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Follicle Development and Hormonal Interactions in the Female Cycle Female Reproductive Histology Polycystic Ovary Syndrome Patient H

Female reproductive tract ovary: female gonad; where eggs develop Fallopian tube: passageway through and where steroid hormones (estrogen and which egg travels to uterus (also called progesterone) are produced uterine tube or oviduct) uterus: organ embryo implants and where gestation occurs cervix: narrow opening at the inferior end of the uterus; protrudes into vagina vagina: birth canal From Figure 26.9a, p.816

Summary of hormonal regulation of reproduction GnRH: gonadotropin releasing hormone gonadotropins: FSH: follicle-stimulating hormone LH: luteinizing hormone female gonadal steroids: estrogen progesterone

Overview of female cycle luteal phase: high positive feedback; LH progesterone secretion surge and ovulation follicle growth; rising estrogen estrogen and progesterone coordinate uterine changes Figure 26.11, p. 821

Hormonal interactions throughout the female cycle Figure 26.12, p.822

Cell types and follicles in the ovary (textbook term: tertiary follicle) non-developing enlarge during growth phase • growth phase stimulated by FSH, LH •

Estrogen production during the follicular phase requires both thecal cells and granulosa cells thecal cells: produce androgens granulosa cells: express aromatase aromatase: enzyme that converts androgens to estrogens

Hormonal regulation during the early follicular phase Similar to figure 26.12a, p. 822

Switch to positive feedback at high estrogen levels causes LH surge switch to positive hormonal interactions feedback occurs at blue dotted line Figure 26.12b, p. 822 Figure from course web page

Luteal phase early to mid-luteal phase: late: feedback inhibition causes release from feedback declining secretion of inhibition allows increased gonadotropins to prevent FSH and LH secretion and follicle development new follicle development progesterone prepares decreased estrogen and uterus for implantation progesterone secretion after corpus luteum dies

Structure of the uterus Figure 26.9d, p. 817 endometrium myometrium

Phases in the uterine cycle estrogen stimulates proliferation progesterone stops proliferation in the endometrium and promotes secretion by endometrial glands

Schematic ovary with stages of follicle development Figure 26.9e, p. 817

Monkey ovary Figure 19.3a, Wheater’s Functional Histology F: follicles in different stages of development or degeneration Be able to identify organ: ovary

Histology of the ovary primordial follicles antral follicle (tertiary follicle)

Histology of the ovary antrum thecal cells basal lamina granulosa cells zona pellucida oocyte

Primordial follicles are located in the ovarian cortex primordial follicle primordial follicle

Ovarian histology small antral follicle with oocyte, zona pellucida, granulosa cells and antrum; primordial follicles visible in the upper left hand corner of the image

Histology of the uterus endometrial glands Be able to identify organ: uterus; endometrial glands; endometrium; myometrium endometrium myometrium

Polycystic ovary syndrome (PCOS) endocrinopathy causing menstrual irregularity and symptoms of hyperandrogenism • quite common affecting between 5-12% of reproductive age women • most common form of anovulatory infertility • PCOS diagnosed when a woman has two of the following signs: anovulation hyperandrogenism polycystic ovarian morphology associated signs: obesity, insulin resistance, hyperinsulinemia

Signs and symptoms in PCOS sign: can be measured or observed symptom: experienced by the patient anovulation (lack of ovulation) à amenorrhea (lack of menstruation) à infertility oligo-ovulation (infrequent ovulation) à oligomenorrhea (irregular menstruation) à infertility hyperandrogenism à acne à male pattern alopecia (hair loss from head) à hirsutism (male pattern hair growth)

Evaluation of hirsutism Figure 1 in UpToDate “Diagnosis of polycystic ovary syndrome in adults” https://www.uptodate.com/contents/diagnosis-of-polycystic-ovary-syndrome-in-adults

Ultrasound images of ovaries: normal and polycystic ovarian morphology Figure 1: transvaginal ultrasound of a Figure 15B: transvaginal ultrasound of an normal ovary on cycle day 12 ovary in a woman with PCOS multiple, immature follicles; dominant follicle “necklace of black pearls” Figures above from Chizen, D. and Pierson, R. (2010) Global Library of Women’s Medicine ( ISSN: 1756-2228 ) 2010; DOI 10.3843/GLOWM.10326 https://www.glowm.com/section_view/heading/Transvaginal%20ultrasonography%20and%20female%20infertility/item/325

Hormonal interactions in the early follicular phase need sufficient FSH to stimulate • granulosa cells and produce estrogen need estrogen in the ovary for • proper follicle development, selection of dominant follicle, and progression to ovulation

Hormonal interactions in PCOS • LH secretion high FSH secretion deficient • ovary synthesizes • androgens, not estrogen • follicle development does not progress due to lack of FSH, estrogen

Steps in the female cycle that are blocked in PCOS X insufficient FSH to start proper • follicle development X no large rise in estrogen to switch to • positive feedback no LH surge • no ovulation • X no corpus luteum • no rise in progesterone secretion to • switch uterus into secretory phase X X X X

Treatment of PCOS in a woman who does not want to conceive mechanism of action of hormonal contraceptives: prevent ovulation by mimicking feedback inhibition hormonal contraceptives • weight loss • metformin (for women who • are insulin resistant) NOTE: hormonal contraceptives contain either a combination of estrogen and progesterone, or progesterone only

Benefits of hormonal contraceptives in the treatment of PCOS reduce androgen secretion • decrease endometrial proliferation • • decrease heavy and painful menstruation • regular withdrawal bleeds • long-term: reduce risk for endometrial cancer problem in PCOS à ”unopposed estrogen” if ovulation doesn’t occur, no switch to luteal phase and increased progesterone secretion; endometrium is excessively stimulated by estrogen

Treatment of PCOS in women who want to conceive (ovulation induction) clomiphene (estrogen antagonist) à reduces feedback inhibition of FSH secretion • letrozole (aromatase inhibitor) à inhibits estrogen synthesis; reduces • feedback inhibition of FSH secretion exogenous FSH à treats FSH deficiency; risk for multiple • ovulations

Treatments to induce ovulation reduce estrogen’s feedback inhibition of FSH secretion clomiphene: blocks estrogen receptors letrozole: decreases estrogen synthesis Figure 1 in UpToDate “Ovulation induction with letrozole” https://www.uptodate.com/contents/ovulation-induction-with-letrozole

Patient H What is meant by the term “amenorrhea”? What is meant by the term “hirsute”? Hirsutism and acne are clinical evidence of what endocrine disturbance?

elevated LH and serum testosterone • 17-OH progesterone, prolactin, and other hormones measured to • rule out other causes of hyperandrogenism and amenorrhea polycystic ovarian morphology •

This patient has impaired glucose tolerance, indicating that she is insulin resistant. What is another sign that she has insulin resistance? impaired glucose tolerance (prediabetic) Adapted from Figure 22.19a, p. 715

The patient was treated with metformin. What is the effect of insulin on the ovary? Why do you suppose treatment with metformin (and weight loss) resulted in normal menstrual cycles? In this patient, treatment with metformin was able to successfully restore regular menstrual cycles. What is the usual first-line treatment to address menstrual irregularity and hyperandrogenism in a woman with PCOS who does not want to conceive?