Female Reproductive Physiology Fall 2023 PDF

Female Reproductive Physiology Nursing Physiology, Fall 2023 11-17-2023; 10:00-11:00 AM 11-28-2023; 9:00-10:00 AM Maureen Basha, PhD [email protected] Female Reproductive Physiology Outline • • • • • Review of female reproductive anatomy Overview of sex steroid biosynthesis Changes in reproductiv...

Female Reproductive Physiology Nursing Physiology, Fall 2023 11-17-2023; 10:00-11:00 AM 11-28-2023; 9:00-10:00 AM Maureen Basha, PhD [email protected] Female Reproductive Physiology Outline • • • • • Review of female reproductive anatomy Overview of sex steroid biosynthesis Changes in reproductive physiology over female lifespan. Ovarian and Uterine events of the menstrual cycle Contraception, fertilization, and early pregnancy Learning Objective 1 Review female reproductive anatomy and describe the cell types of the follicle. Describe sex steroid biosynthesis by the ovary and the importance of aromatase in sex hormone synthesis. Female Reproductive Anatomy Review INTERNAL Genitalia: • Fimbriae: sweeping action picks up ovulated oocyte • Oviducts: site of fertilization and transport of embryo to uterine cavity Fig 17.16 Oviducts • Body of uterus: Site of implantation of embro • Endometrium: inner layer , nourishes embryo and is shed during menstrual cycle when no embryo • Myometrium: smooth muscle layer • Cervix of uterus: entrance to uterine cavity from vagina, lined by glands. • Vagina: fibromuscular organ lined by epithlium - sexual stimulation and passageway for baby Fig 17.17 TWO MAJOR FUNCTIONS OF FEMALE GONAD (OVARY) 1. Hormone production: Sex steroids 2. Gametogenesis: production of oocytes (gametes) External Genitalia: Vulva Clinical Anatomy, Volume: 28, Issue: 3, Pages: 376-384, First published: 02 March 2015, DOI: (10.1002/ca.22524) • • • • New York Artist, Sophia Wallace Vulva is an umbrella term for ALL of the structures of the female external genitalia Vestibule refers specifically to the area surrounded by labia minora The clitoris is much more than simply the glans clitoris. The clitoris extends from the glans to structures beneath the surface: • root of the clitoris connects the glans to the two crura and together form a wishbone shape below the vestibular surface. • the two bulbs of the clitoris are sandwiched between the urethra and crura Proposed that we should consider female sexual organs as a “distal vagina clitoral complex” Dr. Helen O’Connell Smallest functional unit of the ovary is the FOLLICLE thecal cells oocyte granulosa cells “nurse cells” ➢ Follicles located in outer layer of ovary (cortex) • Oocyte: female gamete in the core of the follicle • Granulosa cells: innermost layer(s) of cells o “nurse cells” : secretions that support oocyte o hormone synthesis • Thecal cells: Outermost layer(s) of cells o hormone synthesis Pathway for Ovarian Sex Steroid Biosynthesis ➢all synthesized from cholesterol ➢Two main biologically active sex steroids produced by ovary: estradiol and progesterone ➢estrogen synthesis is dependent on the activity of an enzyme AROMATASE that converts an androgen to an estrogen ➢Sex steroid circulate in blood bound to carrier proteins ( Sex Hormone Binding Globulin, Albumin) and in “free”/unbound form. Stages of follicular development Antrum: fluid filled cavity in granulosa cell layer ➢ ➢ 1. 2. 3. Fig 17.20 Most follicles in the ovary are in the primordial stage Three overlapping processes occurring in ovary : development of some primordial follicles up to preantral stage: always occurring development of a 7-12 preantral/early antral follicles each menstrual cycle process of “atresia” (programmed cell death): ↓follicular number over time Learning Objective 2 Describe the changes in ovarian function and oocyte number across the female lifespan.. Ovarian Changes across the female lifespan In utero development birth menopause puberty • fetal ovary: • female born with a • ~ 300 000 follicles number of oocytes left in ovaries set number of in ovary increases follicles in ovaries ~ (mitosis) • Pulsatile secretion 3 million of GnRH begins • oocytes packaged • number of follicles into follicles continually/slowly • onset of menstrual • mitosis of oocytes cycle and fertility declining with age begins and ends when ovulation due to ongoing during gestation begins (Menarche: “atresia”: first menstruation) • follicle number very very low • cessation of menstrual cycle: infertile (no ovulation) • dramatic decrease in estrogen and progesterone Learning Objective 3 Describe the follicular changes, HPO axis changes and ovarian hormone changes that occur during the follicular phase. Explain the sequence of events that result in ovulation. Describe the luteal changes, HPO axis changes and ovarian hormone changes that occur during the luteal phase. Menstrual Cycle: Big Picture Menstrual cycle: cyclic changes within ovary and uterus that occur approximately every 28 days of woman during the reproductive years (from onset of menarche ~ 13 yo to menopause ~ 51 yo). Range in length of menstrual cycle 21-35 days Two major goals of the menstrual cycle: 1. Develop ONE follicle to maturity and ovulate its oocyte (release oocyte from follicle at the surface of the ovary). 2. Develop the inner lining of the uterus (endometrium) into a structure that is capable of nourishing an embryo. Body automatically prepares each month for a pregnancy, if fertilization of ovum does not occur, built up endometrium shed and cycle starts again! Overview of Changes in Ovary Across the Menstrual Cycle Fig. 17.21 Follicular phase: Follicles develop (FSH) • small group of follicles (~ 7-12) undergo further development • dominant follicle matures and ovulated middle of the cycle Luteal phase: Corpus luteum present (LH) • emptied follicle remains in ovary: structure called a CORPUS LUTEUM • corpus luteum lifespan ~ 12-14 days and then breaks down and dies if no embryo HPO axis early→mid follicular phase ~day 1-7 Negative feedback of estradiol on the hypothalamus and anterior pituitary Hormones synthesized/secreted by granulosa cells: • estrogens: androgens produced by thecal cells diffuse to the granulosa cells and converted to estrogens • inhibin: peptide hormone that inhibits FSH release from anterior pituitary Remember that Day 1 is the onset of menses. During early follicular phase (what’s happening in ovary), the endometrial lining is being shed (what’s happening in uterus). Fig 17.24 Follicular development and hormonal changes during early follicular phase (~day 1-7) ➢ FSH stimulation of a small group of follicles : 1. follicular growth 2. increases aromatase activity FSH • ↑ estradiol production by follicles ➢ negative feedback of estradiol : GnRH, FSH and LH levels kept at relatively low level Estradiol into bloodstream Mid Follicular (~ day 7-day 12) Phase : Dominant Follicle selected and grows ➢ ~Day 7: One (usually) antral follicle of cohort selected as dominant follicle Dominant follicle selected ➢ ~Day 7-12: Dominant follicle continues to grow in size and increases its production of estradiol in response to FSH and estrogen stimulation. ➢ Dominant follicle also increases production of inhibin • Outcompetes other follicles for a limited FSH supply: atresia of other follicles FSH RECEPTORS; Lots! Estrogen receptors Throughout this time the dominant follicle is increasing its estradiol production Mid-cycle LH surge triggers ovulation ! Near the end of the follicular phase ( ~ day 12 of cycle) increasing estrogen production by dominant follicle results in a switch to positive feedback of estrogen on Hypothalamic-Pituitary-Ovarian Axis LH surge: sharp increase in release of LH from anterior pituitary due to positive feedback of estradiol LH binds to receptors on preovulatory follicle to stimulate: 1. rupture of the follicle and release of oocyte → ovulation (~24-36 hours after LH surge) 2. conversion of emptied follicle into a corpus luteum ( this takes a bit of time: occurs after ovulation) Fig 17.25 Seeing is believing Ovulation! Oocyte being released from follicle Follicle ovary LUTEAL PHASE : Corpus Luteum formed from ruptured follicle and secretes LOTS OF PROGESTERONE ➢ Corpus luteum is specialized for progesterone secretion: • Corpus luteum also produces estrogen ( lesser amounts) ➢ Progesterone into bloodstream : converts the endometrium into a structure capable of nourishing an early embryo If the ovulated oocyte has NOT been fertilized, (no embryo in uterus) the corpus luteum degenerates within ~ 14 days. HPO Axis : Luteal Phase NEGATIVE FEEDBACK of progesterone and estradiol on the hypothalamus and anterior pituitary ➢ Corpus luteum secreting high amounts of progesterone (and also some estrogen) ➢ Negative feedback of progesterone and estrogen: • GnRH low • LH low • FSH low Fig 17.26 Summary of shifts in Hypothalamic Pituitary Ovarian (H-P-O) Axis across the menstrual cycle From: Costanzo, Physiology, Chapter 10 • Ovary produces mostly estradiol • Negative feedback of estradiol on brain • Progesterone levels are very low Switch to POSITIVE FEEDBACK of estradiol on brain OVULATION • Ovary produces more progesterone than estradiol • Negative feedback of progesterone (and estradiol) on brain SUMMARY: Menstrual Cycle 1. FSH/LH levels increase (due to release from neg. feedback) 2. Stimulation of follicles to grow and secrete estrogen 3. ↑ plasma estrogen 4. Dominant follicle begins to secrete larger amounts of estrogen 5. Plasma estrogen levels rapidly rise 6. Estrogen/inhibin neg. feedback on FSH causes reduction of FSH, & atresia of nondominant follicles 7. Increasing estrogen begins to exert a positive feedback on gonadotropins… 8. Triggering an LH surge! Fig 17.22 Figure 17.22 Menstrual cycle Cont’d 9. oocyte matures...follicle ruptures: wait for it... Figure 17.22 10. Ovulation! 11. The corpus luteum forms and begins to secrete large amounts of progesterone and estrogen 12. Plasma progesterone and estrogen increase 13. Plasma FSH and LH decrease 14. Corpus luteum begins to degenerate & decreases hormone secretion 15. Plasma progesterone and estrogen decrease 16. This relieves the negative feedback on FSH and LH, beginning a new cycle Note: body temperature rises AFTER ovulation Learning Objective 4 Explain the uterine changes that occur (including the hormones responsible for these changes) during the follicular and luteal phase of the menstrual cycle. End of Luteal Phase ↓ progesterone and estradiol (Corpus Luteum dies) Loss of hormonal support of the endometrial layer: • Spasm of blood vessels cuts off blood supply to layer: breakdown of layer • Release of prostaglandins: stimulate contractions of myometrium: CRAMPS (dysmennorhea)  Followed by onset of menstruation This is overlapping with the beginning of the next follicular phase of the ovary Uterine changes across the menstrual cycle OVARY menses proliferative secretory UTERUS ➢ First ~ 5 days of follicular phase of ovary: Uterus is in menstrual phase (endometrial shedding) due to big drop in progesterone and estrogen when CL breaks down • Estrogen lowest value at beginning of menses ➢ Second half of follicular phase of ovary ( ~ day 5-14):Uterus in proliferative phase: • Rebuilding of endometrium by rising estradiol produced by follicles ➢ Luteal phase of ovary (~ day 14-28): Uterus is in secretory phase • Conversion of endometrium into secretory structure by high progesterone (corpus luteum) • Estrogen helps maintain endometrium Learning Objective 5 A. Explain the window of fertility and the mechanism of action of combined oral contraceptives B. Describe the source of hCG in a pregnant woman and its role in maintaining pregnancy. Explain the basis of a urine pregnancy test. Window of fertility • Spermatozoa can live within female reproductive tract for ~ 5 days • Once ovulated, oocyte can live for 12-24 hours • Fertile window: ~ 5 days prior to ovulation and one day following ovulation Rise in body temperature~ 12- 24 hours AFTER ovulation Hormonal Oral Contraceptives: Combination Formulations Synthetic estrogen and Synthetic progestin ➢ Mechanisms of action: 1. MAIN MECHANISM: continuous low levels of ovarian hormones keep the hypothalamic-pituitary-ovarian axis in negative feedback mode • No switch to positive feedback, no LH surge, no ovulation! Other effects to prevent fertilization: - limit development of endometrial layer - cervical mucus thickened: barrier to spermatozoa entry into uterus ➢ many formulations include 3 weeks of hormone pill, 1 week of a placebo pill • note: bleeding that occurs during the placebo week is from sudden removal of hormonal support of uterus from a pill. Fertilization occurs in the oviducts Fertilization blastocyst 4-5 days after fertilization of ovum Fig 17.30 • • • • union of ovum and spermatozoa occurs in oviduct and forms a zygote zygote undergoes mitotic divisions and travels down oviduct ~ 4-5 days post-fertilization, embryo reaches the uterine cavity in the blastocyst stage. At this point embryo is floating in uterine cavity and relying on uterine secretions for support Pregnancy: Implantation occurs in the uterine cavity Blastocyst (early embryo) IMPLANTS in uterine wall 5~9 days after fertilization Inner cell mass: stem cells that develop into fetus Trophoblast: stem cells that develop into placenta • produces hormone human chorionic gonadotropin (hCG) • hCG will begin to show up in maternal circulation after trophoblast invades endometrial layer • Pregnancy test: measuring hCG in urine indicating that embryo is in the uterus! hCG production Fig 17.31 Pregnancy: hCG “Rescues” the Corpus Luteum ➢ hCG produced by developing placenta (from trophoblast) : ➢ hCG is delivered to corpus luteum in the bloodstream ➢ hCG keeps corpus luteum alive so it can continue to secrete progesterone and maintain pregnancy Developing placenta hCG (similar to Mom’s LH) LH/CG R Progesterone Corpus Luteum Pregnancy test!!! 1st Trimester Summary ➢ The sex steroids of the ovary are 17-β estradiol and progesterone. These hormones circulate in the bloodstream and have widespread effects on the body and exert feedback on the hypothalamus and anterior pituitary. ➢ Mitosis of oocytes begins and ends in utero and as a female ages the number of oocytes continually decline. At menopause, the loss of oocytes leads to an end of fertility and low estrogen levels. ➢ The menstrual cycle is a carefully orchestrated sequence of hormonal changes that lead to ovulation of an oocyte and preparation of the uterus for a potential embryo. If fertilization doesn’t occur, the corpus luteum dies resulting in a big drop in progesterone (and estrogen) and the cycle begins again. • during the follicular phase, FSH stimulates follicles to grow and produce 17-β estradiol which proliferates the endometrium. Most of this estradiol comes from one dominant follicle. • during the luteal phase, the corpus luteum formed by the LH surge produces lots of progesterone which differentiates the endometrium into a secretory structure. ➢ A unique event of the menstrual cycle is the switch to positive feedback of the HPO axis at the end of the follicular phase. This results in the LH surge which triggers ovulation mid cycle. Combined oral contraceptives prevent the switch to positive feedback and ovulation. ➢ Fertilization takes place in the oviducts and a blastocyst implants in the uterus. Human chorionic gonadotropin (hCG) produced by the trophoblast/developing placenta prevents breakdown of the corpus luteum which maintains high progesterone levels required for pregnancy. For those interested, these are two great books. Written by Ob/GYN, Dr. Jen Gunther, 2019 Written by science writer for NY Times, Natalie Angier , 1999