Current Concepts in Polycystic Ovarian Syndrome

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Current Concepts inPolycystic Ovarian Syndrome

• Mark N. Simon, MD
• Exempla Uptown Womens
• Healthcare Specialists
• October 17, 2003

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Disclosure

• Dr. Simon has no significant financial interests
  or other relationships with industry relative to
  the subject of this lecture.

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Objectives

• Cite the physical manifestations of PCOS.
• Describe the pathophysiology of PCOS.
• Formulate a treatment plan for patients with PCOS.

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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

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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

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Diagnosis

• Europe
• Morphological features of polycystic ovaries
• Menstrual disturbance AND/OR
• Hyperandrogenism
• Hirsuitism
• Acne
• Alopecia
• Laboratory data are not needed

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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

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European Diagnosis

• Increases prevalence to about 15
• Proposed unifying protocol
• Determine if symptoms are present
• If present, proceed with ultrasound
• If ultrasound positive diagnosis confirmed
• If ultrasound negative check lab tests
• Homberg, Human Reproduction, 2002

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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

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Patient Presentation

• Symptoms of hyperandrogenism
• Irregular menstrual cycles
• Infertility Most Common Presentation

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Symptoms of Hyperandrogenism

• Hirsutism
• Acne
• Rarely see Virilization
• Male pattern balding
• Clitoromegaly
• Deepening of voice
• Increased muscle mass

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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

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Hirsutism - DDx

• Idiopathic
• PCOS
• Drugs (Danazol)
• Hyperthecosis
• Ovarian Tumors
• Adrenal Tumors
• CAH

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Ovarian Hyperthecosis

• Ovary has nests of luteinized theca cells
• Signs and Symptoms
• Hirsutism, Alopecia, Obesity
• HTN
• Clitoromegaly
• Markedly elevated testosterone

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Red Flags with Hirsutism

• Rapid onset of hirsutism
• Rapid progression of hirsutism
• Late onset
• Outside of early reproductive years
• Virilization

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Tumors

• RED FLAGS
• Testosterone gt 150ng/dL (gt 200ng/dL)
• LH low
• DHES gt 800mcg/dL
• Further investigation warranted
• MRI abdomen/pelvis

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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

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Nonclassic Congenital Adrenal Hyperplasia

• Consider in patients not responding to typical
  PCOS treatment
• Measure 17-hydroxyprogesterone
• Follicular phase
• Morning
• Levels gt 2 ng/mL need to be tested further
• Adrenal stimulation

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Acne

• Common in adolescent girls (30-50)
• Severe acne is uncommon (lt1)
• Severe acne is a predictor of PCOS

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Irregular Menses

• Most common to have erratic menses
• Due to Anovulation
• Patients present with oligomenorrhea or amenorrhea

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PCOS with Regular Menses?

• Androgens converted to estrogens
• Peripheral conversion
• Aromatase
• Estrogens stimulate uterine lining
• Can have regular shedding of endometrial lining
  despite anovulation

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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

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Infertility

• Usually long-standing infertility
• PCOS typically develops in early reproductive
  years
• Infertility usually due to anovulation

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Clinical Presentations

• Hyperandrogenism
• Hirsutism
• Acne
• Menstrual Irregularity
• Infertility

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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

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What tests to order

• Prolactin
• Rule out hyperprolactinemia
• Cause of menstrual dysfunction
• Little signs of hyperandrogenism
• Lactotroph stimulation from estrogen
• Testosterone
• DHEAS

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Laboratory Tests

• 17-Hydroxyprogesterone
• In patients suspected of NCAH
• TSH
• When symptoms warrant
• Glucose Tolerance Test
• Fasting Lipid Profile

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Laboratory Tests

• LH, FSH
• Little benefit
• Insulin

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Pathophysiology

• Exact problems have not been identified
• Hypothalamic-pituitary abnormalities
• Elevated LH
• Increased frequency and amplitude of pulses
• Low-normal FSH
• LHFSH ratio increased
• GnRH pulse generator may be disrupted causing the
  elevated LH

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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

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Hyperandrogenism
LH
FSH

Ovary
-
Testosterone
Androstenedione
-
Estradiol
SHBG
Estrone
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Insulin Resistance

• Feature of PCOS
• Both obese and lean women are affected
• Affects a number of systems
• Reduction in tissue response to insulin

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Insulin Resistance

• Insulin causes androgen production
• In women with PCOS
• Insulin
• Amplifies LH response in granulosa cells
• Arrest of follicular development

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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

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Insulin
Insulin

-
Peripheral Glucose Uptake
Glycogenolysis
-
Gluconeogenesis
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Insulin Resistance
Insulin
Granulosa Cells

Ovarian Androgen Secretion
Anovulation
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Summary of Pathophysiology

• Elevated LH
• Leads to elevated Androgens
• Hyperandrogen symptoms
• Insulin Resistance

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Treatment

• Depends on symptoms
• Depends on patients goals

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Lifestyle Modification

• Exercise
• 150 minutes per week
• Moderate exertion
• Diet
• Weight Loss
• Most effective with obese patients

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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.

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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)

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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

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Metformin

• Lactic Acidosis
• Severe, potentially fatal
• Concern with elevated creatinine (gt1.4 mg/dL)
• Contraindicated in
• CHF, Sepsis, Liver disease, history of lactic
  acidosis
• Surgery

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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)

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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

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Treatment Algorithms

• Path depends primarily on fertility desires
• Also depends on primary symptoms of patient

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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.

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Weight Loss

• Modest weight loss (5) can help
• Lower androgen levels
• Induce regular cycles
• Other health benefits for pregnancy
• Diabetes
• Hypertension

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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

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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

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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.

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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.

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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

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Other Induction Agents

• Human menopausal gonadotropin
• Follicle-stimulating hormone
• Referral to specialist

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Fertility NOT Desired

• Regulate Cycles
• Hormonal Contraception
• Oral Pills
• Patch
• Ring
• Progesterone withdrawal
• Every 3 months
• Monthly

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Hormonal Contraception

• Reduces gonadotropin stimulation on ovary
• Reduces androgen production
• Can help with hirsutism, acne
• Increase SHBG
• Use newer progestins
• Desogestrel, Norgestimate

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Caution

• Hormonal Contraception
• Not as effective in morbidly obese
• Increased risk of thrombotic event

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Hirsutism - Treatment

• Reduce Androgens
• Weight Loss
• Hormonal Contraception
• Anti-Androgens
• Mechanical Treatment
• Shaving
• Electrolysis
• Laser

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Hirsutism

• Treatment takes a long time
• Spironolactone
• Binds to androgen receptor
• Blocks 5a-Reductase
• 25mg, 50mg,100mg, 200mg divided daily
• Side effects
• Light-headedness, lethargy, menstrual
  irregularity, mastodynia

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Spironolactone

• Use with contraception
• Theoretical risk of teratogenicity
• Minimize menstrual irregularity

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Spironolactone

• Effectiveness
• 40-88 reduction in diameter of hair growth
• 6-12 months of use
• Futterweit, Obs and Gyn Survey, 1999.

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Other Antiandrogens

• Flutamide
• Blocks androgen binding to tissue
• Rare fatal hepatotoxicity
• Finasteride
• 5a-reductase inhibitor
• 5mg/day
• Dont use in pregnancy
• As effective as Spironolactone

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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

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Mechanical Treatment

• Can be used after medical treatment
• Laser
• Most success in light skin, dark hair
• Electrolysis
• Long-term treatments

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Long-Term Consequences of PCOS

• Endometrial Cancer
• Coronary Risk

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Endometrial Cancer

• Most common invasive gyn cancer
• Risks include
• Unopposed estrogen
• Obesity
• High androstenedione levels
• Risks that are common in PCOS patients

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Decreasing Endometrial Risk

• Regulate menses
• Combination hormones
• Progesterone withdrawal

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Coronary Risk

• Prediliction to Diabetes
• Dyslipidemia
• Obesity

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Diabetes Risk

• Study of 122 obese women with PCOS
• Impaired Glucose Tolerance
• 30-40
• Type 2 Diabetes
• 10
• Ehrmann, et al., Diabetes Care, 1999.

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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.

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Dyslipidemia

• Elevated Triglycerides
• Decreased HDL
• Increased LDL/HDL ratio

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Overall Coronary Risk

• Hard to determine
• Studies have been poorly defined
• Ovarian morphology
• Oligomenorrhea
• Can be confounded by other known risk factors
• Diabetes, Obesity

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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

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Take Home

• Treatment needs to be guided by patient desires
  and concerns
• Lifestyle modification
• Protect the endometrium