female reproductive physiology

Obstetrics & Gynecology Hospital

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Female reproductive physiology


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What we are going to discuss

• Female development• Neuroendocrinology

AnatomyReproductive hormones

• Menstrual cycle physiologyNormal menstrual cycleHormone variationOvarian follicular development Cyclic change of endometrium


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Female Development


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Female development

Fetal period

Neonatal period

childhood

Adolescencepuberty

Sexual maturity

Menopausal transition

period

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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The hypothalamic secretory products function as pituitary-releasingfactors that control the endocrine function of the ovaries, the thyroid, and theadrenal glands.

Hypothalamus


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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)----

thyroid-stimulating 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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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 medianeminence outside the blood–brain barrier, permits bidirectional feedback control between the hypothalamus and pituitary.

anterior pituitary (adenohypophysis)

posterior neural pituitary (neurohypophysis)

Pituitary

Intermediate part


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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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HCG

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


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Prolactin• 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

Proliferative phase Secretory phase

Ovarian cycle

Uterine cycle


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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– 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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Ovarian cycle

Uterine cycle

LH

P E2

FSH


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Menstrual cycle

Follicular phase Luteal phase


Ovarian cycle

Uterine cycle


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Cyclic Changes of the Endometrium

Stratum compactum

stratum spongiosum

decidua basalis

decidua functionalis

myometriumAsherman's Syndrome

Loss of function


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• 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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• 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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• 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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• 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



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Ovarian Follicular Development

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oogonia atresia.


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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

• 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,

Primary oocyte

oogonia


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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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Oogonia

Primary oocyte

Primordial follicle

Birth

Follicle development


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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

Preovulatory follicle

FSH-R

E-R

A-R

LH-R

PRL-R

FSH stimulation

cumulus oophorus.


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Two-cell Two-gonadotropin Theory

• there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle

granulosa cells

theca cells


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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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Ovarian cycle

Uterine cycle

LH

P E2

FSH


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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 !

female reproductive physiology

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