Female Reproductive Endocrinology

Chapter 18

Anatomy

• Vulva – external genitalia

• Vagina– Functions:

• Sperm, menstrual flow passage

• Receptacle for penis

• Birth canal

– Rugae– Acidic environment

• Uterus– Functions:

• Sperm transport

• Implantation fert’d ovum

• Fetal dev’t

• Labor

• Menstruation

– Cervix secretes mucus

• 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

• Oviducts– Transport

• Peristalsis

• Cilia

– Isthmus, ampulla, infundibulum– Not static tube

• Ovaries = gonads– Inner medulla, outer cortex– Gametogenesis, hormonogenesis

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

Ovarian Cycle

• Controls, controlled by hormones

• Coupled to uterine cycle

• Related to maturation ovarian follicles– Gonadotropin dependent

• Two phases– Follicular– Luteal

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

• 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

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

• 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

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

• 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

• 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

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.)

• 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

• 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

Granulosa cells

Thecal cells

• 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

• 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

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.)

• 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

Ovulation

• Induced by LH surge

• Rupture– Follicle wall– Follicle cell layers

Corona radiata w/ oocyte expelled into peritoneal cavity

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

• 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

Atresia

• Remaining 99.9% follicles

• Apoptosis of oocyte, granulosa cells– Ligand signalling pathways cell death

• FSH=survival factor– Prevents apoptosis

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

• 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

• 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

• Theca interna express aromatase (androgens estrogens)– BUT once ovulation occurs, expression ceases– So decr’d secr’n estrogens from CL

• 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

• 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

• 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

• Granulosa lutein cells express aromatase– Androgens estrogens– Activated with LH

• If pregnancy, interrelationships balanced also with placental cells

Endometrial (Uterine) Cycle

• Coupled to ovarian cycle– Gametogenesis– Hormonogenesis

• Three phases

• 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

• 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

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