ENDOCRINE SYSTEM  (TABLE 10-7)

FEMALE REPRODUCTIVE SYSTEM

Menstruation is characteristically decreased in volume. With severe thyrotoxicosis, the menstrual cycle may be either shortened or prolonged, and finally amenorrhea develops. The relative importance of a primary action of excess thyroid hormone on the ovary or uterus, and pituitary dysfunction, are unclear. In some cases, amenorrhea with a proliferative endometrium is found. This finding suggests failure of pituitary LH production and ovulation.^254,255

Fertility is depressed, but pregnancy can develop. The incidence of miscarriage is increased.²⁵⁶ Evidence has been presented that high maternal thyroid hormone levels can lead to  supressed fetal TSH, lower fetal weight, and fetal death(256.1). Pregnancy, on the other hand, often ameliorates the symptoms of thyrotoxicosis, but relapse is prone to occur in the 3-4 months following delivery (Figure 10-10). This topic is discussed in Chapter 14.   Premature ovarian failure co-occurs with Graves' disease and thyroiditis in Multiple Endocrine Autoiimmunity Type II ⁶. Reduced fertility and increase miscarriage rates have been associated with AITD and positive antibodies. Increased rates of thyroid dysfunction and positive antibody tests have been reported in infertile women(256.13)

Figure 10-10. Clinical course of a patient who had transient exacerbation of Graves' disease on two occasions shortly following delivery.

Infants born to thyrotoxic mothers usually show no evidence of hyperthyroidism at birth. Fetal and neonatal thyrotoxicosis, fortunately infrequent events, are discussed in Chapter 14. Maternal thyrotoxicosis is associated with increased fetal loss(256.11), generally attributed to effects on the maternal system. However a recent study shows that elevated maternal  thyroid hormone levels lead to elevated thyroid hormone levels in the fetus, and induce fetal loss. Surviving fetuses have lower birth weight(256.1)

MALE REPRODUCTIVE SYSTEM

Gynecomastia, with ductal elongation and epithelial hyperplasia, occurs occasionally.²⁵⁷ The circulating level of free estradiol may be elevated in these men.^258-260 Peripheral conversion of testosterone and androstenedione to estrone and estradiol is increased in both sexes during hyperthyroidism.²⁶¹ This elevation probably accounts in part for the abnormality. In addition, the slightly elevated LH in men with gynecomastia suggests hypothalamic insensitivity to feedback control and some peripheral unresponsiveness to LH.²⁵⁸ An imbalance between testosterone and estrogen may be related to gynecomastia.

Kidd et al.²⁶² found impotence in half of a small group of thyrotoxic men and sperm counts below 40 million in four of five tested. In these studies, the total testosterone level was elevated, but because the testosterone-estrogen binding globulin level was also high, the free testosterone level was reduced and the response to hCG was blunted. In thyrotoxicosis, mean sperm density is lower, and fewer sperm have normal morphology.  Motility is lower in thyrotoxic males.  The abnormalities normalize when the patients become euthyroid(262.2). Thus, both Leydig cell and spermatogenic abnormalities may be present. Abalovich et al (262.1) reported similar findings, and in addition noted a high incidence of sperm abnormalities. All of the abnormalities returned to normal after therapy of the thyrotoxicosis. Hyperthyroidism is assocciated with abnormalities in sperm with reduced motilities, which are reversed after restoration of euthyroidism.  Radioiodine therapy can cause transient reductions in both sperm count and motility but do not seem to cause permanent effects with ordinary doses used in treatment under 14 MBq, equivalent to around 400 mCi.  (Krassas, GE; Perros, P.                Thyroid disease and male reproductive function.         J Endocrinol  Invest             26           372-380 2003).

PRL probably plays no role in these reproductive abnormalities, since in hypothyroidism, its release tends to be inhibited both at the hypothalamic and pituitary level.²⁶³ Surprisingly, galactorrhea, in women with normo-prolactinemia, is reported to occur in increased frequency.²⁶⁴

ADRENAL CORTEX

There are no obvious signs or symptoms of altered adrenal cortical function in thyrotoxicosis, but distinct changes have been detected. In thyrotoxicosis the adrenal cortex is often hyperplastic. Administered adrenal steroids disappear from the plasma at an accelerated rate.²⁶⁵ Their metabolism by reduction of the steroid nucleus is accelerated, and conjugation of the reduced steroids is proportionally increased. Since plasma corticoid levels are normal and their rate of metabolism is increased, total daily metabolism and excretion of 17-ketosteroids and 17 hydroxy-corticoids are usually increased.^255,266

Along with the accelerated plasma cortisol clearance of thyrotoxicosis, the pathways of metabolism are also altered. For example, thyrotoxicosis is associated with a relatively increased excretion of 11-oxycorticoid metabolites.²⁶⁷ The 11-oxy compounds may be biologically inactive. Because of the negative feedback control from the pituitary, this preferential channeling of steroids into the 11-oxy derivatives could be partly responsible for increased steroid production. There is increased production of steroids by the adrenal gland in order to maintain a normal concentration of active steroids in the peripheral blood and in the tissues.²⁶⁸ Secretion of adrenocorticotropic hormone (ACTH) by the pituitary is reported to be increased.²⁶⁹ There are increases in secretory episodes during the day, but the fall to zero secretion after midnight is retained. A reduced response to exogenous ACTH²⁷⁰ indicates that adrenal reserve is reduced. In fact, it has been hypothesized that in severe thyrotoxicosis and in thyroid storm there may be an element of adrenal insufficiency. This contention has not been proved. There is no reason to believe that T4 opposes the peripheral action of adrenal steroids. An increase in the 5-alpha metabolite of testosterone (androsterone) and a relative decrease in the 5-beta metabolite (etiocholanolone) are seen in the urine of thyrotoxic patients,²⁷¹ but no comparable change in adrenal corticoid metabolism has been observed. These interesting biochemical alterations could have physiologic significance, for the ketosteroid 5-alpha metabolites, such as androsterone, are biologically active. In hypothyroidism the reverse change occurs, that is, an increase in the biologically inactive 5-beta metabolites such as etiocholanolone. Because administration of large amounts of androsterone depresses the level of serum lipids, Hellman and co-workers²⁷¹ have hypothesized that this change in steroid metabolism may be a way in which T4 (or its lack) affects lipid metabolism and produces a depression or elevation in serum cholesterol concentration.

OTHER METABOLIC ASPECTS

The basal oxygen consumption in thyrotoxicosis, as measured by the BMR, is elevated. The increase is above the level of metabolism that the person would have if he or she were not thyrotoxic. In extreme thyrotoxicosis, the BMR may be double the standard, that is, according to the usual mode of expression, + 100. In moderately severe thyrotoxicosis it may be from +30 to +60, and in mild thyrotoxicosis from +10 to +30.

In addition to the BMR, one should consider the total metabolism, that is the basal plus the increments occasioned by work, food, or emotion. An increased cost of muscular work in thyrotoxicosis was reported many years ago by Plummer and Boothby²⁷² and Briard et al.,²⁷³ among others. These studies, whose results have been disputed, suggested that the thyrotoxic subject has less efficient coupling of oxidation and energy use than either the normal subject or, for example, the hypermetabolic patient with leukemia. More recent studies indicate that the increase in energy expenditure caused by work is not altered by thyrotoxicosis.²⁷⁴

CARBOHYDRATE METABOLISM

Absorption of carbohydrate from the intestine is accelerated, as is its removal from the plasma. After a standard oral glucose load is given, the thyrotoxic patient characteristically has an early and rapid rise in blood glucose concentration in 30 - 60 minutes (possibly to more than 200 mg/dl) and a rapid fall, so that by two hours the concentration is normal. The early peak may be associated with glycosuria. Intravenous administration does not usually elevate the blood glucose level beyond the rise found in normal subjects.

Thyrotoxicosis increases the demand for insulin, perhaps by accelerating its metabolism. In addition, resistance to the action of insulin is present, since in nondiabetic thyrotoxic patients normal fasting blood glucose levels are associated with double the normal insulin concentration,²⁷⁵ and resistance is found on incubation of adipocytes in vitro.²⁷⁶ Diabetes may be activated or intensified, and is ameliorated or may disappear when the thyrotoxicosis is treated. Long ago experimental diabetes was shown to result from long-standing thyrotoxicosis in the presence of partial pancreatectomy.²⁷⁷ The adverse effect of hyperthyroidism on glucose control in patients with non-insulin dependent diabetes is caused by increased basal hepatic glucose production and reduced ability of insulin and glucose to suppress hepatic glucose production.^278,279 Although hyperthyroidism increases the requirement for insulin, the effectiveness of exogenous insulin on carbohydrate metabolism is actually enhanced. If glucose is administered intravenously and continuously to a thyrotoxic subject so that blood sugar is maintained at a high level, administered insulin has an effect on glucose removal from the blood ²⁷⁹ that is greater than that in the normal subject.

Type I diabetes mellitus co-occurs with increased frequency in autoimmune thyroid disease. Post-partum thyroid dysfunction is especially common in patients with diabetes.²⁸⁰ In recent years many similarities in immunologic phenomena have been noted in the two diseases, including insulin receptor antibodies and islet cell antibodies.

LIPIDS

The serum cholesterol level is depressed in thyrotoxicosis. There is an increase both in synthesis and in degradation, but the balance results in a new lower steady-state concentration in the serum. The cholesterol pool in the body is altered by thyroid hormone in different directions, depending on the species involved, and does not necessarily parallel the serum cholesterol level. Hypocholesterolemia may be produced without a distinct decrease in total body or liver cholesterol.^281-287 Part of the cholesterol-lowering action of thyroid hormone may be due to the effects of malnutrition and weight loss, and part may be simply a manifestation of hypermetabolism, since agents that elevate metabolism, such as salicylates, also lower serum lipid levels. Thyroid hormone directly enhances conversion of cholesterol to bile acids and their excretion in the bile. This metabolic route accounts for the disposal of 70-90% of the cholesterol formed in the body.²⁸³ Thyroid hormone may also affect cholesterol metabolism by directly increasing the number of membrane surface low-density lipoprotein (LDL) receptors.²⁸⁴  The increased cholesterol synthesis, and even more enhanced clearance rate in hyperthyroidism has been confirmed in a recent study.  Hepatic lypogenesis is also strikingly increased, probably both by direct action of thyroid hormones and an increase in insulin.  Triglyceride levels tend to be slightly elevated (284a).

Levels of the other serum lipid components are lowered as well.^285-288 Plasma triglycerides are in the low normal range, and the clearance rate of infused triglycerides may be elevated. Postheparin lipolytic activity^285,286   may be low or normal.  Hyperthyroidism causes lower levels of apo(a), HDL, and ratio of total/HDL choloesterol ^282,286.  Plasma leptin levels are normal in hyperthyroid patients (286a). The free tocopherol level of the plasma changes in parallel with the cholesterol alterations in thyrotoxicosis.²⁸⁸

Rich et al.²⁸⁹ found the level of nonesterified fatty acids elevated in thyrotoxic patients. This response can be seen within six hours after administration of L-T3 to normal subjects, and might be related to the observation that ketosis occurs more readily in thyrotoxic patients than in normal subjects.

PROTEIN METABOLISM

Protein formation and destruction are both accelerated in hyperthyroidism. Nitrogen excretion is increased, and nitrogen balance may be normal or negative, depending on whether intake meets the demands of increased catabolism. Testosterone is able to exert its anabolic effects in thyrotoxicosis.

Lewallen et al. ²⁹⁰ found that administration of thyroid hormone increases albumin synthesis and degradation in normal subjects, increases the fractional rate of degradation, and reduces the quantity of exchangeable albumin.

Thyroid hormone in vivo²⁹¹ or in vitro, ²⁹² as reviewed in Chapter 2, may exert its basic action through stimulation of transcription and mRNA translation. Thyroid hormone stimulates incorporation of amino acids into protein by liver microsomes. This action is at least partially explained by increased production of mRNA and by an increased transfer of soluble tRNA- bound amino acids into microsomal protein.²⁹³ Clinically, a great excess of thyroid hormone appears to have the opposite effect. Crispell et al. found that protein synthesis may be depressed by feeding thyroid hormone to normal humans.²⁹¹ Catabolism of collagen is increased, ²⁹⁴ and urinary hypodroxyproline excretion is characteristically increased. Gluconeogenesis from alanine is stimulated by thyroid hormone.²⁹⁵ Probably the elevated somatomedin levels found in thyrotoxicosis ²⁹⁶ contribute to augmented protein synthesis.

cAMP Metabolism

Basal cAMP levels are on average elevated in serum of thyrotoxic humans , and there is hyperresponsiveness to stimuli such as epinephrine and glucagon²⁹⁷. Urinary cAMP is likewise increased.²⁹⁹ Treatment with propranolol (in some studies) lowers basal cAMP toward, but not to, normal.³⁰⁰ Opposite changes occur in hypothyroidism. -adrenergic receptors are increased in number, and responses are enhanced as compared to the normal state (see Chapter 2).

Vitamin Metabolism

The absorption of vitamin A is increased and conversion of carotene to vitamin A is accelerated in thyrotoxicosis. The requirements of the body are likewise increased, and low blood concentrations of vitamin A may be found.

Requirements for thiamine and vitamin B6 are increased.³⁰⁰ Lack of the B vitamins has been implicated as a cause of liver damage in thyrotoxicosis. It has been demonstrated that vitamin B12 requirements are increased in experimental thyrotoxicosis.

Radiosensitivity

Radiosensitivity of animal and human tumors may be enhanced by administration of L-T3.³⁰¹