“DON’T TELL ME HOW MUCH I WEIGH!” , THE SENSITIVE MANAGEMENT OF WEIGHT AND THE PCOS PATIENT CAROL LESSER, MSN, NP BOSTON IVF JUNE 19, 2014 Midwest Reproductive Symposium International
Dec 17, 2015
“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
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
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
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
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
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 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.
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
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
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!