Issues in Endocrinology

Educational Objectives

The goal of this program is to improve management of thyroid disorders and polycystic ovary syndrome (PCOS). Af­ter hearing and assimilating this program, the clinician will be better able to:

1.   Screen women for hypothyroidism and hyperthyroidism.

2.   Describe appropriate therapies for hypothyroidism and hyperthyroidism.

3.   List criteria for the diagnosis of PCOS.

4.   Explain pharmacologic strategies for treating hirsutism.

5.   Compare efficacy of lifestyle changes, metformin, and clomiphene for promoting fertility in patients with PCOS.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee 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 faculty and planning committee reported nothing to disclose. In her lecture, Dr. Huddleston discusses the off-label or investigational use of a therapy, product, or de­vice.

Acknowledgments

Dr. Lee was recorded at Controversies in Internal Medicine, presented May 4-8, 2009, in Hilton Head Island, SC, by the Boston University School of Medicine. Dr. Huddleston was recorded at Obstetrics and Gynecology Update: What Does the Evidence Tell Us?, presented October 7-9, 2009, in San Francisco, CA, by the University of California, San Francisco, School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences. The Audio-Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

Thyroid Disorders in Women

Stephanie L. Lee, MD, Associate Professor of Medicine and Associate Chief, Department of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, and Director, Thyroid Disease Center, Boston Medical Center, Boston, MA

Overview: thyroid nodules  —  common; found in 50% of patients on ultrasonography (US), and  ³10% of patients on palpation; thyroid dysfunction  —  occurs in up to 1 in 8 patients, especially in elderly population; thyroid conditions found predominantly in women

Thyrotropin (TSH) as monitoring tool: only 0.04% of TSH in free bioactive form; remainder bound (ie, inactive hormone) to thyroxine-binding globulin (TBG) and albumin; therefore, never use total T₄ to assess thyroid function

Factors affecting T₄ levels: estrogen  —  increases TBG; pregnancy  —  total T₄ can increase (to 14-16 mg/dL), because of increased binding proteins, and stay within normal range; other estrogen sources  —  replacement therapy, contra­ception, and infertility treatments with follicle-stimulating hormone (FSH) injections; long-term narcotic use  —  elevates T₄; leuprolide (eg, Lupron)  —  lowers TBG and T₄; changes in pregnancy  —  TGB levels rise quickly at start, plateau at 20 wk, then stabilize; 50% increase in T₄ during first 20 wk (eg, from 9 to 13 µg/dL); estimate thy­roid functions with TSH (levels decrease when thyroid hormone increases, and vice versa); 2-fold change in T₄ lev­els results in 100-fold change in TSH; TSH more sensitive, accurate, and can diagnose euthyroidism, hypothyroidism, and hyperthyroidism

Hypothyroidism

Prevalence: men  —   »2% to 3% over decades,  until >70 yr of age (increases to »10% of men); women  —  stepwise in­crease starting at 30 yr of age; by >70 yr of age, 1 in 7 or 8 women has unsuspected hypothyroidism

Screening: TSH  —  most sensitive and specific test for hypothyroidism; inexpensive

Causes: Hashimoto disease most common; other causes  —  radioactive iodine therapy or thyroid surgery

Hashimoto disease: ask about family history of thyroid and other autoimmune diseases (eg, lupus erythematosus, colitis); environmental factors include pregnancy (presence of fetus can activate maternal immune system and initiate autoimmune disease); thyroperoxidase (TPO) antibody rises before onset of disease; predicting disease  —measure TPO antibody levels rather than antithyroglobulin antibodies; after destruction, TSH will rise; patient with mildly elevated TSH and positive antibody has 5% per year chance of developing hypothyroidism

TSH and TPO antibody in diagnosis: slightly elevated TSH does not always lead to disease; study of elderly pa­tients with mildly elevated TSH  —  in patients positive for TPO, 80% developed hypothyroidism after 4 yr (vs very few in negative TPO group); if hypothyroidism suspected  —  measure TSH; if TSH low  —  patient possibly hyperthy­roid; 0.3 to 3.5 mg/dL considered restricted normal range; if >9 mg/dL  —  patient hypothyroid; requires treatment; if 3.5 to 9 mg/dL  —  repeat TSH 2 mo later (»50% of patients normalize) and measure TPO antibody; treat if positive

Treatment: levothyroxine standard treatment; structure identical to that of natural thyroid hormone; long half-life (7-10 days); once-daily dosing (can take 2 next day if 1 dose missed); T₃  —  50 to 100 times more active than T₄; dose  —  determined by age and weight; drastic weight loss may require reduction in dose; younger patients need more thyroid hormone because of faster metabolism

Contraindications: drugs  —  estrogen therapy and antiseizure drugs increase binding protein; may need more hor­mone to fill binding sites; pregnancy  —  50% to 80% of pregnant women taking thyroid hormone require 25% to 50% increase in dose; interference with thyroid hormone  —  absorption blocked by supplementation with iron or calcium, use of sucralfate, history of malabsorption (eg, celiac disease), and ingestion of high-fat foods

Importance of thyroid hormone brand: study of patients using 4 brands of hormone  —  normal thyroid function at start of study; change in brand (not dose) increased risk for abnormal thyroid function by 40% to 50% (50% of affected patients hyperthyroid, 50% hypothyroid); take-home messages  —  specify “no substitution of brand”; in­struct patient to verify that same manufacturer used for each refill; if manufacturer changes, patient must return for recheck of thyroid hormone levels after 1 mo

Maintenance of thyroid function: study data show only »60% of patients taking thyroid hormone fall within normal range; »20% have excess hormone; »20% undertreated; New England Journal of Medicine (NEJM) study  —  after initiation of oral contraceptives in 25 women on thyroid hormone, 10 had elevated TSH levels; Hashimoto disease  —  add »25 to 50 mg of thyroid hormone (»25% dose increase); no thyroid function  —  after, eg, radioactive iodine or thyroid surgery, »50% dose increase required

Changes in thyroid function during pregnancy: if untreated, increases risk of worsening of hypothyroidism and for preeclampsia, anemia, postpartum hemorrhage, and cardiac ventricular dysfunction; effects on offspring  —  increased risk for spontaneous abortion, low birthweight, abnormal brain development, and lower intelligence quo­tient (IQ); controversial NEJM study  —  IQ <85 in 4% of children born to control women vs 13% born to women with hypothyroidism; thyroid testing by primary care physicians  —  may see pregnant women earlier than obstetri­cians (in first trimester); hypothyroidism may occur in first 20 wk (when TBGs rising); check TSH as soon as preg­nancy confirmed; check every 4 wk until week 20; increase dose by 50 to 75 mg/day; after delivery, return to previous dose

Subclinical hypothyroidism: signs and symptoms  —  weight gain, fatigue, or TPO antibody positivity; treatment  —  L-thyroxine (brand name or consistent generic manufacturer), taken on empty stomach; avoid calcium and iron

Hyperthyroidism

Graves disease: most common cause of thyrotoxicosis; autoimmune disease caused by thyroid-stimulating immuno­globulin (TSI); occurs predominantly in women 30 to 49 yr of age; pregnancy  —  condition exacerbated during first trimester; improves in second and third trimesters (ie, can stop antithyroid medicine); worsens 1 to 6 mo postpar­tum; fluctuations most likely due to changes in immune status

Treatment: methimazole or propylthiouracil (PTU)  —  interfere with thyroid hormone synthesis; complications  —  pruritus  occurs in 20% of patients (treat with antihistamines); 3 in 1000 have agranulocytosis; if extreme sore throat or fever >101ËšF develop, stop medication and obtain complete blood count; hepatitis and arthralgia (rare); dosage during pregnancy and breastfeeding  —  PTU preferred (less transfer through placenta and breast milk) to de­crease likelihood of fetal goiter; give lowest possible dose of antithyroid drug; T₃ and T₄ in pregnancy  —  maintain higher limits of normal, or slightly high (studies show no negative outcomes of mild thyrotoxicosis); check thyroid functions monthly in pregnant women taking antithyroid drugs; TSI  —  extremely high levels at end of pregnancy predict neonatal hyperthyroidism; fetal US recommended, as large fetal goiter can cause asphyxiation during deliv­ery; if noncompliant or requiring high doses of antithyroid medication  —  recommend surgery during second tri­mester  

Alternative cause of low TSH during pregnancy:  b-human chorionic gonadotropin  (b-hCG) structurally similar to TSH; b-hCG rises to maximal level at 12 wk, then falls to high but stable level; b-hCG binds to TSH receptors and causes slight increase in thyroid hormone; therefore, TSH drops during first trimester, then rises as b-hCG drops; take-home message  —low TSH during pregnancy not always indicative of hyperthyroidism; measure thyroid func­tion at end of first trimester; if TSH suppressed and T₄ or free T₄ normal or slightly elevated, do not treat; check lev­els next month

Polycystic Ovary Syndrome (PCOS)

Heather G. Huddleston, MD, Assistant Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, School of Medicine

Overview: characterized by oligo-ovulation, hirsutism, other signs of hyperandrogenism, and polycystic ovaries; af­fects 5% to 10% of reproductive-aged women; pathogenesis  —possible role of pituitary, androgens, and insulin; probably polygenic (ie, familial clustering suggests underlying genetic etiology, but environmental factors also im­plicated)

Diagnosis: 2003 Rotterdam criteria  —  now used in place of 1990 National Institutes of Health criteria; patients must have 2 of 3; 1) oligo-ovulation or anovulation, 2) clinical or laboratory evidence of hyperandrogenism, and 3) poly­cystic ovaries; exclude other etiologies; oligo-ovulation  —  <8 menses per year; unpredictable onset or heavy bleed­ing and spotting; hyperandrogenism  —  clinical diagnosis based on hirsutism, acne, and male-pattern alopecia; laboratory diagnosis based on elevated total testosterone, free testosterone, or dehydroepiandrosterone (testosterone assays not accurate in women); ovarian characteristics  —  ³12 follicles in 1 ovary (controversial); increased ovarian volume; other findings not part of criteria  —  obesity; acanthosis nigricans

Diagnostic exclusions: congenital adrenal hyperplasia; thyroid disease; hyperprolactinemia; Cushing’s syndrome  —consider excluding in patient with features of PCOS and elevated blood pressure, striae, and lipodystrophy ("buf­falo hump"); androgen-producing tumors  —  excluded with testosterone level; functional hypothalamic amenorrhea  —consider if patient exercises frequently and has negative progesterone withdrawal test

Rotterdam criteria: allow 4 potential PCOS phenotypes with differing combinations of 3 features; implications of each phenotype currently under investigation

Management of PCOS

Control of menstrual cycle: educate patient on importance of progesterone in preventing uterine hyperplasia due to unopposed estrogen; cyclic progestin  —  once every 2 mo for 1 wk; oral contraceptive (OC)  —  easiest; added bene­fits; hormone-releasing intrauterine device (eg, Mirena)  —acceptable alternative

Management of hyperandrogenism: Endocrine Society guidelines on management of hirsutism (2008 ) —treatment based on importance to patient; previously based on modified Ferriman-Gallwey (MFG) score; MFG  —unfamiliar to many physicians; not adjusted to account for varying norms among ethnicities

Treatment of hirsutism: mechanical removal  —  laser, electrolysis, or tweezing; pharmacologic  —  oral contracep­tives with antiandrogens (eg, spironolactone, flutamide, finasteride); eflornithine (eg, Vaniqa); mechanisms of OCs  —  increase sex hormone-binding globulin (SHBG); bind free testosterone; directly decrease production of androgens; no significant differences seen with different formulations of OCs (choose drug based on side effect profile); takes »6 mo to prevent regrowth; acceptable to combine with direct removal; consider second agent (eg, spironolactone) after 6 mo

Treatment of fertility concerns: anovulation or PCOS  —  weight loss and lifestyle change, clomiphene (eg, Clomid), and metformin; mechanisms — metformin and weight loss believed to affect insulin sensitivity and function, and thereby improve ovarian function; clomiphene triggers brain to increase pituitary production of follicle-stimulat­ing hormone

Effect of lifestyle changes: studies found improved ovulation and pregnancy rates with weight loss and exercise; weight reduction also reduces complications of pregnancy; should be considered first-line

Clomiphene: first choice if lifestyle changes fail; synthetic antiestrogen; convenient and inexpensive; 1998 study  —50% of women ovulated on 50 mg daily; additional subsets ovulate with 100 mg or 150 mg daily; 45 of 201 pa­tients remained anovulatory, even at 150 mg daily; study of conception  —  160 patients with anovulatory infertil­ity and successful response to clomiphene; »60% conceived after 6 menstrual cycles (»70% after 9)

Metformin: insulin sensitizer; not approved by Food and Drug Administration for treatment of infertility; category B for pregnancy; 2003 meta-analysis  —  metformin vs placebo successful (odds ratio [OR] for ovulation 3.8); metformin and clomiphene more effective than clomiphene alone (OR 4.4); Reproductive Medicine Network study (United States)  —  626 women with PCOS; randomized to clomiphene, metformin, or both; mean body mass index (BMI) 34; androgenized (ie, high MFG scores); chance of conception highest in clomiphene and met­formin group, but difference from clomiphene alone not statistically significant; over 6 mo, chance of conception much higher with clomiphene, compared to metformin; metformin may take longer to work than clomiphene; highest miscarriage rate in metformin group (close to statistical significance); invalidates previous theory that metformin reduced miscarriage rates

Predictors of fertility success: youth; lower BMI; lower hirsutism score; unclear if specific subgroups benefit from metformin

PCOS and Long-Term Health

Insulin resistance: Dunaif study (1996)  —  obese women with PCOS more insulin resistant than obese women with­out PCOS; lean women with PCOS more insulin-resistant than lean women without PCOS, but less so than obese women without PCOS; glucose tolerance  —  found to be impaired in 30% of women with PCOS; 10% had type 2 diabetes; metabolic syndrome  —  common in PCOS; 5 criteria (waist circumference, low high-density lipoproteins, high triglycerides, hypertension, and high fasting blood glucose); risk factor for cardiometabolic or cardiovascular disease; 33% of women with PCOS found to have metabolic syndrome

Metabolic impact of obesity: 2001 study  —  67 women with PCOS and impaired glucose tolerance followed for 6 yr; 54% developed type 2 diabetes; 15% normalized glucose; 31% had no change; relative risk for conversion to type 2 diabetes in high BMI group vs low BMI group »10

Avoiding type 2 diabetes in PCOS (2002 Diabetes Prevention Trial): 4-yr study of individuals with impaired glu­cose tolerance and family history of diabetes; development of type 2 diabetes  —  14% of patients on diet and exer­cise; 22% of patients on metformin; 29% on placebo; recommendations  — var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E"));