Challenges and Management of Polycystic Ovarian Syndrome

1. Challenges and Management of Polycystic Ovarian Syndrome Sue Cote’ RNC WHNP

2. Menstrual Cycle • The cycle begins with the first day of menstrual bleeding • A new ovum begins to mature in the ovaries • The sac around the maturing ovum produces estrogen, increasing the levels in the body • Increasing estrogen levels prompt the uterine lining to thicken • Estrogen levels peak around day 14 and the sac, containing the mature ovum, splits open releasing it from the ovary • The empty sac (corpus luteum) left in the ovary begins to produce both estrogen and progesterone • Around day 22 the corpus luteum stops producing estrogen and progesterone and if the egg has not been fertilized, both levels will drop. • Blood vessels in the uterine walls contract and spasm due to the lack of estrogen and progesterone and the uterine lining is shed

3. Gonadotropins • Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are called gonadotropins because the stimulate the gonads-in males, the testes, and in females, the ovaries • Theca cells in the ovary respond to LH stimulation by secretion of testosterone, which is converted into estrogen by adjacent granulosa cells. • Ovulation of mature follicles on the ovary is induced by a large burst of LH secretion. • FSH stimulates the maturation of ovarian follicles

4. LH • LH is present in low levels throughout the woman’s cycle except for 1 ½ days prior to ovuation. • Ovulation occurs about 10-12 hours after the peak LH surge (this is what the ovulation kits pick up), then returns to its low levels. • As a result of the ruptured follicle an increase in the production of progesterone occurs to help prepare the uterus for implantation.

5. PCOS • Most common endocrine disorder in women of reproductive age • These women often have elevated androgen and LH levels, an increased LH:FSH ratio, some increase in serum estrogens, increases in fasting or challenged insulin levels, decreased HDL levels with increased triglycerides, and occasionally increased prolactin levels. • Its etiology is not completely understood • Its treatment is based primarily on signs and symptoms • Recent findings demonstrate that PCOS has significant metabolic sequel including increased risk for diabetes and CVD, (seven times increased risk of heart attack and heart disease than other women)

6. Present to Gynecologists • Irregular menstrual cycles • Infertility • Signs of androgen excess

7. Patient Appearance • Can not rule out or make a diagnosis by the appearance of the women • Increased abdominal girth • Increased dark hair • Facial and back acne-cystic

8. Prevalence • 6.5% or approximately 5 million women in the United States. • When you add polycystic ovaries as a criteria this increases to 25 %

9. History of PCOS • Enlarged, smooth cystic ovaries were first described in 1844-at that time it was recommended to remove the ovary or do a wedge resection. • 1930’s-The notion that androgen production, (which was always before felt to be the province of the adrenal gland only), may be associated with the ovary

10. Points to Remember • Menstrual cycle is fundamentally regulated by the rhythmic release of the neuropeptidegonadotropin-releasing hormone (GnRH) • Increased output of GnRH from the hypothalamus is thought to be responsible for the hyper-secretion of LH that acts on the theca cells to augment ovarian androgen production • CNS stimulates the pituitary gland to secrete LH which results in cyclical ovarian steroid output • Women with PCOS have an increased LH • Androgen production by the theca cells is LH dependent

11. Pathophysiology of PCOS Defect associated with PCOS is unknown, however women with this syndrome have several interrelated characteristics • Insulin resistance • Evidence of androgen excess-for which there is no other cause • Chronic oligo or anovulation (altered gonadotropin dynamics) • An ultrasound appearance of polycystic ovaries in the absence the above three characteristics is NOT a basis for defining PCOS and should not prompt a full evaluation

12. Insulin • Insulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy source.

13. Insulin • Abnormal insulin creates increased androgen, but not the reverse. Weight loss will help correct the symptoms of increased androgen, but administration of gonadotropins does not result in a reduction of insulin. • Insulin stimulates steroidogenesis, (the process wherein desired forms of steroids are generated by transformation of other steroids), in the ovarian cells • Products of steroidogenesis include: androgens, thestosterone, estrogens, progesterone, corticoids, cortisol and aldosterone

14. Insulin Resistance • The condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. • The patients are not technically diabetic because their glucose levels are normal. • Although obesity is associated with insulin resistance, it can not be explained entirely by obesity. • Difficult to diagnosis, fasting insulin levels may be normal. Glucose tolerance testing where you also measure the insulin levels may be more accurate.

15. Androgen Excess • Increased output of GnRH from the hypothalamus is thought to be responsible for the hypersecretion of LH that acts on the theca cells to augment ovarian androgen production • Reason unknown • Hyperinsulinism also increases the levels of bioavailable androgen by reducing the amount of sex hormone-binding globulin (SHBG) produced by the liver

16. Androgen Excess - Common Signs • Hirsutism – presence of terminal hair in a male like pattern. Androgens directly transform vellus hair to terminal hair in androgen sensitive areas. Male pattern distribution includes hair growth on the face, chest, upper back, abdomen and inner thighs. • Acne –sebaceous glands are strongly influenced by androgens. The degree and severity of the acne is directly associated with circulating androgen concentrations.

17. Altered Gonadotropin Dynamics • Follicles in the ovaries of women with PCOS do not mature fully-therefore estradiol production by these follicules is limited. • Follicle Stimulating Hormone (FSH) is absolutely essential for preovulatory follicle growth-so impaired FSH signaling is a reason for anovulation. • FSH secretion is constrained by negative feedback inhibition

18. Oligo-ovulation • Cycle duration greater than 35 days in duration or less than eight cycles per year • Usually begins at menarche • Anovulation bleeding represents endometrial breakthrough bleeding resulting from continual estrogen stimulation unopposed by progesterone. • Exclusion of other disorders-hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors, 21-hydroxylase deficiency

19. Risk Factors Associated with Polycystic Ovaries • Dyslipidemia • Non-insulin-dependent diabetes mellitus • Gestational diabetes • Hypertension • Cardiovascular disease • Thrombosis • Endometrial cancer • Ovarian cancer • Breast cancer

20. Lab Testing • Baseline testosterone-greater than 40mg per dL is significant • LH and FSH-greater than a 3:1 ratio significant • Fasting Lipid Profile-triglycerides to HDL-greater than 5:1 significant • Insulin • DHEAS- levels vary with sex and age

21. DHEAS • DHEA is a weak male hormone produced by the adrenal gland. A naturally produced prohormone. • Increase in DHEAS may be due to: • Congenital adrenal hyperplasia (rare genetic disorder) • Non-cancerous tumor of the adrenal gland • PCOS

22. Treatment • Exercise • Weight loss • Hair removal • Medications

23. Treatment-Does Not Desire Pregnancy • Oral contraceptives are used to both regulate the menstrual cycle and suppress the androgens. • Spironolactone affects the androgen receptors and will, over a prolonged period of time, reduce the hirsutism on its own. • Metformin has been shown to directly inhibit androgen production in the human thecal cells and to have a direct effect on ovarian steroidogenesis. It also lowers insulin levels.

24. Management of Infertility Diet and exercise Ovulation No Ovulation Clomiphene citrate use 50-150 mg Consider metformin at this time Ovulation No ovulation Use of clomiphene citrate with referral

25. Bibliography • Guzick David; Hoeger Kathleen Polycystic Ovary Syndrome Clinical Updates in Women’s Health Care Vol. VIII, Number 1, January 2009 • Helfer Elizabeth A Practical Approach to Treating Hirsutism Women’s Health Vol. 5 Number I January-February 2005 • Ruby Laura Polycystic Ovarian Syndrome The Journal for Nurse Practitioners October 2008 697-704 • Freeman Sarah Polycystic Ovary Syndrome: Diagnosis and Management Women’s Health Care Vol. 1, No.4 June 2002 15-20

26. Management of Woman Desiring Pregnancy Dietand Exercise