Steroid Hormone

Sex Steroid Hormones and the Heart

Cardiac contractility is more intense in premenopausal women than in age-matched men, and withdrawal of hormone replacement therapy in postmenopausal women leads to a reduction in cardiac contractile function. The gender dimorphism in heart function and its adaptive responses to injury and disease states are partly mediated by sex steroid hormones. Indeed, healthy premenopausal women exhibit a lower cardiovascular risk compared to men, which suggests a mechanism for sex hormones in the modulation of cardiac function.⁷⁶

The most extensively studied sex steroid hormones are estradiol-17β (E2) and its bioactive metabolites. They bind and act on the two subtypes of estrogen receptors (ERs) in the heart: ERα and ERβ. Progesterone and testosterone (two other sex steroid hormones) and the enzyme aromatase, which converts testosterone to estrogen, are much less well investigated. Progesterone and testosterone bind and act on their respective progesterone receptors and androgen receptors in the heart. Sex steroid hormones interact with their receptors to affect postsynaptic target cell responses and to influence presynaptic sympathoadrenergic function. Cardiomyocytes are not only targets for the action of sex steroid hormones, but they are also the source of synthesis and the site of metabolism of these hormones.⁷⁷

E2 is derived from testosterone and is primarily metabolized in the liver to form hydroxyestradiols, catecholestradiols, and methoxyestradiols. Estradiol metabolism also takes place in vascular smooth muscle cells, cardiac fibroblasts, endothelial cells, and cardiomyocytes. Cardiomyocytes express nuclear steroid hormone receptors that modulate gene expression and nonnuclear receptors for the nongenomic effects of sex steroid hormones. They interact withmany different coregulators to confer tissue and temporal specificity in their transcriptional actions. These cell-specific coactivator and corepressor proteins are known as estrogen-related receptors.⁷⁸ Sex steroid hormones can activate rapid signaling pathways without changing gene expression (Fig. 14.18). One such example is stimulation of vascular endothelial nitric oxide synthase to mediate vascular dilation. Estrogen’s vasodilatory effect might explain the lower systolic blood pressures of premenopausal women when compared with age-matched men. In men, aromatase-mediated conversion of testosterone to estrogen maintains normal vascular tone. In addition to sex steroid hormone stimulation of nuclear or nonnuclear receptors, sex steroid hormone receptors could also induce rapid signaling of growth factor pathways in the absence of ligands.

Gender differences exist in cardiac electrophysiologic function. The modulatory actions of estrogen on Ca²⁺ channels might be responsible for sex-based differences in repolarization of the heart, such as the faster resting heart rate of women, as well as the increased propensity of women to have prolonged QT syndrome.⁷⁹ Estrogen, through the activation of ERβ, confers protection after ischemia and reperfusion in murine models of myocardial infarction. In contrast, testosterone, in the same model, has the opposite effect. Aromatase also has protective effects, probably through its action to increase estrogen and to decrease testosterone.

Steroid-Hormone Induced Myopathy

Natural Cushing disease and iatrogenic Cushing syndrome from exogenous corticosteroid administration can cause painless, symmetric, progressive proximal weakness, increased serum CK levels, and a myopathic electromyogram and muscle biopsy specimen (seeChapter 595). Myosin filaments may be selectively lost. The 9α-fluorinated steroids, such as dexamethasone, betamethasone, and triamcinolone, are the most likely to producesteroid myopathy. Dexamethasone alters the abundance of ceramides in myotubes in developing muscle. In patients with dermatomyositis or other myopathies treated with steroids, it is sometimes difficult to distinguish refractoriness of the disease from steroid-induced weakness, especially after long-term steroid administration. Vitamin D is another factor altering muscle metabolism and particularly its sensitivity to insulin; vitamin D deficiency may be accentuated and contribute to steroid myopathy, especially in type 2 diabetic patients and insulin resistance.

All patients who have been taking steroids for long periods develop reversible type II myofiber atrophy; this is asteroid effect but is not steroid myopathy unless it progresses to become a necrotizing myopathy. At greatest risk in the pediatric age-group are children requiring long-term steroid therapy for asthma, rheumatoid arthritis, dermatomyositis, lupus, and other autoimmune or inflammatory diseases or who are being treated for leukemia or other hematologic diseases. In addition to steroids, the drugs listed inTable 628.1 can cause acute or chronic toxic myopathies. An incompletely understood entity known as critical illness myopathy is a progressive weakness of patients with extended illnesses who remain in the intensive care unit; it is associated pathologically with selective loss of thick (myosin) myofilaments; immobility and excessive steroid treatment are believed to be important factors. Various steroids are sometimes used chronically in the treatment of Duchenne muscular dystrophy; they may actually exaggerate the weakness because of steroid myopathy superimposed on the dystrophic process (seeChapter 627).

Hyperaldosteronism is accompanied by episodic and reversible weakness similar to that of periodic paralysis. Another clinical presentation is muscle cramps at rest. The proximal myopathy can become irreversible in chronic cases. Elevated CK levels and even myoglobinuria sometimes occur during acute attacks. Arterial hypertension is a frequent manifestation, and in children, aldosterone-secreting adenomas up to 6 mm in diameter or multiple adrenocortical micronodules of 0.5 mm should be considered in the differential diagnosis of idiopathic hypertension and muscle weakness or cramps. Hereditary primary aldosteronism is due to a mutation in one of the potassium channel genesKCNJ5 andGIRK4.

Chronic growth hormone excess (sometimes illicitly acquired by adolescent athletes or seen in acromegaly) produces atrophy of some myofibers and hypertrophy of others, and scattered myofiber degeneration. Despite the augmented protein synthesis induced by growth hormone, it impairs myofibrillar adenosine triphosphatase activity and reduces sarcolemmal excitability, with resultant diminished, rather than increased, strength corresponding to the larger muscle mass. It has been used therapeutically in muscular dystrophy with both a positive effect and complications.Ghrelin is an intestinal hormone that activates a growth hormone secretagogue receptor and stimulates growth hormone release. In addition to its effect as a “hunger hormone” that involves food intake and fat deposition, it also prevents muscular atrophy by inducing myodifferentiation and myoblast fusion.

Measurement of Peptide and Steroid Hormones

Increased levels of immunoreactive human chorionic gonadotropin (HCG) may suggest an HCG-secreting neoplasm, most commonly an ovarian teratoma or dysgerminoma.⁸ In such cases, the HCG, which is antigenically and biologically similar to LH, stimulates ovarian steroid secretion and pseudopubertal development. Because even specific LH immunoassays show some cross-reactivity with HCG, values for serum LH may be elevated in individuals with HCG-secreting tumors. Immunoreactive HCG is always elevated in the presence of such tumors. Levels and ratios of FSH and LH typical of pubertal as opposed to prepubertal girls help in the diagnosis of true precocious puberty. Timed urine collections rather than blood samples can be used to measure gonadotropin secretion if necessary. The use of exogenous GnRH to stimulate endogenous LH and FSH secretion can help differentiate gonadotropin-dependent from gonadotropin-independent precocious puberty and is regarded as the “gold standard” in the diagnosis of central precocious puberty. If GnRH is not available, a GnRH analog can be substituted. Excessively high circulating levels of estrogen (>100 pg estradiol) suggest an estrogen-producing neoplasm or a functioning ovarian cyst. High levels of serum testosterone suggest an ovarian source of excess androgen in girls with heterosexual development, whereas increased levels of dehydroepiandrosterone or its sulfate (the principal precursors of 17-ketosteroids) suggest an adrenal source. High levels of serum l7-hydroxyprogesterone imply congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency, whereas high levels of serum 11-deoxycortisol imply an 11β-hydroxylase deficiency (Chapter 220). In congenital adrenal hyperplasia, these hormone levels should decrease promptly after the oral administration of suppressive doses of dexamethasone. Suppression in response to exogenous corticoids occurs much less consistently in individuals with adrenal cortical adenomas and carcinomas (Chapter 214) and rarely in those with ovarian androgen-secreting neoplasms.