Polycystic Ovarian Syndrome (PCOS):
Paul A. Berez, M.D.
Polycystic ovarian syndrome (PCOS) is defined by the presence of ovulatory dysfunction and either clinical hyperandrogenism (called hirsutism) or hyperandrogenemia, along with the exclusion of known disorders which can mimic PCOS (10).In more detail, the criteria are as follows:
1. Ovulatory dysfunction means 8 or fewer menstrual cycles in a year, or cycles less than 26 days or more than 35 days in length, or a cycle day 22-24 progesterone level of less than 4ng/ml (indicating anovulation) in subjects with cycles of 26-35 days in length.
2. Clinical hirsutism is assessed using the modified Ferriman-Gallwey (mF-G) method, which scores the presence of terminal hairs over nine body areas (upper lip, chin, chest, upper and lower abdomen, thighs, upper and lower back and upper arms) each with a score of 0-4, then added up-scores greater than or equal to 6 are positive (11).Inappropriately severe acne may also be evidence for hyperandrogenism.
3. Hyperandrogenemia is defined as total testosterone=84.7ng/dl or greater, or free testosterone= 0.75ng/dl or greater, or androstenedione=2496pg/ml or greater, or DHEAS=2459 ng/ml or greater, in patients not on hormonal therapy.
4. Any patient with elevated androgen levels as defined above has to have both 17-hydroxyprogesterone level to look for 21-OH)-deficient NCAH which occurs in about 2% of cases (12)-17-HP levels > 2ng/ml need further evaluation by an Endocrinologist for an hyperadrenal syndrome.Prolactin level also needs to be drawn in hyperandrogenemia..Both of these conditions can cause a PCOS-like picture.
Insulin resistance is generally considered to be an essential component in the pathogenesis of (PCOS) (1,2,3).The insulin resistance may have arose from lifestyle choices (i.e. overeating/underexercising), or from polymorphisms (genetic defects) coding forproteins involved in the insulin receptor or postreceptor insulin signaling (3,4,5).It has been postulated that the hyperinsulinemia associated with insulin resistance partly augments LH-stimulated androgen secretion from the ovary, and to decrease sex hormone binding globulin (SHBG) which increases free testosterone levels (3,6).Insulin has two modes of action: working through the PI kinase cascade to result in glucose entering the cell, and working through MAP kinase which encourages mitosis (cellular proliferation).It has been established that there are 2 isoforms of insulin receptors: IR isoform A which works on the promitotic pathway and predominates in CNS, hemopoietic, fetal tissues, some tumors, and ovaries, and IR isoform B, which works on the glucose metabolism pathway, and predominates in muscle, liver and adipose tissues (7).There is strong evidence supporting the role of insulin in combination with FSH and LH to accelerate granulosa cell differentiation and proliferation, which would result in typical polycystic ovaries (8,9).
There are 2 strategies in treating PCOS with medicine:
1. Treat the hyperandrogenism and imbalance between estrogens and androgens with a combination of estrogen such as ethinyl estradiol (usual dose 30 ug qd) plus an anti androgen such as spironolactone (usual dose 100 mg/day in mild to 200mg qd in severe) or the newer drospirenone 3mg qd (available only as Yasmin mixed with the above dose of ethinyl estradiol).
2.Go after the underlying insulin resistance with metformin and/or a thiazolidinedione (TZD, i.e. Actos or Avandia).Both approaches work, but of course I feel more comfortable treating the insulin resistance.Neither approach is FDA-approved.Obviously, diet and exercise are always critical parts of the treatment plan.Important considerations include whether the patient is trying to conceive-hormonal therapy blocks ovulation, while metformin is pregnancy category B and TZD's are both category C, and the later needs to be stopped immediately if pregnancy is suspected or discovered-patients need to be followed very carefully regarding pregnancy since both metformin and TZD's favor increased ovulation (2).In a head-to-head trial between spirololactone and metformin in 82 adolescent and young women with PCOS, hirsutism and menstrual cycle frequency were better with spirololacone, while insulin sensitivity was better with metformin-however, both medications improved all perameters (3). A review of the use of insulin sensitizing agents in PCOS is available (2).
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2. De Leo, V, et. al.:Insulin-lowering agents in the management of polycystic ovary syndrome.Endocr Rev 24:633-667, 2003
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4. Jose, L.et.al.: Association of the Polycystic Ovary Syndrome with Genomic Variants Related to Insulin Resistance, Type 2 Diabetes Mellitus, and Obesity. J Clin Endocrinol Metab 89: 2640-2646, 2004
5. Alcoser, S. et.al.: Association of the (AU)AT-Rich Element Polymorphism in PPP1R3 with Hormonal and Metabolic Features of Polycystic Ovary Syndrome.J Clin Endocrinol Metab 89: 2973-2976, 2004
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8. Willis, D. et.al.:Modulation by Insulin of Follicle-Stimulating Hormone and Luteinizing Hormone Actions in Human Granulosa Cells of Normal and Polycystic Ovaries. J Clin Endocrinol Metab 81:302-309, 1996
9. Willis, D., et.al.: Insulin Action in Human Granulosa Cells from Normal and Polycystic Ovaries is Mediated by the Insulin Receptor and the type1 Insulin-Like Growth Factor Receptor.J Clin Endocrinol Metab 80:3788-3790, 1995
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11. Hatch, R, et.al.:Hirsutism: Implications, Etiology, and Management.Am J Obstet Gynecol 140: 815-830, 1981
12. Azziz, R., et.al.:Androgen Excess in Women: Experience with Over 1000 Consecutive Patients.J Clin Endocrinol Metab 89: 453-462, 2004