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

Female reproductive tract

Fallopian tube: passageway through which egg travels to uterus (also called uterine tube or oviduct) vagina: birth canal uterus: organ embryo implants and where gestation occurs cervix: narrow opening at the inferior end of the uterus; protrudes into vagina

• vary: female gonad; where eggs develop

and where steroid hormones (estrogen and progesterone) are produced

From Figure 26.9a, p.816

Summary of hormonal regulation of reproduction

gonadotropins: FSH: follicle-stimulating hormone LH: luteinizing hormone GnRH: gonadotropin releasing hormone female gonadal steroids: estrogen progesterone

Overview of female cycle

Figure 26.11, p. 821

follicle growth; rising estrogen positive feedback; LH surge and ovulation luteal phase: high progesterone secretion estrogen and progesterone coordinate uterine changes

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

Similar to figure 26.12a, p. 822

Hormonal regulation during the early follicular phase

Figure from course web page

hormonal interactions

Figure 26.12b, p. 822

Switch to positive feedback at high estrogen levels causes LH surge

switch to positive feedback occurs at blue dotted line

Luteal phase

feedback inhibition causes declining secretion of gonadotropins to prevent follicle development progesterone prepares uterus for implantation

early to mid-luteal phase: late:

release from feedback inhibition allows increased FSH and LH secretion and new follicle development decreased estrogen and 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 in the endometrium progesterone stops proliferation and promotes secretion by endometrial glands

Figure 26.9e, p. 817

Schematic ovary with stages of follicle development

Figure 19.3a, Wheater’s Functional Histology

Monkey ovary

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)

basal lamina granulosa cells thecal cells

• ocyte

zona pellucida antrum

Histology of the ovary

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

endometrium myometrium endometrial glands Be able to identify

• rgan: uterus;

endometrial glands; 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 anovulation (lack of ovulation) àamenorrhea (lack of menstruation) àinfertility

• ligo-ovulation (infrequent ovulation) àoligomenorrhea (irregular menstruation)

àinfertility hyperandrogenism àacne àmale pattern alopecia (hair loss from head) àhirsutism (male pattern hair growth) symptom: experienced by the patient

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

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

Figure 1: transvaginal ultrasound of a normal ovary on cycle day 12 Figure 15B: transvaginal ultrasound of an

• vary in a woman with PCOS

Ultrasound images of ovaries: normal and polycystic ovarian morphology

dominant follicle multiple, immature follicles; “necklace of black pearls”

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
• vary 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 X X X X X X

• insufficient FSH to start proper

follicle development

• no large rise in estrogen to switch to

positive feedback

• no LH surge
• no ovulation
• no corpus luteum
• no rise in progesterone secretion to

switch uterus into secretory phase

Treatment of PCOS in a woman who does not want to conceive

• hormonal contraceptives
• weight loss
• metformin (for women who

are insulin resistant) mechanism of action of hormonal contraceptives: prevent ovulation by mimicking feedback inhibition 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 PCOSà”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 inhibits estrogen synthesis; reduces feedback inhibition of FSH secretion

• letrozole (aromatase inhibitor)

à reduces feedback inhibition of FSH secretion

• exogenous FSH

à treats FSH deficiency; risk for multiple

• vulations

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

Treatments to induce ovulation reduce estrogen’s feedback inhibition of FSH secretion

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

Adapted from Figure 22.19a, p. 715

impaired glucose tolerance (prediabetic) This patient has impaired glucose tolerance, indicating that she is insulin resistant. What is another sign that she has insulin resistance?

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?