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C. Matthew Peterson, M.D. Park City, Utah 2015

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1 C. Matthew Peterson, M.D. Park City, Utah 2015
PCOS Update 2015 C. Matthew Peterson, M.D. Park City, Utah 2015 Last Tgiving had a generational experience – buy turkey- 22 lb Forzen bin – couldn’t find Can I get a bigger turkey No these turkey are all dead Tomorrow you will partake and some of you will overindulge- Please keep it in persepctive and don’t binge or purge Iyou eat 5 lb of food It is only 7 x 10-5% of your lifetime consumption of 70,000 lbs Practical approach to fertility care in what could be considred an insuracne resource Poor environment

2 Disclosure No conflicts related to this presentation
Will discuss off label use of letrozole, metformin and N acetyl cysteine (NAC)

3 Objectives Opportunity to gauge your care of PCOS to Endocrine Society recommendations/suggestions based on the respective strength of evidence (GRADE criteria) Review some safe, cost effective oral ovulation induction regimens for clomid resistant PCOS Familiarize the group regarding weight loss interventions for obese PCOS

4 PCOS Endocrine Society Practice Guidelines
Grade System Guidelines Strength of Recommendation Quality of Evidence GRADE Working Group 2004, Schünemann 2006b, Guyatt 2008a, Guyatt 2008b).  Over 20 organizations including the World Health Organization (WHO), the American College of Physicians, the American College of Chest Physicians (ACCP), the American Endocrine Society, the American Thoracic Society (ATS), the Canadian Agency for Drugs and Technology in Health (CADTH), BMJ Clinical Evidence, the National Institute for Health and Clinical Excellence (NICE) in the UK, and  UpToDate® have adopted the GRADE system in its original format or with minor modifications (Schünemann 2006b, Guyatt 2006a, Guyatt 2006b) The Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE Working Group) has developed a system for grading the quality of evidence (GRADE Working Group 2004, Schünemann 2006b, Guyatt 2008a, Guyatt 2008b).  Over 20 organizations including the World Health Organization (WHO), the American College of Physicians, the American College of Chest Physicians (ACCP), the American Endocrine Society, the American Thoracic Society (ATS), the Canadian Agency for Drugs and Technology in Health (CADTH), BMJ Clinical Evidence, the National Institute for Health and Clinical Excellence (NICE) in the UK, and  UpToDate® have adopted the GRADE system in its original format or with minor modifications (Schünemann 2006b, Guyatt 2006a, Guyatt 2006b). The BMJ encourages authors of clinical guidelines to use the GRADE system (www.bmj.com/advice/sections.shtml). The Cochrane Collaboration has adopted the principles of the GRADE system for evaluating the quality of evidence for outcomes reported in systematic reviews. This assessment is being phased in together with the introduction of the ‘Summary of findings’ table (see Chapter 11, Section 11.5). For purposes of systematic reviews, the GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest. Quality of a body of evidence involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias, as described in Section The GRADE system entails an assessment of the quality of a body of evidence for each individual outcome. The GRADE approach specifies four levels of quality (Table 12.2.a). The highest quality rating is for randomized trial evidence. Review authors can, however, downgrade randomized trial evidence to moderate, low, or even very low quality evidence, depending on the presence of the five factors in Table 12.2.b. Usually, quality rating will fall by one level for each factor, up to a maximum of three levels for all factors.  If there are very severe problems for any one factor (e.g. when assessing limitations in design and implementation, all studies were unconcealed, unblinded, and lost over 50% of their patients to follow-up), randomized trial evidence may fall by two levels due to that factor alone. Review authors will generally grade evidence from sound observational studies as low quality.  If, however, such studies yield large effects and there is no obvious bias explaining those effects, review authors may rate the evidence as moderate or – if the effect is large enough – even high quality (Table 12.2.c). The very low quality level includes, but is not limited to, studies with critical problems and unsystematic clinical observations (e.g. case series or case reports).

5 GRADE Strength of Recommendation 1 We recommend 2 We suggest Strength of Evidence High quality  Moderate quality  Low quality  Very low quality 

6 DIAGNOSIS – Adults (TSH, Prolactin, 17OHP) ROTTERDAM CRITERIA (2 of 3)
1. Androgen Excess (clinical/biochem) 2. Anovulation 3. PCO morphology > 12 (2-9 mm) 2  DIAGNOSIS – Adolescents (TSH, Prolactin, 17OHP) 2 

7 Associated Morbidity Cutaneous manifestations (Document) 1 Infertility 1 Pregnancy complications (BMI,BP,GTT)1 Fetal origins 2 Endometrial Cancer (EndoBx) 2 Obesity (BMI, Waist circumference)1 Depression (Screen) 2 Obstructive Sleep Apnea (Screen) 2 NASH 2 T2DM(GTT or HgbA1c) 1 CVD Risks 1

8 Treatment OCPs for menstrual abnormalities 1 Exercise 2
Weight loss 2 No Metformin for Skin, pregnancy, obesity 2 Metformin for T2DM or IGT 1 Metformin (2nd line) for non OCP users 2 Clomid or Letrozole for anovulation 1 Metformin to avoid OHSS 2 No Inositol/thiazolidines prophylactically 1 No Statins prophylactically 2

9 Metabolic Syndrome (3 of 5)
Abdominal obesity Waist > 35 and 40 inches for women and men, respectively Hypertension >135/85 TG >150mg/dl HDL-C <50 mg/dl (men <40 mg/dl) Fasting Glucose > 110 mg/dl JAMA 2001; 285;

10 Ovulation – Detection in Oral Regimens without US
$33.49 at Target $1.00 at Dollar Tree

11 Ovulation Detection Kroegers

12 Ovulation prediction by LH kit testing
You have been advised to use LH kit testing to determine when ovulation will be occurring so we can optimize the timing of egg and sperm activity for fertilization.  LH KIT TESTING  We utilize and strongly recommend "Clear Blue Digital Ovulation tests" for LH kit testing (not the electronic monitor or digital read out). Please begin testing on cycle day ____. TESTING: Test twice per day: First Test: Should be the second time you urinate in the morning (before (9:00 am). Second Test: Should be between 6:00 – 9:00 pm. POSITIVE RESULTS: ____Intercourse: After having your LH kit turn positive, plan intercourse for the same day and the following day. ____ IntrauterineInsemination (IUI) or artificial insemination (AI): When positive, promptly call Andrology at to schedule an insemination for the next day. The sooner you call to schedule, the better we are to accommodate you. Questions about your LH kit test results may be directed to Andrology. If you are using an artificial insemination, your partner will come in the day of the insemination (the day after your LH kit turns positive) to give a sperm sample. If you are using donor sperm, you will come in the day after a positive test. SPERM PREPARATION/METHOD: ____ Refrigeration/heparin incubation (Please call the Andrology Lab for specific instructions.) ____ Gradient Prepared sperm for intrauterine insemination ____ Washed sperm for intrauterine insemination ____ Donor insemination ____ Intercourse

13 Ovulation - ovulatory “The test cannot reliably define the time of ovulation and can become tedious. Consequently, BBT is no longer considered the best or preferred method for evaluating ovulatory function for most infertile women.”

14 Ovulation - anovulatory

15 Interventions for anovulation
Weight loss #1 intervention Metformin - often added in women with characteristics of metabolic syndrome or who failed clomid or letrozole alone Metformin is an antihyperglycemic that is widely used off label as an adjunct to ovulation induction or superovulation. The net effect of lowering serum glucose in women who are anovulatory is a reduction of androgens and potential resumption in ovulation. Although numerous case series and cohort studies have demonstrated a favorable impact on pregnancy rates following ovulation induction, randomized trials have yielded mixed results. Metformin has not been shown to increase the chances of a live birth in women with unexplained infertility. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T1, Lord JM, Norman RJ, Yasmin E, Balen AH. Error! Hyperlink reference not valid. Update in Cochrane Database Syst Rev. 2010;(1):CD Abstract BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogaenemia and insulin resistance. Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES: To assess the effectiveness of insulin sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS and menstrual disturbance. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched September 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, third Quarter 2008), CINAHL (searched September 2008), MEDLINE (January 1966 to September 2008), and EMBASE (January 1985 to September 2008). All searches were rerun 13 August RCTs were located and await classification. SELECTION CRITERIA: Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS: Thirty one trials (2537 women) were included for analysis, 27 of them using metformin and involving 2150 women. MAIN RESULTS: There is no evidence that metformin improves live birth rates whether it is used alone (Pooled OR = 1.00, 95% CI 0.16 to 6.39) or in combination with clomiphene (Pooled OR = 1.48, 95% CI 1.12 to 1.95). However, clinical pregnancy rates are improved for metformin versus placebo (Pooled OR = OR 3.86, 95% C.I to 6.84) and for metformin and clomiphene versus clomiphene alone (Pooled OR =1.48, 95% C.I to 1.95) ). In the studies that compared metformin and clomiphene alone, there was no evidence of an improved live birth rate (OR= 0.67, 95% CI 0.44 to 1.02) but the pooled OR resulted in improved clinical pregnancy rate in in the clomiphene group (OR = 0.63 , 95% 0.43 to 0.92), although there was significant heterogeneity.There is also evidence that ovulation rates are improved with metformin in women with PCOS for metformin versus placebo (Pooled OR 2.12, 95% CI 1.50 to 3.0) and for metformin and clomiphene versus clomiphene alone (Pooled OR = 3.46, 95% CI 1.97 to 6.07).Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. AUTHORS' CONCLUSIONS: In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited. Error! Hyperlink reference not valid Feb 24;2:CD doi: / CD pub2.

16 Oral Agents - Letrozole and clomid
Background Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Methods In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Results Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. Full Text of Results... Conclusions As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT ) N Engl J Med 2014; 371: July 10, 2014 Cochrane Database Syst Rev Feb 24;2

17 Advantage of Letrozole - singletons
able 4. Outcome characteristics of representative prospective, randomized trials of SO/IUI using letrozole. First author (reference) Year Cycles (n) Individ (n)Preg/cycle (%)Twin(%)High-order (%) Al-Fozan (70)        Al-Fadhli (74)         (5 mg) 0 0 Al-Fadhli (74) (2.5 mg) Badawy (71)       Abu Hashim (72)   Fouda (73)        Fertil Steril Apr;97(4):802-9. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Franik S1, Kremer JA, Nelen WL, Farquhar C. Error! Hyperlink reference not valid. 1Faculty of Medical School, Radboud University Nijmegen, Geert Grooteplein 9, PO Box 9101, Nijmegen, Netherlands, 6500HB. Abstract BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). OBJECTIVES: To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS. SEARCH METHODS: We searched the following sources from inception to 24/10/2013 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles.The search was not restricted by language or publication status. SELECTION CRITERIA: We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods. MAIN RESULTS: We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole. Live birth (12 RCTs) One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.63, 95% CI 1.31 to 2.03, n=1783, I²=3%)Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%) OHSS (16 RCTs) There was no evidence of a difference in OHSS rates when letrozole was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179), clomiphene citrate (with or without adjuncts) followed by intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS. Clinical pregnancy (25 RCTs) One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Fourteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.32, 95% CI 1.09 to 1.60, n=2066, I²=25%)Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)Three RCTs compared letrozole versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth). AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with

18 Oral Agents – Letrozole – Informed Consent
Informed Consent for (Letrazole/Femara) for Infertility Treatment We have chosen to use the aromatase inhibitor, letrozole (common available brand name Femara), for ovulation induction or enhancement. I understand that letrazole is currently FDA approved only for the indication of decreasing the risk of recurrence of breast cancer. The drug manufacturer does not support the use of letrazole for infertility treatment and, in fact, has issued a “blackbox” warning indicating it should not be used for infertility therapies. In contrast to the manufacturers warnings, clinical research has shown some benefits of letrazole for infertility treatment. Letrazole works by blocking the enzyme conversion of androgenic hormones to estrogenic hormones, thus lowering levels of estrogen in the body. This results in mild ovarian stimulation from pituitary hormones. Additionally, letrazole does not seem to have some of the adverse side-effects such as decreased cervical mucus, thinning of the endometrial lining, emotional irritability or multiple pregnancy risks associated with clomiphene citrate. The overall incidence of multiple pregnancies appears to be less than that with clomiphene citrate (5-8%). Concerns about letrazole were first raised in an abstract presented at the American Society for Reproductive Medicine meeting in Montreal in October 2005 suggesting the incidence of birth defects in babies born after the use of letrozole was approximately 4.7% (based on approximately 150 births). Subsequent studies suggests that the incidence of birth defects may be as low as 2.4% consistent with normal background population rates (Fertil. Steril 2006). Multiple other studies suggest its use for ovulation induction is safe. Additional research continues to further document its safety. Our doctor feels that in light of available evidence, and for particular situations such as ours, letrazole may be an appropriate option. Because of the method of action and the concerns raised, letrazole may be harmful to a developing baby, especially if taken early in pregnancy. Thus, a urine pregnancy test is required before each prescription and this will be my responsibility (Clear Blue pregnancy test is adequate). We understand that these agents have been used for infertility therapy for only a short time, and there may be more risks, which are currently unknown. We acknowledge that letrazole has not been approved by the FDA for infertility treatment and carries a “blackbox” warning. We understand that if these medications are used for treatment of infertility, we do so with full knowledge that a woman should not be pregnant while taking the letrazole and it is OUR responsibility to insure we have a negative pregnancy test prior to use. We have had the risks and benefits of letrazole explained to us and we have had our questions answered. We accept full responsibility for pregnancy testing before letrazole use and for any potential adverse effects associated its use. Date_________________________ Signature _______________________________________ Background Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Methods In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Results Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. Full Text of Results... Conclusions As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT )

19 Oral Agents - letrozole/clomid combo
Treatment outcome in patients Formation of dominant follicle (82.9%) Number of dominant follicles ±1.1 Mean endometrial diameter (mm) ±1.3 Number of recombinant human follicle-stimulating hormone treatments used ±0.9 Occurrence of pregnancy (42%) Miscarriage (23.8%) Single fetus (88%) Twin fetus (12%) Data are mean ± standard deviation, or mean (percentage). Drug Des Devel Ther Dec 3;7: doi: /DDDT.S eCollection 2013. Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome. Hajishafiha M1, Dehghan M2, Kiarang N1, Sadegh-Asadi N1, Shayegh SN3, Ghasemi-Rad M2. Author information 1Department of Gynecology, Reproductive Health Research Center, Urmia University of Medical Sciences, Ajman, United Arab Emirates. 2Urmia University of Medical Sciences, Ajman, United Arab Emirates. 3Gulf Medical University, Ajman, United Arab Emirates. Abstract BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age (6.8%-18%), is among the most common causes of infertility due to ovulation factors, and accounts for 55%-70% of infertility cases caused by chronic anovulation. In this study, we used a combination of letrozole and clomiphene in patients resistant to both drugs individually, and studied the effects of this combination in ovulation and pregnancy in resistant PCOS patients. METHODS: The study population included infertile couples diagnosed as PCOS in the wife. The women used clomiphene for at least six cycles in order to ovulate after failure to form the dominant follicle, and were then put on letrozole for four cycles. Patients who were unable to form the dominant follicle were enrolled on letrozole and clomiphene combination therapy. RESULTS: One hundred enrolled patients underwent 257 cycles of a combination of letrozole and clomiphene, in which 213 were able to form the dominant follicle (82.9%) and 44 were unable to do so (17.1%). The number of mature follicles was 2.3±1.1. The mean endometrial thickness in patients on the day of human chorionic gonadotropin administration was 8.17±1.3 mm. The pregnancy rate was 42%. CONCLUSION: According to the results of this study, it can be proposed that in PCOS patients resistant to clomiphene and letrozole used as single agents, a combination of the two drugs can be administered before using more aggressive treatment that may have severe complications or surgery. This combination may also be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense. Drug Des Devel Ther Dec 3;7:

20 Oral agents – C/Dex, generalizable to Let
Clomid/Dex Trial Eighty infertile women with CC-resistant PCOS were randomly assigned into two groups. Group I: Clomiphene citrate 100 mg/day was given from day 3 to day 7 of the cycle and DEX 2 mg/day from day 3 to day 12 of the cycle. Group II: Same protocol of CC combined with placebo (folic acid tablets) was given from day 3 to day 12 of the cycle. The main outcome was ovulation. Secondary measures included number of follicles >18 mm endometrial thickness and pregnancy rate. Ovulation (75 versus 15%) (P<0.001) and pregnancy (40 versus 5%) (P<0.05) in the DEX group In cases of CC resistance in the setting of normal and elevated dehydroepiandrosterone, daily dexamethasone (0.5–2.0 mg) or prednisone (5 mg) during the follicular phase have been used adjunctively with CC. The combination of glucocorticoids and CC has been shown to significantly increase the rate of ovulation and pregnancy when compared with CC alone in randomized trials.42–44 Oral Contraceptives and Clomiphene Citrate Two months of oral contraceptive pill treatment before ovulation induction with CC may improve the observed rate of ovulation and pregnancy.45 Treatment with Oral Contraceptive Pills (OCPs) is associated with lower levels of testosterone and androstenedione, which probably accounts for the improved ovarian response to CC. Hum Reprod Jul;21(7): Epub 2006 Mar 16.

21 Oral Agents – C or L plus NAC
Aim: The aim of this study was to evaluate the effect of oral N-acetylcysteine (NAC) administration as an adjuvant to clomiphene citrate (CC) on induction of ovulation outcomes in patients with polycystic ovary syndrome (PCOS). Material and Methods: In this placebo-controlled double-blind randomized clinical trial, 180 PCOS infertile patients were randomly divided into two groups. Patients in group 1 received CC 100 mg/d plus NAC 1.2 g/d and patients in group 2 received CC plus placebo for 5 days starting at day 3 of the cycle. On the 12th day in the presence of at least one follicle 18–20-mm diameter, U hCG was injected IM and timed intercourse was advised 36 h after hCG. b-hCG level was measured on the 16th day after hCG injection. Results: The number of follicles >18 mm and the mean endometrial thickness on the day of hCG administration were significantly higher among the CC+NAC group (P-value = 0.001). The ovulation and pregnancy rates were also significantly higher in the CC+NAC group (P-value = 0.02 and 0.04, respectively). No adverse side-effects and no cases of ovarian hyperstimulation syndrome were observed in the group receiving NAC. Conclusion: NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and endometrial thickness as well as the pregnancy rate. J. Obstet. Gynaecol. Res. Vol. 38, No. 9: 1182–1186, September 2012

22 Oral ovulation induction in clomid resistant PCOS
Cost efficient methodology Let 5; if fails, Let 7.5 OR Met/Let 5 then Met/Let 7.5 if signs of Metabolic Syndrome If failed to ovulate on Let 7.5 w or w/o Met then a) Let 5-7.5/Dex or b) Let 5/C100 then Let 7.5/C150 or c) Let 5/C100+Dex then Let 7.5/C100+Dex A final alternative is: e) Let or C and NAC 1.2 g/day Metformin is added initially to those with signs of Metabolic Syndrome Peterson CM, based on experience and applicable literature

23 Weight Loss in PCOS 1
Metabolic Syndrome

24 Metabolic Syndrome (3 of 5)
Abdominal obesity Waist > 35 and 40 inches for women and men, respectively Hypertension >135/85 TG >150mg/dl HDL-C <50 mg/dl (men <40 mg/dl) Fasting Glucose > 110 mg/dl JAMA 2001; 285;

25 Weight Loss Intervention
The principal components of an effective intervention include: (1) prescription of a moderately reduced-calorie diet, (2) prescription of increased physical activity, and (3) the use of behavioral strategies to facilitate adherence to diet and activity recommendations. All three components should be included. Strength of evidence: High The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies. https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

26 Reduced Calorie Diet To achieve weight loss, an energy deficit is required. Specification of an energy intake target that is less than that required for energy balance, usually 1,200 to 1,500 kcal/day for women and 1,500 to 1,800 kcal/day for men (kcal levels are usually adjusted for the individual’s body weight and physical activity levels); Estimation of individual energy requirements according to expert guidelines and prescription of an energy deficit of 500 kcal/day or 750 kcal/day or 30 percent energy deficit; and Ad libitum approaches where a formal energy-deficit target is not prescribed but lower calorie intake is achieved by restriction or elimination of particular food groups. Strength of evidence: High The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies. https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

27 Avoiding Diabetes Inverse-variance random-effect meta-analysis of eight long term prospective cohort and one RCT published between 122, 810 subjects For highest v. lowest adherence to the Mediterranean diet score, the pooled risk ratio was 0.81 (95 % CI 0.73, 0.90, P<0.0001, I 2-55 %). Sensitivity analysis including only long-term studies confirmed the results of the primary analysis (pooled risk ratio was 0.75; 95 % CI 0.68, 0.83, P< , I 2-0 %). No publication bias detected by Egger regression test (P=0.254) Public Health Nutr Aug 22:1-8. [Epub ahead of print] Adherence to a Mediterranean diet and risk of diabetes: a systematic review and meta-analysis. Schwingshackl L1, Missbach B1, König J1, Hoffmann G1. Author information Abstract OBJECTIVE: Adherence to a Mediterranean diet is associated with significant improvements in health status. However, to date no systematic review and meta-analysis has summarized the effects of Mediterranean diet adherence on the risk of type 2 diabetes mellitus. DESIGN: Electronic searches for randomized controlled trials and cohort studies were performed in MEDLINE, SCOPUS, EMBASE and the Cochrane Trial Register until 2 April Pooled effects were calculated by an inverse-variance random-effect meta-analysis using the statistical software Review Manager 5·2 by the Cochrane Collaboration. SETTING: Meta-analysis of randomized controlled trials and cohort studies. SUBJECTS: Eligibility criteria: 19+years of age. RESULTS: One randomized controlled trial and eight prospective cohort studies ( subjects) published between 2007 and 2014 were included for meta-analysis. For highest v. lowest adherence to the Mediterranean diet score, the pooled risk ratio was 0·81 (95 % CI 0·73, 0·90, P<0·0001, I 2=55 %). Sensitivity analysis including only long-term studies confirmed the results of the primary analysis (pooled risk ratio=0·75; 95 % CI 0·68, 0·83, P<0·00001, I 2=0 %). The Egger regression test provided no evidence of substantial publication bias (P=0·254). CONCLUSIONS: Greater adherence to a Mediterranean diet is associated with a significant reduction in the risk of diabetes (19 %; moderate quality evidence). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of type 2 diabetes mellitus. Schwingshacki, L. Public Health Nutr Aug 22:1-8.

28 DASH Dietary Approaches to Stop Hypertension
The DASH eating plan: Emphasizes vegetables, fruits, and fat-free or low-fat dairy products Includes whole grains, fish, poultry, beans, seeds, nuts, and vegetable oils Limits sodium, sweets, sugary beverages, and red meats

29 DASH Dietary Approaches to Stop Hypertension
In terms of nutrition content, DASH is: Low in saturated and trans fats Rich in potassium, calcium, magnesium, fiber, and protein The DASH eating plan sodium content (2,300 mg per day) lowered BP. 1,500 mg per day even further lowered BP. The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies.

30 Mediteranean and DASH Total fat 27% v 27% of calories
Daily Nutrient Goals Mediterranean v DASH (2,000-Calorie Eating Plan) Total fat 27% v 27% of calories Saturated fat 4% v 6% of calories Protein 18 v 18% of calories Carbohydrate 50 v 55% of calories Cholesterol 150 v 150 mg Sodium 2,300 v 2,300 mg* Potassium 4,700 v 4,700 mg Calcium v 1,250 mg Magnesium 500 v 500 mg Fiber 30 v 30 g The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies.

31 Diet Plans https://healthyeating.nhlbi.nih.gov

32 Physical Activity Increased physical activity. Comprehensive lifestyle intervention programs typically prescribe increased aerobic physical activity (such as brisk walking) for ≥150 minutes per week (≥30 minutes a day, most days of the week). Higher levels of physical activity, approximately 200 to 300 minutes per week, are recommended to maintain lost weight or minimize weight regain long term (>1 year). Strength of evidence: High The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies. https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

33 Behavioral Strategies
Behavioral strategies. Comprehensive lifestyle interventions usually provide a structured program that includes guidance on behavioral strategies and approaches to accomplish prescribed dietary intake and physical activity goals. One common strategy is regular self-monitoring, including monitoring of food intake, physical activity, and weight. These same behaviors are recommended to maintain lost weight, with the addition of frequent (i.e., weekly or more often) monitoring of body weight. Options: Structured Program, Lose It, Fit Bit, Body Media Core Strength of evidence: High The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies. https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

34 Summary PCOS Online Resources
The polycystic ovary syndrome: a position statement from the European Society of Endocrinology Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline Androgen Excess and PCOS Society

35 Oral ovulation induction in clomid resistant PCOS
Summary Oral ovulation induction in clomid resistant PCOS Cost efficient methodology Let 5; if fails, Let 7.5 OR Met/Let 5 then Met/Let 7.5 if signs of Metabolic Syndrome If failed to ovulate on Let 7.5 w or w/o Met then a) Let 5-7.5/Dex or b) Let 5/C100 then Let 7.5/C150 or c) Let 5/C100+Dex then Let 7.5/C100+Dex A final alternative is: e) Let or C and NAC 1.2 g/day Metformin is added initially to those with signs of Metabolic Syndrome Peterson CM, based on experience and applicable literature

36 Weight Loss Intervention
Summary Weight Loss Intervention The principal components of an effective intervention include: Reduced-calorie diet; Deficit of 500 cal per day, Mediterranean/DASH Increased physical activity; 30 min per day brisk walking Behavioral strategies; Structured Program, Lose It, Fit Bit, Body Media Core Strength of evidence: High The "Dietary Guidelines for Americans, 2010" advises reducing sodium intake to less than 2300 mg per day.  People in the following groups should reduce sodium intake further, to 1,500 mg of sodium per day: People who already have high blood pressure People who have diabetes or chronic kidney disease African Americans Adults aged 51 and older Below is a table that shows the daily nutrient goals used in the DASH studies. https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

37 Summary Diet Plans https://healthyeating.nhlbi.nih.gov


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