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OBJECTIVES
Define PCOS Understand pathophysiology Form an appropriate differential diagnosis Establish the work-up for PCOS Develop an array of therapies to treat complaints and prevent bad outcomes
PATHOPHISIOLOGY
Insulin
secretion and action Gonadotropin secretion and action Androgen biosynthesis and action Weight and energy regulation Environment factor
NIH Criteria
presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume
* In addition, other etiologies (congenital adrenal hyperplasias, androgen-secreting tumors, Cushing's syndrome) must be excluded.
MENSTRUAL DYSFUNCTION
Oligo
or amenorrhea
Reduction
in ovulatory events leads to deficient progesterone secretion Chronic estrogen stimulation of the endometrium with no progesterone for differentiationintermittent breakthrough bleeding or dysfunctional uterine bleeding Increased risk for endometrial hyperplasia and/or endometrial CA
Ovulation
6 8 10 12 14 16 18 20 22 24 26 28
Endometrial Thickness
0 20 Endometrial Thickness
10
12
14
16
18
Breakthrough
Withdrawal
0 20 2 4 6 8 10 Weeks 12 14 16 18
HYPERANDROGENISM
Hirsutism, acne, male pattern balding, alopecia 50-90% patients have elevated serum androgen levels Free testosterone levels most sensitive Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm)
OVARIAN ABNORMALITIES
Thickened
sclerotic cortex
Multiple
80%
cysts
Uterus
Polycystic Ovaries
Cystic Follicles
INFERTILITY
Intermittent ovulation or anovulation Inherent ovarian disorderstudies show reduced rated of conception despite therapy with clomid
OBESITY
Prevalence of obesity varies from 30-75% 2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity Obese patients can be hirsute and/or have menstrual irregularities without having PCOS
Acanthosis Nigricans
Velvety plaques on nape of neck and intertriginous areas Epidermal hyperkeratosis Associated with insulin resistance
DIFFERENTIAL DIAGNOSIS
1.
Hyperprolactinemia
Prominent menstrual dysfunction Little hyperandrogenism
2.
TESTING
Serum HCG Serum prolactin Thyroid function test FSH: r/o ovarian failure Serum luteinizing hormone (LH)elevated Serum estradiolnormal Serum estroneelevated
TESTING
Fasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevated DHEA-S: normal 17-hydroxyprogesterone: normal Pelvic US Lipids
LABORATORY EVALUATION
Total Testosterone (T) DHEA-S (DS) 17-hyroxyprogesterone (17-OHP)
T Elevated DS Elevated
T > 200 ng/dl DS > 700 g/dl Suspect Tumor 17-OHP > 2 ng/ml Suspect CAH
PCOS
TREATMENT
Depend
on goal of treatment
WEIGHT LOSS
Weight loss Weight loss Weight loss
HIRSUTISM
Mechanical hair removal Vaniqa (eflornithine hydrochloride) OCPs with minimal androgenicity OCP plus antiandrogen (spironolactone) Spironolactone, 50-200 mg per day Flutamide
ORAL CONTRACEPTIVES
Suppress ovarian androgen Increase SHBG
ANTI-ANDROGENS
Spironolactone
Flutamide
Finasteride
SPIRONOLACTONE
Androgen
Steroid
receptor blockade
enzyme inhibition
Aldosterone
Dose:
FLUTAMIDE
Non-steroidal,
selective anti-
androgen
Liver
function tests
Dose:
125-250 mg/day
OLIGOMENORRHEA
Decrease in LH secretion and decrease in androgen production Increase in hepatic production of sex-hormone binding globulin Decreased bioavailablity of testosterone Decreased adrenal androgen secretion Regular withdrawal bleeds Prevention of endometrial hyperplasia
antiandrogenic OCP
insulin-sensitizing agents
Metformin
will
restore ovulation and menses in > 50% of patients Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained
METFORMIN
Decreases hepatic glucose production Reduces need for insulin secretion Improves insulin sensitivity (increases peripheral glucose uptake and utilization) Antilipolytic effectreduces fatty acid concentrations and reduces gluconeogenesis
SIDE EFFECTS
Diarrhea,
Lactic
acidosisrare
Avoid in CHF, renal insufficiency, sepsis Discontinue for procedures using contrast (withhold X 48 hours) Temporarily suspend for all surgical procedures that involve fluid restriction Cimetidine causes increased metformin levels
INFERTILITY TREATMENT
Metformin
Metformin 500 mg once a day with breakfast for 4 days Metformin 500 mg twice a day with breakfast and dinner for 4 days Metformin 500 mg with breakfast and 1,000 mg with dinner for 4 days Metformin 1,000 mg twice daily
Clomid
METFORMIN DOSING
Target1500-2000 mg per day Clinically significant responses not regularly observed at doses less than 1000 mg per day
INFERTILITY
Weight
lossreduction in serum testosterone concentration and resumption of ovulation Clomid: 80% will ovulate, 50% will conceive Metformin: when added to clomid, improves ovulatory rates Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery IVF
Key point
PCOS is the most common endocrine disorder in reproductive-aged women. PCOS is a lifelong disease beginning in fatal life and extending into the postmenopausal period. Hyperinsulinemia is the pivotal factor in the pathogenesis. PCOS is an inherited disorder the follows an autosomal dominant inheritance pattern although the gene or genes involve are unknown
Hyperandrogenemia
with or without hyperandrogenism along with oligomenorrhea are hallmark features of PCOS Anovulatory resulting in infertility is a common presentation Obesity worsens metabolic abnormalities such as hyperinsulinemia and hyperandrogenemia.
Diabetes,
lipid disorder, heart disease and endometrial cancer are metabolic sequelae of PCOS. Insulin-sensitizing agent heave dramatically changes the management of PCOS. Metformin, an insulin-sensitizing agent, is now first choice for the treatment of anovulation in PCOS. Weight loss and exercise are the best long term therapy to decrease the metabolic sequelae of PCOS.
REFERENCES
Berek & Novaks Gynecology Clinical gynecology / [edited by] Eric J. Bieber, Joseph S. Sanfilippo, Ira R. Horowitz Uptodate.com Polycystic ovary syndrome : a guide to clinical management / Adam Balen ... [et al.] Polycystic ovary syndrome / edited by R. Jeffrey Chang, Jerrold J. Heindel, Andrea Dunaif. ACOG practice bulletin, polycystic ovary syndrome The ovary / editors, Peter C.K. Leung, Eli Y. Adashi Clinical gynecologic endocrinology and infertility / Leon Speroff, Marc A. Fritz
THANK YOU
Wt. increase
Insulin receptor disorder
SHBG decrease
atresia
Insulin increase
IGFBP-I **** decrease
Theca (IGF-I)
Androstenandion increase
Testosteron increase
Endometrial cancer
hirsutism
Estrone increase
INSULIN SENSITIVITY
Liver
Hepatic Glucose Output
Muscle
Insulin
Glucose Utilization
Pancreas
INSULIN RESISTANCE
Liver
Hepatic Glucose Output
Muscle
Insulin
Increased
Glucose Utilization
Pancreas