“DON’T TELL ME HOW MUCH I WEIGH!” , THE SENSITIVE MANAGEMENT OF WEIGHT AND THE PCOS PATIENT

CAROL LESSER, MSN, NPB OST ON I VF

JUNE 1 9 , 2 0 1 4

Midwest Reproductive Symposium International

Disclosure and Off label Information

Speakers Bureau: ActavisNurse Advisory Board: Good Start geneticsWill discuss the off label use of Letrozole for

ovulation induction

Learning Objectives

Discuss the difficulties in defining PCOSDescribe the association between PCOS,

insulin resistance, and obesityReview reasons for the global rise in

obesityDescribe strategies to assist patient in

achieving impactful weight loss Review off label treatment option for

PCOS

PCOS: An Ancient Disorder

Hippocrates (460-377 BC):

“But those women whose menstruation is less than 3 days or is meager, are robust, with a healthy complexion and a masculine appearance; yet they are not concerned about rearing children nor do they become pregnant.”

Azziz R et al: Polycystic Ovary Syndrome: an ancient disorder? Fertil Steril. 95, No 5, 1544-8(2011)

PCOS DIAGNOSIS

1st described in 1935 by Stein and LeventhalFirst thought to be an anatomic disorderMultiple attempts to refine the definition of

PCOSConsensus statements change over time

Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29, 181-191 (1935).The Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group, 2004

PCOS

PCOS: a syndrome not a diseaseList of potential signs or symptoms

and no one single test can make the diagnosis

Creates confusion. Many with PCOS are not diagnosed and many more do not understand their diagnosis

Only in last decade has PCOS been gaining recognition

PCOS DIAGNOSIS

Androgen Excess and PCOS Meeting(2006)

Must meet all 3 criteria:

1. Hyperandrogenism (hirsuitism, acne or hyperandrogenemia)

2. Ovarian dysfunction (oligoovulation, anovulation and/or polycystic ovaries)

3. Exclusion of other androgen excess disorders (CAH , Androgen secreting tumors)

NIH 2012 Proposal

Androgen excess + polycystic ovarian morphology

Ovarian dysfunction + polycystic ovarian morphology

Androgen excess+ ovarian dysfunction + polycystic ovarian morphology

NIH 2012 Conclusions

Complex metabolic, hypothalamic, pituitary, ovarian and adrenal interaction

Need better definition and recognition of different phenotypes

Need better androgen assay

NIH 2012 Conclusions

Need lab ranges that are ethnic and age specific

Pregnancy related complications are greater in more classic PCOS as opposed to non hyperandrogenic profile

Suggest renaming this syndrome

PCOS

• Most common endocrine disorder in females (6-15%)

• Subfertile not infertile• Heterogeneous condition: different

phenotypes• Associated with extremes in body habitus• BMI extremes affect health status, fertility

impairment, ART success and pregnancy outcome

Stein-Leventhal Description

Boston IVF

Stein and Leventhal: enlarged ovaries smooth surface - not

the typical rugae that are present in normal women

multiple small cysts that were identified to be follicles

histologic hypertrophy of the theca

PCO-Like Ovaries“String of pearls sign”

Ovulatory Dysfunction

Greater LH pulse frequency and amplitude

Causes excess androgen productionFSH level too low to mature the

folliclesFSH suppressed by mid follicular E2

levels that cause negative feedbackBaseline E2 levels tend to be higherAMH levels are elevated

Hyperandrogenism

VirilizationDecreased breast sizeClitoral enlargement-rareMale pattern baldnessVoice can deepenAcneAcanthosis nigrans associated with >

metabolic risk

Hyperandrogenism

Hirsuitism is best marker for hyperandrogensim: 70%-90 of PCOS women have this (acne and alopecia less common)

Hyperandrogenism and oligomenorrhea- > metabolic risk

Adams J, Polson DW, Franks S. Prevalence of PCO in nornal woemn with anovulation and idiopathic hirsuitism. BrMed j. 1986;293(65430:355-9

Pathophysiology of PCOS

Thecal cells produce increased androgens

Results in elevated LH and a relative FSH deficiency favoring androgen synthesis

Increased androgens result in many small follicles

May result in anovulation, hirsuitism, typical PCOS ovarian morphology

A VICIOUS CYCLE

Increased body weight results in increased IR and compensatory hyperinsulinemia

Insulin stimulates ovarian synthesis of testosterone

Insulin inhibits SHBG in the liver resulting in increased free testosterone

High testosterone causes more abdominal fat and increased IR

IR causes hyperandrogenism

Etiology of PCOS

Strong evidence of genetic link supported by familial incidence and twin studies

Prenatal exposure to androgens is associated with PCOS

Most likely poly-genetic disorderInsulin resistance (IR) is a socioecologic

adaptation to changes in diet and lifestyle. IR favors PCOS

Obesity varies between ethnic groups of PCOS women

Etiology of PCOS

Mothers and sisters of women with PCOS are more likely to acquire PCOS after menarche

Female children of women with PCOS more likely to develop insulin resistance after puberty

PCOS is inherited equally from father and mother

J CEM January 1999 |Govind et al. 84 (1): 38

PCOS and Body ImageHyperandrogenism is exacerbated by

hyperinsulinemia and associated with: -Acanthosis nigricans -Acrochordons (skin tags) -Purple-tip abdominal striae -Centripetal apple obesity

Obviously these changes affect body image!!!

PCOS Hirsuitism/Acanthosis Nigricans

Ferriman-Gallwey score

Stigmata of hyperinsulinemia:Acanthosis nigricans (axillary)

Who Is At Highest Risk?

Central obesity (apple or visceral adiposity)Genetic and predisposes an individual to IR,

dyslipidemia and hypertensionAndrogens inhibit hepatic and peripheral

insulin effectPCOS associated with truncal fat

Elevated waist circumference at highest risk for metabolic syndrome within several years

Obesity

PCOS and IR

Not included in diagnostic criteriaCells stop responding well to insulinBody perceives elevated glucoseIncreases insulin. Cells bombarded, but not

receptiveAbdominal fat aggravates IR and worsens the

sxs of PCOS.

Goal: sensitize cells or to find ways to increase the insulin effect

Abnormal Glucose Metabolism

64% of PCOS pts have IR40%of PCOS pts have impaired GTT10% develop Type 2 diabetes by their 4th

decadePrevalence of obesity among women with

PCOS in the US has increased to 74% in 2002, paralleling the increase in obesity in the general population

PCOS and Mood Disorders

Increased depression and anxietyMood disorders, social phobias and sleep disorders

increasedPsychological issues should be considered in all

PCOS pts

Unclear if due to disorder or the comorbiditiesAppropriate counseling should be offered

Consensus on women’s health aspects of PCOSThe Amsterdam ESHRE/ASRM sponsored 3rd consensus workshop group 2011Fert Steil vol 97, no1, january 2012

NAFLD

PCOS is associated non-alcoholic fatty liver disease

NAFLD is the hepatic manifestation of metabolic syndrome

Endometrial Effects

Chronic amenorrhea, oligoovulation or DUBUnopposed estrogenAt risk for hyperplasiaCan progress to EINImportance of ultrasound and endometrial

biopsy

PCOS and Subfertility

MetabolicInflammatoryOocyte quality-impaired oocyte competence-affects

meiosis, fertilization, embryo development via premature granulosa cell luteinization, impaired cytoplasmic and or nuclear maturation

Endometrial receptivityFetal affects, especially femalesInfants; increased morbidity and mortalityAffects are not universal

Dumesic DA,Padmanabhan V, Abbott DH. Polycystic ovary syndrome and oocyte developmental competence. Obstet Gynecol Surv 2008; 63:39-48

Weight gain Increased

Insulin

Insulin resistance and

abdominal obesity

Decreased SHBG

Metabolic disorders

Type 2 Diabetes

Increased testosterone

Anovulation, hirsuitism, acne

AnovulationInfertility

OBESITY

HYPERINSULINEMIA

IGFBP-1IGFBP-2

IGF-1 Bioavailability

PLASMA SHBG

Free Androgens

Free Estrogens

CA

NC

ER

RIS

K

Making the Diagnosis

Often a diagnosis of exclusion, so rule out:

CAHAndrogen secreting tumorsHyperprolactinemiaThyroid diseaseCushings

PCOS Labs

LH FSH/LH ratio (40% have normal ratio) E2; AMH Testosterone Androstenedione Hgb A1C 5.6-6.4=“at risk” Insulin, Glucose tests

Differential includes: DHEA-S, 17OH-P,TSH,Prolactin 24 hr urine cortisol

*Provera challenge may help with diagnosis*Lipid panel to assess CVD risk (triglycerides too)

Importance of Education

Patients want to understand their condition

Can empower them to make radical change if they understand why and the high stakes

They need our help!!

Explaining PCOS to your patient

Insulin: hormone secreted by the pancreas in response to the rise in glucose (sugar) after the digestion of carbohydrates – e.g. grains, fruits, milk, yogurt, sweets, and starchy vegetables like potatoes, sweet potatoes, squash, yams, corn, peas and legumes.

Once released, insulin "unlocks" muscle, fat

and liver cells so that glucose can pass into the cells either used as fuel or stored as an energy reserve

Explaining PCOS to your patient

With IR, cells are not as sensitive to insulin, stimulating the pancreas to secrete more insulin in an attempt to keep blood sugars normal. (This "overdrive" may over time, exhaust the pancreas and lead to diabetes)

The excess circulating insulin is thought to trigger the hormonal changes seen in PCOS (ovaries are not insulin insensitive!)

Patients need to know

Obesity negatively impacts ART success rates:

Difficulty with oocyte retrievalLess oocytes with morbidly obeseDecreased oocyte and embryo qualityDecreased uterine receptivityMore difficulty with ETsDecreased IR and PR (? not with DE)Pregnancy related risks and general health risks

Martinuzzi K et al. J assist Reprod Genet. 2008;25(5):169

BIVF Study of 4,609 women undergoing 1st IVF cycle

68% lower chance for live birth for OW and obese

BMI > 25: 42% lower IR; 57% decline in CPRCPR dropped slightly for underweight

women but declined significantly for OW women

“A modest amount of weight loss might improve IVF success rates.”

Jones ,S. 2011 ASRM Orlando

SART data analysis of BMI and cycle outcomes (2011)

Higher cancellation w/ BMI >30Reduced clinical pregnancy rate with

autologous cycles w/ BMI > 30 Worse prognosis with increasing BMI

Reduced live birth rate with autologous cycles w/ BMI >25 Higher risk of SAB/IUFD with increasing

BMI Variable with thaw and DE cycles

Luke, Increasing Obesity and ART Outcomes. Fertil Stertil 2011

WHAT HAS CHANGED?

Our foods and lifestyles have drastically changed:

-toxic food environment

-collective reduced energy expenditure (80% of jobs are sedentary)

-Lack of public awareness/will to push for the necessary policy changes

Fast Food and Advertising

High Fructose Corn Syrup(HFCS)

Corn subsidies support millions of acres of cornMore than half of US field corn go into animal feed which affects

quality of our meat and poultryUSDA (2003) estimates the average American eats 79 pounds of

corn sweetener per yearAdded to: boxed cereal, ketchup, fruit juice, soda and soft drinks,

margarine, chips

Resulting in approximately 500 more calories a day

King Corn 2007

1 Lifesaver per day= 1.5 lbs per year

Fat Monkeys

Monkeys eat when they are bored and not even hungry

Unlike humans who underreport their intake, rhesus monkeys can be closely monitored

When fed a poor diet they become 3 times their normal weight

High fat diets alone have not tended to make monkeys obese, but a high fructose corn sweetened punch ignites weight gain and IR

Obesity

Is it genetic?

Genes affect both energy intake and energy expenditure Metabolic rate of people matched for body weight, sex

and age may differ by up to 500 calories/day Some people burn more calories even when not trying

to exerciseTwin studies show hereditary componentGenetic differences explain radically different

weight gains and losses between individuals

Twin Studies

6 days a week they ate 1000 extra cals per dayWeight gain was between 10-29 poundsThese studies suggest a biologic determinism that makes

a person susceptible to weight gain or loss and how much

32 distinct genetic variations assoc with obesity. Those carrying a common variant known as FTO faced increased risk: 30 % if 1 copy and 60% if 2 copies. Those with the gene tend to eat more foods with higher fat and calories

De Bouchard and Tremblay

Oct 2010 J of N G

Nature and Nurture

Genetics loads the gun, environment pulls the trigger

One’s own prenatal environment may play a role (epigenetics)

Leptin and Gherlin

Leptin and GherlinWomen with PCOS may have abnormal

gherlin and leptin levelsGherlin is the gastric and pancreatic

hormone that makes us feel hungry. (Also produced by hypothalamus)

Leptin is the hormone made in adipose tissue that makes us feel full

Women with PCOS maintain higher gherlin levels after a meal and report difficulty feeling full

Anti obesity vaccine targets gherlin

Importance of Diet & Exercise

Women with PCOS who lose weight are more likely to have:

Decreased androgensRestored ovulationHigher pregnancy ratesLower rates of hypertension and metabolic

syndrome

Managing Glucose and Insulin levels

Less

insulin

Lowers androgens

Less hirsutism, acne,alopecia,

weight loss

5-10% weight loss in women with

PCOS can have a positive effect on insulin resistance, impaired glucose tolerance, metabolic

syndrome and fertility

Setting Measurable and Realistic Goals

The Challenge

Difficult to gain or lose weight at the extreme ends

More challenging to maintain weight loss (no FDA approval for this class of medications)

The Power of Food

We celebrate with food; we take care of our sorrow with food; and we all approach food differently. It partly has to do with the family we grew up in: was food a reward or was food withheld as a punishment?

We should eat to live, not live to eat

Obstacles to Weight Loss

Never raising the issue with patientNever taking the time to explain the

detrimental effects of elevated BMI and reproductive outcome

Telling your patient: Lose weight and then come back to see me

Using insensitive words, tone and actions that shame the patient so they never return

Obese patients are more likely to delay and cancel medical appointments

Obstacles to Weight Loss

Obesity doesn’t carry the same cultural stigma it once did.

As Americans increase in size, there is less urgency to lose weight because on average, others are heavier too.

How to Motivate?

SUGGESTION: Food Journaling

In fact, one study on people trying to lose weight showed that, along with attending weekly classes on nutrition and portion control, those who kept a food diary six days per week lost twice as much as those who logged only once per week or less.

Hollis, J. American Journal of Preventive Medicine, August 2008; vol 35.

Balance Your FatsDecrease Saturated Fat

Include Healthy Mono and Polyunsaturated fats- olive & canola oil, avocados, walnuts, flax, sunflower, sesame, almonds, peanuts, fish

REMOVE ALL Trans Fat- These are manmade chemical fats that negatively affect ovulation and increase cholesterol and inflammation.

Focus on Fiber

Opt for at least 3 daily servings of unrefined grains (such as whole grain breads and cereals, brown rice and whole wheat pasta). Because fiber is not digestible, it slows the digestion process, which then slows the release of sugar into the blood. High-fiber diets are also strongly linked to weight loss.

Exercise

Metabolism slows down when you don’t move for long periods of time

Little steps important: take the stairs

Try to MOVE!Get a workout buddy or join an

online community like: www.sparkpeople.com

Exercise

Decreases stress, lowers blood pressure and cholesterol

Increases muscle mass (which increases glucose storage). Muscle burns 12 x more calories than fat.

Increases insulin sensitivity even in the absence of weight loss

Probably has the greatest ability to improve insulin sensitivity of all of the lifestyle modifications

Which Diet is Best?

Most popular diets result in similar weight loss over 1 year

Insulin, cholesterol and C-RP levels are similarMain problem: 60-86% of weight will be

regained within 3 yearsRecent NEJM study: Mediterranean diet is

best (good fat vs bad fat) re: CVD risks.

Dansinger ML et al. JAMA.2005;293(1):43

Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; DOI:10.1056/NEJMoa200303. Available at: http://www.nejm.org/.

.

Changing the Attitudes of Staff

Admitting negative associations is necessary for some care providers

Admitting difficulty in raising the issue

Staff may have weight issues that need to be addressed simultaneously

Suggested Positive Changes

Create a compassionate environmentProvide a mix of support and educationPrivate weigh-insProper equipment for BP checksConsider starting an in house weight loss

program or refer to a reputable program or person

Educational Tools and Resources

Myths, Presumptions vs Facts

Myth: Patients should set realistic goals for weight loss. Otherwise they might become frustrated and not lose as much.

Fact: Studies have shown that patients who set more ambitious goals are likely to lose more weight

KCasazza et al NEJM 2013; 368:446-454 January 2013

Setting Goals

Recognizing that patients respond to different approaches to weight loss Individual counseling Groups Multidisciplinary approach Involving family members

Approach should be similar to nicotine and alcohol addictions or

lifelong conditions like hypertension

Helpful Interventions

Recent research supports the efficacy of a combined individual and group intervention

RMA-CT has had good patient results by adding different components to the group sessions

Certain sessions are mandatory and billable

Appel et al, NEJM 2011

N Engl J Med 2013; 368:446-454Januay 31, 201Appel et al, NEJM 201Appel et al, NEJM 2011

Weight Loss at BIVF

BIVF Weight Loss Program

One session will be held at a local grocery store, where the nutritionist will lead participants to the healthiest food sections, and teach them how to read food labels

For the last session, participants will each bring in a healthful dish to share

During each session, the nutritionist will be teaching participants how to incorporate life-long healthier eating habits, rather than dieting tips

Possible Motivators

You can try: medical facts demonstrating the health risks medical facts demonstrating the obstetrical risks increasing one’s chance for pregnancy sooner desire to be a good role model for child desire to prevent childhood obesity acknowledge how hard it is to lose weight and even

harder to maintain weight loss similar approach to treating other addictions

Lifestyle changesDiet and Exercise

Medications: Metformin or antiobesity

Severe; Bariatric surgery

Pregnancy

Anovulation

Ovulation Induction:

clomiphene or Letrozole

Clomiphene resistant; add

metformin or try Letrozole

ART: Aim for Singleton and

no OHSS

Anti- Obesity Drugs

Exanatide once weekly (Byetta)and Liraglutide once daily(Victoza)

Glucagon-like peptide-1 receptor (GLP-1R) agonists led to greater weight loss than other diabetes treatments and should be considered for obese diabetic patients

BMJ 2012;344:d7771

Anti-Obesity Drugs

FDA Approves Weight management drug Qsymia

July 2012Indications: BMI> 30 or BMI >27 with HTN,

T2D or hyperlipidemiaCombo drug: phentermine and topiramate ERPhentermine is approved for OW pts who

exercixe and dietTopiramate is an anti seizure and anti

migraine drug

Encourage a Singleton Pregnancy

SERM: selective estrogen receptor modulator (Clomiphene Citrate)

Clomiphene Citrate and MetforminAromatase Inhibitor (Letrozole) IVF with SET (avoid OHSS)

BUT WEIGHT LOSS FIRST!

Letrozole

Off label statusMechanism of action and dosingAdvantages over Clomiphene Citrate

Should be first-line or at least used more often for patient benefit

Aromatase Inhibitorsalternative to clomiphene citrate

No antiestrogenic peripheral side effects No negative effect on endometrial lining No negative effect on cervical mucus

Short half life – fast clearance from body

Used similarly to Clomiphene Citrate

Letrozole: 2.5 mg tablets 1-3 pills x 5 days

Used in some centers with fertility preservation patients who may benefit from decreasing peripheral estrogen levels during stimulation for certain types of cancers

Insulin Sensitizers

Metformin is a biguanide that inhibits the production of hepatic glucose which decreases insulin secretion, enhancing insulin sensitivity in peripheral tissues

The effect of metformin on weight and fat distribution in PCOS ptsis unclear. Some studies demonstrate weight loss and reduction in wastecircumference while others have not

Palomba et al.Endocr. Rev. 30(1), 1-50 (2009).

Insulin Sensitizers

Metformin:No serum insulin level agreed upon to initiate txCan decrease Type 2 Diabetes riskCan improve ovulationNo clear effect on weight or hirsuitismNot as effective as ovulation induction agents for

infertility tx

Remember, weight loss increases insulin sensitivity without side effects

5-10% weight loss improves hirsuitism and anovulation

Decreased hepatic production of glucoseIncreased glucose uptakeDose- 500mg up to 2 gm or 500/750mg XRNausea, diarrhea, bloatingWeight loss or no change

Metformin

Metformin

Not recommended as first line therapyNot a panacea even with “classic PCOS’Reduces hirsuitism but not as well as other

methodsNo benefit on lipidsAppropriate first line for T2D

Metformin

Should be offered to pts with IGT who do not respond to diet and exercise advise

No evidence for improved LBR or decreased pregnancy complications with use of metformin before or during pregnancy

Improves ovulation rates in CC resistant ptsNo support for universal use in all PCOS ptsBest for those with IR, can be lean or obese

Fertil and Steril Vol 97 No 1 January 2012

Summary: Tx Options for PCOS

Diet and exerciseClomiphene citrate: more effective than metformin

for the induction of ovulation and pregnancy. Clomiphene-resistant patients with PCOS,

metformin in combination with clomiphene increases ovulation or Aromastase Inhibitor

Antiobesity drugs may potentiate the effect of diet and exercise, resulting in weight loss

In patients with severe obesity, bariatric surgery appears to be the most effective way to lose weight and to improve fertility.

FRANCE APPROVES SODA TAXFRANCE'S TOP CONSTITUTIONAL BODY APPROVED A NEW TAX

ON SUGARY DRINKS THAT AIMS TO FIGHT OBESITY WHILE GIVING A BOOST TO STATE COFFERS

Mayor Bloomberg: Health Panel Approved Restriction On Sale of Large Sugary Drinks, later

struck downSeptember 2012

Is There Any Good News?

More Intake of Chocolate May Yield Lower Body Mass Index

Arch Intern Med. 2012;172: 519-521.

FUTUREIt is of great importance to develop strategies for

the prevention of overweight and obesity in order to improve reproductive and metabolic health

The most important challenge is to develop programs favoring sustained lifestyle modification

Policies must change to curb the obesity epidemic!!

PREVENTION WILL BE THE KEY!

Helpful Websites

www.soulcysters.comwww.projectPCOS.orgwww.PCOSnetwork.comwww.PCOStoday.netwww.PCOSupport.orgwww. PCOSnutrition.comEatbetter goalgetter: free iphone ap from

BCBS and goalgetter pedometerMeYou Health free iphone ap called: Munch 5

a day and monumental app to track stairs