Cardiac Physiology

Michael A. Gropper MD, PhD, in Miller's Anesthesia, 2020

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 hormones

J.C. Cook-Botelho, ... D. French, in Mass Spectrometry for the Clinical Laboratory, 2017


Steroid hormones are commonly measured in patients for the diagnosis, treatment, and prevention of hormone-related diseases in men, women, and children. The methods used to measure these hormones require a large dynamic measurement range, but also in many cases need to be capable of detecting down to pg/mL concentrations. Mass spectrometry offers the capability of this measurement range and is also precise and accurate when assays are developed and calibrated correctly. However, due to the structural similarities seen between steroid hormones, it is imperative that sufficient interference testing be undertaken to ensure that no cross-reactivity exists between the different hormones in the mass spectrometry method. This chapter summarizes some key concepts that should be considered during development and validation of steroid hormone mass spectrometry assays, focusing primarily on LC-MS/MS assays.

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Endocrine and Toxic Myopathies

Robert M. Kliegman MD, in Nelson Textbook of Pediatrics, 2020

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.

Steroid Hormones

Gerald Litwack Ph.D., in Human Biochemistry, 2018


Steroid hormones. The chapter opens with a discussion of stress from the clinical to the molecular levels. This is followed by several topics: nociception, Cushing’s and Addison’s diseases, adrenal cortex, structures of steroid hormone receptors, coactivators and corepressors, physiological functions of steroid hormones from receptor knockouts, steroid transporting proteins in plasma, enzymatic inactivation of cortisol, cortisol and aldosterone, dehydroepiandrosterone, structural considerations of steroid hormones, receptor activation, vitamin D hormone, thyroid hormone, crosstalk between steroid receptors and peptide hormones, sex hormones, and peroxisome proliferators and their receptors. This is followed by a summary, a list of references, review multiple choice questions, and a case-based problem.

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Ovaries and Pubertal Development

Lee Goldman MD, in Goldman-Cecil Medicine, 2020

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.

Steroid Hormones

Anthony W. Norman Ph.D., Helen L. Henry Ph.D., in Hormones (Third Edition), 2015

B Serum Binding Proteins for Steroid Hormones

The steroid hormones are transported from their sites of biosynthesis to their target steroid hormones, and their transport is facilitated by a family of plasma transport proteins (see Table 2-6). All steroid hormones, except one, have their cognate plasma binding protein. The exception is aldosterone, which is believed to circulate as the free steroid in the plasma compartment. Although the five plasma transport proteins listed in Table 2-6 are all synthesized in the liver, they have no amino acid sequence homology. Also, there is no discernable sequence homology between the ligand-binding domains of the five plasma transport proteins, or the nuclear–cytosol receptor’s ligand-binding domain, or the substrate-binding domain of the P450 enzyme(s) that generated the steroid.

Table 2-6. Plasma Transport Proteins for Steroids, Thyroxine, and Retinoid Hormones

Plasma protein Code Principal steroids bound Molecular weight (× 103)
Vitamin D-binding protein DBP Vitamin D3, 25(OH)D3, 1α,25(OH)2D3, 24,25(OH)2D3 50
Corticosteroid-binding globulin (transcortin) CBG Glucocorticoids, progesterone 52 (glycoprotein)
Sex hormone-binding globulin SHBG Testosterone, estradiol A dimer, each subunit 42
Thyroxine-binding globulin TBG Thryoxine (T4), triiodothyronine (T3) 63 (glycoprotein)
Retinol-binding protein RBP Retinol 41

In the plasma compartment, the steroid hormones move through the circulatory system bound to their partner transport protein. However, an important issue concerns the details of the mode of delivery of steroid hormones to their target cells. Since the “free” form of the steroid hormone is believed to be the form of steroid that moves across the outer plasma membrane of a target cell, it had been postulated that the steroid ligand bound to a plasma transport protein dissociates from its plasma transport protein and then diffuses first through the capillary wall and then through the outer wall membrane of target cells. However, as illustrated in Figure 2-23 it is apparent that the endothelial wall of capillaries contains fenestrations. Thus, it is also possible for the plasma steroid transport protein (with bound steroid horone) to exit the capillary bed via a fenestration and move to be immediately adjacent to the outer cell membrane of the appropriate target cell for the steroid hormone in question. Here the steroid hormone will dissociate from the transport protein, diffuse through the plasma membrane, and then bind to an unoccupied partner steroid receptor.

Figure 2-23. Examples of capillary wall fenestration.

(A) Diagram representing the exit or entry processes of hormones via capillary orifices or fenestrations. (B) A fenestrated diaphragm in the endothelium of an adrenal cortex capillary. Note the eight, dark, wedge-shaped communicatory channels. The existence of fenestrations or pores in the capillary wall allows plasma steroid transport proteins to exit the circulatory system and approach the outer cell membrane of the target cell for the steroid hormone in question.

[Adapted with permission from Figures 2 and 6 of Bearer, E., and Orci, L. (1985). Endothelial fenestral diaphragms: A quick-freeze, deep-etch study. J. Cell Biol 100, 418–428.]
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Steroid Hormone Action

Shannon Whirledge, John A. Cidlowski, in Yen and Jaffe's Reproductive Endocrinology (Eighth Edition), 2019


Steroid hormones are a group of hormones derived from cholesterol that act as chemical messengers in the body. The steroid hormones regulate many physiologic processes, including the development and function of the reproductive system. The actions of the steroid hormones are mediated by the steroid hormone receptors, intracellular proteins belonging to the nuclear family of transcription factors. These receptors mediate signal transduction through genomic and nongenomic actions in a context-specific manner. The complex molecular events orchestrated by the steroid hormones and their receptors reflect the diversity in signals activating the receptors and the dynamic mechanisms by which the steroid hormone receptors integrate these signals into a physiologic response.

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Clinical Reproductive Endocrinology

Håkan Andersson, in Clinical Biochemistry of Domestic Animals (Sixth Edition), 2008

2 Steroid Hormones

Steroid hormones are derived from a common precursor molecule, cholesterol, via the metabolic pathway schematically outlined in Figure 21-1. More than 1500 biologically active steroids have been isolated from biological material or have been produced synthetically. The molecular weight of steroid hormones is low, usually below 500 (Table 21-1). Examples of steroids that play an important role in reproductive processes are estrogens, androgens, and progestagens, with the main source being the gonads. The structure of the most important sex steroids is presented in Figure 21-2. The most common steroid hormones are usually designated by a trivial name (e.g., estradiol, testosterone, or progesterone). The International Union of Pure and Applied Chemistry (IUPAC; has recommended systemic names for steroid hormones. These systemic names describe the chemical and stereoisomeric characteristics of the particular steroid hormone (Table 21-1).

Figure 21-1. Pathway for the synthesis of biologically active steroids from acetate. The steroids secreted from the gonads and the adrenals are formed from acetate and cholesterol.

Table 21-1. Nomenclature and Molecular Weights of Some Biologically Important Steroids and Prostaglandins

Trivial Name Systematic Name Molecular
Androstenedione 4-Androstene-3, 17-dione 286
17β-Estradiol 1,3,5(10)-Estratriene-3, 17β-diol 272
Estrone 3-Hydroxy-1,3,5(10)-estatrien-17-one 270
17α-Hydroxyprogesterone 17α-Hydroxy-4- pregnene-3,20-dione 331
Pregnenolone 3β-Hydroxy-5-pregnen- 20-one 317
Progesterone 4-Pregnene-3,20-dione 315
Testosterone 17β-Hydroxy-4- androsten-3-one 288
PGF2α 9α,11α,15-Trihydroxyprosta-5, 13-dienoic acid 354
15-Keto-13, 14-dihydro-PGF2α 9α,11α,Dihydroxy-15-ketoprost-5-enoic acid 354

Figure 21-2. The number of sequence for the carbon atoms of the steroid skeleton and lettering sequence for the four rings are shown for testosterone. The structures of three other important sex steroid hormones, estrone, estradiol-17β, and progesterone, as well as the structure of prostaglandin F2α and its blood plasma metabolite 15-keto-13,14-dihydroprostaglandin F2α are also depicted.

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Steroid Hormone Action in Health and Disease

R.J. Handa, ... T.J. Wu, in Reference Module in Biomedical Sciences, 2014


Steroid hormones are the main secretory products of specialized tissues in the body. The actions of steroid hormones are powerful, affecting almost every tissue including the central nervous system. These myriad effects are mediated by receptor proteins that are specific for each steroid hormone class (estrogens, androgens, progestogens, glucocorticoids, and mineralocorticoids). Although the actions of steroid hormones are broad, their effects are similarly mediated in each tissue through their individual expression of the various steroid hormone receptors and through tissue-selective expression of co-regulatory proteins. Thus, a unique property of steroid hormone receptors is their ability to regulate gene transcription through direct and indirect interactions with DNA or influence signaling pathways through associations with the cell membrane. This article will provide an overview of how steroid hormone receptors function normally and in disease.

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Androgen Action and Stress

M.A. Holschbach, R.J. Handa, in Stress: Neuroendocrinology and Neurobiology, 2017

Secretion and Transport

Steroid hormones are secreted along a concentration gradient from synthetic cells to the circulating plasma and do not utilize a vesicular membrane fusion pathway. Consequently, circulating levels of androgens accurately reflect rates of synthesis. Steroid hormones are lipophilic and thus, are usually transported in the plasma bound to a serum binding protein, such as albumin- or sex hormone–binding globulin (SHBG). These binding proteins protect the steroid from degradation, which would otherwise shorten their half-life, and also inhibit renal excretion. Only free, unbound steroid is biologically active, so once at a target tissue, steroid hormones are released from the binding protein and because of their lipophilic nature, are able to easily enter cells by diffusing across the plasma membrane. Inside the cell, steroid hormones are bound by intracellular receptors. In the case of androgens, such as T and DHT, the specific receptor has been termed the AR.

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