Current Concepts inPolycystic Ovarian Syndrome
Mark N. Simon, MD
Exempla Uptown Women’s
Healthcare Specialists
October 17, 2003
Disclosure
Dr. Simon has no significant financial interests or other relationships with industry relative to the subject of this lecture.
Objectives
Cite the physical manifestations of PCOS. Describe the pathophysiology of PCOS. Formulate a treatment plan for patients with
PCOS.
Scope of the Problem
PCOS is the MOST common endocrine disorder of reproductive age women
Effects 5-10% of these women Commonly presents to primary care
providers
Diagnosis
North America (NIH Consensus):– Menstrual Irregularity (oligo- or anovulation)– Hyperandrogenism
Clinical evidence OR Laboratory evidence
– Absence of other endocrine disorders Congenital Adrenal Hyperplasia Hyperprolactinemia Thyroid dysfunction
Diagnosis
Europe:– Morphological features of polycystic ovaries– Menstrual disturbance AND/OR– Hyperandrogenism
Hirsuitism Acne Alopecia Laboratory data are not needed
Ultrasound
Polycystic Ovaries– Found in around 20% of general population– May be a predictor of future development of
PCOS– Found in 80% of women with PCOS
Appearance– Many, peripheral, small follicles– Increased ovarian stroma
European Diagnosis
Increases prevalence to about 15% Proposed unifying protocol:
1. Determine if symptoms are present
2. If present, proceed with ultrasound
3. If ultrasound positive – diagnosis confirmed
4. If ultrasound negative – check lab tests
Homberg, Human Reproduction, 2002
Diagnosis
North America (NIH Consensus):– Menstrual Irregularity (oligo- or anovulation)– Hyperandrogenism
Clinical evidence OR Laboratory evidence
– Absence of other endocrine disorders Congenital Adrenal Hyperplasia Hyperprolactinemia Thyroid dysfunction
Patient Presentation
Symptoms of hyperandrogenism Irregular menstrual cycles Infertility – Most Common Presentation
Symptoms of Hyperandrogenism
Hirsutism Acne Rarely see Virilization
– Male pattern balding– Clitoromegaly– Deepening of voice– Increased muscle mass
Hirsutism
Occurs in 80% of PCOS patients Excess terminal body hair
– Male Pattern Back, Sternum, Upper Abdomen, Shoulder
More common areas– Upper Lip, Around breast nipples, Linea alba– ¼ of women have hair in these areas
Excluding Scandinavian, Asian
Hirsutism - DDx
Idiopathic PCOS Drugs (Danazol) Hyperthecosis Ovarian Tumors Adrenal Tumors CAH
Ovarian Hyperthecosis
Ovary has nests of luteinized theca cells Signs and Symptoms
– Hirsutism, Alopecia, Obesity– HTN– Clitoromegaly– Markedly elevated testosterone
Red Flags with Hirsutism
Rapid onset of hirsutism Rapid progression of hirsutism Late onset
– Outside of early reproductive years
Virilization
Tumors
RED FLAGS Testosterone > 150ng/dL (> 200ng/dL) LH low DHES > 800mcg/dL Further investigation warranted
– MRI abdomen/pelvis
Nonclassic Congenital Adrenal Hyperplasia
Partial deficiency of 21-hydroxylase Elevation of 17-hydroxyprogesterone
– Precursor of androgens
Rare Do NOT have adrenal insufficiency Treat with anti-androgen therapy
Nonclassic Congenital Adrenal Hyperplasia
Consider in patients not responding to typical PCOS treatment
Measure 17-hydroxyprogesterone– Follicular phase– Morning– Levels > 2 ng/mL need to be tested further
Adrenal stimulation
Acne
Common in adolescent girls (30-50%) Severe acne is uncommon (<1%) Severe acne is a predictor of PCOS
Irregular Menses
Most common to have erratic menses– Due to Anovulation
Patients present with oligomenorrhea or amenorrhea
PCOS with Regular Menses?
Androgens converted to estrogens– Peripheral conversion– Aromatase
Estrogens stimulate uterine lining Can have regular shedding of endometrial
lining despite anovulation
PCOS with Regular Menses?
Hyperandrogenism does NOT automatically cause anovulation
Women with hyperandrogenism and polycystic ovaries may still ovulate regularly
Affect on fertility is unclear
Infertility
Usually long-standing infertility PCOS typically develops in early
reproductive years Infertility usually due to anovulation
Clinical Presentations
Hyperandrogenism– Hirsutism– Acne
Menstrual Irregularity Infertility
Initial Evaulation
History to determine onset PCOS usually has long course
– Rapid onset of hirsutism – Red Flag
Usually develops early in reproductive years PCOS is diagnosis of exclusion Lab tests help to exclude other problems
What tests to order
Prolactin– Rule out hyperprolactinemia– Cause of menstrual dysfunction– Little signs of hyperandrogenism– Lactotroph stimulation from estrogen
Testosterone DHEAS
Laboratory Tests
17-Hydroxyprogesterone– In patients suspected of NCAH
TSH– When symptoms warrant
Glucose Tolerance Test Fasting Lipid Profile
Laboratory Tests
LH, FSH– Little benefit
Insulin
Pathophysiology
Exact problems have not been identified Hypothalamic-pituitary abnormalities
– Elevated LH Increased frequency and amplitude of pulses
– Low-normal FSH– LH:FSH ratio increased– GnRH pulse generator may be disrupted causing
the elevated LH
Hyperandrogenism
Androstenedione– Produced in ovarian thecal cells– Production is stimulated by LH– Converted to estradiol by FSH-stimulated
aromatase– Excess is converted to estrone which suppresses
FSH and is tonic to LH
LH
Ovary
Androstenedione
EstroneEstradiol
FSH
+
-
Hyperandrogenism
Testosterone
SHBG
-
Insulin Resistance
Feature of PCOS Both obese and lean women are affected Affects a number of systems Reduction in tissue response to insulin
Insulin Resistance
Insulin causes androgen production– In women with PCOS
Insulin– Amplifies LH response in granulosa cells– Arrest of follicular development
Insulin Resistance
Insulin-like growth factor 1 (IGF-1)– Amplifies LH and androgen synthesis– Helps to regulate follicular maturation
Insulin-like growth factor binding protein 3 (IGFBP-3)– Decreased in patients with ovarian hirsuitism– When decreased, more bioavailability of IGF-1
Shobokshi, et al, J Soc Gynecol Investig, 2003
Insulin
Insulin
Glycogenolysis
Gluconeogenesis
PeripheralGlucoseUptake
- +
-
Insulin Resistance
Insulin
OvarianAndrogenSecretion
Anovulation
Granulosa Cells +
Summary of Pathophysiology
Elevated LH Leads to elevated Androgens
– Hyperandrogen symptoms
Insulin Resistance
Treatment
Depends on symptoms Depends on patient’s goals
Lifestyle Modification
Exercise– 150 minutes per week– Moderate exertion
Diet Weight Loss Most effective with obese patients
Weight Loss
Improves ovulatory and fertility rates– 5-7% loss– Restored ovulation in 75%
Decreases LH pulse amplitude– Decreases androgen production
Reduces insulin levels
Kiddy et al., Clin Endocrinol, 1992.
Insulin Sensitizers
Metformin – Most extensively studied– Increases peripheral uptake of glucose– Decreases gluconeogenesis– Does not cause hypoglycemia– Relatively inexpensive
Generic 500mg, 60 tabs $33.99 (drugstore.com 10/15/03)
Metformin
Side Effects– Gastrointestinal distress– Most common in first few weeks of use– Improves over time– Lactic acidosis
Dosage is 500mg TID or 875mg BID
Metformin
Lactic Acidosis– Severe, potentially fatal– Concern with elevated creatinine (>1.4 mg/dL)
Contraindicated in – – CHF, Sepsis, Liver disease, history of lactic
acidosis
Surgery
Rosiglitazone
Insulin-sensitizing agent Stimulate production of glucose transporter
proteins Few studies in PCOS Dosage is 4mg BID More expensive
– 4mg, 30 tabs cost $77.99 (drugstore.com, 10/15/03)
Rosiglitazone
Improved clinical symptoms Corrects insulin resistance Improves ovulation rates Fewer side effects
– Especially GI
Fertility rates not studied Shobokshi, et al, J Soc Gynecol Investig, 2003 Ghazeeri, et al, Fertil Steril, 2003
Treatment Algorithms
Path depends primarily on fertility desires Also depends on primary symptoms of
patient
Desires Fertility
The Problem: Anovulation The Solution: Reestablish Ovulation Question for patient: Willingness to wait?
– Weight Loss– Insulin-sensitizers may take 3-5 months– Ovulation induction much quicker
Harborne et al, The Lancet, April 8, 2003.
Weight Loss
Modest weight loss (5%) can help– Lower androgen levels– Induce regular cycles
Other health benefits for pregnancy– Diabetes– Hypertension
Metformin
5 weeks of treatment Ovulation rate of 34 % vs. 4% in placebo No ovulation – Given Clomiphene citrate
– Increased ovulation rate to 90%
Nestler et al, NEJM, 1998
Metformin and Pregnancy
Pregnancy Class B PCOS increases risk of miscarriage
– 30-50% higher
Plaminogen activator inhibitor (PAI)– Causes placental insufficiency– Increases with increased insulin levels
Kosasa, Contemporary OB/Gyn, March 2003
Metformin and Pregnancy
Patients receiving 1.5g to 2.55g per day Decreased rate of miscarriage
– From 73% to 10%
Thought to be related to decrease PAI activity
Glueck et al, Fertil Steril, 2001.
Metformin and Gestational Diabetes
PCOS increases risk of GDM Metformin treatment decreases development
of GDM– From 31% to 3%
Further studies are warranted
Glueck et al, Fertil Steril, 2002.
Ovulation Induction
Clomiphene citrate– Can start at 50mg/day on days 5-9– Up to 150mg/day
Some sources up to 200mg/day in morbidly obese
– Effective in about 85% of women with PCOS– Metformin-CC combination even more effective
90% in small study Further studies ongoing
Stovall, OBG Management, June 2003
Other Induction Agents
Human menopausal gonadotropin Follicle-stimulating hormone Referral to specialist
Fertility NOT Desired
Regulate Cycles– Hormonal Contraception
Oral Pills Patch Ring
– Progesterone withdrawal Every 3 months Monthly
Hormonal Contraception
Reduces gonadotropin stimulation on ovary Reduces androgen production Can help with hirsutism, acne Increase SHBG Use newer progestins
– Desogestrel, Norgestimate
Caution
Hormonal Contraception– Not as effective in morbidly obese– Increased risk of thrombotic event
Hirsutism - Treatment
Reduce Androgens– Weight Loss– Hormonal Contraception– Anti-Androgens
Mechanical Treatment– Shaving– Electrolysis– Laser
Hirsutism
Treatment takes a long time Spironolactone
– Binds to androgen receptor– Blocks 5α-Reductase– 25mg, 50mg,100mg, 200mg divided daily– Side effects
Light-headedness, lethargy, menstrual irregularity, mastodynia
Spironolactone
Use with contraception Theoretical risk of teratogenicity Minimize menstrual irregularity
Spironolactone
Effectiveness– 40-88% reduction in diameter of hair growth– 6-12 months of use
Futterweit, Obs and Gyn Survey, 1999.
Other Antiandrogens
Flutamide– Blocks androgen binding to tissue– Rare fatal hepatotoxicity
Finasteride– 5α-reductase inhibitor– 5mg/day– Don’t use in pregnancy– As effective as Spironolactone
Other treatments of hirsutism
Eflornithine– Topical agent– Slows hair growth– Apply twice a day– Mechanical hair removal is required– Hair will reappear 2 months after stopping tx
Mechanical Treatment
Can be used after medical treatment Laser
– Most success in light skin, dark hair
Electrolysis– Long-term treatments
Long-Term Consequences of PCOS
Endometrial Cancer Coronary Risk
Endometrial Cancer
Most common invasive gyn cancer Risks include
– Unopposed estrogen– Obesity– High androstenedione levels– Risks that are common in PCOS patients
Decreasing Endometrial Risk
Regulate menses Combination hormones Progesterone withdrawal
Coronary Risk
Prediliction to Diabetes Dyslipidemia Obesity
Diabetes Risk
Study of 122 obese women with PCOS Impaired Glucose Tolerance
– 30-40% Type 2 Diabetes
– 10%
Ehrmann, et al., Diabetes Care, 1999.
Diabetes Risk
What screening test?– Fasting Glucose– 75 gram GTT
Risk of Diabetes with PCOS– 254 women with PCOS– 3.2% by fasting glucose alone– 7.5% with GTT
Legro, et al, J Clin Endocrinol Metab, 2002.
Dyslipidemia
Elevated Triglycerides Decreased HDL Increased LDL/HDL ratio
Overall Coronary Risk
Hard to determine Studies have been poorly defined
– Ovarian morphology– Oligomenorrhea
Can be confounded by other known risk factors– Diabetes, Obesity
Long-Term Therapy
Cyclic Estrogen/Progesterone– Reduces risk of endometrial hyperplasia and
cancer
Insulin-sensitizers– Uncertain of long-term benefit– May reduce risk of diabetes
Need further studies
Take Home
Treatment needs to be guided by patient desires and concerns
Lifestyle modification Protect the endometrium