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PCOS
นพ.โอฬาริ�ก มุ�สิ�กวงศ์�ผศ์ . พญ . ศ์ริ�นาริ� แก�วฤดี�
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
POLYCYSTIC OVARIAN SYNDROME (PCOS) OVERVIEW
PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatory dysfunction
Prevalence 6-8% of normal populationLeading cause of anovulatory
infertility and hirsutismWomen with PCOS have an increased
risk of miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, and endometrial cancer
PCOS AND STEIN-LEVENTHAL SYNDROME
oPCOS was first identified by Stein and Leventhal in 1935
oThey described a group of women who were obese and infertile, with enlarged ovaries with multiple cysts
oFew of these original features are now considered consistent findings in PCOS
PATHOPHISIOLOGY
Insulin secretion and actionGonadotropin secretion and action
Androgen biosynthesis and action
Weight and energy regulationEnvironment factor
DIAGNOSTIC CRITERIA
AND CLINICAL MANIFESTATIONS
NIH Criteria Menstrual irregularity due to anovulation
or oligo-ovulation Evidence of clinical or biochemical
hyperandrogenism Hirsutism, acne, male pattern baldness High serum androgen levels
Exclusion of other causes (CAH, tumors, hyperprolactinemia)
Rotterdam Criteria (2 out of 3) Menstrual irregularity due to anovulation
oligo-ovulation Evidence of clinical or biochemical
hyperandrogenism Polycystic ovaries by US
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.
AES criteriapresence of three features
androgen excess (clinical and/or biochemical hyperandrogenism)
ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology)
exclusion of other androgen excess or ovulatory disorders
MENSTRUAL DYSFUNCTION
Oligo or amenorrheaMenstrual irregularity typically begins
in the peripubertal periodDelayed menarche
Reduction in ovulatory events leads to deficient progesterone secretion
Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding
Increased risk for endometrial hyperplasia and/or endometrial CA
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Hormone Level
EstradiolProgesteroneFSHLH
Menstrual Cycle Day
Ovulation
Endometrial Thickness
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Normal Menstrual Cycle
Hormone Level
EstradiolProgesterone
Endometrial Thickness
0 2 4 6 8 10 12 14 16 18 20
0 2 4 6 8 10 12 14 16 18 20 Weeks
Breakthrough
Withdrawal
Anovulatory Bleeding in
PCOS
Lower limit of normal
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 follicles in peripheral location
80% of women with PCOS have classic cysts
Polycystic Ovaries
Cystic Follicles
Uterus
Tube
Anatomic Features of the Polycystic Ovary
INFERTILITY
Intermittent ovulation or anovulation
Inherent ovarian disorder—studies 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
OBESITY AND INSULIN RESISTANCE ½ patients with PCOS are obese > 80% are hyperinsulinemic and have
insulin resistance (independent of obesity)
Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver
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. Congenital Adrenal Hyperplasia morning serum 17-
hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis
confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL
3. Ovarian and adrenal tumors serum testosterone concentrations are
always higher than 150 ng/dL adrenal tumors: serum DHEA-S
concentrations higher than 800 mcg/dL LOW serum LH concentrations
4. Cushing’s syndrome5. Drugs: danazol; OCPs with high
androgenicity
TESTING
Serum HCG Serum prolactin Thyroid function test FSH: r/o ovarian failure Serum luteinizing hormone (LH)—
elevated Serum estradiol—normal Serum estrone—elevated
TESTING
Fasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevated DHEA-S: normal 17-hydroxyprogesterone: normal Pelvic US Lipids
Total Testosterone (T)DHEA-S (DS)17-hyroxyprogesterone (17-OHP)
T > 200 ng/dlDS > 700 μg/dl
Suspect Tumor
17-OHP > 2 ng/ml
Suspect CAH
T Elevated ±DS Elevated
DS Elevated
T & DS Normal PCOS
Adrenal
Idiopathic
LABORATORY EVALUATION
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
Potential hepatic dysfunction
ORAL CONTRACEPTIVES
• Suppress ovarian androgen
• Increase SHBG
• Regular menstrual cyclicity
• Progestin opposition
• Contraception
ANTI-ANDROGENS
Spironolactone
Flutamide
Finasteride
SPIRONOLACTONE
Androgen receptor blockade
Steroid enzyme inhibition
Aldosterone antagonismLower blood pressurePotassium sparing
Dose: 100-200 mg/day
FLUTAMIDE
Non-steroidal, selective anti-androgen
Liver function tests
Dose: 125-250 mg/day
OLIGOMENORRHEA Combination estrogen-progestin pill
first line when fertility is not desired 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
TREATMENT—NO FERTILITY DESIRED
Monophasic antiandrogenic OCPON 1/35 (norethindrone)Orthocyclen (norgestimate)Desogen or Orthocept
(desogestrel)Yasmin
- insulin sensitizing agents
Metforminwill restore ovulation and menses in > 50% of patients
Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained10 mg for 7 to 10 days every two to four months
METFORMIN
Decreases hepatic glucose production Reduces need for insulin secretion Improves insulin sensitivity (increases
peripheral glucose uptake and utilization)
Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis
SIDE EFFECTSDiarrhea, nausea, vomiting,
flatulence, indigestion, abdominal discomfortCaused by lactic acid in the bowel wallMinimized by slow increase in dosage
Lactic acidosis—rareAvoid in CHF, renal insufficiency, sepsisDiscontinue for procedures using
contrast (withhold X 48 hours)Temporarily suspend for all surgical
procedures that involve fluid restrictionCimetidine 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 50 mg days 3-7 for 3 months 100 mg days 3-7 for 3 months
METFORMIN DOSING Target—1500-2000 mg per day
Clinically significant responses not regularly observed at doses less than 1000 mg per day
INFERTILITY
Weight loss—reduction 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 diso
- rder in reproductive aged women. PCOS is a lifelong disease beginning in fa
tal life and extending into the postmeno pausal period.
Hyperinsulinemia is the pivotal factor in the pathogenesis.
PCOS is an inherited disorder the follows an autosomal dominant inheritance patt ern although the gene or genes involve a
re unknown
Hyperandrogenemia with or witho ut hyperandrogenism along with ol
igomenorrhea are hallmark feature s of PCOS
Anovulatory resulting in infertility i s a common presentation
Obesity worsens metabolic abnorm alities such as hyperinsulinemia an
d hyperandrogenemia.
Diabetes, lipid disorder, heart dise ase and endometrial cancer are me
tabolic sequelae of PCOS. - Insulin sensitizing agent heave dra
matically changes the managemen -t of PCOS. Metformin, an insulin se
nsitizing agent, is now first choice f or the treatment of anovulation in
PCOS. Weight loss and exercise are the best long term therapy to decr
ease the metabolic sequelae of PCOS.
REFERENCES Berek & Novak’s 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
Insulin increase
Free estradiolincrease
High LHLow FSH
Free testosteronincrease
Androstenandion increase
SHBG decrease
atresia
Theca (IGF-I)
Endometrial cancer
Testosteronincrease
Estroneincrease
hirsutism
IGFBP-I **** decrease
IGFBP*** insulin like growth factor binding protein
INSULIN SENSITIVITY
Insulin
Liver Muscle
Pancreas
Hepatic Glucose Output
Glucose Utilization
INSULIN RESISTANCE
Insulin
Liver Muscle
Pancreas
Hepatic Glucose Output
Glucose Utilization
Increased
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