Transcript Don`t Tell Me How Much I Weigh! - Midwest Reproductive Symposium

Midwest Reproductive
Symposium International
“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
Disclosure and Off label Information
 Speakers Bureau: Actavis
 Nurse Advisory Board: Good Start genetics
 Will discuss the off label use of Letrozole for
ovulation induction
Learning Objectives
 Discuss the difficulties in defining PCOS
 Describe the association between PCOS,
insulin resistance, and obesity
 Review reasons for the global rise in obesity
 Describe 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 Leventhal
 First thought to be an anatomic disorder
 Multiple attempts to refine the definition of
PCOS
 Consensus 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 disease
 List 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
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(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
 Stein and Leventhal:
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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
Boston IVF
PCO-Like Ovaries
“String of pearls sign”
Ovulatory Dysfunction
 Greater LH pulse frequency and amplitude
 Causes excess androgen production
 FSH level too low to mature the follicles
 FSH suppressed by mid follicular E2 levels
that cause negative feedback
 Baseline E2 levels tend to be higher
 AMH levels are elevated
Hyperandrogenism
 Virilization
 Decreased breast size
 Clitoral enlargement-rare
 Male pattern baldness
 Voice can deepen
 Acne
 Acanthosis 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
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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
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incidence and twin studies
Prenatal exposure to androgens is associated with
PCOS
Most likely poly-genetic disorder
Insulin 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
PCOS and Body Image
 Hyperandrogenism 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 hypertension
 Androgens inhibit hepatic and peripheral insulin
effect
 PCOS associated with truncal fat
 Elevated waist circumference at highest risk for
metabolic syndrome within several years
Obesity
PCOS and IR
 Not included in diagnostic criteria
 Cells stop responding well to insulin
 Body perceives elevated glucose
 Increases insulin. Cells bombarded, but not receptive
 Abdominal 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 IR
 40%of PCOS pts have impaired GTT
 10% develop Type 2 diabetes by their 4th decade
 Prevalence 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 anxiety
 Mood disorders, social phobias and sleep disorders
increased
 Psychological issues should be considered in all PCOS
pts
 Unclear if due to disorder or the comorbidities
 Appropriate counseling should be offered
Consensus on women’s health aspects of PCOS
The Amsterdam ESHRE/ASRM sponsored 3rd consensus workshop group 2011
Fert 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 DUB
 Unopposed estrogen
 At risk for hyperplasia
 Can progress to EIN
 Importance of ultrasound and endometrial biopsy
PCOS and Subfertility
 Metabolic
 Inflammatory
 Oocyte quality-impaired oocyte competence-affects
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meiosis, fertilization, embryo development via premature
granulosa cell luteinization, impaired cytoplasmic and or
nuclear maturation
Endometrial receptivity
Fetal affects, especially females
Infants; increased morbidity and mortality
Affects 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
Insulin resistance
and abdominal
obesity
Metabolic
disorders
Type 2
Diabetes
Increased
Insulin
Increased
testosterone
Anovulation,
hirsuitism, acne
Anovulation
Infertility
Decreased
SHBG
OBESITY
CANCER RISK
HYPERINSULINEMIA
IGFBP-1
IGFBP-2
IGF-1
Bioavailability
PLASMA
SHBG
Free
Androgens
Free
Estrogens
Making the Diagnosis
 Often a diagnosis of exclusion, so rule out:
 CAH
 Androgen secreting tumors
 Hyperprolactinemia
 Thyroid disease
 Cushings
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 retrieval
 Less oocytes with morbidly obese
 Decreased oocyte and embryo quality
 Decreased uterine receptivity
 More difficulty with ETs
 Decreased 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 CPR
 CPR 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 >30
 Reduced clinical pregnancy rate with autologous
cycles w/ BMI > 30
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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
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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 corn
 More than half of US field corn go into animal feed
which affects quality of our meat and poultry
 USDA (2003) estimates the average American eats
79 pounds of corn sweetener per year
 Added to: boxed cereal, ketchup, fruit juice, soda
and soft drinks, margarine, chips
Resulting in approximately 500
more calories a day
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
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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
exercise
 Twin studies show hereditary component
 Genetic differences explain radically different weight
gains and losses between individuals
Twin Studies
 6 days a week they ate 1000 extra cals per day
 Weight gain was between 10-29 pounds
 These 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 Gherlin
 Women with PCOS may have abnormal gherlin and
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leptin levels
Gherlin 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 androgens
 Restored ovulation
 Higher pregnancy rates
 Lower rates of hypertension and metabolic
syndrome
Managing Glucose and Insulin levels
Less insulin
Lowers
androgens
Less hirsutism,
acne,alopecia,
weight loss
Setting Measurable and Realistic Goals
5-10% weight loss in women with PCOS
can have a positive effect on insulin
resistance, impaired glucose tolerance,
metabolic syndrome and fertility
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 patient
 Never 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 Fats
 Decrease 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 similar
 Main problem: 60-86% of weight will be regained
within 3 years
 Recent 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 environment
 Provide a mix of support and education
 Private weigh-ins
 Proper equipment for BP checks
 Consider 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
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:
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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 changes
Diet 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 2012
 Indications: BMI> 30 or BMI >27 with HTN, T2D or
hyperlipidemia
 Combo drug: phentermine and topiramate ER
 Phentermine is approved for OW pts who exercixe
and diet
 Topiramate is an anti seizure and anti migraine drug
Encourage a Singleton Pregnancy
 SERM: selective estrogen receptor modulator
(Clomiphene Citrate)
 Clomiphene Citrate and Metformin
 Aromatase Inhibitor (Letrozole)
 IVF with SET (avoid OHSS)
BUT WEIGHT LOSS FIRST!
Letrozole
 Off label status
 Mechanism of action and dosing
 Advantages over Clomiphene Citrate
 Should be first-line or at least used
more often for patient benefit
Aromatase Inhibitors
alternative 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 pts
is unclear. Some studies demonstrate
weight loss and reduction in waste
circumference 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 tx
 Can decrease Type 2 Diabetes risk
 Can improve ovulation
 No clear effect on weight or hirsuitism
 Not 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
Metformin
 Decreased hepatic production of glucose
 Increased glucose uptake
 Dose- 500mg up to 2 gm or 500/750mg XR
 Nausea, diarrhea, bloating
 Weight loss or no change
Metformin
 Not recommended as first line therapy
 Not a panacea even with “classic PCOS’
 Reduces hirsuitism but not as well as other methods
 No benefit on lipids
 Appropriate first line for T2D
Metformin
 Should be offered to pts with IGT who do not respond to
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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 pts
No support for universal use in all PCOS pts
Best 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 exercise
 Clomiphene 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 TAX
FRANCE'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 down
September 2012
Is There Any Good News?
More Intake of Chocolate May Yield
Lower Body Mass Index
Arch Intern Med. 2012;172: 519-521.
FUTURE
 It 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.com
 www.projectPCOS.org
 www.PCOSnetwork.com
 www.PCOStoday.net
 www.PCOSupport.org
 www. PCOSnutrition.com
 Eatbetter goalgetter: free iphone ap from BCBS and
goalgetter pedometer
 MeYou Health free iphone ap called: Munch 5 a day
and monumental app to track stairs