CREATING A PCOS TREATMENT PLAN Ricardo Azziz, M.D., M.P.H., M.B.A. Georgia Regents University
PCOS: CREATING A TREATMENT PLAN Good treatment plans are based on sound and complete evaluations History of the disorder Evaluation history Treatment history Past medical/surgical history Family history Physical exam TV U/S Laboratory
EVALUATING PATIENTS WITH POSSIBLE PCOS Who should be assessed for possible PCOS? Data suggests two major features may be sufficient to identify PCOS Signs & complaints consistent with clinical hyperandrogenism (alopecia, persistent acne, and excess male-like terminal hair growth History & complaints suggestive of ovulatory dysfunction (polymenorrhea, and oligo-amonerrhea)
EVALUATION OF THE HYPERANDROGENIC/HIRSUTE PATIENT HISTORY: Drugs/skin irritants/menses/ onset and progression/ change in weight/ change in head or extremity size/ family PHYSICAL: Hair pattern and type/ galactorrhea/ acanthosis/ cushingoid features/ clitoromegaly or virilization/ regional distribution of obesity
THE FAMILY HISTORY: A POWERFUL PREDICTOR OF PCOS Mothers Sisters Total No. 78 50 PCOS 19 (24%) 16 (32%) Hirsutism only 5 (6%) 1 (2%) Oligomenorrhea 8 (10%) 6 (12%) Kahsar-Miller & Azziz. Fertil Steril 2001;75:53-8
DIFFERENTIAL DIAGNOSIS AMONG 873 CONSECUTIVE UNTREATED PATIENTS EVALUATED FOR ANDROGEN EXCESS Azziz et al. J Clin Endocrinol Metab 89:453-62, 2004
EVALUATING PATIENTS WITH POSSIBLE PCOS What criteria for PCOS to use? Currently there are three sets in use 1. National Institute of Health (NIH)1990 criteria 2. ESHRE/ASRM, also called Rotterdam, 2003 criteria 3. Androgen Excess & PCOS Society (AE-PCOS) 2006 criteria
COMPARING THE PHENOTYPES OF PCOS BY NIH 1990, ROTTERDAM 2003, AND AE-PCOS 2006 Phenotypes Characteristics A B C D Hirsutism/HA Ovulatory Dysfunction Polycystic ovaries NIH 1990* Rotterdam 2003* AE-PCOS 2006* *Always exclude related/similar/mimicking disorders (17-HP, TSH, Prl)
EVALUATING FOR CLINICAL HYPERANDROGENISM: THE MODIFIED F-G (mfg) SCORE Yildiz et al, Hum Reprod Update 2010;16:51 64
EVALUATING FOR CLINICAL HYPERANDROGENISM: THE MODIFIED F-G (mfg) SCORE Yildiz et al, Hum Reprod Update 2010;16:51 64
LABORATORY EVALUATION OF THE HIRSUTE OR POTENTIALLY HYPERANDROGENIC PATIENT To exclude associated/similar/mimicking disorders: TSH & PRL In oligo-ovulatory patients, to R/O other causes of ovulatory dysfunction 17-HP In hyperandrogenic/oligo-ovulatory patients, to R/O 21-OH deficient NCAH To include anovulation in eumenorrheic hyperandrogenic patients d. 22-24 P4 level In hirsute eumenorrheic women, 40% of which are anovulatory To include biochemical hyperandrogenism Total & free T, and DHS Most important in evaluating non-hirsute or minimally hirsute patients MUST USE HIGH-QUALITY WELL-REFERENCED ASSAY
METABOLIC EVALUATION OF THE PATIENT DIAGNOSED WITH PCOS Fasting Glucose To R/O Type 2 DM (1997 ADA criteria) Fasting Insulin To R/O hyperinsulinemia Hgb A1c (or Glycosylated Hgb) To R/O Type 2 DM 2-3 hr. ogtt for Insulin & Glucose To R/O GIT & Type 2 DM (1985 WHO), and hyperinsulinemia
PREDICTIVE VALUE OF A FASTING GLUCOSE VALUE ON OGTT STATUS 110 mg/dl 126 mg/dl Legro et al. J Clin Endocrinol Metab 1999;84:165-9
DEGREE OF IR ESTIMATED FROM THE PEAK INSULIN LEVELS DURING A 75 gm ogtt IN NORMOGLYCEMIC WOMEN WITH PCOS Very dependent on quality of insulin assay General cut-off values Normal-weight normal: <60 I/mL Obese normal: <80 I/mL Mild IR: 80-150 I/mL Moderate IR: 151-300 I/mL Severe IR: >300 I/mL Marin & Azziz. Contempo Ob/Gyn, March, 2005, pp. 66-74
POSITION STATEMENT OF THE ANDROGEN EXCESS & PCOS SOCIETY Recommends that women with PCOS, regardless of weight, be screened for IGT/DM with the use of an ogtt at the initial presentation and every 2 years thereafter Notes that the use of metformin to treat or prevent progression to IGT may be considered but should not be mandated until there have been well-designed randomized, controlled trials demonstrating efficacy Salley et al. J Clin Endocrinol Metab 2007;92:4546-4556
HYPERANDROGENISM IN PCOS IS ASSOCIATED WITH RISK OF METABOLIC SYNDROME Age-adjusted prevalence of MS is higher in all hyperandrogenic phenotypes of PCOS, compared to the nonhyperandrogenic PCOS phenotype and to controls Shroff et al. Fertil Steril 2007; 88:1389-1395
PREVALENCE OF LIPID ABNORMALITIES ACCORDING TO NCEP CRITERIA All subjects (n=398) % High Total cholesterol (mg/dl) 8.8% % Low HDL-C (mg/dl) 14.6% % High LDL-C (mg/dl) 8.5% % High TTG (mg/dl) 2.5% Legro et al. J Clin Endocrinol Metab 2003;88:5137-5144
TREATMENT OF PCOS Goals include treatment & prevention of: Dermatologic disorders (hirsutism, acne, alopecia) Ovulatory & menstrual dysfunction (DUB, endometrial hyperplasia or Ca) Metabolic abnormalities, incl. dyslipidemia, glucose intolerance & obesity Infertility Optimum treatment is generally combination therapy
LIFESTYLE MODIFICATION IN PCOS Dietary restriction has beneficial effects on ovulation, fertility, pregnancy outcome, QOL, and various metabolic/inflammatory markers in overweight PCOS women Compliance is difficult with up to a 50% drop-out rate No obvious difference in outcome or satiety has been observed with different dietary regimens long-term, although most studies are short and limited in size However, higher stimulated GLU levels during ogtt have been observed with the lower protein diets
EFFECTS OF A EUCALORIC REDUCED-CHO DIET ON BODY COMPOSITION AND FAT DISTRIBUTION IN WOMEN WITH PCOS *p<0.05 In a crossover-diet intervention, 30 women with PCOS consumed a reduced-cho diet (41:19:40% energy from CHO:protein:fat) for 8 weeks and a standard diet (55:18:27) for 8 weeks Change in fat mass, adjusted for baseline total fat, and change in total lean mass was greater following reduced-cho diet compared to STD diet in PCOS Goss et al. Metabolism 63:1257-1264, 2014
COMBINATION ORAL CONTRACEPTIVE SHBG LH Testosterone Binding Capacity Testosterone Production Free Testosterone Levels
ANTIANDROGENS IN HIRSUTISM 120 100 Ferriman-Gallwey score * 120 100 Hair shaft diameter * D % D % 80 80 60 40 Flutamide Spironolactone Finasteride Placebo Basal After treatment 60 40 Basal After treatment *p<0.01 placebo vs. other groups Moghetti et al. J Clin Endocrinol Metab 2000; 85:89-94
TREATMENT OF HIRSUTISM IN PCOS WITH DIANE-35 ALONE OR DIANE-35+FINASTERIDE 30 25 20 15 10 5 PCOS * * Diane-35 Diane-35+finasteride 0 Baseline 3 months 6 months *P<.005 vs. basal values P <.002 vs. basal values P <.05 vs. Diane-35 at the respective time point Tartagni et al. Fertil Steril 2000;73:718
LONG-TERM OUTCOME OF HIRSUTISM TREATMENT WITH AN OCP + SPIRONOLACTONE* COMBINATION IN 138 WOMEN WITH PCOS, ACCORDING, TO INITIAL mfg SCORE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Proportion improved by FG score-cox model FG=5 FG=10 FG=15 FG=20 0 6 12 18 24 30 36 42 48 54 60 mos follow up *OCP = Mostly 35 mg Ethinyl Estradiol and 1 mg Ethynodiol Diacetate; Spironolactone = 100mg/d for initial mfg 3-7; or 200 mg/d for initial mfg>8 Ezeh unpublished
METFORMIN THERAPY IN PCOS Metformin is an agent that acts indirectly and modestly to: Improve ovulation Reduce long-term metabolic complications
FG score METFORMIN VS. DIANE NOVA IN OBESE PCOS: A 6 MOS RANDOMIZED STUDY 14 12 NS <0.01 10 8 6 Pre Post 4 2 0 Metformin* (n=8) Diane Nova (n=10) *Metformin administered as 1000 mg/d x 3 mos, then 2000 mg/d x 3 mos Morin-Papunen et al. J Clin Endocrinol Metab 2000;85:3161
METFORMIN, FLUTAMIDE & DIET: A Controlled Randomized 6 mos. Study 40 obese PCOS patients Randomized to: Placebo + Diet Metformin (1500 mg/d) + Diet Flutamide (250 mg/d) + Diet Metformin +Flutamide + Diet Metformin improved hirsutism Addition of Flutamide further improved hirsutism Metformin, but not flutamide, improved menstrual function Gambineri et al. Clin Endocrinol 2004;60:241
DIABETES PREVENTION TRIAL 3234 subjects with IGT randomized to: Metformin 1700 mg/d Intensive lifestyle intervention PBO Average follow-up 2.8 years Compared with PBO, the incidence of DM was reduced: By 58% (95 th CI: 48-66%) with lifestyle intervention By 31% (95 th CI: 17-43%) with metformin Knowler et al. N Engl J Med 2002;346:393-403
PCOS VS. NON-PCOS FOR LONG-TERM TREATMENT OF METABOLIC RISK PCOS Meta-analysis of pooled results of 31 trials with 4570 participants followed for 8267 patient-years No significant differences in response between PCOS and non-pcos women Except lesser decrease in Fasting INS (-5.7% in PCOS vs. -16.1% in non-pcos) No PCOS trials to date have evaluated the effect of treatment on the incidence of DM Salpeter et al. Am J Med 2008;121:149-157.e2
SELECTING PCOS PATIENTS FOR All PCOS? Probably not METFORMIN THERAPY Selected PCOS? IGT or GDM Family history of T2DM Laboratory evidence of IR, i.e. hyperinsulinemia (ogtt, metabolic syndrome) Clinical evidence of hyperinsulinemia (acanthosis nigricans, obesity, android obesity)
Rate of Live Births PPCOS-I TRIAL: METFORMIN VS. CC, ALONE OR TOGETHER, FOR FERTILITY Legro et al. N Engl J Med 2007;356:551-66
PPCOS-II TRIAL: LETROZOLE VS. CC IN PCOS FOR FERTILITY Legro et al. N Engl J Med. 2014;371:119-29
PCOS: CREATING A TREATMENT PLAN Good treatment plans are based on sound and complete evaluations History of the disorder Evaluation history Treatment history Past medical/surgical history Family history Physical exam TV U/S Laboratory
PCOS: CREATING A TREATMENT PLAN Rx includes: OCs or progestins, for endometrial protection/ha Antiandrogens, for hirsutism, alopecia Metformin for metabolic dysfunction Ovulation induction for infertility Life-style modification Cosmetic care Adjunct/alternative therapies PCOS treatment generally requires combination Rx, and life-long care and counseling
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