Download - Female Reproductive Endocrinology
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Female Reproductive Endocrinology
Chapter 18
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Anatomy
• Vulva – external genitalia
• Vagina– Functions:
• Sperm, menstrual flow passage
• Receptacle for penis
• Birth canal
– Rugae– Acidic environment
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• Uterus– Functions:
• Sperm transport
• Implantation fert’d ovum
• Fetal dev’t
• Labor
• Menstruation
– Cervix secretes mucus
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• Uterus – cont’d– Three histological layers
• Perimetrium – outside
• Myometrium – sev muscle layers + connective tissue
– Forms bulk of uterine wall
• Endometrium – closest to uterine cavity– Covered w/ epithelium
– Vascular w/ tubular glands
– Further divided 3 layers
» Innermost shed w/ menstruation
» Outermost new inner layer during cycle
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• Oviducts– Transport
• Peristalsis
• Cilia
– Isthmus, ampulla, infundibulum– Not static tube
• Ovaries = gonads– Inner medulla, outer cortex– Gametogenesis, hormonogenesis
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Ovaries• Prepubertal
– Anatomy• Smooth outer germinal epithelium• Connective tissue• Cortex w/ ovarian follicles in stroma
– Low quantities of sex steroid• Feedback inhibition of gonadotropins
• Puberty gonadotropins sex steroids– LH PKA StAR P450scc in partic cells– FSH E2 secr’n in partic cells
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Ovarian Cycle
• Controls, controlled by hormones
• Coupled to uterine cycle
• Related to maturation ovarian follicles– Gonadotropin dependent
• Two phases– Follicular– Luteal
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Follicular Phase
• Variable length• Maturing follicles secrete
– 17-estradiol– Inhibin
• Absence functional CL– Plasma progesterone low
• FSH elevated @ beginning, diminishes– High FSH impt to follicle selection, early
maturation
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• As follicle dev’s, more E2, inhibin – Decr’d FSH (neg feedback)– Decr’d LH– Upregulation ant pit GnRH receptors
• E2 peaks @ midcycle FSH/LH surge
• Now new ability some ovarian cells to produce sex steroids (progesterone)
• Now ovum released from mature follicle
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Luteal Phase
• Invariant 14+2 d length• CL begins, develops, dies• CL secretes progesterone (also E2, inhibin)
as matures– Progesterone postov decr LH, FSH (neg
feedback)– Midluteal peak over week– E2 minimally elevated
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• Hormone secretion diminishes as CL declines – If no fertilization– Get sharp decline in plasma progesterone
• Now less neg feedback due to progesterone FSH/LH again secreted– FSH influences new follicle selection, early
maturation
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Gametogenesis
• Ovarian follicles named by maturation stage
• Primordial– Primary oocyte– Squamous epithelium; single layer
• Dev’s granulosa cells
– Growth & remodeling– 40 ; oocyte 15-25 – Quiescent
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• Primary follicle– Oocyte enlarges (80-100 m)– Follicle epithelium
• Simple cuboidal
• “Granulosa cells”
• Express FSH receptors
– FSH response organize, stratify granulosa cell layers
– Zona pellucida (glycoprotein layer) deposits– Stroma begins to organize as theca
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• Secondary=preantral follicle– Granulosa proliferates, stratifies
• Signaled by oocyte growth factors– Growth Differentiation Factor 9 (GDF-9)– Bone Morphological Protein 15 (BMP-15)
• Mitosis and/or pattern of arrangement stim’d– Simple cuboidal stratified, pseudostratified columnar– Diff layers have diff morphology, function
– Granulosa cells produce activin• Stim’s FSH receptor synth
– Granulosa cells become sensitive to FSH• Impt to selection• Impt to differentiation• Impt to maturation
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Figure 9. The early differentiation of the granulosa cells during preantral folliculogenesis involves the expression of FSH receptors. Animal studies support the concept that this process involves an activin autocrine/paracrine mechanism. (Erickson GF: Dissociation of Endocrine and Gametogenic Ovarian Function. In Lobo, R. (ed.): Perimenopause. Serono Symposia, Springer-Verlaag, 1997. Reproduced with permission from Springer-Verlag, New York.)
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• Secondary follicle – cont’d– Granulosa cells connected by gap junctions
• Synchronization
• Nutrient transfer
– Basement membr dev’s– When 6 layers granulosa
• Definitive theca layer
• Angiogenesis blood supply to theca
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• Secondary follicle (cont’d)– Final 2o follicle 100-200
• Fully grown oocyte w/ zp
• Approx 9 layers granulosa
• Basal lamina
• Theca interna w/ capillary net
• Theca externa
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Granulosa cells
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Thecal cells
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• Tertiary=antral follicle– Chamber– Follicular fluid contains hormones
• Blood-derived
• From oocyte
• From granulosa cells
– Cavitation signalled by follicle cells– Corona radiata = granulosa cells anchored to zp– Theca fully developed
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• Tertiary follicle – cont’d– Theca interna = steroid producing
(androstenedione)• Extensive sER, cytoplasmic lipid droplets, tubular
mitoch cristae
• Receptors for LH, insulin
• Richly vascularized
– Theca externa• Smooth muscle cells
• Autonomic neurons
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Figure 12. Photomicrograph of an early tertiary follicle 0.4 mm in diameter at the cavitation or early antrum stage. zona pellucida (ZP); granulosa cells (GC); basal lamina (BL); theca interna (TI); theca externa (TE); granulosa mitosis (arrowheads). (Bloom W, Fawcett DW In A Textbook of Histology. Philadelphia, WB Saunders Company, Philadelphia 1975. With permission from Arnold.)
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• Preovulatory=Graafian follicle– Now single, dominant follicle– Overall size varies; deter’d by amt follicular
fluid– Cumulus oophorus = oocyte + corona radiata
• Will be expelled @ ovulation
– Hyaluronic acid accumulates• Break attachment corona radiata and granulosa
– LH surge induces completion 1st meiotic division 2o oocyte
• 2nd meiotic division @ fert’n
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Ovulation
• Induced by LH surge
• Rupture– Follicle wall– Follicle cell layers
Corona radiata w/ oocyte expelled into peritoneal cavity
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Luteinization
• Initiated by LH surge• CL forms from
– Graunulosa lutein– Theca lutein– Assoc’d microvasculature
• Defined life span– If no fertilization, involution & apoptosis 14 d
after form’n
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• Contributes to next developing cohort of follicles– CL degeneration decr’d E2, inhibin A incr’d FSH incr’d FSH in follic fluid of Graafian follicle dominant follicle selection, maturation
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Atresia
• Remaining 99.9% follicles
• Apoptosis of oocyte, granulosa cells– Ligand signalling pathways cell death
• FSH=survival factor– Prevents apoptosis
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Ovarian Steroidogenesis
• Maturing follicles and CL• Maturing follicles – 2 adjacent impt pop’ns
– Granulosa cells– Theca interna cells
• CL – impt cells der’d from follicle after ov’n– Granulosa lutein– Theca lutein
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• Sex steroids– Prior to ov’n (from maturing follicle): E2– After ov’n (from CL): progesterone + E2
• Book notes progesterone=distinctive female hormone– CL and placenta only
• Cell pop’ns coordinate in prod’n sex steroids
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• Theca (interna & externa) express P450scc– Cholesterol pregnenolone– Sensitive to LH
cAMP PKA StAR PBR P450scc activity in inner mitoch membr
– Pregnenolone androgen pathway• Uses P450c17
– Preovulatory LH surge • Ovulation
• Luteinization theca interna, granulosa
• Development CL
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• Theca interna express aromatase (androgens estrogens)– BUT once ovulation occurs, expression ceases– So decr’d secr’n estrogens from CL
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• Granulosa cells lack P450scc, P450c17– No cholesterol pregnenolone– No further androgen synth– Rely on theca cell androgens– Insensitive to LH signal for androgen prod’n
• EXCEPT when advanced follicle dev’d– Just prior to ov’n
– Small numbers LH receptors expressed
– LH stim’s steroidogenesis in these cells
– Impt to luteinization
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• Granulosa cells – cont’d– BUT sensitive to FSH
• FSH stim’n – Proliferation granulosa cells
– Secretion inhibin B
– Expression aromatase through cAMP, PKA act’n
• Granulosa cells express aromatase– Androgens estrogens– Most impt source of E2
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• Granulosa lutein cells express P450scc– So can produce pregnenolone
• BUT granulosa lutein cells lack P450c17– No androgen synth from pregnenolone
• Rely on theca lutein cells for androgens
– BUT progesterone synth from pregnenolone– Insensitive to LH signal to produce androgens
• BUT small numbers LH receptors expressed in advanced follicle
• LH secr’n progesterone, secr’n inhibin A
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• Granulosa lutein cells express aromatase– Androgens estrogens– Activated with LH
• If pregnancy, interrelationships balanced also with placental cells
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Endometrial (Uterine) Cycle
• Coupled to ovarian cycle– Gametogenesis– Hormonogenesis
• Three phases
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• Menstruation – during follicular phase– With demise of CL– Plasma progesterone decr’d– Uterine endometrium shed
• Leaves basal portion of endometrial glands
– 2-7 d (4 d avg)– 30 mL blood loss avg
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• Proliferative – during follicular phase– E2 dependent regeneration, growth of
endometrium– E2 receptor binding @ remaining basal stratum
stromal, epithelial cell growth
• Secretory – during luteal phase– Progesterone-dependent maturation of
endometrium– Requires E2 prep’n endometrium– Now suitable for blastocyst implantation
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Vaginal Cycle
• After puberty• In response to estrogens
– Changes w/ menstrual cycle
• Early follicular phase– Epithelium rounded basal cells
• Late follicular phase – maximum growth– Basal cells covered w/ flattened cells
– Outermost cells keratinized
• End luteal– Epith invaded w/ leukocytes, dead cells degen’d