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By Sarah L. Berga, MD
We have all been taught various heuristics for when to screen for hypothyroidism, but most of us wonder if we are doing so correctly. Several lines of converging evidence suggest that the untoward consequences of subclinical hypothyroidism pose a serious threat to long-term health, especially for fetuses. Therefore, I thought a brief review of the topic would be timely.
First, I would like to offer some background. Hypothyroidism comes in 2 main flavors. Primary hypothyroidism occurs when the thyroid gland cannot adequately respond to adequate or increased thyroid-stimulating hormone (TSH) stimulation. In contrast, secondary hypothyroidism occurs when the thyroid-releasing hormone (TRH) or TSH message is too low to adequately stimulate the thyroid. In primary hypothyroidism, the TSH signal is generally modestly to greatly elevated. This is the type of hypothyroidism that can often be detected by obtaining a serum TSH. However, as we will review, occult primary hypothyroidism can exist when the TSH is at the upper limit of normal and thyroxine (T4) is at the lower limit of normal. This condition is often referred to as subclinical hypothyroidism or hypothyroxinemia. The major cause of hypothyroxinemia worldwide is iodine deficiency. Another common cause is autoimmune thyroiditis. The most common cause of secondary hypothyroidism is stress, either psychogenic and/or metabolic, such as is induced by poor nutrition, chronic or severe acute illness, surgical procedures, and excessive exercise. In secondary hypothyroidism, the circulating TSH signal does not rise because there is decreased hypothalamic TRH drive. Thus, secondary hypothyroidism cannot be detected by measuring TSH alone. Given the above considerations, it should be obvious that to adequately screen for hypothyroidism, one must measure both TSH and free thyroxine. The question is not so much how to detect hypothyroidism, but when or in whom to look for it.
It is well recognized that primary hypothyroidism is associated with altered menstrual patterns.6 Less well known is that functional forms of hypothalamic hypogonadism ranging from amenorrhea to luteal insufficiency have as a concomitant a spectrum of hypothalamic hypothyroidism.1 Several mechanisms may be operant, but the most obvious is that the increased cortisol characteristic of functional hypothalamic hypogonadism blunts the thyroidal response to TSH and the pituitary response to TRH. Further, metabolic deficits induced by excess energy expenditure or inadequate or imbalanced energy intake may suppress TRH drive by mechanisms independent of cortisol. The combination of psychogenic and metabolic stress suppresses hypothalamic TRH drive maximally. This form of secondary hypothyroidism presents with TSH levels that are in the lower range of normal and thyroxine levels that are at or below the lower limit of normal. It represents an adaptive mechanism for ensuring survival in the face of challenge. Firm epidemiological data are not available to tell us how often menstrual disturbances are due to primary hypothyroidism or primary hyperthyroidism. However, the most common cause of amenorrhea in reproductive- age women is functional forms of hypothalamic hypogonadism. Further, nearly 50% of recreational runners had a mild form of hypothalamic hypogonadism, even when the menstrual interval was preserved.3 Thus, there is good reason to recommend that all women with altered menstrual patterns be screened for hypothyroidism (and hyperthyroidism) by obtaining a TSH and free T4.
Another circumstance when thyroidal function is assessed is in the evaluation of infertility. It seems to be an almost universal practice to obtain a TSH level on the female partner even when ovulatory function is adequate. In the past, I have not felt that there was a sufficiently strong rationale for this practice. However, as I will review later in this article, based on emerging concepts, the main rationale for assessing thyroidal function in the female partner (with a TSH and free T4) is to detect occult hypothyroxinemia before pregnancy ensues.
The main reason for screening for hypothyroidism in perimenopausal and menopausal women seems clearer. The prevalence of primary forms of hypothyroidism increases with age and is sufficiently common in women 40 years of age so as to make screening worthwhile. Further, hypothyroidism can mimic many of the symptoms often attributed to the altered ovarian secretion that is the hallmark of the perimenopause and menopause. Since decreased T4 alters the clearance of sex steroids, failure to recognize hypothyroidism in this population may make hormone therapy problematic. For instance, delayed clearance of sex steroids may increase the risk menometrorrhagia or may alter (blunt or exaggerate) the response to customary estrogen doses. In my experience, hypothyroidism is more often a concomitant of menopause rather than the only cause of menopausal symptoms. It is also a cause of altered lipoprotein profiles that are often seen in this age group. Milder forms of hypothyroidism are common in women and deleterious to long-term health. Thus, screening for hypothyroidism in asymptomatic women at 5 year-intervals starting at 35 years of age has been shown to be cost effective.2
My main purpose in bringing this topic to your attention has to do with the terrible fetal consequences of maternal hypothyroxinemia.5 In their review article, Morrelae de Escobar and colleagues offer a wealth of valuable information. Their article, in turn, was inspired by the recently published study by Haddow and colleagues.4 This study demonstrated that clinically occult maternal thyroid deficiency due to autoimmune thyroiditis during pregnancy resulted in impaired neuropsychological development in the offspring. However, the study by Haddow et al heralds just the tip of the iceberg. As the article by Morreale de Escobar et al documents in detail, motor and cognitive impairment of progeny correlates with degree of maternal hypothyroxinemia, not circulating thyronine (T3) or TSH levels. The dependence upon T4 reflects the expression of nuclear thyroid receptors in the brain by the 10th week of human gestation, a period of active cortical neurogenesis. Since the fetal thyroid does not begin to function until 18-22 weeks of gestation, the maternal supply is the only fetal source until midgestation. Although T3 is the active hormone for the nuclear receptors, the developing brain must synthesize T3 in situ by converting T4 to T3. Thus, T4 is the critical substrate for cortical neurogenesis, not T3. The clinical consequences of maternal hypothyroxinemia can result in a spectrum that ranges from severe mental retardation to milder forms of impaired neuropsychological development. Further, the most common reason for subclinical hypothyroxinemia is not autoimmune thyroiditis but iodine deficiency, an entity that is simply prevented by increasing dietary iodine. Apparently, 15% of North American women have outright iodine deficiency. While iodine deficiency is easy to treat, one must make certain that sufficient iodine is supplied before pregnancy, or failing that, as early in pregnancy as possible. The recommended intake is 200-300 mg daily, and it can be taken as potassium iodine or as part of a multivitamin. I checked the various multivitamin preparations at home in my cupboard and found that most did not contain iodine. The only one that did was the children’s formulation.
Morreale de Escobar et al recommend that all pregnant women be screened early in pregnancy (no later than the 12th week) by obtaining TSH, free T4, thyroid peroxidase (TPO) antibodies, and possibly antithyroglobulin antibodies. When the manuscript by Haddow et al was published, the Endocrine Society issued a similar alert but did not call for testing of free T4 or antibodies. For the general Ob/Gyn, the critical take-home point is to screen early in pregnancy and to make sure that pregnant women or those who could become pregnant have sufficient iodine intake. For those of us involved in infertility care, the take-home message is to delay infertility treatment in hypothyroxinemic women until it is corrected. One must have a diagnosis first. Thus, rather than screening with a TSH, one must obtain also free T4 and possibly also antithyroid antibodies. For women with functional forms of hypothalamic hypogonadism, the optimal course of action is to initiate lifestyle changes that permit restoration of ovulatory adequacy. Ovulation induction is relatively contraindicated in recognition of the fact that women with functional hypothalamic hypogonadism also have functional hypothalamic hypothyroidism of the same magnitude as that found with subclinical autoimmune thyroiditis. Functional hypothalamic hypothyroidism corrects when ovulatory function resumes but persists if ovulation induction is undertaken in the absence of lifestyle and attitudinal adjustments. In the case of organic thyroidal disturbances, replacement with exogenous thyroxine or increasing iodine intake should correct the problem. It is not clear that thyroxine will have the same beneficial effects in the face of hypothalamic forms of hypothyroidism.
1. Berga SL, et al. J Clin Endocrinol Metab. 1989;68:301-308.
2. Danese MD, et al. JAMA. 1996;276:285-292.
3. De Souza MJ, et al. J Clin Endocrinol Metab. 1998;83:4220-4232.
4. Haddow JE, et al. N Engl J Med. 1999;341:549-555.
5. Morreale de Escobar G, et al. J Clin Endocrinol Metab. 2000;85:3975-3987.
6. Winters SJ, Berga SL. The Endocrinologist. 1997;7:167-173.