Thyroid Disease in Women at Midlife

Thyroid disease, one of the most common endocrine disorders in women, can be particularly vexing when presenting at midlife (age range, 40–60). Many symptoms overlap with those of the menopause transition, including menstrual cycle changes, fatigue, sleep disturbances, changes in mood, skin, and hair, and heat intolerance. Subclinical thyroid disorders are challenging dilemmas that further complicate the clinical picture as women age.

Screening

A decade ago, the U.S. Preventive Services Task Force found insufficient evidence to recommend thyroid screening in adults.1 Since then, screening recommendations specific to women have varied by expert groups, but all allow for increased suspicion and aggressive case finding in older women (particularly those with incidental findings suggestive of thyroid disease).2 In the Study of Women's Health across the Nation, almost 1 in 10 midlife women had some abnormality of thyroid-stimulating hormone (TSH).3 Family history of thyroid disorders, personal history of postpartum thyroiditis, previous treatment for Graves disease, or autoimmune disorders such as type 1 diabetes increase the likelihood of developing thyroid dysfunction.

Hypothyroidism

Hashimoto thyroiditis is the most common underlying cause of thyroid disorders in women. Symptoms include cold intolerance, sluggishness, fatigue, dry skin, constipation, and abnormally heavy menstrual cycles. Laboratory abnormalities that may suggest hypothyroidism include hypercholesterolemia, hypertriglyceridemia, hyperprolactinemia, hyponatremia, anemia, and elevated creatine phosphokinase levels. On laboratory evaluation, TSH is elevated in the presence of low free thyroxine (FT4). Positive test results for antithyroperoxidase antibodies (TPOAb) indicate an autoimmune etiology. If the clinical picture is consistent with hypothyroidism — and both TSH and FT4 are low — the possibility of central hypothyroidism should be considered and the hypothalamus and pituitary evaluated.4

Management of hypothyroidism is straightforward and clinically satisfying, as symptoms usually respond promptly. For women older than 50 to 60 without evidence of coronary heart disease (CHD), therapy should be started with synthetic thyroxine (levothyroxine) at a dose of 50 µg daily.2 Patients with CHD should be started at lower doses (12.5–25 µg levothyroxine daily). Patients should be informed that taking thyroid hormone with food or calcium, vitamins, or iron supplements may interfere with the hormone's absorption. Some patients take their daily dose with water 30 to 60 minutes before breakfast; others find evening dosing (3–4 hours after the day's last meal) to be more convenient.

Serum TSH should be measured 6 to 8 weeks after initiating thyroxine therapy or changing the dose. Depending on TSH levels and patient considerations, titrate at intervals of 6 to 8 weeks by increasing the dose by 12.5 to 25 µg. When the patient's thyroid hormone is adequately replaced, the TSH level should fall within the normal range. If oral estrogen therapy is either initiated or discontinued, TSH should be reevaluated 6 to 8 weeks later. Oral estrogens increase thyroxine-binding globulin concentration, which in turn lowers FT4, potentially necessitating a higher dose of thyroxine; conversely, when oral estrogen is discontinued, reduction of thyroxine dosing should be anticipated.5

Subclinical Hypothyroidism

Mild elevation of TSH with normal FT4 might be consistent with subclinical hypothyroidism. Some experts suggest, however, that aging itself contributes to modest increases in TSH.6 Before making a diagnosis of subclinical hypothyroidism (which occurs in 4%–8% of the population and as many as 15% of the elderly), repeat the thyroid hormone panel in 3 to 6 months. Within 5 years, almost two thirds of cases will regress to euthryoidism.7 Although concerns have been voiced that untreated subclinical hypothyroidism might contribute to CHD, heart failure, and mortality, evidence from randomized clinical trials that treatment is beneficial is lacking.8 Expert guidelines recommend an individualized approach to treatment that takes into account degree of TSH elevation, patient age, and cardiovascular health.2 Consider treatment in patients with TSH between the upper limit of normal and 10 mIU/L, hypothyroid symptoms, positive TPOAb, or evidence of atherosclerotic cardiovascular disease (CVD), heart failure, or risk factors for CVD, as well as patients with TSH >10 mIU/L.2 Daily doses in the range of 25 to 75 µg thyroxine are usually adequate.2 Careful titration is important to prevent inadvertent thyroid-hormone excess.

Hyperthyroidism

Hyperthyroidism is characterized by heat intolerance, palpitations, anxiety, and lighter, less-frequent menstrual periods. The condition is most often caused by Graves disease, toxic multinodular goiter or a solitary hyperfunctioning (i.e., “hot”) nodule, and, less commonly, by autoimmune thyroiditis.9 The first diagnostic step is TSH measurement. If TSH levels are suppressed, FT4 assessment should follow. If FT4 is elevated, a radioactive iodine uptake scan can distinguish Graves disease and toxic multinodular goiter from other etiologies while also helping to define the thyroid gland's anatomy. If a hyperfunctioning nodule is detected, triiodothyronine (T3) should be measured.

Treatment of hyperthyroidism includes beta blockers for symptom relief and the antithyroid drug methimazole to reduce synthesis and release of thyroid hormone. Thyroid ablation with radioactive iodine provides definitive therapy, but often results in permanent hypothyroidism and the need for lifelong thyroid hormone replacement. Usually an endocrinologist should be consulted when managing a hyperthyroid patient.

Subclinical Hyperthyroidism

TSH suppression in the presence of normal FT4 could signify subclinical hyperthyroidism. This condition occurs in about 2% of individuals and is associated with osteoporosis and fractures, atrial fibrillation, heart failure, and possibly excess risk for CHD and associated death.7 In an otherwise healthy, asymptomatic woman, monitoring TSH over a period of 3 to 6 months is a reasonable way to document persistent TSH suppression. However, if TSH is <0.1 mIU/L, the specific thyroid disorder (most commonly toxic multinodular goiter) should be identified.9 Treatment is recommended in patients 65 or older, in postmenopausal women at risk for accelerated bone loss, and in patients younger than 65 with CHD, osteoporosis, or persistent hyperthyroid symptoms.9 Depending on the clinical situation, treatment might also be appropriate in individuals with TSH between 0.1 and 0.4 mIU/L. Exercise caution to avoid transitioning the patient from subclinical hyperthyroidism to hypothyroidism as a result of therapy.

Thyroid Nodules

Thyroid nodules are palpable in about 5% of women and detectable by ultrasound in up to two thirds of the general population. Between 5% and 15% of nodules are malignant, and thyroid cancer is most commonly detected in women aged 40 to 60. Thyroid nodules can arise from benign nodular goiter, chronic lymphocytic thyroiditis, simple or hemorrhagic cysts, follicular adenomas, subacute thyroiditis, various carcinoma types (e.g., papillary, follicular, medullary, anaplastic), primary thyroid lymphoma, sarcoma, teratoma, and metastatic tumors. Risk factors for malignancy include history of head and neck irradiation, family history of thyroid carcinoma, growing nodule, firm or hard consistency of nodule, cervical adenopathy, fixed nodule, persistent dysphonia, dysphagia, or dyspnea.10 Most thyroid nodules appear hypofunctioning (i.e., “cold”) on radioactive thyroid uptake scanning, but up to 3% of hyperfunctioning (“hot”) nodules have also been found to harbor malignancy. Clinical findings, ultrasound characteristics, and cytology examination following fine-needle aspiration of the nodule all serve to establish the diagnosis and guide appropriate management.

Conclusion

Thyroid disorders are common in midlife women and can be associated with significant symptoms, morbidity, and possibly death. Maintaining a high index of suspicion and conducting the appropriate evaluation should identify affected women and facilitate prompt referral and initiation of therapy.