Hormones of the Adrenal Cortex

For nearly 50 years, cortisol and its synthetic analogues have been in widespread clinical use for the treatment of a variety of disorders. During this time, research has greatly expanded our understanding of the physiology, biochemistry, and pharmacology of steroids, resulting in numerous publications which discuss the therapeutic uses and toxicologic hazards of corticosteroids. This chapter will review the physiologic and pharmacologic actions of corticosteroids and then discuss the use of these agents in the treatment of neoplasms. Finally, the current understanding of the mechanism of action of these hormones will be considered in the context of their therapeutic efficacy.

In the 1850s, observations by Addison¹ of patients with destructive diseases of the adrenal gland and experiments done by Brown-Séquard² on adrenalectomized animals revealed the requirement of functional adrenal glands for survival. By the 1930s, the effects of adrenal insufficiency were found to be separable into two distinct categories: those due to electrolyte imbalances and those resulting from altered carbohydrate metabolism.^3,4 In 1932, Cushing⁵ described the syndrome of hypercorticism, and in the 1940s and 1950s, adrenocorticotropic hormone (ACTH) was discovered in the anterior pituitary, and its role in the stimulation of the adrenal cortex was demonstrated.^6,7 ACTH release was found to be regulated by, a precise balance between negative feedback by adrenal corticosteroids and positive stimulation from the nervous system. Both these effects are mediated at the level of the hypothalamus and pituitary.⁸ Concurrently, several bioactive steroids were isolated from the adrenal cortex and their structures elucidated. These newly characterized steroids included cortisol and aldosterone, the principal active corticosteroids in humans.

In 1949, Hench⁹ reported the efficacy of cortisol and ACTH in the treatment of rheumatoid arthritis. This observation evoked wide interest, and therapeutic applications of these hormones were subsequently extended to a wide variety of diseases. This surge in clinical investigation was accompanied by a rapid expansion of the basic scientific examination of these compounds. During the 1950s, most of the biochemistry involved in the synthesis and metabolism of adrenocortical steroids was elucidated, and the majority of synthetic corticosteroid analogues available today were developed. Along with these advances, practical methods for plasma cortisol determinations were developed, allowing rapid advances in the field of corticosteroid therapy.

Eventually, synthetic adrenocorticosteroid analogues which separated anti-inflammatory potency from effects on electrolyte balance were developed. However, despite continuing efforts, chemists have not yet effectively separated desirable clinical effectiveness from toxicity. Consequently, these drugs are very powerful, yet have slow cumulative toxic side effects on many tissues. Therefore, damage resulting from corticosteroid therapy may not be apparent until made manifest in a catastrophic manner.

Biosynthetic Pathways

Corticosteroid biosynthesis has been well characterized and is presented in a simplified form in Fig. 54.1. Cholesterol, the precursor for the biosynthesis of all steroids, is converted to various steroid molecules in a series of reactions that are mediated by several cytochrome P-450 enzymes.¹⁰ While the adrenal cortex can synthesize cholesterol to some extent, 60 to 80% of the cholesterol used in steroid synthesis originates from sources outside the adrenal cortex.¹¹ The primary source of cholesterol for steroid synthesis is the pool which circulates in plasma bound to low-density lipoproteins, for which the adrenal cortex has a large number of receptors. Once synthesized, corticosteroids are not stored within the adrenal cortex but are rapidly secreted. The adrenal cortex harbors only enough steroid to maintain normal serum corticosteroid levels for a few minutes once synthesis is halted. Therefore, the rate of corticosteroid synthesis is essentially equal to the rate of secretion from the adrenal gland.

Figure 54.1

Principal pathways for the biosynthesis of adrenocorticosteroids. With permission from Haynes RC Jr, Murad F. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of adrenocortical steroid biosynthesis. In: The (more...)

Control of Corticosteroid Secretion

Pharmacokinetics of Corticosteroids

Steroid Synthesis Inhibitors

There are several inhibitors of steroid biosynthesis that are used clinically to treat corticosteroid hypersecretion or to eliminate the synthesis of a specific class of steroids.³¹ Metyrapone blocks the 11β hydroxylation of steroids.³² Synthesis, therefore, terminates after the formation of 11-deoxycortisol, the immediate precursor to cortisol. This compound does not negatively feed back on ACTH secretion; therefore, serum ACTH and 11-deoxycortisol levels remain high. Metyrapone also inhibits the synthesis of aldosterone, but no sodium balance problems accrue because the synthesis of 11-deoxycortisone, which has mineralocorticoid activity, remains intact. Aminoglutethimide inhibits the conversion of cholesterol to 20α-hydroxycholesterol and blocks the synthesis of both cortisol and aldosterone, as well as other classes of steroid hormones.³³ Mitotane is an adrenocorticolytic drug, which is thought to exert its corticolytic function by accumulating in the cell membrane and damaging membrane ion channels/pumps. The membrane damage leads to activation of lipid peroxidation and subsequently to DNA and protein destruction in the adrenal cortex.³⁴ Selective destruction of adrenocortical cells by mitotane causes a rapid decrease in plasma corticosteroid levels. Aromatase inhibitors have also come into use as steroid synthesis inhibitors, exhibiting increased potency and selectivity. These compounds, currently available as third-generation derivatives, including vorozole, letrozole, and anastrozole, lower estrogen levels effectively and with minimal side effects, while abrogating the need for corticosteroid replacement.³⁵

Pharmaceutical Derivatives

The molecular structure of steroid hormones is a critical determinant of their physiologic activities. Organic chemists have studied the structure-activity relationships of these molecules and have synthesized a myriad cortisol analogues with varying potencies that effectively separate the glucocorticoid and mineralocorticoid activities of the natural corticosteroids. This has made the synthetic glucocorticoids clinically useful, even though it has not been possible to separate glucocorticoid activity from the toxic side effects of these molecules. Table 54.1 lists some of the available natural and synthetic corticosteroids with their relative ratio of specificity and equivalent doses. All corticosteroids are absorbed readily from the gastrointestinal tract. Water-soluble esters are given intravenously (IV) to achieve absorption rapidly, while intramuscular injection provides more prolonged effects. Corticosteroids are also well absorbed from several sites of topical application, and large doses can lead to systemic absorption.

Table 54.1

Relative Potencies and Equivalent Dose of Corticosteroids.

Changes in steroid activity also result in changes in absorption, plasma protein binding, and clearance rates. There is wide variability in the free fraction of synthetic steroids from patient to patient at comparable total plasma concentrations. There is also variability in patient sensitivity to generation of Cushing-like symptoms. These differing sensitivities are reflected in different plasma corticosteroid concentrations, suggestive of pituitary resistance to corticosteroid feedback. Additionally, differences in the pharmacokinetics of glucocorticoids between men, women, and children should continue to be considered when designing therapeutic regimens.^36,37

Physiologic and Pharmacologic Effects of Corticosteroids

The primary functions of the corticosteroids are to (1) regulate whole body homeostasis, and (2) maintain balance in the body’s host-defense system to protect against over-reaction to environmental changes and the invasion of foreign substances. The effects of corticosteroids on the human body are widespread and include profound alterations in carbohydrate, protein, and lipid metabolisms, as well as effects on electrolyte and water balance. Corticosteroids affect all the major systems of the body, including the cardiovascular, musculoskeletal, nervous, and immune systems, and play critical roles in fetal development, including the maturation of the fetal lung. Because so many systems are sensitive to corticosteroid levels, tight regulatory control is exerted on the system. The direct effects of corticosteroids are sometimes difficult to separate from their complex relationship with other hormones, in part due to the permissive action of low levels of corticosteroid on the effectiveness of other hormones, including catecholamines and glucagon. Nevertheless, the effects of corticosteroids can be classified into two general categories: the effects of glucocorticoids (intermediary metabolism, inflammation, immunity, wound healing, myocardial and muscle integrity) and the effects of mineralocorticoids (salt, water, and mineral metabolisms). Although the following section will discuss the separate effects of glucocorticoids and mineralocorticoids, it must be emphasized that the natural steroids possess both glucocorticoid and mineralocorticoid activity to some extent. The ratio between the two activities ranges from all glucocorticoid and almost no mineralocorticoid activity (cortisol) to all mineralocorticoid and almost no glucocorticoid activity (aldosterone).

Corticosteroids in the Treatment of Neoplasms

Once corticosteroids became available, many studies were designed to assess effect of these compounds on experimental neoplasms. It was first discovered that cortisone caused tumor regression in a transplantable mouse lymphosarcoma,⁸⁸ and this finding was soon extended to a wide variety of mouse lymphatic tumors. The effects of corticosteroids were also evaluated on many nonendocrine and nonlymphoid transplantable rodent tumors. Pharmacologic doses of steroid inhibited growth of various tumor systems.⁸⁹ Tissue culture studies subsequently confirmed that lymphoid cells were the most sensitive to glucocorticoids and responded to treatment with decreases in the synthesis of DNA, RNA, and protein.⁹⁰ Studies of proliferating human leukemic lymphoblasts supported the hypothesis that glucocorticoids have preferential lymphocytolytic effects, and the mechanism of action was initially thought to be due to a decrease in glucose transport and/or phosphorylation, which would lead to decreased energy utilization from the lack of glucose.⁹¹ Subsequently, however, it was discovered that glucocorticoids induce apoptosis, or programmed cell death, in certain lymphoid cell populations.⁹² Despite an incomplete understanding of the mechanism of action of glucocorticoids, it is clear that these steroids have great clinical value in the treatment of neoplasms of lymphoid origin and, to a much lesser extent, other endocrine-responsive cancers. Glucocorticoids are also efficacious in the treatment of several frequently occurring side effects of malignancies, as well as for general palliative therapy.

Symptomatic Uses of Corticosteroids

Palliative Care

Glucocorticoid treatment produces rapid symptomatic improvements in critically ill patients, including temporary relief of fever, sweats, lethargy, weakness, nausea, and other nonspecific effects of cancer. Glucocorticoids also cause mild euphoria, a general feeling of well being, and a stimulation of appetite.^155,156 These effects are transient, and only short-term treatment is possible due to side effects of the high doses. Also, when glucocorticoids are withdrawn, adrenocortical insufficiency and patient discomfort can occur. For these reasons, corticosteroid treatment is normally reserved for patients whose life expectancy is brief (a few weeks or less). While for most terminal patients opiods are the commonly employed option for pain management, corticosteroid therapy remains a viable option, especially in cancers of the central nervous system where edema is common. For palliative care, doses of 25 mg/d prednisolone are used initially with a decrease to 7.5 to 15 mg/d for maintenance of effects.

Hypercalcemia

Hypercalcemia is a common complication of many malignancies.¹⁵⁷ It is caused in many cases by increased bone resorption and renal calcium reabsorption and is thought to be due to many factors that may be secreted by various tumors, especially those of lymphoid origin. Although glucocorticoids do not lower normal calcium levels, glucocorticoids in large doses have been used for treatment of hypercalcemia (100 mg/d prednisolone, 400 mg/d hydrocortisone). The mechanisms by which glucocorticoids reduce serum calcium are thought to be cytolytic action on lymphoid cells, decrease in lymphokine secretion, and inhibition of vitamin D action on calcium metabolism. Glucocorticoids are most effective on hypercalcemia that is secondary to high vitamin D levels. They are less effective in patients with solid tumors. The results in treatment of patients with multiple myeloma have been inconsistent. Glucocorticoids are, therefore, a poor choice, except in cases of vitamin D–mediated hypercalcemia.

Central Nervous System Tumors

Neurologic symptoms from primary and metastatic brain and spinal cord tumors are partially due to peritumoral edema.¹⁵⁸ Glucocorticoids can ameliorate these symptoms in about 70 to 80% of cases after several days of treatment.^159,160 There is evidence that glucocorticoids cause both a decrease in edema production and an increase in edema reabsorption. Dexamethasone is the recommended steroid for this treatment because it contains essentially no mineralocorticoid activity and is highly potent. A dose of 16 mg/d is used with an increase to 100 mg/d if no response occurs. This dose is continued until the maximum response is obtained. Doses are then decreased gradually and are maintained at the smallest effective dose. In a cautionary note, recent findings suggest that currently used doses are greatly in excess of the therapeutic level since 2 to 4 mg/d of dexamethasone was found to be sufficient for controlling edema during radiotherapy for brain metastases.^161,162 Glucocorticoid effects on the brain and spinal cord are short lived and only increase survival time slightly unless other measures, such as radiotherapy and surgery, are taken. Glucocorticoids are often administered during these therapies to alleviate the edema that is normally induced by these treatments. It has been observed that glucocorticoids can decrease the amount of a cytotoxic drug, such as methotrexate, that gets to a tumor, possibly by decreasing capillary permeability. For this reason, a recent pilot study eliminated dexamethasone from the standard high-dose methotrexate protocol for children with brain tumors. The results indicated that dexamethasone could be eliminated from such treatment protocols without increased toxicity and with no occurrence of serious brain edema. The occurence of liver toxicity was also reduced when dexamthasone was excluded from the regimen.¹⁶³

Antiemetic Action

Glucocorticoids have been shown to decrease the severity of chemotherapy-induced emesis.¹⁶⁴ Both dexamethasone (8–20 mg) and methylprednisolone (125–250 mg) have been used successfully, with vomiting episodes reduced by as much as 74%.

Glucocorticoids are most effective when used at low doses to enhance the antiemetic efficacy of other drugs. Recent findings suggest that the combination of glucocorticoids with serotonin receptor antagonists (e.g., ondansetron, granisetron, tropisetron) is extremely effective.^165–167 The mechanism by which antiemesis occurs is unknown, but it may be associated with decreases in prostaglandin synthesis. Alternatively, glucocorticoids may act directly on the chemoreceptor trigger zone by modifying capillary permeability or stabilizing lysosomal membranes.

Dyspnea Caused by Lymphangitic Carcinomatosis

The dyspnea caused by lymphangitic carcinomatosis may be a result of tumor edema and is effectively relieved in most cases by glucocorticoid treatment.¹⁶⁸ If the primary tumor is chemosensitive, then cytotoxic agents are also given. Prednisone is initially given at a dose of 60 to 100 mg/d and is then reduced rapidly to the minimum level that maintains the response. The benefits of this treatment may be short lived, and high doses may be indicated with the attendant danger of long-term complications.

Other Uses of Glucocorticoids

Acute upper airway obstruction can result from direct tumor growth or by compression from thyroid, lung, and esophageal cancers. This obstruction can be reduced by glucocorticoid treatment either alone or in combination with radiotherapy.^169,170 Other cancer-related obstructions and mass effects can be partially and temporarily controlled by glucocorticoids. These include superior vena cava syndrome; lymphedema; liver metastases; masses in the pelvis, mediastinum, or retroperitoneum; and blockages of the large bowel or ureter.¹⁷¹ Therapeutic effects are due to reduction in peritumoral inflammation and edema. The pain that can accompany bone metastases or metastatic arthralgia from a variety of solid tumors often responds to glucocorticoid treatment.¹⁷² Several chemotherapeutic agents (mitomycin, bleomycin, busulfan, carmustine), as well as radiotherapy, are associated with pulmonary toxicity. This lung injury can be decreased, at least partially, by preventive glucocorticoid administration during chemotherapy. This treatment is most effective during mitomycin therapy. Dexamethasone (10–12 mg at each treatment) during mitomycin chemotherapy for non-small cell lung cancer was found to effectively prevent lung injury.¹⁷³ A decrease in the antineoplastic effect of mitomycin was observed, suggesting that further study on this type of treatment is necessary. Loss of vision associated with pseudotumor cerebri can be treated with glucocorticoids.¹⁷⁴

Mechanism of Glucocorticoid Action

The majority of the biologic effects of steroid hormones are mediated by intracellular receptor proteins that are specific for each steroid. The glucocorticoid receptor (GR), a cytoplasmic protein with an approximate molecular weight of 98,000, is present in all tissues that are targets of glucocorticoid action.¹⁷⁵ Recent studies on mice with a disrupted GR gene recapitulate earlier observations that a functional glucocorticoid signaling pathway is essential for life, since mice lacking a functional GR die shortly after birth from respiratory failure.¹⁷⁶ The concentration of glucocorticoid receptors in a given cell depends on many factors, including cell type, state of differentiation, phase of the cell cycle, endocrine status, and age. Glucocorticoid receptors are generally required for glucocorticoid-induced changes to occur, but hormonal sensitivity is not guaranteed by the presence of receptors. While in general, a good correlation between the concentration of glucocorticoid receptors in a cell and the cellular sensitivity to glucocorticoids exists, other factors may modulate glucocorticoid sensitivity. Such factors include the presence of nonfunctional or modified receptors and other cellular factors that modify receptor function.

In the current model for glucocorticoid action (Fig. 54.2), free glucocorticoids diffuse passively into the cell. The steroid then binds noncovalently and with high affinity to the cytoplasmic glucocorticoid receptor, which is held in a ligand-binding competent conformation by its association with regulatory proteins, including heat shock protein-90. Upon ligand binding, the glucocorticoid receptor becomes activated. The activation process includes a conformational change in the receptor, increased phosphorylation of the receptor protein, dissociation of the associated regulatory proteins, and the unmasking of the receptor DNA–binding domain. The activated steroid-receptor complex then translocates to the nucleus, where it binds as a homodimer to specific DNA sequences called glucocorticoid-responsive elements (GREs). After binding to a GRE, the steroid-receptor complex alters the transcription rate of specific genes which are associated with GREs. A classical glucocorticoid-responsive gene is depicted in Fig. 54.3. The GRE, shown with the consensus DNA sequence, is located in the 5’-regulatory region of the gene. A glucocorticoid receptor dimer bound to this GRE can interact with transcriptional cofactors, as well as with DNA-binding transcription factors that bind to other regulatory elements located in the 5’ region, such as the TATA and CAAT boxes. By this mechanism, glucocorticoids acting via the glucocorticoid receptor can increase the transcription rate of a positive GRE-containing gene, or decrease the transcription rate of a negative GRE-containing gene. These alterations in the transcription rate lead to changes in the amount of messenger RNA and ultimately the level of protein that is synthesized from these genes, and thus alter cellular functions. Glucocorticoid receptors have also been shown in a variety of experimental systems and cultured cells to negatively regulate the transcription of genes indirectly by interfering with the activity of other transcriptional activators, such as AP-1 and NF- κB. These repressive actions are the result of protein-protein, rather than protein-DNA, interactions. GR physically interacts with AP-1 heterodimers of fos and jun, thereby inhibiting the binding of this transcription factor to AP-1 responsive elements in the DNA. Via this mechanism, GR can inhibit the transcription of genes which do not contain a GRE, but are activated by AP-1. GR also negatively interacts with the transcription factor NF-κB, but the mechanism(s) by which this interaction represses the transcription of NF-κB responsive genes seems to differ from that described for GR and AP-1. The p65 subunit of the NF-κB heterodimer binds to GR, but the interaction does not appear to block p65 binding to DNA. Rather, the negative effect of GR/NF-κB binding appears to involve altered interactions with transcriptional cofactors which bind to both NF-κB and GR. A second mechanism by which GR is known to indirectly block transcription of NF-κB–responsive genes is by increasing the expression of the inhibitory subunit of NF-κB, IκBα.¹⁷⁷ The anti-inflammatory effects of glucocorticoids are largely attributable to these repressive effects of GR on the ability of AP-1 and NF-κB to activate pro-inflammatory genes.

Figure 54.2

Mechanism of action for the glucocorticoid signaling pathway. GR = glucocorticoid receptor;. GRE = glucocorticoid responsive element; nGRE = negative GRE; HSP = heat shock protein; GTM = general transcriptional machinery; AP-1 = AP-1 responsive element; (more...)

Figure 54.3

Structural characteristics of a classical glucocorticoid regulated gene. GRE=glucocorticoid responsive element; N=unspecified nucleoside.

One important aspect of receptor regulation that is especially relevant to glucocorticoid therapy is glucocorticoid-induced downregulation (tachyphylaxis) of the glucocorticoid receptor. The ability of glucocorticoid to downregulate its own receptor is mediated by the receptor itself.¹⁷⁷ The maximum effect is a 50 to 75% decrease in receptor protein, which is reflected by a decrease in receptor messenger RNA that occurs within 24 hours of treatment. Long-term administration of glucocorticoids is not only associated with the downregulation of the glucocorticoid receptor but also with decreased function of other genes that are glucocorticoid sensitive.¹⁷⁸ This phenomenon implies that continuous glucocorticoid treatment can have widespread deleterious effects on cell function and may explain why alternate-day glucocorticoid therapy is associated with a lesser risk of unwanted side effects.¹⁷⁹ These results indicate that it may be important, in terms of efficacy and safety, to administer therapeutic doses of glucocorticoids in a manner that simulates the natural diurnal rhythm of glucocorticoid secretion.

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