PCOS Update2015

C. Matthew Peterson, M.D.

Park City, Utah 2015

Disclosure

• No conflicts related to this presentation• Will discuss off label use of letrozole,

metformin and N acetyl cysteine (NAC)

Objectives1. Opportunity to gauge your care of PCOS to

Endocrine Society recommendations/suggestions based on the respective strength of evidence (GRADE criteria)

2. Review some safe, cost effective oral ovulation induction regimens for clomid resistant PCOS

3. Familiarize the group regarding weight loss interventions for obese PCOS

PCOSEndocrine 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)

GRADEStrength of Recommendation

1 We recommend

2 We suggest

Strength of Evidence

High quality Moderate quality Low quality Very low quality

DIAGNOSIS – Adults (TSH, Prolactin, 17OHP)

ROTTERDAM CRITERIA (2 of 3) 1. Androgen Excess

(clinical/biochem) 2. Anovulation3. PCO morphology > 12 (2-9 mm)

2

DIAGNOSIS – Adolescents (TSH, Prolactin, 17OHP)

1. Androgen Excess (clinical/biochem)

2. Anovulation2

Associated MorbidityCutaneous 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

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

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; 2486-97

Ovulation – Detection in Oral Regimens without US

$33.49 at Target $1.00 at Dollar Tree

Ovulation Detection

Kroegers

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 801-581-3740 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

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.”

Ovulation - anovulatory

Interventions for anovulation

Weight loss #1 intervention

Metformin - often added in women with characteristics of metabolic syndrome or who failed clomid or letrozole aloneMetformin 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.

Oral Agents - Letrozole and clomid

N Engl J Med 2014; 371:119-129July 10, 2014 Cochrane Database Syst Rev. 2014 Feb 24;2

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)2004115       74 11.500• Al-Fadhli (74)200538       38 26.3 (5 mg)00• Al-Fadhli (74) 34 34 5.9(2.5 mg)0 0• Badawy (71)2009400      205 18.200• Abu Hashim (72)2011 220  15.900• Fouda (73)2011211      107 19.0 10.00

Fertil Steril. 2012 Apr;97(4):802-9.

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 _______________________________________

Signature _______________________________________

Signature _______________________________________

Oral Agents - letrozole/clomid combo

Treatment outcome in patients• Formation of dominant follicle 213 (82.9%)• Number of dominant follicles 2.3±1.1• Mean endometrial diameter (mm) 8.17±1.3• Number of recombinant human follicle-stimulating hormone

treatments used 3.7±0.9• Occurrence of pregnancy 42 (42%)• Miscarriage 10 (23.8%)• Single fetus 37 (88%)• Twin fetus 5 (12%)

Data are mean ± standard deviation, or mean (percentage).

Drug Des Devel Ther. 2013 Dec 3;7:1427-31.

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

Hum Reprod. 2006 Jul;21(7):1805-8. Epub 2006 Mar 16.

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, 10 000 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

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 5-7.5 or C100-150 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

Weight Loss in PCOS 1

• Metabolic Syndrome

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; 2486-97

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

https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

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

https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

Avoiding Diabetes• Inverse-variance random-effect meta-analysis of eight

long term prospective cohort and one RCT published between 2007-14

• 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<0.00001, I 2-0 %). No publication bias detected by Egger regression test (P=0.254)

Schwingshacki, L. Public Health Nutr. 2014 Aug 22:1-8.

DASHDietary 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

http://www.nhlbi.nih.gov/health/health-topics/topics/dash

DASHDietary 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.

http://www.nhlbi.nih.gov/health/health-topics/topics/dash

Mediteranean and DASH 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 1300 v 1,250 mg– Magnesium 500 v 500 mg– Fiber 30 v 30 g

http://www.nhlbi.nih.gov/health/health-topics/topics/dash

Diet Plans

https://healthyeating.nhlbi.nih.gov

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

https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

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

https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

Summary

PCOS Online Resources

http://eje-online.org/content/171/4/P1.longThe polycystic ovary syndrome: a position statement from the European Society of Endocrinology

http://www.alabmed.com/uploadfile/2014/0221/20140221030519199.pdf/Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

http://www.ae-society.org/resources_patientAndrogen Excess and PCOS Society

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 5-7.5 or C100-150 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

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

https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/obesity-evidence-review

Summary

Diet Plans

https://healthyeating.nhlbi.nih.gov

Summary