Blood transport of ovarian steroids
→ Some Estrogen are free while some binds to both SHBG (Sex
Hormone Binding Globulin) and Albumin in the Blood
→ Only a few percent are free, and the free hormones are the
ones active
→ One action of your pills is to increase your SHBG

Steroid Metabolism The Ovarian-Hypothalamic-Pituitary Feedback Loops

o The metabolic clearance rate of sex steroid is inversely
related to their affinity to SHBG.
o The level of SHBG and therefore the level of free active
hormone maybe influenced by various clinical conditions.
Metabolism of Estrogen in the Liver
o FEEDBACK between the ovaries and the H-P is important
for normal reproductive cycles.
o The hypothalamus and pituitary gland modulate their
secretion in response to ovarian signals.
o These signals are in the form of estradiol and
progesterone which interact with their respective
receptors in the H-P.
o Nonsteroidal compounds may also be involved in this
feedback mechanisms

The NEGATIVE Steroid Feedback Loop

→ Again to be
mentioned, the ovaries
send negative feedback to
the Ant. Pit and
Hypothalamus when
estrogen levels are high to
Role of Prostaglandins reduce production of GnRH
o Modulation of ovarian stimulation by LH (PGF2α) and eventually FSH
o Control of early follicular growth by increasing blood
supply to certain follicles
o Follicular rupture by proteolysis which increases your
PGF2α and PGE
o Regulation of menstrual process and myometrial
contraction

JOSE TORRES III, RN, EMT 4

The POSITIVE Estradiol Feedback Loop → Granulosa cells are not capable of producing cholesterol
→ Again, an increase in the estrogen would send a positive because it is avascular compared to theca cells which are
feedback to the Ant. Pit. leading to LH surge capable of producing androstenedione and testosterone
→ If estrogen peak is not achieved, there would be no The Dominant Follicle (Morphology)
ovulation
→ The follicle is important to produce enough estrogen to
reach its peak At maturation, the
mean diameter of the
Ovarian Peptides Feedback Loop (Effect is on FSH) follicle is about 18-25
mm.

→ Inhibin has an inhibitory effect

on FSH and LH
Ovulation
→ Before you have ovulation, you should have estradiol
THE MENSTRUAL CYCLE peak, which occurs 14-20 hours followed by the LH peak
o Mean duration: 28 ± 7 days (normal cycle 21-35 days) which happens 10-12 hours before ovulation
o Length of follicular phase is variable (depends on estrogen → The LH surge initiates resumption of
producing capacity of follicle until it reaches the estrogen meiosis of the fully grown oocyte. It proceeds
peak that would lead to LH surge) from the diplotene stage of meiosis one (started
o Length of luteal phase is more fixed (depends on the life during fetal life) to metaphase of meiosis ii. At
span of c. luteum is 14 days) ovulation, meiosis is again arrested and this will
o Mean age of menarche: 12 years old
only be completed upon fertilization.
o Menopause: 45-55 years old (Asians: 48-49 y/o)
→ Ovulation occurs about 32 hours after
The Follicular Phase
the initial rise of the LH surge and about 16
Three periods
hours after its peak
o Recruitment of a cohort of antral follicles
→ In fertility patients, we request a transvaginal UTZ The Luteal Phase
to check for number of free antral follicles → After the egg
o Selection of dominant follicle is extruded from the
→ By Day 5, you already know if there would be a follicle, the amount
dominant follicle structurally of fluid is markedly
→ DOMINANT FOLLICLE: reduced, the
§ Well vascularized follicular wall
§ Most number of gonadotropin receptors becomes
§ Most sensitivity to FSH convoluted. The
§ Greatest local estradiol production
diameter and volume decreases greatly which becomes
o Growth of the dominant follicle
→ Usually measures 18-25mm seen in UTZ the corpus luteum
The Corpus Luteum
Estrogen Production in the Growing Follicle RESULTS FROM 2 IMPORTANT EVENTS INITIATED AT OVULATION:
o Requires successive events within different locations in o Hypertrophy of granulosa cells
the growing follicle o Disruption of the basal lamina (layer separating theca
o An important change is the acquisition of the theca cell and granulosa layers)
layer which surrounds the granulosa cell layer
OVARIAN STEROIDOGENESIS: Luteal Phase
The Two Cell Two Gonadotropin Theory of Ovarian Steroidogenesis

→ FSH → LH will act upon the cholesterol and androstenedione and FSH
will act upon the granulosa cell which would produce an end that will eventually produce Estradiol as end-product
product of Estrone and Estradiol
→ LH would be the one that will act on theca cells which will
produce androstenedione and testosterone and these
hormones would be acted upon by Aromatase enzyme found in
the granulosa cell that will convert it to estradiol

JOSE TORRES III, RN, EMT 5

Endocrine Factors and The Corpus Luteum Endometrium in Secretory (Luteal) Phase
The Progesterone Negative Feedback Loop o Rapid secretory differentiation
→ The high progesterone levels activate this feedback loop o Well developed subnuclear vacuoles in all endometrial
on the GnRH pulse generator so that GnRH pulse frequency gland cells
decreases (and thus, LH pulse frequency also decrease) o NO mitoses in the glands
→ That’s why during the luteal phase, the GnRH production o Rising levels of Progesterone
MENSTRUATION
is less frequent but higher amplitude because of
progesterone Intense tissue breakdown by proteolytic enzymes (MMPs) which
Progesterone and Basal Body Temperature are stimulated by products of inflammatory process.
→ Duration: 3-5 days (2-7 is normal)
→ Interval: 28 ± 7 days
BIPHASIC NATURE OF THE
→ Mean blood loss: 35ml (10-80 is normal)
BBT IN THE OVULATORY
MENSTRUAL CYCLE
The Menstrual Cycle and the Cervix
→ During the
proliferative phase, there is
(Cevix on Day 25 of menstrual cycle
no corpus luteum yet, the
in a 21 year old)
temperature is the same but
upon production of
Changes in the production and
progesterone there would be an increase in temperature and would
property of mucus from the cervical
be maintained during the whole luteal phase.
glands correlate to the hormonal (e
and p) changes during the menstrual
Corpus Luteum Regression (LUTEOLYSIS)
cycle.
o LIFE SPAN: 14 DAYS (leading to Corpus Albicans)
o Luteal cells degenerate and steroid secretion declines
Cervical Mucus (High Estrogen)
Luteal-Follicular Transition
→ Spinnbarkeit sign; “Ferning” sign
End of luteal phase

Dramatic decline in Progesterone →

Increase in FSH → LH heralds a new
menstrual cycle and recruitment of new
cohort

THE MENSTRUAL CYCLE AND THE ENDOMETRIUM

The Endometrium
→ With endometrial biopsy, you can see on what stage the
patient is either in proliferative (hyperplastic glands) or
secretory
Two major layers:
o STRATUM FUNCTIONALE (the one being shed off)
§ S.COMPACTUM
§ S.SPONGIOSUM
o STRATUM BASALE
ENDOMETRIUM IN PROLIFERATIVE (FOLLICULAR) PHASE

SUBNUCLEAR VACUOLIZATION
→ The first indication of progesterone
effects
→ Reflects the small but significant
increase in progesterone at the time of
the LH surge shortly before ovulation
→ Signifies the patient is in luteal phase
or secretory phase

JOSE TORRES III, RN, EMT 6