PCOS Update
2015
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)
Objectives
1. 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
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)
GRADE
Strength 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. Anovulation
3. PCO morphology > 12 (2-9 mm)
2 
DIAGNOSIS – Adolescents
(TSH, Prolactin, 17OHP)
1. Androgen Excess (clinical/biochem)
2. Anovulation
2 
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
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 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.
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) 2004
115
74
11.5
0
0
• Al-Fadhli (74) 2005
38
38
26.3 (5 mg) 0
0
• Al-Fadhli (74)
34
34
5.9(2.5 mg)0
0
• Badawy (71) 2009
400
205
18.2
0
0
• Abu Hashim (72)
2011
220
15.9
0
0
• Fouda (73)
2011
211
107
19.0
10.0
0
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.
DASH
Dietary Approaches to Stop Hypertension
The DASH eating plan:
• Emphasizes vegetables, fruits, and fatfree 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
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.
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
Saturated fat
Protein
Carbohydrate
Cholesterol
Sodium
Potassium
Calcium
Magnesium
Fiber
27% v 27% of calories
4% v 6% of calories
18 v 18% of calories
50 v 55% of calories
150 v 150 mg
2,300 v 2,300 mg*
4,700 v 4,700 mg
1300 v 1,250 mg
500 v 500 mg
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.long
The 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_patient
Androgen Excess and PCOS Society
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 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