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Current Concepts in Polycystic Ovarian Syndrome

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Title: Current Concepts in Polycystic Ovarian Syndrome


1
Current Concepts inPolycystic Ovarian Syndrome
  • Mark N. Simon, MD
  • Exempla Uptown Womens
  • Healthcare Specialists
  • October 17, 2003

2
Disclosure
  • Dr. Simon has no significant financial interests
    or other relationships with industry relative to
    the subject of this lecture.

3
Objectives
  • Cite the physical manifestations of PCOS.
  • Describe the pathophysiology of PCOS.
  • Formulate a treatment plan for patients with PCOS.

4
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

5
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

6
Diagnosis
  • Europe
  • Morphological features of polycystic ovaries
  • Menstrual disturbance AND/OR
  • Hyperandrogenism
  • Hirsuitism
  • Acne
  • Alopecia
  • Laboratory data are not needed

7
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

8
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

9
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

10
Patient Presentation
  • Symptoms of hyperandrogenism
  • Irregular menstrual cycles
  • Infertility Most Common Presentation

11
Symptoms of Hyperandrogenism
  • Hirsutism
  • Acne
  • Rarely see Virilization
  • Male pattern balding
  • Clitoromegaly
  • Deepening of voice
  • Increased muscle mass

12
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

13
Hirsutism - DDx
  • Idiopathic
  • PCOS
  • Drugs (Danazol)
  • Hyperthecosis
  • Ovarian Tumors
  • Adrenal Tumors
  • CAH

14
Ovarian Hyperthecosis
  • Ovary has nests of luteinized theca cells
  • Signs and Symptoms
  • Hirsutism, Alopecia, Obesity
  • HTN
  • Clitoromegaly
  • Markedly elevated testosterone

15
Red Flags with Hirsutism
  • Rapid onset of hirsutism
  • Rapid progression of hirsutism
  • Late onset
  • Outside of early reproductive years
  • Virilization

16
Tumors
  • RED FLAGS
  • Testosterone gt 150ng/dL (gt 200ng/dL)
  • LH low
  • DHES gt 800mcg/dL
  • Further investigation warranted
  • MRI abdomen/pelvis

17
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

18
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

19
Acne
  • Common in adolescent girls (30-50)
  • Severe acne is uncommon (lt1)
  • Severe acne is a predictor of PCOS

20
Irregular Menses
  • Most common to have erratic menses
  • Due to Anovulation
  • Patients present with oligomenorrhea or amenorrhea

21
PCOS with Regular Menses?
  • Androgens converted to estrogens
  • Peripheral conversion
  • Aromatase
  • Estrogens stimulate uterine lining
  • Can have regular shedding of endometrial lining
    despite anovulation

22
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

23
Infertility
  • Usually long-standing infertility
  • PCOS typically develops in early reproductive
    years
  • Infertility usually due to anovulation

24
Clinical Presentations
  • Hyperandrogenism
  • Hirsutism
  • Acne
  • Menstrual Irregularity
  • Infertility

25
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

26
What tests to order
  • Prolactin
  • Rule out hyperprolactinemia
  • Cause of menstrual dysfunction
  • Little signs of hyperandrogenism
  • Lactotroph stimulation from estrogen
  • Testosterone
  • DHEAS

27
Laboratory Tests
  • 17-Hydroxyprogesterone
  • In patients suspected of NCAH
  • TSH
  • When symptoms warrant
  • Glucose Tolerance Test
  • Fasting Lipid Profile

28
Laboratory Tests
  • LH, FSH
  • Little benefit
  • Insulin

29
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

30
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

31
Hyperandrogenism
LH
FSH

Ovary
-
Testosterone
Androstenedione
-
Estradiol
SHBG
Estrone
32
Insulin Resistance
  • Feature of PCOS
  • Both obese and lean women are affected
  • Affects a number of systems
  • Reduction in tissue response to insulin

33
Insulin Resistance
  • Insulin causes androgen production
  • In women with PCOS
  • Insulin
  • Amplifies LH response in granulosa cells
  • Arrest of follicular development

34
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

35
Insulin
Insulin

-
Peripheral Glucose Uptake
Glycogenolysis
-
Gluconeogenesis
36
Insulin Resistance
Insulin
Granulosa Cells

Ovarian Androgen Secretion
Anovulation
37
Summary of Pathophysiology
  • Elevated LH
  • Leads to elevated Androgens
  • Hyperandrogen symptoms
  • Insulin Resistance

38
Treatment
  • Depends on symptoms
  • Depends on patients goals

39
Lifestyle Modification
  • Exercise
  • 150 minutes per week
  • Moderate exertion
  • Diet
  • Weight Loss
  • Most effective with obese patients

40
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.

41
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)

42
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

43
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

44
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)

45
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

46
Treatment Algorithms
  • Path depends primarily on fertility desires
  • Also depends on primary symptoms of patient

47
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.

48
Weight Loss
  • Modest weight loss (5) can help
  • Lower androgen levels
  • Induce regular cycles
  • Other health benefits for pregnancy
  • Diabetes
  • Hypertension

49
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

50
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

51
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.

52
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.

53
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

54
Other Induction Agents
  • Human menopausal gonadotropin
  • Follicle-stimulating hormone
  • Referral to specialist

55
Fertility NOT Desired
  • Regulate Cycles
  • Hormonal Contraception
  • Oral Pills
  • Patch
  • Ring
  • Progesterone withdrawal
  • Every 3 months
  • Monthly

56
Hormonal Contraception
  • Reduces gonadotropin stimulation on ovary
  • Reduces androgen production
  • Can help with hirsutism, acne
  • Increase SHBG
  • Use newer progestins
  • Desogestrel, Norgestimate

57
Caution
  • Hormonal Contraception
  • Not as effective in morbidly obese
  • Increased risk of thrombotic event

58
Hirsutism - Treatment
  • Reduce Androgens
  • Weight Loss
  • Hormonal Contraception
  • Anti-Androgens
  • Mechanical Treatment
  • Shaving
  • Electrolysis
  • Laser

59
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

60
Spironolactone
  • Use with contraception
  • Theoretical risk of teratogenicity
  • Minimize menstrual irregularity

61
Spironolactone
  • Effectiveness
  • 40-88 reduction in diameter of hair growth
  • 6-12 months of use
  • Futterweit, Obs and Gyn Survey, 1999.

62
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

63
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

64
Mechanical Treatment
  • Can be used after medical treatment
  • Laser
  • Most success in light skin, dark hair
  • Electrolysis
  • Long-term treatments

65
Long-Term Consequences of PCOS
  • Endometrial Cancer
  • Coronary Risk

66
Endometrial Cancer
  • Most common invasive gyn cancer
  • Risks include
  • Unopposed estrogen
  • Obesity
  • High androstenedione levels
  • Risks that are common in PCOS patients

67
Decreasing Endometrial Risk
  • Regulate menses
  • Combination hormones
  • Progesterone withdrawal

68
Coronary Risk
  • Prediliction to Diabetes
  • Dyslipidemia
  • Obesity

69
Diabetes Risk
  • Study of 122 obese women with PCOS
  • Impaired Glucose Tolerance
  • 30-40
  • Type 2 Diabetes
  • 10
  • Ehrmann, et al., Diabetes Care, 1999.

70
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.

71
Dyslipidemia
  • Elevated Triglycerides
  • Decreased HDL
  • Increased LDL/HDL ratio

72
Overall Coronary Risk
  • Hard to determine
  • Studies have been poorly defined
  • Ovarian morphology
  • Oligomenorrhea
  • Can be confounded by other known risk factors
  • Diabetes, Obesity

73
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

74
Take Home
  • Treatment needs to be guided by patient desires
    and concerns
  • Lifestyle modification
  • Protect the endometrium
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