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 fertd ovum
• Fetal devt
• Labor
• Menstruation
• Cervix secretes mucus

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• Uterus contd
• 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 secrn 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
• 17b-estradiol
• Inhibin
• Absence functional CL
• Plasma progesterone low
• FSH elevated _at_ beginning, diminishes
• High FSH impt to follicle selection, early
  maturation

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• As follicle devs, more E2, inhibin ?
• Decrd FSH (neg feedback)
• Decrd LH
• Upregulation ant pit GnRH receptors
• E2 peaks _at_ 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 142 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
• Devs ? granulosa cells
• Growth remodeling
• 40 m oocyte 15-25 m
• 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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• Secondarypreantral 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 stimd
• Simple cuboidal ? stratified, pseudostratified
  columnar
• Diff layers have diff morphology, function
• Granulosa cells produce activin
• Stims 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 contd
• Granulosa cells connected by gap junctions
• Synchronization
• Nutrient transfer
• Basement membr devs
• When 6 layers granulosa
• Definitive theca layer
• Angiogenesis ? blood supply to theca

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• Secondary follicle (contd)
• Final 2o follicle 100-200 m
• 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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• Tertiaryantral 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 contd
• 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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• PreovulatoryGraafian follicle
• Now single, dominant follicle
• Overall size varies deterd by amt follicular
  fluid
• Cumulus oophorus oocyte corona radiata
• Will be expelled _at_ ovulation
• Hyaluronic acid accumulates
• Break attachment corona radiata and granulosa
• LH surge induces completion 1st meiotic division
  ? 2o oocyte
• 2nd meiotic division _at_ fertn

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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
• Assocd microvasculature
• Defined life span
• If no fertilization, involution apoptosis 14 d
  after formn

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• Contributes to next developing cohort of
  follicles
• CL degeneration ? decrd E2, inhibin A
• ? incrd FSH
• ? incrd 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
• FSHsurvival factor
• Prevents apoptosis

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Ovarian Steroidogenesis

• Maturing follicles and CL
• Maturing follicles 2 adjacent impt popns
• Granulosa cells
• Theca interna cells
• CL impt cells derd from follicle after ovn
• Granulosa lutein
• Theca lutein

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• Sex steroids
• Prior to ovn (from maturing follicle) E2
• After ovn (from CL) progesterone E2
• Book notes progesteronedistinctive female
  hormone
• CL and placenta only
• Cell popns coordinate in prodn 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 decrd secrn 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 prodn
• EXCEPT when advanced follicle devd
• Just prior to ovn
• Small numbers LH receptors expressed
• LH stims steroidogenesis in these cells
• Impt to luteinization

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• Granulosa cells contd
• BUT sensitive to FSH
• FSH stimn ?
• Proliferation granulosa cells
• Secretion inhibin B
• Expression aromatase through cAMP, PKA actn
• 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 ? secrn progesterone, secrn 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 decrd
• 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 _at_ remaining basal stratum ?
  stromal, epithelial cell growth
• Secretory during luteal phase
• Progesterone-dependent maturation of endometrium
• Requires E2 prepn 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 degend