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