Body Owner’s Guide to diagnosis and therapy of Polycystic Ovarian Syndrome (PCOS)

Charles J. Glueck MD, Naila Goldenberg MD, Jewish Hospital Cholesterol Center.
11/22/10

Polycystic Ovarian Syndrome (PCOS) is the most common endocrine disorder seen in women. It affects 6-8% of Caucasian, 8-10% of African Americans, and >10% of Hispanics.

Polycystic ovary syndrome (PCOS) is defined most commonly according to the expert conference held in Rotterdam in May 2003, after the exclusion of related disorders (Congenital Adrenal Hyperplasia, Cushing’s syndrome, Hyperprolactenemia, Androgen secreting neoplasms, and other pituitary or adrenal disorders), by two of the following three features:

1. oligo- or anovulation
2. clinical and/or biochemical signs of hyperandrogenism, or
3. polycystic ovaries

What are the common signs and symptoms of PCOS?
 

Oligomenorrhea/ amenorrhea	Menstrual periods less than seven per year)
Infertility	Inability to conceive after one year of trying; is often associated with chronic anovulation (lack of ovulation).
Hirsutism	Excessive hair growth pattern, is often associated with hyperandrogenism.
Clinical signs of hyperandrogenism	Excessive hair growth pattern noticed in different parts of body: Upper lip (moustache), Chin Chest (around the nipples, midline hair) Upper/lower back Upper/lower abdomen (commonly a line of hair from the umbilicus to the pelvis) Arm Forearm Thigh Leg- requires shaving daily Acne – scaly skin, blackheads/whiteheads/ pinheads, pimples and scars
Biochemical hyperandrogenism	Elevated androstenedione Elevated total and free testosterone Elevated dehydroepiandrosterone-sulfate (DHEA-S). Abnormal LH/FSH ratio Low sex hormone binding globulin (SHBG)
Other Clinical tip-offs to diagnosis	Premature Pubarche- breast buds , pubic hair starting as early as 6-8 years old  Premature Adrenarche- appearance of pubic hair as early as 6-8 years old History of prematurity History of small for gestational age Acanthosis Nigricans- brown to black, poorly defined, velvety hyperpigmentation of the skin around the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas. Explosive weight gain >20 lbs  over an 8 month period Weight gain marked around the belt-line

Health ramifications of PCOS:
 

Adolescence	Obesity Hirsutism Acne Oligomenorrhea/Amenorhea Acanthosis Nigricans Miscarriages Infertility
Young Adult	All of the above Infertility Anovulation Gestational diabetes Type II diabetes
Adults	All of the above Increased coronary heart disease Increased Ischemic (thrombotic) stroke

Lab Tests for the Evaluation of PCOS:
 

Lab Tests	Functions/Associations	Typical in untreated PCOS
Total and free testosterone Androstenedione DHEAS	Excess body hair excess weight	High Increase body hair Inhibits pituatary Acne
PAI-Fx (Plasminogen Activator Inhibitor activity)	Inhibitors of fibrinolysis (chop up blood clots)	High increase clots
Cortisol	Adrenal function	Normal
Creatinine (Kidney function test)	Kidney function	Normal
E2 (Estradiol)	Ovary is not normally stimulated by pituatary to produce this hormone Excess body hair excess weight	often low Rises during luteal phase of the menstrual cycle
FSH (Follicle stimulating hormone)	Regulates ovarian function	Often >2.5 during follicular phase (cycle day 4-6) or during amenorhea
LH (leutinizing hormone)	regulates ovarian function	often higher during follicular phase or during amenorhea
HCG (Human Chorionic Gonadotrophin)	Test for pregnancy
Gluco (Glucose)	Test for diabetes	Often high
HbA1C (Hemoglobin A1 C)	Test for diabetes	Often high
Insulin C-peptide		Most but not all are insulin resistant Fasting insulin and C-peptide levels are high
HDL (High Density Lipoprotein- H for happy/good cholesterol )	reduces risk of heart attack and stroke	Often low
LDL (L for lousy/bad cholesterol	increases risk of heart attack and stroke	often high (>130)
Lp (a) – cousin of LDL	increases risk of heart attack and stroke	Does not appear to be related to PCOS
LA (lactic acid)	Very rarely may rise if taking metformin Extreme fatigue is a symptom of lactic acidosis	We will contact you if we are concerned or vice versa
PAI-G (Plasminogen Activator Inhibitor gene: may control PAI-Fx and insulin reistance to a large degree)	5G5G normal 4G5G heterozygous 4G4G homozygous	most PCOS are 4G4G (associated with high PAI Fx and insulin resistance) or 4G5G 4G4G is associated with miscarriages
Progest (progesterone)	ovary is not normally stimulated by pituatary to produce this hormone	usually low during luteal phase: rises to >2.3 if ovulation occurs
Prolactin	testing for galactorrhea; cause symptoms like PCOS	very rare
SHBG (sex hormone binding protein)	affected in PCOS	low; rises when treated
WT	weight gain in symtoms	on metformin, most loose weight
T (Testosterone)	causes body hair excess weight	high inhibits pituatary
TC (Total Cholesterol)		elevated
TG (Triglyceride)		elevated
T Free (free testosterone)	Causes body hair Excess weight	high, inhibits pituatary
T sat. (% of free testosterone)	Causes body hair Excess weight	high, inhibits pituatary
LH/FSH ratio	Affected in PCOS	Usually normal 1:1 ratio  in premenopausal women  Ratio of greater than 2:1 or 3:1 is  considered diagnostic for PCOS

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What are the treatment options:

1. Regular exercise and maintaining a healthy weight will help reduce the hormonal imbalance, restore ovulation and fertility, and improve acne and hirsutism.
2. Low Carbohydrate diets- obtain carbohydrates from whole grain sources and also fruit and vegetables
3. Medications- Glucophage or newer thiazolinedione(glitazones)
4. Infertility- combination of diet modification, weight loss, and treatment with metformin and clomiphene citrate or assisted reassisted reproductive technology procedures such as controlled ovarian hyperstimulation with FSH injections and in vitro fertilisation (IVF)
5. Hirsutism and acne-cyproterone acetate, flutamide, or spironolactone
6. Menstrual irregularity and endometrial hyperplasia- uterine progesterone  such as as the intrauterine system (Mirena) or the progestin implant (Implanon), which provides simultaneous contraception and endometrial protection for years
7. Glucophage throughout pregnancy has been shown to reduce otherwise high levels of miscarriage (>40%) to much lower levels, which approximate normal pregnancies (~15%).
8. Glucophage throughout pregnancy reduces the development of gestational diabetes from ~40% to 4% (the level in normal pregnancies).
9. Glucophage throughout pregnancy reduces fetal macrosomia (birth weight >4500 grams), and shoulder distocia (dislocation of the shoulder when baby is too big to fit through the pelvic canal.
10.  Glucophage thoughout pregnancy is not teratogenic, and followup of infants born to mothers who took glucophage during pregnancy has shown normal growth, development, and normal development of motor, social, and intellectural growth.
11. Glucophage has been shown to be safe during lactation.

 

	Insulin Sensitizers: Glucophage 750-850 mg TID Glumetza 2.5 g QD Fortamet 2.5 mg QD Actos 45 mg QD	E-P oral contraceptives	Spironolactone
Reduces hirsutism	Yes	Yes	Yes
Reduces acne	Yes	Yes	Yes
Reduces androgen	Yes	Yes	No
Reduces weight	Yes	No! Increase weight	No
Induces normal ovulation	>80% of women	Drug driven menses >90%	No
Facilates pregnancy	Yes	No	NO, contraindicated
Safe during pregnancy	Yes	No	NO, contraindicated
Safe during lactation	Yes	No	NO, contraindicated

Bibliography:

1. Metformin-diet ameliorates coronary heart disease risk factors and facilitates resumption of regular menses in adolescents with polycystic ovary syndrome.
   Glueck CJ, Goldenberg N, Wang P. J Pediatr Endocrinol Metab. 2009 Sep;22(9):815-26.
2. Coronary heart disease risk factors in adult premenopausal white women with polycystic ovary syndrome compared with a healthy female population. Glueck CJ, Morrison JA, Goldenberg N, Wang P. Metabolism. 2009 May;58(5):714-21.
3. Insulin resistance, obesity, hypofibrinolysis, hyperandrogenism, and coronary heart disease risk factors in 25 pre-perimenarchal girls age < or =14 years, 13 with precocious puberty, 23 with a first-degree relative with polycystic ovary syndrome. Glueck CJ, Morrison JA, Wang P. J Pediatr Endocrinol Metab. 2008 Oct;21(10):973-84.
4. Enoxaparin-metformin and enoxaparin alone may safely reduce pregnancy loss. Ramidi G, Khan N, Glueck CJ, Wang P, Goldenberg N. Transl Res. 2009 Jan;153(1):33-43. Epub 2008 Dec 4.
5. An observational study of reduction of insulin resistance and prevention of development of type 2 diabetes mellitus in women with polycystic ovary syndrome treated with metformin and diet. Glueck CJ, Goldenberg N, Sieve L,
   Wang P. Metabolism. 2008 Jul;57(7):954-60.
6. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation.  Goldenberg N, Glueck C. Minerva Ginecol. 2008 Feb;60(1):63-75. Review.
7. Prevention of gestational diabetes by metformin plus diet in patients with polycystic ovary syndrome. Glueck CJ, Pranikoff J, Aregawi D, Wang P. Fertil Steril. 2008 Mar;89(3):625-34. Epub 2007 Aug 6. 9.
8. Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia. Glueck CJ, Golnik KC, Aregawi D, Goldenberg N, Sieve L, Wang P. Transl Res. 2006 Nov;148(5):215-22.
9. Metformin-diet ameliorates coronary heart disease risk factors and facilitates resumption of regular menses in adolescents with polycystic ovary syndrome.
   Glueck CJ, Aregawi D, Winiarska M, Agloria M, Luo G, Sieve L, Wang P.
   J Pediatr Endocrinol Metab. 2006 Jun;19(6):831-42.
10. Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome. Glueck CJ, Salehi M, Sieve L, Wang P. J Pediatr. 2006 May;148(5):628-632.
11. Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents. Glueck CJ, Morrison JA, Friedman LA, Goldenberg N, Stroop DM, Wang P. Metabolism. 2006 Apr;55(4):508-14.
12. Plasminogen activator inhibitor activity, 4G5G polymorphism of the plasminogen activator inhibitor 1 gene, and first-trimester miscarriage in women with polycystic ovary syndrome. Glueck CJ, Sieve L, Zhu B, Wang P. Metabolism. 2006 Mar;55(3):345-52.
13. Obesity and extreme obesity, manifest by ages 20-24 years, continuing through 32-41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy. Glueck CJ, Dharashivkar S, Wang P, Zhu B, Gartside PS, Tracy T, Sieve L. Eur J Obstet Gynecol Reprod Biol. 2005 Oct 1;122(2):206-12.
14. Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia. Glueck CJ, Aregawi D, Goldenberg N, Golnik KC, Sieve L, Wang P. J Lab Clin Med. 2005 Feb;145(2):72-82.
15. Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance. Goldenberg N, Glueck CJ, Loftspring M, Sherman A, Wang P. Metabolism. 2005 Jan;54(1):113-21.
16. Pregnancy loss, polycystic ovary syndrome, thrombophilia, hypofibrinolysis, enoxaparin, metformin. Glueck CJ, Wang P, Goldenberg N, Sieve L. Clin Appl Thromb Hemost. 2004 Oct;10(4):323-34.
17. Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome. Glueck CJ, Bornovali S, Pranikoff J, Goldenberg N, Dharashivkar S, Wang P. Diabet Med. 2004 Aug;21(8):829-36.
18. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Hum Reprod. 2004 Jun;19(6):1323-30. Epub 2004 Apr 29.
19. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A. Hum Reprod. 2004 Mar;19(3):510-21. Epub 2004 Jan 29.
20. Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss. Glueck CJ, Wang P, Bornovali S, Goldenberg N, Sieve L. Metabolism. 2003 Dec;52(12):1627-32.
21. Idiopathic intracranial hypertension: associations with coagulation disorders and polycystic-ovary syndrome. Glueck CJ, Iyengar S, Goldenberg N, Smith LS, Wang P. J Lab Clin Med. 2003 Jul;142(1):35-45.
22. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang P. Hum Reprod. 2003 Aug;18(8):1618-25.
23. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Glueck CJ, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Metabolism. 2003 Jul;52(7):908-15.
24. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Hum Reprod. 2002 Nov;17(11):2858-64.
25. Treatment of polycystic ovary syndrome with insulin-lowering agents.
    Glueck CJ, Streicher P, Wang P. Expert Opin Pharmacother. 2002 Aug;3(8):1177-89.
26. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Fertil Steril. 2002 Mar;77(3):520-5.
27. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. J Adolesc Health. 2001 Sep;29(3):160-9.
28. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Fertil Steril. 2001 Jan;75(1):46-52.
29. Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage.
    Glueck CJ, Awadalla SG, Phillips H, Cameron D, Wang P, Fontaine RN.
    Fertil Steril. 2000 Aug;74(2):394-7.
30. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome.
    Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Tracy T, Moore SK.
    Metabolism. 1999 Dec;48(12):1589-95.
31. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metabolism. 1999 Apr;48(4):511-9.
32. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metabolism. 1997 Apr;46(4):454-7.
33. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metabolism. 1994 May;43(5):647-54.
34. Metformin before and during pregnancy and lactation in polycystic ovary syndrome. Glueck CJ, Wang P. Expert Opin Drug Saf. 2007 Mar;6(2):191-8. Review.
35. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053. Review.
36. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003053. Review. Update in: Cochrane Database Syst Rev. 2010;(1):CD003053.
37. Consensus on infertility treatment related to polycystic ovary syndrome.
    Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
    Hum Reprod. 2008 Mar;23(3):462-77. Erratum in: Hum Reprod. 2008 Jun;23(6):1474.
38. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation. Goldenberg N, Glueck C. Minerva Ginecol. 2008 Feb;60(1):63-75. Review.
39. How should we manage atherogenic dyslipidemia in women with polycystic ovary syndrome? Rizzo M, Berneis K, Carmina E, Rini GB.
    Am J Obstet Gynecol. 2008 Jan;198(1):28.e1-5. Review.
40. Oral antidiabetic agents in pregnancy and lactation: a paradigm shift?
    Feig DS, Briggs GG, Koren G. Ann Pharmacother. 2007 Jul;41(7):1174-80. Epub 2007 May 29. Review.
41. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005552. Review.
42. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Lord JM, Flight IH, Norman RJ. Cochrane Database Syst Rev. 2003;(3):CD003053. Review. Update in: Cochrane Database Syst Rev. 2009;(3):CD003053.