Thyroid dysfunction is more common in women than in men. The female predominance is attributed to sex differences in immune function, similar to many autoimmune diseases. More than 80% of patients with acute or chronic thyroiditis and resulting hypothyroidism have antithyroid autoantibodies , as well as infiltration of B cells and T cells of the thyroid gland, consistent with an autoimmune etiology.
In a US sample, the prevalence of autoantibodies against the thyroid antigen thyroid peroxidase (TPO) ranged from 3% of adolescent males and 7% of adolescent females to 12% of adolescent males and 30%. Of women over age 80, women were twice as likely to have TPO antibodies as men, and black women were half as likely to have TPO antibodies as white women.
Although sensitive to thyroid dysfunction, TPO antibodies are nonspecific and frequently occur in the absence of thyroid dysfunction and the presence of other autoimmune diseases.
Antibodies against the thyroid antigen thyroglobulin are less prevalent and less associated with thyroid dysfunction, while those that act as thyrotropin receptor agonists are pathogenic in Graves’ disease, which is more common in black women. Because many individuals with TPO antibodies have normal thyroid function, other factors play an important role in determining when, if ever, thyroid dysfunction develops.
For women, profound physiological changes associated with different stages of life affect the timing of thyroid disease.
The pregnancy
Pregnancy increases thyroid hormone requirements beginning in the first trimester as a result of increased thyroid hormone metabolism by placental deiodinases, estrogen-stimulated increases in serum thyroid binding globulin (TBG), and an increased volume of distribution.
Cross-reactivity of β-human chorionic gonadotropin at the thyrotropin receptor directly stimulates thyrocytes to help meet this demand. Due to higher levels of TBG, total thyroxine levels are usually elevated. Thyrotropin remains the preferred thyroid test during pregnancy. Trimester-specific reference ranges reflect the lowest average thyrotropin in early pregnancy.
Women with decreased thyroid reserve (e.g., from iodine deficiency or autoimmunity) may not be able to fully compensate for the increased demand for thyroid hormone during pregnancy, leading to an elevation of thyrotropin. It is essential that women take a prenatal vitamin with 150 μg of potassium iodide, preferably starting before pregnancy and continuing throughout breastfeeding.
Thyroid dysfunction has been associated with infertility and early pregnancy loss.
Therefore, thyrotropin testing is recommended before assisted reproductive technology and during pregnancy in women with risk factors for thyroid dysfunction. In women recently found to have elevated thyrotropin levels during pregnancy, autoimmunity should be evaluated as a predictor of thyroid reserve.
The American Thyroid Association proposes treatment thresholds for thyrotropin greater than 4 mIU/L in women with TPO antibodies and thyrotropin greater than 10 mIU/L in women without TPO antibodies, with a thyrotropin treatment goal less than 2.5 mIU/L3 .
Most women already receiving levothyroxine will require a dose increase early in the first trimester of pregnancy. Doubling the daily dose 2 days per week (a 28% increase in total dose) at the time of a positive pregnancy test result well anticipates increased requirements. For women receiving treatment, thyrotropin should be tested every 4 weeks until 20 weeks of gestation. and once at approximately 30 weeks of gestation.
A higher incidence of autoimmune diseases in the postpartum period is attributed to a rebound of the immune system , which is suppressed during pregnancy to protect the fetus. Postpartum thyroiditis occurs in 5% of all women after giving birth, up to half of whom will have persistent hypothyroidism a year later.
In women with Grave’s disease , lower doses of antithyroid drugs are generally required during pregnancy, with higher doses after delivery. All women with a history of Graves’ disease should be screened for thyrotropin receptor antibodies during pregnancy.
Women who increased their levothyroxine dose during pregnancy should return to the prepregnancy dose after delivery, and women who started levothyroxine during pregnancy and are receiving 50 μg or less can discontinue it completely.
Fertility
The prevalence of TPO antibodies is increased in women with infertility and in those with a history of early miscarriage, raising the question of whether thyroid autoimmunity itself negatively affects reproductive health. Randomized trials of early thyroid hormone replacement showed no effects on pregnancy outcomes in euthyroid women with anti-TPO antibodies. Antibodies against TPO may indicate the presence of increased inflammation without directly contributing to poor pregnancy outcomes.
Middle age
There is little data to guide the treatment of women aged 40 to less than 60 years. During the menopause transition, decreased estrogen levels result in decreased TBG production. This decrease reduces the amount of thyroid hormone needed to maintain free thyroid hormone levels, reducing demand on the thyroid, but it is unknown if this reduction alters the thyrotropin set point.
Common but nonspecific symptoms, such as fatigue and weight gain, drive a large proportion of thyrotropin testing. Before treatment of an isolated elevated thyrotropin level (with free thyroxine level in the reference range), persistence should be confirmed in repeated testing after 1 to 3 months for thyrotropin levels less than 15 mIU/L and after 1 to 2 weeks for thyrotropin levels of 15 mIU/L or greater, in light of a high frequency of spontaneous resolution of thyrotropin elevations in repeat testing results.
Additionally, if there is no sustained symptomatic improvement with therapy, alternative explanations for persistent symptoms should be sought and discontinuation of levothyroxine considered for those with thyrotropin level less than 7 mIU/L before initiation.
Aging
A shift in thyrotropin distribution to higher levels with age, even in people without TPO antibodies, and increased life expectancy in women lead to a high prevalence of mildly elevated thyrotropin levels in older women. However, these thyrotropin elevations may not represent thyroid dysfunction .
Even in healthy older adults, an increase in thyrotropin may reflect hypothalamic and pituitary adaptation to physiological stressors, such as chronic inflammation or altered circadian rhythm.
Observational data suggest that there are no adverse consequences from leaving thyrotropin levels of 4.5 to 7 mIU/L untreated.
A randomized trial of thyroid hormone therapy for adults aged 65 years and older with a mean thyrotropin level of 5.8 mIU/L showed no symptomatic benefit. Therefore, the degree and persistence of thyrotropin elevation should be considered before initiating levothyroxine treatment.
Furthermore, excessive doses of levothyroxine, which increase the risk of arrhythmia and fracture, are more common in older women than in older men (25.2/1000 vs. 4.8/1000 person-years of levothyroxine exposure) suggesting the need for greater attention. to the dose of levothyroxine in women.
Conclusions
- Proper interpretation of thyroid function tests and treatment of thyroid dysfunction is an important women’s health issue (box).
- Correct identification and treatment of thyroid disease during pregnancy has consequences for maternal and fetal health.
- In non-pregnant women, the degree and persistence of thyrotropin elevation, age, and other mitigating factors need to be considered before initiating levothyroxine replacement.
- Understanding changes in physiology across the lifespan allows doctors to optimize care for women with thyroid disease.
Thyroid disease in women
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