Female reproductive physiology

1. Female reproductive physiology

2. 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

3. Female Development

4. Female development Fetal period Menopausal transition period Neonatal period Adolescencepuberty Postmenopausal period Sexual maturity childhood

5. 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

6. 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

7. 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

8. Female Reproductive Physiology

9. 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.

10. 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.

11. Hypothalamus-pituitary-ovary axis

12. Neuroendocrinology

13. Hypothalamus The hypothalamic secretory products function as pituitary-releasing factors that control the endocrine function of the ovaries, the thyroid, and the adrenal glands.

14. Anatomy

15. 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)

16. 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

17. 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

18. 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

19. 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)

20. Major secretory products of the anterior pituitary Gonadotropins： FSH，LH Growth factor (GH) Prolactin (PRL) ACTH TSH

21. 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，TSHand HCG share the same a -subunit HCG

22. 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

23. 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.

24. Major secretory products of the posterior neural pituitary Oxytocin Arginine-vasopressin

25. 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

26. 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

27. Menstrual Cycle Physiology

28. 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

29. Menstrual cycle Follicular phase Luteal phase Ovarian cycle Uterine cycle Proliferative phase Secretory phase

30. 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

31. 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

32. HormoneVariation 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

33. LH P E2 FSH Ovarian cycle Uterine cycle

34. Menstrual cycle Follicular phase Luteal phase Ovarian cycle Uterine cycle Proliferative phase Secretory phase

35. Cyclic Changes of the Endometrium Stratum compactum decidua functionalis stratum spongiosum decidua basalis Loss of function myometrium Asherman's Syndrome

36. 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

37. 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.

38. 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) Cyclic Changes of the Endometrium

39. 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 Cyclic Changes of the Endometrium

40. Uterine cycle Proliferative phase Secretory phase

41. Ovarian Follicular Development oogonia atresia.

42. Meiotic Arrest of Oocyte and Resumption Meiosis (the germ cell process of reduction division) prophase Metaphase Anaphase telophase

43. 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, oogonia Primary oocyte

44. 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

45. 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.

46. Follicle development Oogonia Primary oocyte Primordial follicle Birth

47. 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

48. Primordial follicle Preantral follicle FSH-R E-R A-R Antral follicle FSH stimulation FSH-R E-R A-R LH-R PRL-R Preovulatory follicle cumulus oophorus.

49. Two-cell Two-gonadotropin Theory there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle theca cells granulosa cells

50. 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