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Female reproductive
physiology
Obstetrics & Gynecology Hospital
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What we are going to discuss
• Female development
• Neuroendocrinology
Anatomy
Reproductive hormones
• Menstrual cycle physiology
Normal menstrual cycle
Hormone variation
Ovarian follicular development
Cyclic change of endometrium
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Female Development
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Female development
Fetal
period
Neonatal
period
Menopausal
transition
period
Adolescence
puberty
childhood
Sexual
maturity
Postmenopausal
period
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Female development
• Fetal period
– Ovary develops during 8-10 week’s of pregnancy
• Neonatal period
– Within 4 weeks after birth
– Temporary lactation or vaginal bleeding may occur
• Childhood
– 4 weeks after birth – 10 years old
– Low hypothalamus - pituitary gland – ovary axis function
– Uterine body : cervix 1:2
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Female development
• Adolescence / puberty
– 10-19 years old
– Onset of hypothalamus - pituitary gland – ovary
axis function
– Uterine body : cervix 2:1
– Development of second sexual characteristics
•
•
•
•
Thelarche
Adrenarche
Growth spurt
Menarche
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Female development
• Sexual maturity
– From 18 years old and lasts for about 30 years
– Mature hypothalamus - pituitary gland – ovary axis
function
– Reproductive age
• Menopausal transition period
– Lasts 1-10 years till menopause
– Declined ovarian function
– Vasomotor symptoms
• Postmenopausal period
– Ceased ovarian function
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Female Reproductive Physiology
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• The female reproductive process involves the central
nervous system (primarily hypothalamus), the
pituitary gland, the ovary, and the uterus
(endometrium). All must function appropriately for
normal reproduction to occur.
• Hypothalamic gonadotropin-releasing hormone
(GnRH) simultaneously regulates both luteinizing
hormone (LH) and follicle-stimulating hormone (FSH)
in the pituitary, and does so by being secreted in a
pulsatile manner. The pulse frequency determines the
relative amounts of LH and FSH secretion.
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•
The ovary responds to FSH and LH in a defined, sequential
manner to produce follicular growth, ovulation, and corpus
luteum formation. The cycle is designed to produce an
optimal environment for pregnancy; should this not occur, the
cycle begins again.
•
The ovary produces estrogen in the early menstrual cycle,
which is responsible for endometrial growth. Following
ovulation, progesterone is also produced in significant
quantities, which transforms the endometrium to a form ideal
for implantation of the embryo.
•
If no pregnancy occurs, the ovary ceases to produce estrogen
and progesterone, the endometrium is sloughed, and the cycle
begins again.
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Hypothalamus-pituitary-ovary axis
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Neuroendocrinology
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Hypothalamus
The hypothalamic secretory
products function as
pituitary-releasing
factors that control the
endocrine function of the
ovaries, the thyroid, and the
adrenal glands.
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Anatomy
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Major secretory products of the hypothalamus
----pituitary-releasing factors
• Gonadotropin-releasing hormone (GnRH)---luteinizing hormone (LH) and follicle-stimulating
hormone (FSH)
• Corticotropin-releasing hormone (CRH)---adrenocorticotrophic hormone (ACTH)
• Growth hormone–releasing hormone (GHRH)---growth hormone (GH)
• Thyrotropin-releasing hormone (TRH)----thyroidstimulating hormone (TSH)
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Gonadotropin-releasing Hormone
• A decapeptide produced by neurons with cell
bodies primarily in the arcuate nucleus of the
hypothalamus
• Simultaneously regulates the secretion FSH and
LH
• Must be secreted in a pulsatile fashion to be
effective
• Continual exposure of the pituitary gonadotroph
to GnRH results in downregulation of the number
of gonadotroph cell surface GnRH receptors
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Gonadotropin-releasing Hormone
•
Extremely short half-life (only 2–
4 minutes)
•
The pulsatile secretion varies in
both frequency and amplitude
throughout the menstrual cycle
•
GnRH agonist & antagonist---medical castration
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Endogenous Opioids and Effects on GnRH
• Endorphins appear to inhibit GnRH release within
the hypothalamus, resulting in inhibition of
gonadotropin secretion
• Endorphin levels vary significantly throughout the
menstrual cycle, with peak levels in the luteal
phase and a nadir during menses ---- dysphoria
in the premenstrual phase
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Pituitary
The rich capillary plexus of the
portal vessels that originate in
the median eminence of the
hypothalamus and descend along
the pituitary stalk combined with
the location of the median
eminence outside the blood–brain
barrier, permits bidirectional
feedback control between the
hypothalamus and pituitary.
anterior pituitary
(adenohypophysis)
Intermediate part
posterior neural pituitary
(neurohypophysis)
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Major secretory products of
the anterior pituitary
•
•
•
•
•
Gonadotropins： FSH，LH
Growth factor (GH)
Prolactin (PRL)
ACTH
TSH
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Gonadotropins
•
•
•
•
The gonadotropins FSH and LH are produced
by the anterior pituitary gonadotroph cells
responsible for ovarian follicular stimulation
Structurally, there is great similarity between
FSH and LH
FSH，LH，TSH and HCG share the same a subunit
HCG
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Prolactin
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•
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•
Secreted by the anterior pituitary lactotroph
Responsible for the synthesis of milk by the breast
Principally stimulated by estrogen
Under inhibitory control by dopamine
Stimulated by: breast manipulation, drugs, stress, exercise, and
certain foods
Hyperprolactinemia : amenorrhea galactorrhea
Thyroid-stimulating Hormone
•
•
•
Secreted by the pituitary thyrotrophs in response to TRH
Stimulates release of T3 and T4 from the thyroid gland
Abnormalities of thyroid secretion (both hyper- and
hypothyroidism) are frequently associated with
ovulatory dysfunction
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Adrenocorticotrophic Hormone
• secreted in response to CRH
• stimulates the release of adrenal glucocorticoids.
• diurnal variation ： early morning peak and a late
evening nadir
• negatively regulated by feedback from cortisol.
Growth Hormone
• greatest absolute amount of the anterior pituitary
hormone
• secreted in response to GHRH, thyroid hormone
and glucocorticoids
• secreted in a pulsatile fashion with peak release
occurring during sleep.
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Major secretory products of
the posterior neural pituitary
• Oxytocin
• Arginine-vasopressin
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Oxytocin
• A nine–amino acid peptide
• Produced by the paraventricular nucleus of the
hypothalamus
• Primary function : stimulation of uterine
muscular contraction; breast lactiferous duct
myoepithelial contractions
• Oxytocin release may be stimulated by suckling
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Arginine-vasopressin (antidiuretic
hormone, or ADH, AVP)
• Synthesized by neurons with cell bodies in the
supraoptic nuclei
• Major function : increase blood pressure
– arteriolar vasoconstriction
– renal free-water conservation
– decrease in blood osmolality
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Menstrual Cycle Physiology
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Menstrual cycle
Normal menstrual cycle
– orderly cyclic hormone production
– parallel proliferation of the uterine lining
– prepare for implantation of the embryo
Disorders of the menstrual cycle /
menstrual physiology
– infertility
– recurrent miscarriage
– malignancy
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Menstrual cycle
Follicular phase
Luteal phase
Ovarian cycle
Uterine cycle
Proliferative phase
Secretory phase
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Menstrual cycle
• Follicular phase
– development of a single dominant follicle, which should be
mature at midcycle and prepared for ovulation.
– average length : 10 to 14 days
– variable in length
• Luteal phase
– the time from ovulation to the onset of menses
– an average length of 14 days
• Normal menstrual cycle
– 21 to 35 days, with 2 to 6 days of flow
– an average blood loss of 20 to 60 mL
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Hormone variation
• Beginning of menstrual cycle
–
–
–
Low gonadal steroids
FSH begins to rise with a cohort of growing follicles recruited
Follicles secrets estrogen↑---- stimulates uterine endometrial
proliferation
• Midpoint of the follicular phase
–
–
Rising estrogen and inhibin-B inhibits pituitary FSH secretion
Low estrogen inhibits LH
• Late in the follicular phase
–
High estrogen stimulates LH secretion (biphasic response).
• Before ovulation
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–
–
FSH-induced LH receptors are present on granulosa cells
LH stimulates progesterone secretion
Estrogenic stimulation triggers pituitary LH surge, causes ovulation
24 to 36 hours later
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Hormone Variation
• Ovulation
– Heralds the transition to the luteal–secretory phase
• Early luteal phase
– Estrogen level decreases
• Midluteal phase
– Estrogen, inhibin-A increase (secreted by the corpus
luteum)
• Progesterone levels rise precipitously after
ovulation : presumptive sign of ovulation
• Progesterone, estrogen, and inhibin-A
– act centrally to suppress gonadotropin secretion and new
follicular growth.
– remain elevated through the lifespan of the corpus luteum
and then wane with its demise
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LH
P
E2
FSH
Ovarian cycle
Uterine cycle
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Menstrual cycle
Follicular phase
Luteal phase
Ovarian cycle
Uterine cycle
Proliferative phase
Secretory phase
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Cyclic Changes of the Endometrium
Stratum compactum
decidua functionalis
stratum spongiosum
decidua basalis
Loss of
function
myometrium
Asherman's Syndrome
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Cyclic Changes of the Endometrium
• Proliferative Phase
– progressive mitotic growth of the decidua
functionalis in response to rising circulating
levels of estrogen
– endometrial glands: straight, narrow, short ￫￫
longer, tortuous structures
– mitotic cells lining proliferating glands: low
columnar pattern ￫￫ pseudostratified pattern
– stroma: dense compact layer
– vascular structures: infrequently seen
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Cyclic Changes of the Endometrium
• Secretory Phase
– ovulation occurs 14 days before mense
– Endometrium shift to secretory phase within 48 to
72 hours following ovulation in response to
progesterone secretion
– presence of eosinophilic protein-rich secretory
products in the glandular lumen
– acid–Schiff positive–staining, glycogen-containing
vacuoles.
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Cyclic Changes of the Endometrium
• Secretory Phase
– Stroma: progressive increase in edema at
approximately the seventh postovulatory day,
– spiral arteries progressively lengthen and coil
– Pseudodecidual d24
– Leukocytic infiltration heralds the collapse of the
endometrial stroma and the onset of the menstrual
flow.(2 days before mense)
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Cyclic Changes of the Endometrium
• Menses
– In the absence of implantation
– Shedding of decidua functionalis is termed menses.
– The destruction of the corpus luteum and its
production of estrogen and progesterone is the
presumed cause of the shedding.
– Prostaglandins release: vasospasm ; endometrial
ischemia； myometrial contractions
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Uterine cycle
Proliferative phase
Secretory phase
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No oocytes
Ovarian Follicular Development
8000000
7000000
6000000
5000000
4000000
3000000
2000000
1000000
0
6-7 million
oogonia atresia.
1-2 million
20 weeks of
gestation
birth
300,000
500
puberty
released ovum
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Meiotic Arrest of Oocyte and Resumption
• Meiosis (the germ
cell process of
reduction division)
–prophase
–Metaphase
–Anaphase
–telophase
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Meiotic Arrest of Oocyte and Resumption
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•
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primary oocytes ：
During fetal stage
oogonia develops into
primary oocyte through
first meiotic division.
Begins at 8 weeks of
gestation
Meiosis stops at meiotic
prophase I
Meiosis resumes until
the time of ovulation
Only one final daughter
cell (oocyte) forms from
each precursor cell,
oogonia
Primary
oocyte
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Follicle development
• A dynamic process that continues from
menarche until menopause.
• Designed to allow the monthly
recruitment of a cohort of follicles and,
ultimately, to release a single mature
dominant follicle during ovulation
• Start from previous cycles
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Primordial Follicles
• Primordial follicles- Primary oocyte surrounded
by primary granulosa cells---the only source of
oocyte.
• About 300,000 follicles remained in puberty.
• The initial recruitment and growth of the
primordial follicles is gonadotropin independent
and affects a cohort over several months
• FSH assumes control of follicular differentiation
and growth shortly after recruitment.
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Follicle development
Oogonia
Primary oocyte
Primordial follicle
Birth
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Preantral Follicle
• Several days following the breakdown of
the corpus luteum
• Driven by FSH stimulation
• Zona pellucida--separates oocyte from
the surrounding granulosa cells
• Follicles selected for dominance or
undergo atresia
• Granulosa cells and theca cells continue
proliferate and produce estrogen---Two-cell Two-gonadotropin Theory
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Primordial follicle
Preantral
follicle
FSH-R
E-R
A-R
Antral follicle
FSH
stimulation
FSH-R
Preovulatory
follicle
E-R
A-R
LH-R
PRL-R
cumulus oophorus.
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Two-cell Two-gonadotropin Theory
theca cells
granulosa cells
•
there is a subdivision and compartmentalization of steroid
hormone synthesis activity in the developing follicle
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Preovulatory Follicle
• Characterized by a fluid-filled antrum that is
composed of plasma with granulosa-cell
secretions
• The oocyte remains connected to the follicle by
the cumulus oophorus.
• Rising estrogen ￫ ￫ negative feedback on FSH
secretion
• Estrogen has biphasic regulation on LH
– Lower level ￫ ￫ inhibit LH secretion
– Sustained High level((200 pg/mL) for more than 48 hours) ￫ ￫
enhances LH release
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Theca cells: LH-R(+), produce sex steroids
Granulosa cells: FSH-R,E-R,A-R,LH-R,PRL-R (+)
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Ovulation
• LH surge ￫ ￫ initiation of ovulation
• Ovulation will occur in the single mature,
or Graafian, follicle 10 to 12 hours after
the LH peak or 34 to 36 hours after the
initial rise in midcycle LH
• Dramatic increase in local concentrations
of prostaglandins and proteolytic
enzymes in the follicular wall
• Slow extrusion of the oocyte through
perforation of follicular wall
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Luteal Phase
• the remaining follicular shell after
ovulation is transformed into the
corpus luteum.
• Membranous granulosa cells begin to
take up lipids
• produce progesterone to support
endometrium
• Produce estrogen and inhibin A
• Inhibit FSH, LH
• Inhibit follicular development and
recruitment
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Luteal phase
• Continued corpus luteum function
depends on continued LH production.
• No pregnancy: corpus luteum regress
after 12 to 16 days and form the scarlike
corpora albicans
• Pregnancy : placental hCG stimulates the
corpus luteum to secrete progesterone
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KEY POINTS
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LH
P
E2
FSH
Ovarian cycle
Uterine cycle
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• GnRH is produced in the arcuate nucleus of the
hypothalamus and secreted in a pulsatile fashion
into the portal circulation, where it travels to the
anterior pituitary.
• Ovarian follicular development moves from a
period of gonadotropin independence to a phase
of FSH dependence.
• As the corpus luteum of the previous cycle fades,
luteal production of progesterone and inhibin A
decreases, allowing FSH levels to rise.
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• In response to FSH stimulus, the follicles grow and
differentiate and secrete increasing amounts of
estrogen and inhibin-B.
• Estrogen stimulates growth and differentiation of
the functional layer of the endometrium, which
prepares for implantation. Estrogens work with
FSH in stimulating follicular development.
• The two-cell two-gonadotropin theory dictates
that with LH stimulation, the ovarian theca cells
will produce androgens that are converted by the
granulosa cells into estrogens under the stimulus
of FSH.
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• Rising estrogen and inhibin levels negatively feed
back on the pituitary gland and hypothalamus and
decrease the secretion of FSH.
• The one follicle destined to ovulate each cycle is
called the dominant follicle. It has relatively more
FSH receptors and produces a larger
concentration of estrogens than the follicles that
will undergo atresia. It is able to continue to grow
despite falling FSH levels.
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•
Sustained high estrogen levels cause a surge in pituitary
LH secretion that triggers ovulation, progesterone
production, and the shift to the secretory, or luteal,
phase.
•
Luteal function is dependent on the presence of LH.
However, the corpus luteum secretes estrogen,
progesterone, and inhibin-A, which serve to maintain
gonadotropin suppression. Without continued LH
secretion, the corpus luteum will regress after 12 to 16
days. The resulting loss of progesterone secretion
results in menstruation.
•
If pregnancy occurs, the embryo secretes hCG, which
mimics the action of LH by sustaining the corpus
luteum. The corpus luteum continues to secrete
progesterone and supports the secretory endometrium,
allowing the pregnancy to continue to develop.
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Thank you !
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