Thyroxine replacement is initiated in patients with clinically overt hypothyroidism or sub-clinical hypothyroidism with a goiter. Regression of gland size usually does not occur, but treatment often prevents further growth of the thyroid gland. Treatment is recommended for patients with subclinical hypothyroidism in the setting of a TSH greater than 10 mIU/L on repeat measurements, pregnant patients, a strong habit of tobacco use, signs or symptoms associated with thyroid failure, or patients with severe hyperlipidemia (380). All pregnant patients with an elevated TSH level should be treated with levothyroxine. Treatment does not slow progression of the disease. The initial dosage of levothyroxine may be as little as 12.5 μg per day up to a full replacement dose. The mean replacement dosage of levothyroxine is 1.6 μg/kg of body weight per day, although the dosage varies greatly between patients (368). Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate may interfere with absorption. Rifampin and sertraline hydrochloride may accelerate the metabolism of levothyroxine. The half-life of levothyroxine is nearly 7 days; therefore, nearly 6 weeks of treatment are necessary before the effects of a dosage change can be evaluated.
Hypothyroidism appears to be associated with decreased fertility resulting from disruption in ovulation, and thyroid autoimmune disease is associated with an increased risk of pregnancy loss with or without overt thyroid dysfunction (381). A meta-analysis of case-control and longitudinal studies performed since 1990 reveals a possible association between miscarriage and thyroid antibodies with an odds ratio of 2.73 (95% CI, 2.20–3.40). This association may be explained by a heightened autoimmune state affecting the fetal allograft or a slightly higher age of women with antibodies compared with those without antibodies (0.7 ± 1 year, p <.001) (382). Studies suggest that early subclinical hypothyroidism may be associated with menorrhagia (383).
Severe primary hypothyroidism is associated with menstrual irregularities in 23% of women, with oligomenorrhea being the most common (382). Reproductive dysfunction in hypothyroidism may be caused by a decrease in the binding activity of sex hormone–binding globulin, resulting in increased estradiol and free testosterone and from hyperprolactinemia (382). The increase in prolactin levels is the result of enhanced sensitivity of the prolactinsecreting cells to TRH (with elevated TRH seen in primary hypothyroidism) and defective dopamine turnover resulting in hyperprolactinemia (384–387). Hyperprolactinemia-induced luteal phase defects are associated with less severe forms of hypothyroidism (388,389). Replacement therapy appears to reverse the hyperprolactinemia and correct ovulatory defects (390,391).
Combined thyroxine and triiodothyronine therapy is no more effective than thyroxine therapy alone, and patients with hypothyroidism should be treated with thyroxine alone (392). Treatment should target normalizing TSH values, and a daily dose of 0.012 mg up to a full replacement dose of levothyroxine (1.6 μg/kg of body weight per day) may be required with dosage dependent on the patient’s weight, age, cardiac status, and duration and severity of hypothyroidism (368).