Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues

Abstract

Purpose: Subclinical hypothyroidism is found in about 7.5% of females and in about 3% of males. It appears to be a risk factor for atherosclerosis and for coronary heart disease and can affect various other target organs. The morbidity and clinical significance of subclinical hypothyroidism are controversial. Therefore, we evaluated the metabolic impact of progressive thyroid failure in patients with various degrees of hypothyroidism compared with control subjects.

Patients and methods: We investigated 86 female patients with the whole spectrum of subclinical hypothyroidism (n = 69) and of overt hypothyroidism (n = 17) and 52 euthyroid women as controls. All subjects underwent full medical and endocrine evaluations (including measurements of thyrotropin [TSH], TSH beta- and alpha-subunits, and prolactin before and after oral administration of thyrotropin-releasing hormone [TRH]) as well as lipid profiles and different tests of peripheral thyroid hormone action. All hypothyroid patients were divided into five categories according to disease severity: grades I to III (subclinical hypothyroidism, with normal thyroxine [T4] levels) and grades IV and V (overt hypothyroidism, with diminished T4).

Results: In grade I subclinical hypothyroidism (basal TSH below 6 mU/L), we found significant changes in the clinical index (p less than 0.05), apoprotein A-I level (p less than 0.05), and stimulated prolactin level after oral TRH (p less than 0.001). The findings were similar in grade II (TSH 6 to 12 mU/L). Further changes could be demonstrated in grade III (TSH above 12 mU/L) with a definite elevation of ankle reflex time (p less than 0.001), serum myoglobin level (p less than 0.01), and, to a lesser extent, creatine kinase (p greater than 0.1). The mean low-density lipoprotein cholesterol (LDL-C) level showed an increase of 18%, which was not significant because of marked individual variations (p = 0.15). The frequency of elevated LDL-C levels was definitely higher in patients with grade III disease compared with the controls (42.9% versus 11.4%, p less than 0.05) and with patients with grades I and II disease. Total cholesterol, triglycerides, apoprotein B, and the systolic time intervals (pre-ejection period, corrected for heart rate [PEPc]) were clearly elevated only in overt hypothyroidism (grades IV and V) (p less than 0.01).

Conclusion: Subclinical hypothyroidism has significant effects on some peripheral target organs at an early stage (grades I and II), but affects LDL-C, skeletal muscle, and myocardial contractility only at a later stage (grades III, IV, and V). Our data of elevated LDL-C in grade III subclinical hypothyroidism provide a likely pathophysiologic explanation for the reported association of coronary heart disease with this syndrome. The impact of increased prolactin secretion, observed in subclinical hypothyroidism, on gonadal function and infertility has yet to be clarified. Therapy with thyroxine should be recommended in at least some patients with subclinical hypothyroidism. Patients with high TSH levels (above 12 mU/L) will require treatment because of the metabolic effects on several target organs. Before treatment is advocated in all patients with subclinical hypothyroidism, the benefits and long-term side effects of thyroid hormone therapy should be clarified by prospective studies in larger groups of patients.