Chapter 28, Part 2! Chapter 28, Part 2! Female Reproductive System! The Female Reproductive System!

Chapter 28, Part 2! Female Reproductive System! Chapter 28, Part 2! The Female Reproductive System! SECTION 18-3! Oogenesis occurs in the ovaries, a...
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Chapter 28, Part 2! Female Reproductive System!

Chapter 28, Part 2! The Female Reproductive System!

SECTION 18-3! Oogenesis occurs in the ovaries, and hormones from the pituitary gland and gonads control female reproductive functions!

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The Female Reproductive System

Figure 28-13!

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Chapter 28, Part 2! Female Reproductive System!

Ovaries, Uterine Tube and Uterus

Figure 28-14!

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Ovaries! Female gonads - homologous to testes! Ligaments hold ovaries loosely in place! Broad ligament! •  Double fold of peritoneum! •  Encloses internal reproductive structures! Round ligament! •  Uterus → inguinal canal→ CT of external genitalia! Ovarian ligaments! •  Anchor ovaries to uterus! Suspensory ligaments! •  Anchor ovaries to pelvic wall!

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Ovarian Histology! Germinal epithelium! •  Serosa of ovary! Tunica albuginea! •  White, dense irregular CT! •  Deep to germinal epithelium! Ovarian stroma! 1.  Cortex! •  Deep to tunica albuginea! •  Dense CT + follicles! 2. Medulla! •  Loose CT! •  N.A.V.a.L.!

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Chapter 28, Part 2! Female Reproductive System!

Oogenesis

Figure 28-15!

Mitosis !

2n! 1D!

before birth!

2n! 2D!

Meiosis I begun!

before birth! Meiosis I completed!

n! 1D !

after puberty!

Error in 9th edition

Meiosis II!

Completed if fertilization occurs!

n! 1/2D!

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Oogenesis! Production of eggs (ova)! Primordial germ cells migrate to ovaries from endoderm! •  Differentiate within ovary into oogonia! •  Mitosis before birth produces millions of germ cells! •  Most degenerate (atresia)! •  Some differentiate into primary oocytes!

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Primary Oocytes! Enter meiosis I, stop in prophase! Do not complete Meiosis I until after puberty! •  At birth, up to 2 million primordial follicles (with primary oocytes) remain (number is highly variable)! •  By puberty, atresia leaves about 400,000! •  About 400-500 will mature and ovulate! •  FSH stimulates development of oocyte!

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Chapter 28, Part 2! Female Reproductive System!

Review Article on Follicle Development! Erickson, GF, Follicle Growth and Development! Glob. libr. women’s med., (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10289! Link: http://www.glowm.com/section_view/heading/ Follicle Growth and Development/item/288! !

134 references! You are not responsible for the information on slides that are grayed out. This is very interesting newer information, but is FYI only.! 10!

Ovarian Follicles – 1! Reproductive physiologists recognize:! •  Primordial follicles! •  Primary preantral follicles! •  Secondary preantral follicles! •  Tertiary (early antral follicles)! •  Graafian (antral) follicles:! 1.  Healthy Graafian! •  One of several in a cohort is usually SELECTED for ovulation! 2.  Atretic Graafian! 11!

Ovarian Follicles – 2

Figure 2 from Erickson, 2008!

v  Note that many follicles of each type (except dominant follicle) would be present at any one time.!

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Chapter 28, Part 2! Female Reproductive System!

Primordial Follicles! Consist of a primary oocyte and a single layer of squamous cells! •  Oocyte arrested in prophase of Meiosis I! •  Primordial follicle development (RECRUITMENT) is independent of FSH, LH! •  Evidence for this:! o  Basement membrane of granulosa cells and lack of own blood supply limits endocrine effects! o  Development to primary follicle occurs in fetus soon after formation! o  Development and antrum formation occurs even after removal of pituitary!

Ovary Reserve!

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Erickson, 2008!

Pool of primordial follicles is the ovary reserve! 1 million ! at birth!

Recruitment leaves about 24,000 at 37 years!

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Recruitment Mechanism! Recruitment = process in which primordial follicles start to develop into primaries! •  Granulosa cells become mitotic! Mechanism unknown! •  Independent of pituitary hormones! •  Probably paracrine/autocrine changes in granulosa cells! •  May be loss of inhibitory signal(s)! o  Recruitment occurs rapidly after primordials are removal from ovary! 15!

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Chapter 28, Part 2! Female Reproductive System!

Recruitment Hypotheses! 1. Exposure to nutrients or regulators in the blood! •  Occurs in primordials that are nearest medulla where most vessels are found! 2. Internal oocyte clock! •  Depends upon when oocyte began meiosis in the embryo! Some type of ligand-receptor pathway probably involved! •  Recruitment slowed in newborn rats by: thymus removal, starvation, opioid injections! 16!

Primary Follicles (Preantral) – 1! Squamous EPI → cuboidal! •  Cells divide → several layers of cells! •  No antrum! •  Cells begin to express FSH receptors! •  But normal plasma FSH not important because primary follicles lack a blood supply! •  Development from primordial follicle to healthy Graafian follicle takes about one year.! 17!

Primary Oocyte in Primary Follicle! Oocyte growing and differentiating! 1. ZP genes activated → Zona pellucida appears! •  Glycoprotein layer between oocyte and granulosa cells! •  Microvilli of granulosa cells and oocyte merge! Increases surface area for oocyte nutrition! •  ZP contains ZP3 receptor = sperm receptor! 2. Gap junctions forming between oocyte and granulosa cells! •  Follicle becomes an electrical/functional syncytium

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Chapter 28, Part 2! Female Reproductive System!

Secondary (Preantral) Follicle Characteristics! •  Full-sized oocyte! o  Meiosis can now resume, but NORMALLY DOES NOT!

o  Inhibitor unknown ! •  Zona pellucida! •  6-9 layers of granulosa cells (i.e. stratified)! •  Basal lamina! •  Theca interna! •  Theca externa! •  NO ANTRUM (different from lab)!

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Secondary (Preantral) Follicle Regulation of Mitosis!

Regulation of granulosa cell mitosis! •  GDF-9 (growth differentiation factor) required in rats! •  No GDF-9, development stops here! •  I.e. oocyte is important for regulating follicle development by producing factors like GDF-9! !

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Secondary (Preantral) Follicle – Theca (1)! Blood vessels develop around follicle ! •  (i.e. follicle now has blood supply)! •  Nutrients, FSH/LH can reach follicle! All theca cells around follicle now have FSH receptors! •  This MAY allow cells to respond to FSH! Some thecal cells develop LH receptors:! •  Become theca interna! •  Involved in estrogen production together 21 with granulosa cells! !

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Chapter 28, Part 2! Female Reproductive System!

Secondary (Preantral) Follicle – Theca (2)! Some theca cells become smooth muscle cells of theca externa! •  Autonomic innervation! •  May contract during ovulation and atresia! ! Meiosis can now resume, but NORMALLY DOES NOT! •  Inhibitor unknown (may involve cAMP from granulosa cells)! •  Meiosis normally resumes in preovulatory (antral) stage in response to LH!

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Tertiary (Early Antral) Follicle! Defined by appearance of antrum! •  Antrum formation called cavitation! FSH not required for antrum formation ! •  Hypophysectomy → antrum still forms! Probably para-/autocrine mechanism! •  Activin! •  KIT ligand (aka stem cell factor or c-Kit)! o  Treat with activin → antrum forms! o  Block KIT ligand → no antrum, no ovulation! o  Gap junctions required!

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Graafian (antral) Follicle! THERE COULD BE MANY OF THESE PRESENT! Large antral cavity! Almost nothing is known about importance of antrum and antral fluid, but it is present in all mammals! BUT FSH WILL ACCUMULATE IN THE ONE THAT IS SELECTED TO BECOME DOMINANT FOLLICLE! Theca layers are now functional! •  LH regulates androstenedione secretion by theca interna! 24!

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Graafian Follicle Granulosa Cell Layers! 1. Zona (membrana) granulosa (next to theca)! Pseudostratified columnar, anchored to basal lamina! 2. Periantral layer (next to antrum)! 3. Corona radiata (immediately next to oocyte)! 4. Cumulus oophorus (between other layers)! ALL LAYERS EXPRESS FSH RECEPTORS! ! 25!

Types of Graafian Follicles – 1! 1. Healthy! •  Takes 2 months to reach preovulatory state! •  Express genes for differentiation, proliferation, fluid formation! •  Apoptosis inhibited somehow! •  Small → medium → large size! Size depends mostly on antral fluid volume! •  Fluid volume depends on [FSH] in fluid! •  Believed proportional to growth and development! 26!

Types of Graafian Follicles – 2! 2. Atretic! •  Apoptosis genes activated somehow! •  Do not reach large size! ! ! Follicles of different types occur together at any one time in the ovary! !

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Chapter 28, Part 2! Female Reproductive System!

Selection of the Dominant Follicle! Secondary ↑ in FSH required for selection to occur (see Fig. 28-24)! Increase in plasma FSH allows one follicle to accumulate high [FSH] in the antral fluid. ! •  This only occurs in one follicle, but mechanism is unknown! •  High FSH causes growth and development in dominant follicle! Fluid [FSH] → high aromatase → high fluid [estrogen]! •  High [estrogen] inhibits FSH release and prevents other follicles from developing !

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Oogenesis – Polar Bodies! LH surge → Meiosis I resumes! Primary oocyte produces: ! 1. One secondary oocyte! •  Haploid, but chromosomes are bivalents (total 1 “dose” of DNA)! •  Meiosis stops at metaphase II! •  Completed only if fertilized! 2. Other forms first polar body •  Receives little cytoplasm! •  Discarded! 29!

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Chapter 28, Part 2! Female Reproductive System!

Oogenesis!

Life: The Science of Biology! Pruves et al. 2001! 31!

Ovulation! “LH surge”! Graafian follicle releases secondary oocyte! •  Released into pelvic cavity! •  Corona radiata adheres to oocyte! •  Enters uterine tube!

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Formation of Corpus Luteum! Under influence of LH! Granulosa cells remaining in ovary proliferate! •  Produce progestins! e.g. progesterone! •  Prepare uterus for pregnancy!

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Chapter 28, Part 2! Female Reproductive System!

Fate of Corpus Luteum! If no implantation:! •  Degenerates after about 12 days! •  Decreasing [progestins] → menses! •  Corpus albicans (scar) forms! If fertilization and implantation:! •  Corpus luteum maintained (see chapter 29)! •  Completion of Meiosis II follows fertilization! •  Second polar body and ovum formed! •  Nuclei of sperm and ovum unite! •  Zygote formed!

Uterine Tubes - Anatomy

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Figure 28-17!

http://www.britannica.com/science/uterus!

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Uterine Tube Anatomy – 2! Entire tube about 4” long! Anatomy! 1. Infundibulum (“funnel”)! •  Ovarian end of tube! •  Opens into pelvic cavity! •  Has fimbriae! o  Finger-like projections! o  One usually in contact with ovary! o  Highly folded ciliated mucosa! o  Sweep fluid into tube!

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Chapter 28, Part 2! Female Reproductive System!

Uterine Tube Anatomy – 3! 2. Ampulla! •  Widest, longest portion (2/3 of length)! •  Fertilization usually occurs here! Occurs up to 24 h after ovulation! Takes ovum 3–4 days to reach uterus! 3. Isthmus! •  Connection with uterus! •  About 1/3 of length (Figure 28-18 in text is somewhat misleading.)! 37!

Uterine Tube Histology!

Mucosa! •  Ciliated simple columnar EPI! •  Help move oocyte to uterus! •  Secretory cells! Nutrition for oocyte?!

Muscularis! •  Inner circular, outer longitudinal smooth muscle! •  Peristalsis helps move oocyte! •  Begins a few hours before ovulation!

Serosa! •  Part of broad ligament - mesosalpinx!

The Uterus

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Figure 28-18!

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Chapter 28, Part 2! Female Reproductive System!

Uterus! Functions:! •  Menstruation! •  Implantation! •  Fetal development (gestation)! •  Labor! Anatomy:! •  Fundus (“bottom”)! •  Cervix (“neck”)! •  Body ! 40!

Cervix and Cervical Mucus! Cervix has two openings! •  Internal os (os = “mouth”)! Opening into uterus! •  External os! Opening into vagina! Cervical mucus! Glycoprotein, protein, lipids, enzymes, water! A.  Non-ovulatory periods! •  Mucus thick, forms cervical plug! •  Prevents pathogens from entering uterus!

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Cervical Mucus – 2! B.  Ovulatory periods! Protects sperm from vaginal environment! •  Mucus thinner! •  pH higher! •  Contains nutrients for sperm! •  Chemicals may assist in capacitation of sperm!

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Chapter 28, Part 2! Female Reproductive System!

Uterine Histology – 1! Three major layers:! 1. Perimetrium! Perimetrium!

•  Serosa = visceral peritoneum! 2. Myometrium! •  Three smooth muscle layers! •  Thickest in fundus! •  Thinnest in cervix! •  Responds to oxytocin! 43!

Uterine Histology – 2! 3.  Endometrium = mucous membrane! a.  Simple ciliated columnar EPI! b.  Endometrial glands derived from EPI! •  Secrete glycogen and lipids! Growth promoted by estrogen! Secretion promoted by progesterone! •  Produce nutrients for early divisions of fertilized ovum! c.  Endometrial stroma (lamina propria)! •  Loose CT, N.A.V.a.L.! 44!

Endometrial Layers! 1. Stratum functionalis (functional layer)! •  Shed during menses! 2. Stratum basalis!

Perimetrium

•  Temporary lining!

•  Permanent layer! •  Regenerates s. functionalis!

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Chapter 28, Part 2! Female Reproductive System!

The Uterine Blood Supply

Figure 28-19!

Large blood supply Spiral artery! necessary for:! •  Growth of stratum functionalis after menses!

Straight artery!

•  Providing nutrients to implanted blastocyst! •  Development of placenta!

Uterine artery!

Spiral arteries supply the s. functionalis.!

The Uterine Cycle

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Figure 28-20!

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The Uterine Cycle – 1! a.k.a. menstrual cycle, female sexual cycle! Average = 28 days (highly variable)! 1.  Menses (menstruation)! 2.  Proliferative phase! 3.  Secretory phase!

1. Menses Stratum functionalis degenerates! ↓ progesterone → spiral arteries constrict → ! ↓ blood flow → ↓ O2 and nutrients! Tissue dies, sloughs away!

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Chapter 28, Part 2! Female Reproductive System!

Uterine Cycle – 2! 2.  Proliferative phase follows menses! S. Functionalis proliferating (being replaced)! • 

Increased estrogen from developing follicles!

Begin preparing uterus for fertilized ovum! • 

Mucus glands grow, synthesizing glycogen-rich mucus!

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Blood vessels growing (spiral arteries)!

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Uterine Cycle – 3! 3.  Secretory phase •  Increased progestins (and estrogens) from corpus luteum! •  Glands enlarged, very secretory! •  More vessel growth!

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Vagina – Anatomy! Vagina = “sheath”! Passageway for:! •  Sperm (accepts penis during intercourse)! •  Menstrual flow! •  Childbirth! Attaches to uterus via cervix! •  Fornix (arch) extends superiorly, surrounds cervix! Hymen = “membrane”! •  May partially close vaginal orifice! 51!

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Chapter 28, Part 2! Female Reproductive System!

Vagina – Histology! 1. Mucosa! •  Lined by non-keratinized stratified squamous epithelium! •  Has folds called rugae! •  Secretes organic acids! (Low pH retards bacterial growth)!

2. Muscularis! • 

Inner circular, outer longitudinal smooth muscle!

3. Adventitia! •  Anchors to surrounding structures! 52!

External Genitalia (Vulva) – 1! Vulva = “to wrap around”! 1. Mons pubis! •  Adipose, skin, pubic hair over pubic symphysis! 2. Labia (“lips”)! •  Labia majoris (labium majus) = outer! •  Labia minora (labium minus) = inner! 3. (Glans) clitoris (with prepuce)! •  Erectile! •  Homologous to CCP/glans penis! 53!

External Genitalia (Vulva) – 2! 4. Vestibule = region between labia minora! • 

Vaginal orifice!

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External urethral orifice!

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Paraurethral glands (mucus)!

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Greater vestibular glands!

Homologous to prostate! Homologous to bulbourethral glands! 5. Bulb of vestibule! • 

Erectile tissue!

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Homologous to CCU/bulb of penis!

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Chapter 28, Part 2! Female Reproductive System!

Female External Genitalia

Figure 28-22!

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Mammary Glands! Modified sudoriferous glands! Synthesize, secrete, eject milk! •  Process called lactation! Each consists of 15-20 lobes! •  Lobes contain lobules! •  Lobules contain alveolar glands!

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Mammary Glands

Figure 28-23!

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Chapter 28, Part 2! Female Reproductive System!

Hormones! Please be very familiar with Figure 28-24 and the study guide posted for this figure. GnRH! •  Released in pulses! •  Pulse frequency varies, affects release of FSH, LH! FSH! •  Stimulates follicular growth in antral follicles**! LH! •  Maturation of dominant follicle! (FSH and LH receptors upregulated)! •  Ovulation and formation of corpus luteum!

Steroid Hormone Synthesis

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Figure 28-25!

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Estrogens – 1! Primarily β-estradiol (with estrone, and estriol)! Functions:! 1. Development (at puberty) and maintenance of:! a)  Female reproductive structures! b)  Secondary sexual characteristic! •  External genitalia enlarge! •  Vaginal epithelium changes! Simple cuboidal → stratified squamous! •  Uterus enlarges! 60!

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Chapter 28, Part 2! Female Reproductive System!

Estrogens – 2! •  Regional fat distribution pattern! •  Fallopian tubes! Increased number of glands! Increased number of ciliated cells! •  Voice pitch changes! •  Breasts! Increased development of stroma! Increased development of ducts! Increased fat deposition! 61!

Estrogens – 3! 2.  Protein anabolism! • 

Synergistic with hGH!

3. Skeletal effects! • 

Increases o’blast activity!

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Closes epiphyseal plates!

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Broadens pelvis!

4.  Increases metabolic rate! 5.  Skin smooth! • 

Increases thickness!

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Increases vascularity, apocrine gland activity!62!

Estrogens – 4! 6.  Lowers blood cholesterol! 7.  Electrolyte effects! • 

Mimics aldosterone! ↑  Na+ reabsorption → water retention!

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Chapter 28, Part 2! Female Reproductive System!

Progesterone – 1! Mainly from corpus luteum! Acts with estrogen to:! 1. Prepare uterus for implantation! • 

Increased secretion by uterine glands!

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Decreased uterine contractions! (Don’t expel egg!)!

2. Prepare mammary glands for milk secretion! • 

Increase size of cells, secretion!

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Other hormones also involved! 64!

Progesterone – 2! 3. Fallopian tubes! • 

Increase secretion (nutrients for egg)!

4. Electrolyte effects! •  • 

Also binds aldosterone receptor, but LESS EFFECTIVE than aldosterone! Overall effect of progesterone binding is ! ↓ Na+ reabsorption and ↓ water retention!

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Other Hormones! Inhibin! Sources:!

•  Granulosa cells of developing follicles! •  Corpus luteum! Inhibits FSH (and LH)!

Relaxin! From corpus luteum! •  Relaxes uterus to ease implantation! From placenta! •  Relaxes uterus, pubic symphysis! •  May help dilate cervix!

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Chapter 28, Part 2! Female Reproductive System!

Hormone Regulation

Figure 28-24, left!

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Hormonal Regulation – 2

Figure 28-24, right!

Generally:! ! Estrogen increases GnRH pulse frequency! ! Progesterone decreases GnRH pulse frequency!

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Feedback oscillation of hypothalamic-pituitary-ovarian system 1. Post-ovulatory depression of LH, FSH and GnRH by ovarian hormones 1A.

Corpus luteum is producing:

high progesterone moderate estrogens inhibin Negative feedback of progesterone and estrogens on: Anterior pituitary →

decrease LH decrease FSH

Hypothalamus →

decrease GnRH

1A**

Negative feedback of inhibin: Anterior pituitary → 1B.

decrease FSH (and LH)

Corpus luteum is degenerating:

decreased progesterone decreased estrogen decreased inhibin

Removal of negative feedback on GnRH, FSH, LH 2. Follicular growth phase 2A.

GnRH → FSH (and LH) release → Follicles developing

2B.

Slight decrease in FSH and LH caused by:

Follicular development → increased estrogen secretion

Negative feedback from moderate estrogen and low progesterone 3. Pre-ovulatory surge in FSH and especially LH Positive feedback on anterior pituitary from:

Causes: ↑ GnRH →

high estrogens low progesterone (mechanism unknown)

Increased FSH LH surge (required ovulation and corpus luteum formation)

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Chapter 28, Part 2! Female Reproductive System!

Menopause! Reproductive years = menarche → menopause! Pool of ovarian follicles exhausted between ages 40 - 50! Few follicles to respond to FSH and LH! Causes decline in estrogen levels! •  Cessation of reproductive cycle! •  Changes in secondary sex characteristics! •  Some atrophy of reproductive organs! •  Osteoporosis! •  Increased heart disease! Pattern of GnRH pulses may also change! Coincident with hot flashes, sweating! 70!

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