Female Reproductive Physiology

1. Female Reproductive Physiology

2. What you need to know • One axis: H-P-O axis • One figure : menstrual cycle physiology

3. Hypothalamus Pituitary Ovary Axis

4. Menstrual Cycle Physiology LH P FSH Hormone variation E2 Ovarian cycle Uterine cycle

5. Anatomy &Female Development

6. Female genital anatomy

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

8. 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

9. 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

10. 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

11. Hypothalamus—Pituitary Gland —Ovary Axis

12. Hypothalamus Pituitary Thyroid Adrenal glands Ovaries

13. Neuro-endocrine regulation

14. Anatomy

15. 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)

16. 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

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. Pituitary portal vessels ----bidirectional feedback control between the hypothalamus and pituitary. Anterior pituitary (adenohypophysis) Intermediate part Posterior neural pituitary (neurohypophysis)

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

20. Gonadotropins FSHFolicullar stimulating hormone LH Luteinizing hormone Responsible for ovarian follicular stimulation FSH，LH，TSHand HCG share the same a -subunit HCG

21. 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

22. 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.

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

24. Oxytocin A nine–amino acid peptide Stimulates of uterine muscular contraction; breast lactiferous duct myoepithelial contractions Stimulated by suckling

25. Arginine-vasopressin (antidiuretic hormone, or ADH, AVP) Major function : increase blood pressure arteriolar vasoconstriction renal free-water conservation decrease in blood osmolality

26. Menstrual Cycle Physiology

27. Menstrual Cycle Physiology LH P E2 Hormone variation FSH Ovarian cycle Uterine cycle

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 Irregular bleeding 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 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

31. Hormone variation

32. 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 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 LH P E2 FSH

33. 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 LH P E2 FSH

34. Uterine cycle

35. Uterine cycle Proliferative phase Secretory phase

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

37. 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

38. 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

39. 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) Cyclic Changes of the Endometrium

40. 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

41. Ovarian cycle

42. Number of oocytes during life time oogonia atresia.

43. Development of oocyte Enter Meiosis Ⅰ Finish Meiosis Ⅰ Secondary oocyte Primary oocyte oogonia Enter Meiosis Ⅱ birth ovulation • Meiotic arrest • 16-20 weeks of gestation • Stops at prophase I of meiosis I • Meiotic resumption • Meiosis resumes until the time of ovulation

44. Development of oocyte Oogonia Primary oocyte (Primordial follicle) Birth Ovulation

45. Follicle Theca cells: LH-R(+), produce sex steroids Granulosa cells: FSH-R,E-R,A-R,LH-R,PRL-R (+)

46. Follicle development Primordial follicles Preantral follicles Antral follicles preovulatoryfollicle decades 9 months Primary oocyte 3 months Follicular phase Ovulation Dominant follicle recruitment selection

47. Primordial follicle Preantral follicle FSH-R E-R A-R LH-R Antral follicle FSH stimulation Recruitment Selection Dominant follicle FSH-R E-R A-R LH-R PRL-R Preovulatory follicle (18-23mm) cumulus oophorus.

48. Two-cell Two-gonadotropin Theory there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle LH cholesterol theca cells androgen FSH aromatase granulosa cells estrogen

49. 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

50. 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