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Female Reproductive Physiology Obstetrics & Gynecology Hospital Fudan University What you need to know • One axis: H-P-O axis • One figure : menstrual cycle physiology Obstetrics & Gynecology Hospital Fudan University Hypothalamus Pituitary Ovary Axis Obstetrics & Gynecology Hospital Fudan University Menstrual Cycle Physiology LH P FSH E2 Hormone variation Ovarian cycle Uterine cycle Obstetrics & Gynecology Hospital Fudan University Anatomy & Female Development Obstetrics & Gynecology Hospital Fudan University Female genital anatomy Obstetrics & Gynecology Hospital Fudan University Female development Fetal period Neonatal period Menopausal transition period Adolescence puberty childhood Sexual maturity Postmenopausal period Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University Hypothalamus—Pituitary Gland —Ovary Axis Obstetrics & Gynecology Hospital Fudan University Hypothalamus Pituitary Thyroid Adrenal glands Ovaries Obstetrics & Gynecology Hospital Fudan University Neuro-endocrine regulation Obstetrics & Gynecology Hospital Fudan University Anatomy Obstetrics & Gynecology Hospital Fudan University Major secretory products of the hypothalamus ----pituitary-releasing factors • Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH) 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) Obstetrics & Gynecology Hospital Fudan University Gonadotropin-releasing Hormone (GnRH) • A decapeptide produced by hypothalamus • Simultaneously regulates the secretion FSH and LH • Must be secreted in a pulsatile fashion to be effective • Continual exposure to GnRH results in downregulation of GnRH receptors in gonadotroph cells Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University Pituitary portal vessels ----bidirectional feedback control between the hypothalamus and pituitary. Anterior pituitary (adenohypophysis) Intermediate part Posterior neural pituitary (neurohypophysis) Obstetrics & Gynecology Hospital Fudan University Major secretory products of the anterior pituitary • • • • • Gonadotropins： FSH，LH Growth factor (GH) Prolactin (PRL) ACTH TSH Obstetrics & Gynecology Hospital Fudan University Gonadotropins • • • • FSH Folicullar stimulating hormone LH Luteinizing hormone Responsible for ovarian follicular stimulation FSH，LH，TSH and HCG share the same a -subunit HCG Obstetrics & Gynecology Hospital Fudan University Prolactin • • • Responsible for the synthesis of milk by the breast Stimulated by: breast manipulation, drugs, stress, exercise, and certain foods Hyperprolactinemia : amenorrhea galactorrhea Thyroid-stimulating Hormone • • Stimulates release of T3 and T4 from the thyroid gland Abnormalities of thyroid secretion (both hyper- and hypothyroidism) are frequently associated with ovulatory dysfunction Obstetrics & Gynecology Hospital Fudan University 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. Obstetrics & Gynecology Hospital Fudan University Major secretory products of the posterior neural pituitary • Oxytocin • Arginine-vasopressin Obstetrics & Gynecology Hospital Fudan University Oxytocin • A nine–amino acid peptide • Stimulates of uterine muscular contraction; breast lactiferous duct myoepithelial contractions • Stimulated by suckling Obstetrics & Gynecology Hospital Fudan University Arginine-vasopressin (antidiuretic hormone, or ADH, AVP) • Major function : increase blood pressure – arteriolar vasoconstriction – renal free-water conservation – decrease in blood osmolality Obstetrics & Gynecology Hospital Fudan University Menstrual Cycle Physiology Obstetrics & Gynecology Hospital Fudan University Menstrual Cycle Physiology LH P E2 FSH Hormone variation Ovarian cycle Uterine cycle Obstetrics & Gynecology Hospital Fudan University 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 Irregular bleeding Malignancy Obstetrics & Gynecology Hospital Fudan University Menstrual cycle Follicular phase Luteal phase Ovarian cycle Uterine cycle Proliferative phase Secretory phase Obstetrics & Gynecology Hospital Fudan University 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 – Proliferative phase • Luteal phase – the time from ovulation to the onset of menses – an average length of 14 days – Secretory phase • Normal menstrual cycle – 21 to 35 days, with 2 to 6 days of flow – an average blood loss of 20 to 60 mL Obstetrics & Gynecology Hospital Fudan University Hormone variation Obstetrics & Gynecology Hospital Fudan University Hormone variation • Beginning of menstrual cycle LH P E2 FSH – – – 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 • 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 Obstetrics & Gynecology Hospital Fudan University Hormone Variation • Ovulation LH P E2 FSH – 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 Obstetrics & Gynecology Hospital Fudan University Uterine cycle Obstetrics & Gynecology Hospital Fudan University Uterine cycle Proliferative phase Secretory phase Obstetrics & Gynecology Hospital Fudan University Cyclic Changes of the Endometrium Stratum compactum decidua functionalis stratum spongiosum decidua basalis Loss of function myometrium Asherman's Syndrome Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University 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 – Stroma: progressive increase in edema at approximately the seventh postovulatory day – Spiral arteries progressively lengthen and coil – Pseudodecidual d24 Obstetrics & Gynecology Hospital Fudan University Cyclic Changes of the Endometrium • Secretory Phase – Presence of eosinophilic protein-rich secretory products in the glandular lumen – Acid–Schiff positive–staining, glycogen-containing vacuoles. – Leukocytic infiltration heralds the collapse of the endometrial stroma and the onset of the menstrual flow (2 days before mense) Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University Ovarian cycle Obstetrics & Gynecology Hospital Fudan University No oocytes Number of oocytes during life time 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 Obstetrics & Gynecology Hospital Fudan University Development of oocyte Enter Meiosis Ⅰ Primary oogonia oocyte birth Finish Meiosis Ⅰ Secondary oocyte Enter Meiosis Ⅱ ovulation • Meiotic arrest 16-20 weeks of gestation Stops at prophase I of meiosis I • Meiotic resumption Meiosis resumes until the time of ovulation Obstetrics & Gynecology Hospital Fudan University Development of oocyte Oogonia Primary oocyte (Primordial follicle) Birth Ovulation Obstetrics & Gynecology Hospital Fudan University Follicle Theca cells: LH-R(+), produce sex steroids Granulosa cells: FSH-R,E-R,A-R,LH-R,PRL-R (+) Obstetrics & Gynecology Hospital Fudan University Follicle development Primordial follicles Preantral follicles Antral follicles preovulatory follicle decades 9 months Primary oocyte 3 months recruitment selection Follicular phase Dominant follicle Ovulation Obstetrics & Gynecology Hospital Fudan University Primordial follicle Preantral follicle FSH-R LH-R E-R A-R Recruitment Antral follicle FSH stimulation Selection Dominant follicle FSH-R E-R Preovulatory follicle A-R LH-R (18-23mm) PRL-R cumulus oophorus. Obstetrics & Gynecology Hospital Fudan University Two-cell Two-gonadotropin Theory LH cholesterol theca cells androgen FSH aromatase granulosa cells estrogen • there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle Obstetrics & Gynecology Hospital Fudan University Preovulatory Follicle • Fluid-filled antrum • 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 Obstetrics & Gynecology Hospital Fudan University Ovulation • LH surge ￫ ￫ initiation of ovulation • 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 Obstetrics & Gynecology Hospital Fudan University Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University 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 Obstetrics & Gynecology Hospital Fudan University KEY POINTS Obstetrics & Gynecology Hospital Fudan University Hypothalamus GnRH Pituitary LH FSH Ovaries E2 P Endometriium Obstetrics & Gynecology Hospital Fudan University LH P E2 FSH Ovarian cycle Uterine cycle Obstetrics & Gynecology Hospital Fudan University • 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. Obstetrics & Gynecology Hospital Fudan University • 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. Obstetrics & Gynecology Hospital Fudan University • 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. Obstetrics & Gynecology Hospital Fudan University • 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. Obstetrics & Gynecology Hospital Fudan University Thank you ! Obstetrics & Gynecology Hospital Fudan University