ISSUES IN THE CARE OF WOMEN
| INSULIN RESISTANCE, THE METABOLIC SYNDROME, AND CARDIOVASCULAR RISK ----- Pamela B. Morris,
MD, Assistant Professor of Medicine, Director, Preventive Cardiology, and Co-Director, Women’s Heart Care, Medical
University of South Carolina, Charleston
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| Development of type 2 diabetes: spectrum of disease begins with development of risk factors; subclinical stage involves
insulin resistance; pancreas compensates by increasing production of insulin, resulting in hyperinsulinemia;
glucose levels remain normal until islet cells begin to fatigue and insulin levels fall; postprandial glucose levels increase
before fasting levels (undiscovered without oral glucose tolerance test); overt diabetes occurs when levels of
fasting glucose increase; early recognition of hyperinsulinemia and elevated postprandial glucose important
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 | Diagnosis: fasting glucose—prediabetes, 100 to 125 mg/dL; diabetes, ≥126 mg/dL; oral glucose tolerance test—
prediabetes, 140 to 199 mg/dL; diabetes, ≥200 mg/dL
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| Trends: prevalence likely to double by 2030; in some states, ≈25% of adult population obese; increases in diabetes parallel
trends in obesity; ethnic minorities (especially Hispanics and blacks) have elevated lifetime risk; 41 million people in
United States have glucose dysmetabolism
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| Visceral obesity: increased levels of free fatty acids and triglycerides associated with central adiposity (ie, intra-abdominal,
intrahepatic, and intramuscular fat) but not subcutaneous fat; inflammatory response—adipocytes increase in size
with weight gain and produce inflammatory cytokines (adipokines) that recruit macrophages; amplified inflammatory response
results in increased production of atherogenic molecules; waist circumference—reflection of visceral obesity;
measurement of abdomen, at tip of iliac crest
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| Vascular consequences: microvascular complications increase at fasting glucose levels ≥126 mg/dL, but macrovascular
complications begin earlier; reduced levels of high-density lipoprotein (HDL), elevated triglycerides, and increased incidence
of hypertension and atherosclerosis seen in early stages of insulin resistance; “ticking clock” hypothesis; data from
Nurses Health Study show 3-fold increase in risk for myocardial infarction (MI) or stroke occurs ≥15 yr before diagnosis of
diabetes; risk for coronary heart disease (CHD) begins to increase at fasting glucose level of 83 mg/dL; normal “safe”
threshold much lower than previously thought; data from Cardiovascular Health Study suggest postprandial glucose levels
particularly predictive of cardiovascular risk; impaired fasting glucose increases mortality rate 3-fold during percutaneous
coronary intervention (rate increases further with diabetes); red flags—MI; stroke; reduced HDL and elevated triglycerides;
presence of any cardiovascular abnormality should increase index of suspicion for insulin resistance, impaired glucose
tolerance, or diabetes
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| Metabolic syndrome: components—systolic blood pressure (BP) ≥130 mm Hg or diastolic BP ≥85 mm Hg; fasting
glucose ≥100 mg/dL; elevated triglycerides (≥150 mg/dL); HDL <50 mg/dL for women and <40 mg/dL for men; waist
circumference \>35 in for women and \>40 in for men (lower cutoffs for some European and Asian ethnic groups);
prevalence—almost half of men and women have metabolic syndrome by 60 yr of age; risk higher in Hispanic and
black women than in white women; mortality—cardiovascular-associated mortality increases 3.5 times in individuals
with metabolic syndrome
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| Lifestyle modification: diet—avoid excess calories, foods with high glycemic indices (eg, refined carbohydrates), trans
fats, and highly processed foods; encourage diet low in saturated fat, high in fiber and omega-3 fatty acids (especially those
found in fish), and including nuts; alcohol—moderate consumption beneficial (one serving daily; higher intake increases
risk for breast cancer); dietary composition—patients with metabolic syndrome may benefit from diet that includes 25%
to 35% of calories from fat (emphasizing mono- and polyunsaturated fats) and ≈50% of calories from carbohydrates; weight
loss—7% to 10% reduction associated with significant improvement in features of metabolic syndrome; physical
activity—insulin resistance immediately improves; cumulative short bursts of exercise (eg, three 10-min sessions daily) acceptable;
more exercise required for weight loss (60-90 min/day) than for maintenance of cardiovascular health (30 min/
day)
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| Prevention of progression: lifestyle modification—Diabetes Prevention Program showed lifestyle modification
(diet, exercise, and weight loss) reduced progression to diabetes by 60% (over 4 yr), compared to placebo; medical therapy
(eg, metformin) reduced progression by 31%; lifestyle intervention most important factor in all ethnic groups studied;
thiazolidinediones (TZDs)—rosiglitazone decreased progression to diabetes by 60% over 4 yr, but ramipril
(angiotensin-converting enzyme [ACE] inhibitor) not associated with benefit; TZDs reduce inflammation, promote efflux
of cholesterol from macrophages, and improve (indirectly) insulin sensitivity, triglycerides, and HDL levels; studies
show significant decrease in carotid intima-medial thickness (surrogate for vascular inflammation); rosiglitazone associated
with decreased risk for restenosis after angioplasty; prospective trial using pioglitazone found only nonsignificant
reduction in primary outcomes (eg, revascularization), but significant reduction in all-cause mortality, nonfatal MI, and
stroke
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| Medical therapy for patients with metabolic syndrome: treat each component; dyslipidemia—statins; fibric acid
derivatives; omega-3 fatty acids; hypertension—ACE inhibitors and angiotensin receptor blockers (ARBs) may have additional
benefit of renal protection; hyperglycemia and insulin resistance—appropriate medical therapy (eg, metformin, thiazolidinediones,
insulin); platelet activation and aggregation—recommendations for aspirin therapy recently revised;
more women now considered candidates for daily low-dose aspirin
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| Endocannabinoid system: cannabinoid receptor type 1 (CB1) widespread throughout body; stimulation of CB1 results
in increased appetite, increased motivation to eat and smoke, increased lipogenesis in peripheral tissue, and altered
glucose metabolism; rimonabant—inhibits CB1; decreases appetite and lipogenesis; clinical trials show rimonabant 20
mg associated with decreased weight (10-12 lb) and waist circumference (≈2 in), increased HDL, decreased triglycerides,
improved insulin resistance, and decreased level of C-reactive protein (all compared to placebo); treatment associated
with 40% to 50% reduction in diagnosis of metabolic syndrome
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| THYROID DISEASE: HOW TO TREAT A COMMON PROBLEM ----- Kathie L. Hermayer, MD, Associate Professor,
Department of Medicine, Division of Endocrinology, Medical University of South Carolina, Charleston
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| Physiology: hormones—thyroid produces 100% of levorotatory thyroxine (T4 ); most triiodothyronine (T3 ) results from
peripheral conversion of T4 ; feedback axis—thyroid hormones provide negative feedback to hypothalamus and pituitary;
dietary iodine—seafood, bread, and dairy products; iodized salt; fortified foods and multivitamins; recommended
intake, 150 µg/day
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| Circulating thyroid hormones: \>99% of circulating T4 and T3 bound to carrier proteins in plasma; ≈75% bound to
thyroxine-binding globulin (TBG); other carrier proteins include thyroxine-binding prealbumin (TBPA), albumin, and
HDL; free (unbound) hormone—affects metabolism and physiology; represents only ≈0.03% of T4 and ≈0.3% of T3 ;
TBG concentration—increase or decrease in TBG results in parallel changes in total T4 and T3 , but levels of free hormones
remain unchanged; drugs that increase concentration of TBG include oral contraceptives (or other sources of estrogen),
methadone, clofibrate, 5-fluorouracil, heroin, and tamoxifen; conditions that increase TBG include pregnancy,
infectious or chronic active hepatitis, HIV infection, biliary cirrhosis, and acute intermittent porphyria; genetic factors
also important in determining baseline levels; decreases occur with glucocorticoids, androgens, PEG-L-asparaginase, salicylates,
mefenamic acid, antiseizure medications, and furosemide; acute and chronic illness also associated with decreased
TBG
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| Effects of thyroid hormone: cardiovascular system—increases O2 consumption and cardiac output; skeletal
muscle—increases O2 consumption; affects blood flow; liver—affects protein synthesis; kidney—affects blood flow and
vasoactive mediators; overall—affects thermogenesis
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| Hypothyroidism: affects \>10 million Americans; 10 times more common in women than in men; age and risks —risk
increases in women \>40 yr of age; 6.9% of men 65 to 74 yr of age, and 12% of women \>60 yr of age have elevated
TSH; types—primary (95% of cases; elevated TSH; low levels of free T3 and T4 ); secondary (low TSH, free T3 , and
T4 )
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| Primary hypothyroidism: congenital—agenesis of thyroid gland; defective biosynthesis of thyroid hormones; acquired—
iodine deficiency; autoimmune disorder (eg, Hashimoto’s disease); iatrogenic causes (eg, treatment with radioactive iodine
or surgery); drug-induced—propylthiouracil (PTU), methimazole (Tapazole); transient—various forms of thyroiditis
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| Disease progression: patients progress through mild (ie, subclinical) thyroid failure before developing overt hypothyroidism;
effects of hypothyroidism—variable; include menstrual irregularity and menometrorrhagia, weight gain, constipation,
cold intolerance, and fatigue; cardiovascular effects include cardiomegaly, electrocardiographic changes (low
voltage), increased diastolic BP and peripheral vascular resistance, and decreased myocardial contractility; LDL level
increases as T4 decreases, because LDL-T4 complex normally down-regulates LDL receptors; note—consider checking
thyroid function before increasing antihypertensive agents or beginning statin
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| Screening recommendations: American Thyroid Association—screen women and men \>35 yr of age every 5 yr;
American Association of Clinical Endocrinologists—screen older patients, particularly women; American College of
Physicians—screen women \>50 yr of age with incidental findings suggestive of thyroid disease
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| Treatment: T4 replacement therapy; goal—normalize TSH level; options—synthetic T4 (levothyroxine; generic or trade
name); combination T4 and T3 (speaker tends to avoid; long-term effects of T3 supplementation unknown); follow-up—
monitor TSH levels at 6 to 8 wk; special populations—in patients \>50 yr of age or with underlying cardiac disease, begin
with low dose (25-50 µg/day); titrate every 6 to 8 wk; in elderly patients with cardiac disease, begin with very low dose
(12.5 µg every day or every other day); titrate slowly; in pregnant women, normalize thyroid levels as quickly as possible
(fetus depends on maternal thyroid hormone during first 12 wk of gestation); remember that hypothyroidism and hyperthyroidism
may worsen heart failure; thyroid hormone absorption—ferrous sulfate and calcium carbonate interfere; patients
taking multivitamins should wait several hours before taking T4 supplement
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| Subclinical hypothyroidism: 4% to 8% of general population affected; risk increases with age; progression to overt
disease occurs in 20% to 40% of patients within 4 yr; by 60 yr of age, ≥17% of women have elevated levels of TSH;
screening suggestions—all women; older patients; patients with hyper-cholesterolemia; patients with history of thyroid
dysfunction and treatment; patients with diabetes or other endocrinopathies; perhaps all adults; diagnosis—normal levels
of total and free T4 ; patients generally asymptomatic, but may complain of fatigue, cold intolerance, and dry skin;
TSH \>4.2 mIU/L; causes—chronic autoimmune thyroiditis; treatment for hyperthyroidism (radioiodine or surgery); inadequate
replacement therapy for overt hypothyroidism; lithium carbonate therapy (presence of thyroid antibodies increases
risk for hypothyroidism); treatment goals—prevent progression to overt hypothyroidism; alleviate symptoms;
normalize lipids; improve cardiac function; reduce depression
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| Hypothyroidism during pregnancy: diagnosis complicated by overlap with common complaints associated with
pregnancy; symptom severity varies widely; indications for screening—family history of autoimmune thyroid disease;
history of thyroid hormone therapy; presence of goiter; history of high-dose irradiation of neck, treatment for hyperthyroidism,
or postpartum thyroid dysfunction; presence of type 1 diabetes; maternal risks—miscarriage;
pregnancy-induced hypertension; preterm delivery; postpartum hemorrhage; fetal risks—small for gestational age;
intrauterine growth restriction; prematurity; transient congenital hypothyroidism (rare); depressed neuropsychologic
development (eg, lower IQ), especially in children of women with untreated hypothyroidism; treatment—beneficial,
even if euthyroid state not achieved; screening—warranted during first trimester; aggressive case-finding appropriate
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| Guidelines for treatment: encourage adherence to replacement therapy regimen before conception; monitor TSH before
conception and during first trimester; increase dosage by 25% to 50% in athyreotic patients when pregnancy confirmed;
closely monitor TSH throughout pregnancy; reinstate prepregnancy dosage immediately after delivery; overt
hypothyroidism—initiate T4 -replacement therapy (2.5 µg/kg); consider loading dose of 500 µg (efficacy not assessed);
monitor TSH every 2 to 3 wk until low-normal level achieved
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| Postpartum thyroiditis (PPT): thyroid abnormalities that begin after delivery (women euthyroid during pregnancy);
prevalence—≈8%; risk increases with history of PPT or autoimmune diseases (including type 1 diabetes); presentation—
hypothyroidism, hyperthyroidism, or hyperthyroidism followed by hypothyroidism; disease course—≈20% of patients
still have hypothyroidism at 1 yr and require permanent T4 replacement; typical course begins with hyperthyroidism (≈3
mo), followed by hypothyroidism (≈3 mo), then returning to euthyroidism; differential diagnosis—PPT associated with
low uptake of radioactive iodine; Graves’ disease associated with high uptake; treatment—T4 replacement for symptomatic
women, with goal of normalizing TSH; follow-up important (eg, discontinue thyroid hormone if patient reverts to normal)
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| Hyperthyroidism: results in accelerated metabolism in peripheral tissues; signs and symptoms—include menstrual irregularities,
fertility problems, weight loss, heat intolerance, insomnia, tremor, and exophthalmos; causes—Graves’
disease with diffuse toxic goiter; uninodular or multinodular goiter; thyroiditis (painful subacute or silent); toxic
adenoma; certain drugs; radiographic contrast agents; trophoblastic disease (eg, hydatidiform mole, choriocarcinoma);
exogenous thyroid hormone ingestion; radioiodine uptake—high uptake associated with Hashimoto’s disease, toxic
adenoma, molar thyrotoxicosis, TSH-secreting pituitary tumor, and functioning thyroid carcinoma; low uptake associated
with subacute or postpartum thyroiditis, thyrotoxicosis factitia, jodbasedow phenomenon, functioning metastasis
from thyroid carcinoma, and struma ovarii; normal uptake associated with rapid turnover in hyperthyroid gland, iodine
contamination, some cases of toxic adenoma, and treatment with propylthiouracil, methimazole, or iodides; Graves’
disease—most common cause of hyperthyroidism (60%-90% of cases); highest risk occurs in women of reproductive
age; autoimmune disorder
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| Treatment: thionamides; iodine; corticosteroids for treatment of thyroid storm; β-blockers; indications for surgery—
large (80- to 100-g) goiter; failure or refusal of other treatment modalities; thyroid scan showing cold nodules
(increased risk for cancer); procedure—subtotal thyroidectomy; complications—hypoparathyroidism; damage to
recurrent laryngeal nerve
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Suggested Reading
Asvold BO et al: Tobacco smoking and thyroid function: a population-based study. Arch Intern Med 167:1428,
2007; Bungard TJ, Hurlburt M: Management of hypothyroidism during pregnancy. CMAJ 176:1077, 2007; Espinola-Klein
C et al: Impact of metabolic syndrome on atherosclerotic burden and cardiovascular prognosis. Am J
Cardiol 99:1623, 2007; Fox CS et al: Abdominal visceral and subcutaneous adipose tissue compartments: association
with metabolic risk factors in the Framingham Heart Study. Circulation 116:39, 2007; Jeppesen J et al: Insulin
resistance, the metabolic syndrome, and risk of incident cardiovascular disease: a population-based study. J Am
Coll Cardiol 49:2112, 2007; Kolovou GD et al: The prevalence of metabolic syndrome in various populations. Am
J Med Sci 333:362, 2007; Mak KH et al: Impact of sex, metabolic syndrome, and diabetes mellitus on cardiovascular
events. Am J Cardiol 100:227, 2007; Negro R et al: The influence of selenium supplementation on postpartum
thyroid status in pregnant women with thyroid peroxidase autoantibodies. J Clin Endocrinol Metab 92:1263, 2007;
Razvi S et al: The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality
of life in subclinical hypothyroidism: randomized crossover trial. J Clin Endocrinol Metab 92:1715, 2007; Volzke H
et al: The association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship? J
Clin Endocrinol Metab 92:2421, 2007; Wilson PW et al: Prediction of incident diabetes mellitus in middle-aged
adults: the Framingham Offspring Study. Arch Intern Med 167:1068, 2007.
Educational Objectives
| The goal of this program is to improve overall health and quality of life in women, through early recognition and treatment
of common metabolic disorders. After hearing and assimilating this program, the clinician will be better able to:
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| Describe the vascular consequences of insulin resistance and diabetes.
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| Identify patients at risk of developing diabetes and prevent its progression through medical therapy and lifestyle intervention.
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| Explain the relationships among obesity, the metabolic syndrome, and cardiovascular morbidity.
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| Recognize signs and symptoms associated with thyroid gland dysfunction.
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| List maternal and fetal effects of hypothyroidism during pregnancy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Morris is on the
Speakers’ Bureaus for AstraZeneca, Kos Pharmaceuticals, Pfizer, Reliant, and Takeda, and is a consultant for AstraZeneca.
Acknowledgements
Drs. Hermayer and Morris were recorded at 38th Annual Ob/Gyn Spring Symposium, held March 26-28, 2007, in
Charleston, SC, and sponsored by the Medical University of South Carolina, Department of Obstetrics and Gynecology,
and College of Medicine, and co-sponsored by the Office of Continuing Medical Education and College of
Nursing. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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