Adrenal Cortex

Introduction

The adrenal cortex is vital for metabolic balance, fluid and electrolyte regulation, immune control, and vascular stability. Its hormones also influence stress adaptation and puberty, making this gland essential for survival, growth, and normal endocrine function.

• The adrenal glands contain two distinct endocrine regions arranged one within the other.
• The outer part is the adrenal cortex, which forms about 80–90% of the gland.
• The inner part is the adrenal medulla, contributing about 10–20%.
• The adrenal cortex is organized into three layers and secretes steroid hormones. It develops from mesodermal tissue.
• The adrenal medulla develops from neuroectoderm, related to sympathetic ganglia. It secretes catecholamines, mainly adrenaline and noradrenaline.

Functional Anatomy

• The adrenal cortex is the outer region of the adrenal gland and forms about 80–90% of its mass.
• In the fetus, the adrenal cortex is proportionally larger than in adults.
• A large temporary fetal zone occupies most of the fetal cortex, while the future permanent cortex forms a smaller part.
• Near birth and during early infancy, the fetal zone rapidly regresses.
• The remaining permanent cortex develops into the postnatal adrenal cortex.
• During fetal life, the cortex produces sulfate-conjugated androgen precursors. These precursors are converted by the placenta into estrogens that help maintain pregnancy.
• The cortex secretes three major classes of hormones: glucocorticoids, mineralocorticoids, and adrenal androgens.

• Glucocorticoids regulate metabolism, stress responses, inflammation, and immunity.
• Mineralocorticoids maintain extracellular fluid volume, sodium balance, potassium balance, and blood pressure.
• Adrenal androgens contribute to development of secondary sexual characteristics.
• Glucocorticoids and mineralocorticoids are essential for survival.

Histology

• The adrenal cortex is divided into three concentric zones, each with characteristic cells and hormone secretion.
• From outer to inner, these are zona glomerulosa, zona fasciculata, and zona reticularis.

Zona glomerulosa:

• This is the outermost and thinnest cortical layer. It forms roughly 15–20% of the cortex.
• Cells are arranged in rounded clusters or arches. They contain numerous mitochondria and smooth endoplasmic reticulum.
• This zone secretes mineralocorticoids, mainly aldosterone.

Zona fasciculata:

• This is the middle and widest layer of the cortex. It is the largest zone and forms most of the cortical mass.
• Cells are arranged in straight cords separated by sinusoids.
• Cytoplasm contains abundant lipid droplets, giving a vacuolated appearance.
• Cells are rich in mitochondria with tubular cristae.
• This zone mainly secretes glucocorticoids, especially cortisol, and small amounts of adrenal androgens.

Zona reticularis:

• This is the innermost cortical layer adjacent to the medulla.
• Cells form an irregular network of smaller cells.
• Lipid content is less than in the zona fasciculata.
• It secretes adrenal androgens and smaller amounts of glucocorticoids.
• All cortical zones synthesize hormones from cholesterol.

Table 59.1: Hormones secreted from adrenal cortex.

Hormone Class	Major Adrenal Cortical Secretions
Mineralocorticoids	Aldosterone, deoxycorticosterone
Glucocorticoids	Cortisol, corticosterone
Adrenal Sex Steroids	Dehydroepiandrosterone, androstenedione

Synthesis Of Adrenocortical Hormones

• Adrenocortical hormones are steroid hormones synthesized from cholesterol.
• Cholesterol used for steroidogenesis is obtained from circulating lipoproteins or produced within cortical cells.

From blood:

• The major source under basal conditions is plasma cholesterol carried mainly by low-density lipoprotein particles.
• Adrenal cortical cells contain abundant low-density lipoprotein receptors.
• Lipoproteins are internalized, and cholesterol esters are released inside the cell.
• Cholesterol is re-esterified and stored as lipid droplets for future use.
• When hormone synthesis is required, stored esters are hydrolyzed to free cholesterol by cholesterol ester hydrolase.

From the cell itself (de novo synthesis):

• Free cholesterol must enter mitochondria for steroid synthesis to begin.
• Transport is mediated mainly by the steroidogenic acute regulatory protein, with assistance from intracellular carrier systems. This transfer step is highly regulated by adrenocorticotropic hormone.
• Inside mitochondria, cholesterol is converted to pregnenolone. This reaction is catalyzed by cholesterol side-chain cleavage enzyme, also called CYP11A1. It is the first and rate-limiting step of adrenal steroidogenesis.

Cytochrome P-450 enzymes:

• Many subsequent reactions require cytochrome P450 enzymes located in mitochondria and smooth endoplasmic reticulum. These enzymes catalyze hydroxylation and other modifications of steroid precursors.
• Different enzyme combinations in each cortical zone determine final hormone production.

Synthesis of Glucocorticoids

• Glucocorticoids are synthesized mainly in the zona fasciculata of the adrenal cortex.
• Zona reticularis contributes smaller amounts. ·  Principal glucocorticoids are cortisol and corticosterone.

Table 59.2: Adrenal steroidogenic enzymes.

Enzyme Function	Current Enzyme Name
Cholesterol side-chain cleavage	CYP11A1
3-beta hydroxysteroid dehydrogenase	3β-HSD
17-alpha hydroxylase	CYP17A1
21-hydroxylase	CYP21A2
11-beta hydroxylase	CYP11B1
Aldosterone synthase	CYP11B2

Steps of Cortisol Synthesis

• Cortisol is synthesized mainly in the zona fasciculata of the adrenal cortex from cholesterol.
• In mitochondria, cholesterol is converted to pregnenolone by cholesterol side-chain cleavage enzyme (CYP11A1).
• Pregnenolone is then hydroxylated by 17-alpha hydroxylase to form 17-hydroxypregnenolone. This intermediate moves to the smooth endoplasmic reticulum. There, 3-beta hydroxysteroid dehydrogenase converts it to 17-hydroxyprogesterone.
• 21-hydroxylase then converts 17-hydroxyprogesterone to 11-deoxycortisol.
• 11-Deoxycortisol returns to mitochondria.
• 11-beta hydroxylase converts it to cortisol, the final product.
• Adrenocorticotropic hormone stimulates cortisol synthesis by increasing cholesterol availability and promoting transport into mitochondria. It also enhances activity of steroidogenic enzymes during stress.

Synthesis of Mineralocorticoids

• Mineralocorticoids are synthesized in the zona glomerulosa of the adrenal cortex.
• The principal human mineralocorticoid is aldosterone.
• Cholesterol is first converted to pregnenolone inside mitochondria.
• Early steps of synthesis are similar to other adrenal steroids until formation of corticosterone precursors.
• Final conversion to aldosterone is catalyzed by aldosterone synthase (CYP11B2). This enzyme is present only in the zona glomerulosa. Therefore, aldosterone production is restricted to this outer cortical layer.
• Zona glomerulosa lacks 17-alpha hydroxylase, so it cannot synthesize cortisol or adrenal androgens.
• Aldosterone secretion is regulated mainly by angiotensin II and plasma potassium, with a minor short-term effect of adrenocorticotropic hormone.

Synthesis of Sex Steroids

• Adrenal sex steroids are produced mainly in the zona reticularis.
• Smaller contributions may arise from the zona fasciculata.
• Major products are dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These steroids are derived from cholesterol through pregnenolone and 17-hydroxylated intermediates.
• Dehydroepiandrosterone can be sulfated to form dehydroepiandrosterone sulfate.
• Androstenedione may be converted in peripheral tissues to testosterone or estrogens.
• Estradiol formation mainly occurs by peripheral aromatization rather than within the adrenal gland.

Effects of Enzyme Deficiency

• Deficiency of adrenal steroidogenic enzymes reduces cortisol production.
• Low cortisol removes negative feedback on the pituitary, causing increased adrenocorticotropic hormone secretion.
• Excess stimulation enlarges the adrenal cortex, producing congenital adrenal hyperplasia.
• Common enzyme defects include 21-hydroxylase and 11-beta hydroxylase deficiency.

Deficiency of 21β-Hydroxylase

• 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. It impairs synthesis of both cortisol and aldosterone.
• Steroid precursors are diverted toward excess androgen production. This leads to androgen excess and virilization.
• In female infants, ambiguous genitalia may occur at birth.
• Older terminology such as “pseudohermaphroditism” is no longer preferred.
• Girls and women may develop hirsutism, acne, menstrual disturbance, deepened voice, or clitoromegaly.
• Boys may show early virilization and rapid growth with advanced bone age.
• If untreated, final adult height may be reduced.
• Severe deficiency causes marked aldosterone deficiency.
• Renal sodium loss leads to hyponatremia, dehydration, and reduced extracellular fluid volume.

• Hyperkalemia and hypotension may also develop.
• Infants can present with vomiting, shock, or adrenal crisis.

Table 59.3: Daily secretion and plasma concentration of adrenocortical steroids.

Hormone	Daily Secretion (mg/24 h)	Average Plasma Level (µg/dL)
Cortisol	10–15	14
Corticosterone	2–4	0.5
Aldosterone	0.1–0.2	0.0006
Deoxycorticosterone	0.2–0.25	0.0006
Dehydroepiandrosterone	20–25	175

Deficiency of 11β-hydroxylase

• 11-beta hydroxylase deficiency reduces cortisol synthesis and increases adrenocorticotropic hormone secretion.
• Steroid precursors are diverted to excess androgen production, causing virilization.
• Accumulated 11-deoxycorticosterone has mineralocorticoid activity.
• Sodium and water retention lead to hypertension and suppressed renin levels.
• Treatment usually includes glucocorticoid replacement to suppress excess adrenocorticotropic hormone.

Deficiency of 17α-hydroxylase

• 17-alpha hydroxylase deficiency is uncommon. It decreases cortisol and sex steroid synthesis.
• Excess mineralocorticoid precursors cause hypertension and hypokalemia.
• Sexual infantilism or undervirilization may occur depending on genetic sex.
• Female external genital appearance may be present in some genetically male individuals due to absent androgen effects.

3β-hydroxysteroid Dehydrogenase

• This rare disorder impairs formation of cortisol, aldosterone, and potent sex steroids.
• Dehydroepiandrosterone levels may increase.
• Females may show mild virilization.
• Genetic males may develop undervirilization, including hypospadias.
• Salt-wasting can occur because mineralocorticoid synthesis is reduced.

Cholesterol Desmolase Deficiency

• Deficiency of cholesterol desmolase (CYP11A1) blocks conversion of cholesterol to pregnenolone, the first step of steroidogenesis.
• Production of adrenal and gonadal steroids becomes severely impaired.
• Affected infants may develop adrenal failure and disorders of sexual development.
• Severe untreated disease can be life-threatening.

Metabolism of Adrenocortical Hormones

Normal Secretion

• Adrenocortical hormones are secreted continuously in small amounts and vary with circadian rhythm, stress, and physiological demand.
• Cortisol is the major glucocorticoid secreted in humans.
• Aldosterone secretion is lower in quantity but highly important for fluid and electrolyte balance.

Plasma Protein Binding

• Most adrenocortical steroids circulate bound to plasma proteins.
• Main binding proteins are corticosteroid-binding globulin and albumin.
• Only the unbound or free hormone is biologically active and able to enter target cells.

Transcortin Binding

• About 80% of cortisol and corticosterone circulate bound to transcortin, also called corticosteroid-binding globulin.
• Transcortin is a glycoprotein synthesized by the liver. This binding protein transports steroids and acts as a circulating reserve.
• Transcortin levels increase during pregnancy and with estrogen therapy.
• Increased binding initially lowers free cortisol concentration.
• Reduced free cortisol stimulates adrenocorticotropic hormone release, increasing cortisol secretion.
• A new equilibrium then develops in which total cortisol rises, while free cortisol remains near normal. Therefore, high total cortisol in pregnancy usually does not indicate cortisol excess.

Albumin Binding

• About 10–15% of cortisol is loosely bound to albumin, while only a small fraction remains free in plasma.
• Protein binding prolongs cortisol half-life to about 60–90 minutes and reduces urinary loss.
• Aldosterone binds weakly to plasma proteins, so its half-life is shorter, about 20 minutes.

Metabolic Degradation

• Cortisol is metabolized mainly in the liver. It is reduced to inactive metabolites such as dihydrocortisol and tetrahydrocortisol. These metabolites are commonly conjugated with glucuronic acid, making them water soluble.
• Water-soluble products are then excreted rapidly in urine.
• A small fraction of free cortisol in plasma is filtered by the kidneys and appears in urine.
• Measurement of urinary free cortisol helps assess cortisol overproduction.
• Urinary 17-hydroxycorticosteroids represent important metabolites of cortisol and related steroids. Their excretion historically reflected daily cortisol secretion, although newer tests are now preferred.
• Precursors such as progesterone and 17-hydroxyprogesterone are metabolized to pregnanediol and pregnanetriol.

• In adult females, urinary steroid metabolites may reflect ovarian and adrenal steroid activity.
• Increased metabolite excretion in children can suggest congenital adrenal enzyme defects or abnormal cortisol synthesis.

17-Ketosteroids

• 17-Ketosteroids are urinary metabolites derived mainly from androgen metabolism. They arise from adrenal androgens such as dehydroepiandrosterone and from testosterone metabolism.
• Cortisol contributes only minor amounts, while corticosterone does not significantly form 17-ketosteroids.
• Common metabolites include etiocholanolone and androsterone. These compounds are excreted in urine after hepatic metabolism.
• Historically, urinary 17-ketosteroid measurement was used to assess adrenal androgen production.
• Most urinary 17-ketosteroids originate from the adrenal cortex, with the remainder from gonadal androgens.
• Elevated levels may occur in androgen excess states or adrenal disorders.

Glucocorticoids

Regulation of Secretion

Glucocorticoid secretion is regulated mainly by the hypothalamic-pituitary-adrenal axis.

Role of ACTH

• Corticotropin-releasing hormone from the hypothalamus stimulates release of adrenocorticotropic hormone from the anterior pituitary.
• Adrenocorticotropic hormone is the principal stimulus for cortisol secretion from the adrenal cortex.
• Cortisol exerts negative feedback on both the hypothalamus and pituitary, limiting further hormone release.
• Adrenocorticotropic hormone is secreted in pulsatile bursts throughout the day.
• Secretion is greatest in the early morning, usually between 4 AM and 10 AM. Therefore, plasma cortisol also shows a clear circadian rhythm, peaking in the morning and falling at night.
• Stress, illness, and hypoglycemia can increase secretion.
• Other modulators, including angiotensin II, may have minor supportive effects.

Feedback Control

• Glucocorticoid secretion is regulated by feedback control through the hypothalamic-pituitary-adrenal axis.
• The hypothalamus releases corticotropin-releasing hormone, which stimulates the anterior pituitary.
• The anterior pituitary then secretes adrenocorticotropic hormone.
• Adrenocorticotropic hormone stimulates the adrenal cortex to produce cortisol.
• Corticotropin-releasing hormone release is influenced by circadian signals, stress, pain, and neural inputs from higher brain centers.
• When plasma cortisol rises, it exerts negative feedback on both the hypothalamus and pituitary. This reduces corticotropin-releasing hormone and adrenocorticotropic hormone secretion. As a result, cortisol output returns toward normal.
• When cortisol levels fall, feedback inhibition decreases.
• Corticotropin-releasing hormone and adrenocorticotropic hormone then increase, restoring cortisol secretion.

In Stress

• During stress, cortisol secretion increases mainly because hypothalamic corticotropin-releasing hormone release rises.
• Emotional stress, fear, and anxiety activate limbic pathways that stimulate the hypothalamus.
• Painful stimuli and injury also activate neural pathways to the hypothalamus, enhancing cortisol production through the pituitary-adrenal axis.

Angiotensin II

• Angiotensin II mainly stimulates aldosterone secretion, but it can also modestly increase glucocorticoid release.

Other Hormones

• Antidiuretic hormone, serotonin, and vasoactive intestinal peptide may stimulate glucocorticoid secretion, although their normal physiological importance remains uncertain.

Mechanism of Action

• Cortisol acts mainly through intracellular receptors, so its effects usually begin after several hours and may continue for days. It diffuses across the cell membrane because it is a lipid-soluble steroid hormone.
• Inside the cytoplasm, cortisol binds to specific glucocorticoid receptors. This binding removes inhibitory heat shock proteins attached to the receptor.
• The receptor then changes shape and becomes activated by phosphorylation.
• The cortisol–receptor complex moves into the nucleus. It binds to glucocorticoid response elements on deoxyribonucleic acid. This interaction alters gene transcription and increases or decreases messenger ribonucleic acid synthesis.
• Newly formed proteins produce the final cellular effects.

Functions of Glucocorticoids

• Glucocorticoid receptors are present in most body tissues.
• Cortisol strongly regulates carbohydrate, protein, and fat metabolism.
• It supports normal responses to catecholamines and other hormones.
• It helps maintain cardiovascular stability and blood pressure.
• It suppresses excessive inflammation and modulates immune activity.
• It is essential for adaptation to physical and psychological stress. · 
• Because of these actions, cortisol derivatives are widely used in medical treatment.

Effects on Intermediary Metabolisms

On Carbohydrate Metabolism

• Glucocorticoids, especially cortisol, play an essential role in maintaining blood glucose during fasting and stress.
• During prolonged fasting, liver glycogen stores become depleted. Continued glucose supply then depends mainly on gluconeogenesis.
• Cortisol prevents severe hypoglycemia by increasing hepatic glucose production. It stimulates synthesis of key gluconeogenic enzymes in the liver.
• A major effect is increased activity of glucose-6-phosphatase, which converts glucose-6-phosphate into free glucose for release into blood.
• Cortisol also promotes protein breakdown in skeletal muscle. This releases amino acids, which serve as substrates for gluconeogenesis. It enhances lipolysis indirectly, providing glycerol that can also support glucose formation.
• Cortisol increases the effectiveness and secretion of counter-regulatory hormones such as glucagon and epinephrine. These hormones stimulate glycogen breakdown and help restore blood glucose during hypoglycemia.
• Although cortisol supports glucose release, it can also facilitate liver glycogen storage when nutrients are available.
• Cortisol has an anti-insulin action in peripheral tissues. It reduces glucose uptake in skeletal muscle and adipose tissue. This occurs partly by decreasing movement of glucose transport proteins to the cell membrane. It also reduces insulin sensitivity in target tissues.
• In the liver, cortisol opposes insulin-mediated suppression of glucose output.
• Excess cortisol may cause persistent hyperglycemia and worsen diabetes mellitus.
• Deficiency of cortisol increases the risk of fasting hypoglycemia, weakness, and poor stress tolerance.

On Protein Metabolism

• Cortisol promotes proteolysis, especially in skeletal muscle. It increases breakdown of muscle proteins into amino acids. These amino acids are transported to the liver for gluconeogenesis.
• Cortisol also reduces protein synthesis in many tissues.
• Prolonged excess cortisol causes negative nitrogen balance.
• Chronic elevation leads to wasting of muscle mass and weakness.
• Protein depletion also affects bone, skin, and connective tissue.
• As a result, thin skin, poor wound healing, osteoporosis, and easy bruising may occur.

On Fat Metabolism

• Cortisol stimulates lipolysis in adipose tissue. It enhances the fat-mobilizing actions of catecholamines and growth hormone.
• During fasting, triglycerides break down into free fatty acids and glycerol.
• Glycerol can be used by the liver for gluconeogenesis.
• Free fatty acids provide energy to tissues.
• Increased fatty acid delivery to the liver may promote ketogenesis, especially in uncontrolled diabetes mellitus.

On Food Intake and Fat Distribution

• Cortisol increases appetite partly through hypothalamic pathways. It may enhance neuropeptide Y signaling, which promotes food intake.
• Cortisol can stimulate maturation of preadipocytes into adipocytes.
• In some fat depots, it increases lipogenesis by activating metabolic enzymes. Therefore, cortisol may cause both fat breakdown and regional fat accumulation.
• Excess cortisol often produces central obesity, rounded face, dorsocervical fat pad, and relatively thin limbs. This altered distribution is associated with insulin resistance and hyperinsulinemia.
• Cortisol also increases leptin production, which may partly limit excessive feeding.

Permissive Actions of Cortisol

• Permissive action means cortisol is required in small amounts for certain hormones to exert their full normal effects.
• Cortisol itself does not directly produce these responses but enables them.
• It supports the vasoconstrictor and bronchodilator actions of catecholamines.
• It enhances heat-producing metabolic effects of glucagon and catecholamines.
• It facilitates catecholamine-induced lipolysis.
• ·Cortisol contributes to normal mammary gland development during puberty.
• It promotes maturation of fetal hepatic enzyme systems.
• It stimulates surfactant production and fetal lung maturation before birth. · 
• It also aids postnatal intestinal enzyme development and establishment of normal gut flora.

On Protein Metabolism

• Cortisol promotes proteolysis, especially in skeletal muscle. It increases breakdown of muscle proteins into amino acids. These amino acids are transported to the liver for gluconeogenesis.
• Cortisol also reduces protein synthesis in many tissues.
• Prolonged excess cortisol causes negative nitrogen balance.
• Chronic elevation leads to wasting of muscle mass and weakness.
• Protein depletion also affects bone, skin, and connective tissue.
• As a result, thin skin, poor wound healing, osteoporosis, and easy bruising may occur.

On Fat Metabolism

• Cortisol stimulates lipolysis in adipose tissue. It enhances the fat-mobilizing actions of catecholamines and growth hormone.
• During fasting, triglycerides break down into free fatty acids and glycerol.
• Glycerol can be used by the liver for gluconeogenesis.
• Free fatty acids provide energy to tissues.
• Increased fatty acid delivery to the liver may promote ketogenesis, especially in uncontrolled diabetes mellitus.

On Food Intake and Fat Distribution

• Cortisol increases appetite partly through hypothalamic pathways. It may enhance neuropeptide Y signaling, which promotes food intake.
• Cortisol can stimulate maturation of preadipocytes into adipocytes.
• In some fat depots, it increases lipogenesis by activating metabolic enzymes. Therefore, cortisol may cause both fat breakdown and regional fat accumulation.
• Excess cortisol often produces central obesity, rounded face, dorsocervical fat pad, and relatively thin limbs. This altered distribution is associated with insulin resistance and hyperinsulinemia.
• Cortisol also increases leptin production, which may partly limit excessive feeding.

Permissive Actions of Cortisol

• Permissive action means cortisol is required in small amounts for certain hormones to exert their full normal effects.
• Cortisol itself does not directly produce these responses but enables them.
• It supports the vasoconstrictor and bronchodilator actions of catecholamines.
• It enhances heat-producing metabolic effects of glucagon and catecholamines.
• It facilitates catecholamine-induced lipolysis.
• Cortisol contributes to normal mammary gland development during puberty.
• It promotes maturation of fetal hepatic enzyme systems.
• It stimulates surfactant production and fetal lung maturation before birth.
• It also aids postnatal intestinal enzyme development and establishment of normal gut flora.

Table 59.4: Mineralocorticoid and glucocorticoid activities of various naturally occurring steroids in comparison to cortisol (considering cortisol effect as 1).

Steroid	Mineralocorticoid (Cortisol=1)	Glucocorticoid (Cortisol=1)
Cortisol	1	1
Corticosterone	15	0.3
Aldosterone	3000	0.3
Deoxycorticosterone	100	0.2
Cortisone	0.8	0.7

Effects on Central Nervous System

• Cortisol significantly influences mood, behavior, sleep, and cognition.
• Glucocorticoid receptors are abundant in the limbic system and prefrontal cortex.
• It reduces rapid eye movement sleep and may alter slow-wave sleep patterns.
• Excess cortisol can contribute to insomnia.
• Abnormal cortisol levels may cause euphoria, depression, anxiety, or irritability.
• It can impair memory and concentration.
• Cortisol may reduce responsiveness to sensory stimuli.
• In adrenal insufficiency, personality changes, fatigue, apprehension, and irritability may occur.

Effects on Musculoskeletal System

On Muscle

• Physiological amounts help maintain normal function of cardiac and skeletal muscle.
• It supports neuromuscular efficiency and responsiveness to catecholamines.
• Excess cortisol increases proteolysis and reduces protein synthesis.
• Chronic elevation causes loss of muscle mass.
• Patients may develop proximal muscle weakness, fatigue, and reduced strength.

On Bone

• Cortisol suppresses bone formation through several mechanisms.
• It decreases synthesis of type I collagen, a major component of bone matrix.
• It inhibits differentiation of osteoprogenitor cells into osteoblasts. This reduces new bone formation and repair.
• Cortisol decreases intestinal calcium absorption partly by opposing vitamin D action.
• It may also reduce activation of vitamin D.
• Lower calcium availability impairs bone mineralization.
• Cortisol can increase bone resorption, especially with prolonged excess.
• The net effect is reduced bone mass and decreased bone density.
• Long-term glucocorticoid therapy may cause osteopenia, osteoporosis, and fractures.
• Children exposed to excess cortisol may also show impaired linear growth.

Effects on Connective Tissue

• Cortisol affects connective tissue integrity, renal function, and water balance.
• It inhibits collagen synthesis, reducing structural support in skin and vessels.
• Excess cortisol causes thin skin, delayed wound healing, and easy bruising.
• Capillary walls become fragile, leading to small intradermal hemorrhages.

Effects on Kidney and Water Metabolism

• In the kidney, cortisol increases glomerular filtration rate by improving renal blood flow. It supports rapid excretion of excess water after fluid loading. This effect occurs partly through suppression of antidiuretic hormone release.
• Cortisol deficiency impairs free water clearance and limits urine dilution.
• Cortisol also increases urinary phosphate excretion by reducing proximal tubular reabsorption.

Apparent Mineralocorticoid Excess

• Apparent mineralocorticoid excess occurs when 11 beta-hydroxysteroid dehydrogenase type 2 is absent or inhibited. This enzyme normally converts cortisol to cortisone in mineralocorticoid target tissues.
• Excess active cortisol then stimulates mineralocorticoid receptors.
• Patients develop hypertension, sodium retention, hypokalemia, and metabolic alkalosis.
• Plasma renin and aldosterone levels are usually low despite these findings.
• Causes include congenital enzyme deficiency and excessive licorice intake.
• Glycyrrhetinic acid in licorice inhibits the enzyme.
• Increased epithelial sodium channel activity in the kidney further promotes sodium reabsorption.

Effects on Fetus

• Cortisol plays a major role in fetal maturation before birth.
• It supports normal development of the central nervous system during intrauterine life.
• It promotes maturation of the retina, gastrointestinal tract, lungs, and skin.
• Cortisol helps convert fetal intestinal enzyme patterns to postnatal forms. This adaptation is important for digestion of disaccharides after birth.
• In the lungs, cortisol stimulates alveolar growth and thinning of alveolar epithelial cells. It also increases surfactant synthesis. These changes help the newborn lungs expand effectively with the first breath.

Effects on Blood Cells

Cortisol affects all formed elements of blood, with the greatest effect on white blood cells.

On Leucocytes

• It commonly causes leukocytosis.
• Neutrophil count usually increases because of demargination and reduced tissue migration.
• Mild monocytosis may occur.
• Cortisol causes marked lymphocytopenia, eosinopenia, and basopenia.

Causes of Lymphocytopenia

• It reduces proliferation of lymphocyte precursors.
• It decreases thymus and lymph node size.
• It suppresses cytokine production needed for lymphocyte growth and activation.

Causes of Eosinopenia

• Cortisol promotes eosinophil apoptosis.
• It inhibits cytokines required for eosinophil maturation.
• It increases sequestration of eosinophils in spleen and lungs.

On RBC

Cortisol may produce mild erythrocytosis by stimulating erythropoietin.

On Platelets

It can also cause mild thrombocytosis.

Effects on Inflammation

• Cortisol has powerful anti-inflammatory and anti-allergic effects.
• Inflammation is a protective tissue response to injury, infection, or irritation.
• Typical inflammatory changes include vasodilation, increased capillary permeability, leukocyte migration, and release of chemical mediators.
• Cortisol suppresses many stages of this response.

Inhibition of Inflammatory Mediators

• Cortisol induces synthesis of lipocortin (annexin), which inhibits phospholipase A2. This reduces release of arachidonic acid from membrane phospholipids.
• As a result, production of prostaglandins, thromboxanes, and leukotrienes decreases. These changes reduce pain, edema, fever, and vascular reactions.

Stabilization of Cellular Membranes

• Cortisol stabilizes lysosomal membranes. Therefore, release of proteolytic enzymes from damaged cells is reduced.
• Tissue destruction and local inflammatory injury become less severe.

Effects on Mast Cells and Histamine

• Cortisol suppresses mast cell proliferation and activity.
• It decreases release of histamine, an important mediator of allergy and acute inflammation. This reduces vasodilation, itching, and capillary leakage.

Effects on Leukocytes

• Cortisol decreases migration of leukocytes to sites of injury. It reduces adhesion of leukocytes to vascular endothelium.
• Expression of adhesion molecules and chemotactic responses are inhibited.
• Although blood neutrophil count may rise, their tissue movement and function are reduced.
• Cortisol also suppresses phagocytic and bactericidal activity of neutrophils and macrophages.

Effects on Cytokines and Immune Signaling

• Cortisol decreases synthesis of many cytokines, including interleukins and tumor necrosis factor.
• It inhibits activation and proliferation of lymphocytes. These actions contribute to both anti-inflammatory and immunosuppressive effects.

Effects on Fibroblasts and Healing

• Cortisol inhibits proliferation of fibroblasts.
• Collagen synthesis and extracellular matrix deposition decrease.
• Scar formation and granulation tissue are reduced. This helps chronic inflammatory conditions but may delay wound healing.
• It may also impair localization or “walling off” of chronic infections.

Nuclear Factor Kappa B Pathway

• A major mechanism involves inhibition of nuclear factor kappa B, an important inflammatory transcription factor.
• Normally, inflammatory stimuli activate this factor and increase mediator gene expression.
• Glucocorticoids increase inhibitory proteins that keep nuclear factor kappa B inactive.
• Consequently, transcription of inflammatory genes falls markedly.

Clinical Importance

• Because of these actions, glucocorticoids are widely used in asthma, autoimmune disease, dermatitis, cerebral edema, and allergic disorders.
• Prolonged or excessive use can cause infection risk, hyperglycemia, osteoporosis, muscle wasting, hypertension, and adrenal suppression. Therefore, dose, duration, and tapering require careful medical supervision.

Effects on Allergy

• Cortisol has strong anti-allergic actions and reduces hypersensitivity reactions.
• Many allergic symptoms occur after mast cell activation and release of histamine and other mediators.
• Local allergy commonly causes redness, itching, edema, and irritation.
• Severe systemic reactions may produce bronchospasm, hypotension, and circulatory collapse.
• Cortisol inhibits mast cell degranulation, thereby reducing histamine release. It also suppresses mast cell proliferation and inflammatory mediator synthesis. Vascular permeability and tissue swelling decrease.
• Because of these effects, glucocorticoids are widely used in asthma, dermatitis, allergic rhinitis, and adjunct treatment of anaphylaxis. They do not replace emergency epinephrine in anaphylaxis.

Effects on the Immune System

• Cortisol has potent immunosuppressive effects, with greater action on cell-mediated immunity than humoral immunity.
• It is widely used to control autoimmune disease, inflammatory disorders, and transplant rejection.

Effects on Lymphocytes

• Cortisol decreases circulating lymphocyte counts.
• It particularly reduces T lymphocytes, including helper T cells. This occurs through inhibition of cell proliferation and promotion of apoptosis.
• High cortisol levels can shrink the thymus and lymph nodes by reducing immature lymphoid cells.

Effects on T Cell Function

• Cortisol suppresses activation and expansion of T cells after antigen exposure.
• It reduces migration of lymphocytes to sites of antigenic stimulation.
• Cytotoxic T cell responses become weaker.
• These effects lower the ability to eliminate intracellular pathogens and abnormal cells.

Effects on Cytokines

• Cortisol inhibits production of important cytokines such as interleukin 1, interleukin 2, interleukin 6, and interferon gamma.
• Interleukin 2 is essential for T cell proliferation.
• Interferon gamma supports macrophage activation and cellular defense.
• Reduced cytokine production markedly weakens inflammatory and immune signaling.

Nuclear Signaling Mechanism

• A major mechanism is inhibition of nuclear factor kappa B, a transcription factor that promotes inflammatory gene expression.
• This decreases synthesis of multiple immune mediators.

Effects on Monocytes and Macrophages

Cortisol inhibits differentiation of monocytes into macrophages. It reduces antigen presentation, phagocytic activity, and inflammatory mediator release.

Effects on Humoral Immunity

At high doses or prolonged exposure, cortisol can also reduce antibody production by suppressing B cell responses. It does not directly destroy existing antibodies or prevent antigen-antibody binding.

Clinical Importance

• Cortisol lowers fever partly by reducing interleukin 1 activity.
• Excess endogenous or therapeutic glucocorticoids increase susceptibility to infection and may reactivate latent infections.
• Careful dosing and monitoring are necessary during long-term therapy.

Effects on GI tract

• It increases gastric hydrochloric acid secretion from parietal cells.
• Excess or prolonged therapy may cause dyspepsia, gastritis, or peptic ulcer risk, especially with nonsteroidal anti-inflammatory drugs.
• Cortisol also decreases intestinal calcium absorption, which can contribute to bone loss.

Effects on Endocrine Function

• Cortisol suppresses growth hormone secretion and may impair growth in children.
• It can reduce thyroid stimulating hormone release and mildly lower thyroid activity.
• Glucocorticoids inhibit adrenocorticotropic hormone secretion by negative feedback.
• Cortisol also induces phenylethanolamine N-methyltransferase, promoting conversion of norepinephrine to epinephrine in adrenal medulla.

Role in Stress

• Stress activates the hypothalamic-pituitary-adrenal axis.
• The hypothalamus releases corticotropin-releasing hormone. This stimulates secretion of adrenocorticotropic hormone from the anterior pituitary.
• Adrenocorticotropic hormone then increases cortisol release from the adrenal cortex.
• Stressors include pain, fever, infection, hemorrhage, emotional distress, and surgery.
• During stress, cortisol supports the actions of catecholamines.
• It maintains vascular responsiveness, helping preserve blood pressure and tissue perfusion.
• It promotes mobilization of free fatty acids and glucose for emergency energy use.
• Cortisol also limits excessive inflammatory responses that may damage tissues.
• In cortisol deficiency, patients are at risk of adrenal crisis during illness or trauma.

Rapid Actions of Steroid

• Many steroid effects occur through regulation of gene transcription. These slower genomic actions usually develop over hours to days.
• Some steroid effects begin within minutes. These are called nongenomic actions. They occur through direct effects on cell membranes, ion channels, or intracellular enzymes.
• Such actions can rapidly alter signaling pathways and generate second messengers such as cyclic adenosine monophosphate.
• Rapid steroid actions may quickly modify vascular tone, neuronal activity, or cellular metabolism.

Dysfunctions of Glucocorticoids

Cushing’s syndrome

• Cushing syndrome is a disorder caused by chronic excess of glucocorticoids, especially cortisol.
• It may result from endogenous overproduction or prolonged therapeutic steroid use.

Etiology

• Adrenocorticotropic hormone-dependent causes involve excess stimulation of the adrenal cortex.
• The most common endogenous cause is a pituitary corticotroph adenoma, termed Cushing disease.
• Ectopic adrenocorticotropic hormone secretion may occur from tumors such as small-cell lung carcinoma or bronchial neuroendocrine tumors.
• Rarely, ectopic corticotropin-releasing hormone secretion occurs.
• Adrenocorticotropic hormone-independent causes arise from the adrenal gland itself. These include adrenal adenoma, adrenal carcinoma, bilateral nodular hyperplasia, or macronodular adrenal disease.
• Iatrogenic Cushing syndrome results from prolonged use of glucocorticoid medications.

Features

Cushing syndrome produces characteristic metabolic, cardiovascular, musculoskeletal, and skin changes due to chronic cortisol excess.

Body Fat Redistribution

• Central obesity is common, with fat accumulation over the abdomen, trunk, and upper back.
• A dorsocervical fat pad may produce a buffalo hump appearance.
• The face often becomes rounded and plethoric, called moon face.
• Limbs may appear thin because of muscle wasting.

Muscle and Bone Effects

• Patients often develop fatigue, weakness, and reduced exercise tolerance.
• Proximal myopathy commonly affects thighs and shoulder muscles.
• Cortisol excess decreases bone formation and increases bone loss. This may lead to osteoporosis, vertebral compression fractures, and pathological fractures.

Skin Changes

• Skin becomes thin and fragile because of protein catabolism.
• Easy bruising and ecchymoses are frequent.
• Wide reddish-purple striae often appear over the abdomen, thighs, or breasts.
• Wound healing is delayed and infections may occur more easily.
• Hair may become thin; acne can develop.

Cardiovascular and Metabolic Effects

• Hypertension is common due to sodium retention, increased vascular reactivity, and activation of hormonal pathways.
• Many patients develop hyperglycemia, impaired glucose tolerance, or steroid-induced diabetes mellitus.
• Increased appetite and weight gain are frequent.
• Dyslipidemia may also occur.

Reproductive and Endocrine Effects

• Women may develop hirsutism, menstrual irregularity, or amenorrhea because of excess adrenal androgens.
• Men may have reduced libido or hypogonadism.

Neuropsychiatric Effects

• Emotional and cognitive changes are common.
• Symptoms may include irritability, anxiety, insomnia, depression, poor concentration, or rarely psychosis.

Gastrointestinal Effects

• Increased gastric acid secretion may cause dyspepsia.
• Some patients develop gastritis or peptic ulcer disease, especially with additional risk factors.

Diagnosis

• Cushing syndrome is diagnosed by confirming excess cortisol production.
• Common tests include elevated cortisol levels and failure of suppression after dexamethasone administration.
• Plasma adrenocorticotropic hormone helps classify the cause.
• Low levels suggest adrenal disease, whereas high levels suggest pituitary or ectopic sources.

Treatment

• Treatment depends on cause.
• Surgical removal of pituitary or adrenal tumors is preferred when feasible.
• Medicines such as ketoconazole or metyrapone may reduce cortisol synthesis.

Adrenocortical Insufficiency

• Adrenocortical insufficiency results from inadequate adrenal hormone production and may be primary or secondary.
• Primary adrenal insufficiency (Addison disease) is due to adrenal gland damage. Causes include autoimmune destruction, adrenalectomy, tuberculosis, fungal or viral infection, bilateral hemorrhage, metastatic infiltration, and drugs such as ketoconazole or metyrapone.
• Secondary adrenal insufficiency occurs from reduced adrenocorticotropic hormone secretion due to pituitary disease.
• Tertiary insufficiency may result from reduced corticotropin-releasing hormone secretion due to hypothalamic disease or prolonged glucocorticoid withdrawal.

Addison’s Disease

• Addison disease is primary adrenal insufficiency caused by progressive destruction of the adrenal cortex.
• Deficiency usually involves both glucocorticoids and mineralocorticoids.

Etiology

• The most common cause is autoimmune adrenalitis.
• Other causes include tuberculosis, metastatic cancer, amyloidosis, hemorrhage, and opportunistic infections such as cytomegalovirus.

Clinical Features

• Common symptoms include weight loss, fatigue, weakness, and reduced exercise tolerance.
• Hyperpigmentation is a classic sign, especially over pressure areas, scars, and sun-exposed skin. It occurs because low cortisol increases adrenocorticotropic hormone, which stimulates melanocortin receptors.
• Patients often develop hypotension due to sodium loss, volume depletion, and reduced vascular responsiveness.
• Severe cases may progress to shock.
• Nausea, vomiting, abdominal pain, and anorexia are frequent.
• Laboratory findings often show hyponatremia, hyperkalemia, and sometimes eosinophilia.
• Fasting hypoglycemia may occur, especially in children or severe disease.
• Stress, infection, or surgery can precipitate adrenal crisis.

Diagnosis

• Low morning cortisol with elevated adrenocorticotropic hormone suggests primary adrenal insufficiency.
• Cosyntropin stimulation testing helps confirm diagnosis.

Treatment

• Lifelong hormone replacement with glucocorticoid, and usually mineralocorticoid, is the main treatment.
• Stress-dose steroids are required during illness or surgery.

Adrenogenital Syndrome

Etiology

• Adrenogenital syndrome commonly refers to congenital adrenal hyperplasia caused by 21-hydroxylase deficiency.
• Reduced cortisol synthesis increases adrenocorticotropic hormone secretion, causing adrenal hyperplasia.
• Steroid precursors are diverted toward excess androgen production.
• Severe forms may also reduce aldosterone, causing salt wasting.

Features

• In females, prenatal androgen excess may cause virilization of external genitalia.
• Features can include clitoromegaly, hirsutism, acne, reduced breast development, and menstrual disturbance.
• Children may show rapid growth, advanced bone age, and precocious pseudopuberty.
• Diagnosis and treatment are important for normal growth and fertility.

Table 59.5: Conditions that alter aldosterone secretion.

Aldosterone Secretion	Conditions
Increases	Hemorrhage, hypovolemia, hyperkalemia, hyponatremia, standing, anxiety, trauma, surgery, heart failure, cirrhosis, nephrotic syndrome
Decreases	Expanded extracellular fluid volume, hypernatremia, hypokalemia

Mineralocorticoids

Aldosterone is the major mineralocorticoid in humans.

Regulation of Aldosterone Secretion

Aldosterone secretion is regulated mainly by three important stimuli: angiotensin-II, ACTH, and plasma K+ concentration. Many conditions alter aldosterone secretion (Table 59.5) by influencing these stimuli.

Angiotensin II

• Angiotensin II is a major regulator of aldosterone synthesis and secretion. It is produced through the renin–angiotensin–aldosterone system.
• The liver releases angiotensinogen, a plasma protein precursor.
• Renin, secreted by juxtaglomerular cells of the kidney, converts angiotensinogen to angiotensin I.
• Angiotensin converting enzyme, present mainly on vascular endothelium and abundant in the lungs, converts angiotensin I to angiotensin II.
• Angiotensin II strongly stimulates the zona glomerulosa of the adrenal cortex to release aldosterone.
• It also promotes aldosterone synthesis for sustained hormonal response.
• Angiotensin II is further metabolized to angiotensin III, which also stimulates aldosterone secretion.
• Angiotensin I has little direct biological activity in this process.
• Besides endocrine effects, angiotensin II causes potent vasoconstriction, helping maintain arterial pressure.
• It is activated during hypovolemia, sodium depletion, hemorrhage, and reduced renal perfusion.

Angiotensin Receptors

• Angiotensin receptors are of two main types: AT1 and AT2.
• AT1 receptors are present on zona glomerulosa cells of the adrenal cortex.
• Angiotensin II activates AT1 receptors, increasing intracellular calcium through signaling pathways, which stimulates aldosterone secretion.

ACTH

• Zona glomerulosa cells possess adrenocorticotropic hormone receptors.
• Adrenocorticotropic hormone can stimulate aldosterone synthesis and secretion through cyclic adenosine monophosphate and protein kinase signaling.
• Higher hormone concentrations are needed than those required for cortisol release.
• Its effect on aldosterone is usually temporary and declines despite persistent elevation.
• This reduction partly relates to suppressed renin release during volume expansion.

Hyperkalemia

• Hyperkalemia directly stimulates aldosterone secretion from zona glomerulosa cells.
• Increased extracellular potassium depolarizes the cell membrane and opens voltage-gated calcium channels.
• Rising intracellular calcium enhances aldosterone synthesis and release.
• Aldosterone then increases renal potassium excretion, helping restore normal extracellular potassium levels.
• Acute hyponatremia may also support aldosterone secretion indirectly.

Mechanism of Action of Aldosterone

• Aldosterone acts mainly by binding to intracellular mineralocorticoid receptors in target cells.
• The hormone–receptor complex enters the nucleus and modifies gene transcription.
• Newly synthesized proteins then change cellular transport functions.

Genomic Action

• These effects develop over hours.
• Aldosterone induces serum glucocorticoid-regulated kinase 1 expression. This increases activity and membrane insertion of epithelial sodium channels.
• It also enhances synthesis of channel subunits and related transport proteins.
• Sodium reabsorption therefore rises, especially in distal nephron cells.

Nongenomic Action

• These effects occur within minutes.
• Aldosterone can rapidly alter ion transport through membrane signaling pathways involving inositol trisphosphate and intracellular calcium. This helps modulate sodium and potassium transport quickly.

Physiological Actions of Aldosterone

• Aldosterone is the principal mineralocorticoid regulating sodium, potassium, hydrogen ion balance, and extracellular fluid volume.
• Its major renal targets are principal cells of the late distal tubule and collecting duct.

Electrolyte and Water Balance

• Aldosterone increases sodium reabsorption from tubular fluid into blood.
• It upregulates epithelial sodium channels on the luminal membrane.
• It also increases sodium–potassium adenosine triphosphatase activity on the basolateral membrane. These changes move sodium into blood and potassium into tubular cells for secretion.
• Aldosterone enhances potassium excretion in urine.
• It also increases hydrogen ion secretion, especially through intercalated cells, helping acid–base regulation.
• Chloride usually follows sodium to maintain electrical neutrality.
• Water then follows reabsorbed sodium chloride osmotically. Therefore, aldosterone expands extracellular fluid volume and supports arterial pressure.
• Although it directly regulates a small fraction of total filtered sodium, this segment is physiologically crucial.
• Aldosterone deficiency can cause hyponatremia, hyperkalemia, hypotension, dehydration, and metabolic acidosis.
• Excess aldosterone may produce hypertension, hypokalemia, and metabolic alkalosis.

Aldosterone Escape Phenomenon

• Persistent aldosterone excess initially causes retention of salt and water. This increases extracellular fluid volume and venous return to the heart.
• Greater atrial filling stretches the atrial walls.
• Atrial myocytes then release atrial natriuretic peptide.
• Atrial natriuretic peptide promotes natriuresis and diuresis by the kidneys.
• Increased blood pressure and renal perfusion also enhance sodium excretion.
• As a result, extracellular fluid volume moves back toward near normal despite continued aldosterone excess. This protective adaptation is called the aldosterone escape phenomenon.

Dysfunctions of Aldosterone

Hypersecretion of Aldosterone

• Hyperaldosteronism is excess aldosterone secretion and is classified as primary or secondary.
• It commonly causes hypertension, potassium loss, and metabolic alkalosis.

Primary Hyperaldosteronism

• The disorder arises from adrenal gland disease.
• Common causes include aldosterone-producing adenoma (Conn syndrome), bilateral adrenal hyperplasia, and rarely adrenal carcinoma.
• Plasma renin is usually suppressed because sodium retention expands extracellular fluid volume.

Conn’s Syndrome

• This is a common cause of primary hyperaldosteronism due to a zona glomerulosa adenoma.
• Patients often develop hypertension from sodium retention and volume expansion.
• Hypokalemia may cause muscle weakness, cramps, fatigue, or arrhythmias.
• Polyuria and polydipsia can occur because potassium depletion impairs urinary concentrating ability.
• Mild hypernatremia may be present.
• Edema is usually absent because of the aldosterone escape phenomenon.

Secondary Hyperaldosteronism

• Aldosterone rises because the renin–angiotensin system is activated.
• Plasma renin is increased, which helps distinguish it from primary disease. It occurs when effective arterial blood volume is reduced.

Common Causes

• Heart failure
• Cirrhosis with ascites
• Nephrotic syndrome
• Renal artery stenosis
• Rare renin-secreting tumors

Clinical Features

• Edema is common in many secondary causes because the underlying disorder causes fluid retention.
• Hypokalemia may also occur depending on severity.
• Some inherited renal salt-wasting disorders, such as Bartter syndrome and Gitelman syndrome, can cause secondary hyperaldosteronism without edema.

Diagnosis and Management

• Diagnosis uses aldosterone-to-renin testing and confirmatory evaluation.
• Treatment depends on cause and may include surgery, mineralocorticoid receptor antagonists, or correction of the underlying disease.

Bartter Syndrome

• Bartter syndrome is an inherited renal tubular disorder involving defective sodium–potassium–2 chloride cotransport in the thick ascending limb. It causes high renin and secondary hyperaldosteronism.
• Typical findings are hypokalemic metabolic alkalosis and hypercalciuria.
• Blood pressure is usually normal, and edema is absent.

Hyposecretion of Aldosterone

• Hypoaldosteronism commonly occurs with adrenal insufficiency but may also appear with normal cortisol levels.
• Causes include inherited defects of aldosterone synthesis and hyporeninemic hypoaldosteronism. It may follow adrenal surgery or prolonged heparin therapy.
• Rare causes include zona glomerulosa resistance to angiotensin II.
• Typical effects are hyperkalemia, hyponatremia, hypotension, dehydration, and metabolic acidosis.

Sex Steroids

• Sex steroids secreted by the adrenal cortex are mainly adrenal androgens.
• The principal adrenal androgens are dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione.
• Androstenedione can be converted in peripheral tissues to testosterone or estrogens by enzymatic pathways.

Regulation

• Adrenal androgen secretion is stimulated primarily by adrenocorticotropic hormone, not by gonadotropins.
• Production increases before and during puberty, peaks in early adulthood, and gradually declines with age. This age-related rise at puberty is linked to maturation of the zona reticularis.

Adrenarche

• Adrenarche is the early pubertal increase in adrenal androgen secretion, usually preceding full gonadal maturation. It contributes to development of pubic and axillary hair, body odor, and mild sebaceous gland activity.
• It is distinct from gonadarche, which refers to activation of the gonads.

Physiological Functions

• Adrenal androgens have much weaker androgenic activity than testicular testosterone.
• In normal amounts, their masculinizing effect is limited.
• They have mild anabolic effects and can support protein synthesis and growth.
• In adult males, they contribute little to established secondary sexual characteristics.

Importance in Females

• In females, adrenal androgens are a significant source of androgens and influence libido, hair growth, and pubertal development.
• After menopause, peripheral conversion of adrenal precursors becomes an important source of estrogen.

Excess Secretion

• Excess adrenal androgen production can cause hirsutism, acne, menstrual disturbance, virilization, or precocious pseudopuberty in children.
• Common causes include congenital adrenal hyperplasia and adrenal tumors.

Deficiency

• Low adrenal androgen levels are usually subtle but may contribute to reduced libido or low energy in some women.

Dysfunctions of Adrenal Androgens

• Excess adrenal androgens cause virilization syndromes.
• Overproduction often occurs with excess secretion of other adrenal cortical hormones.
• In boys, it may cause precocious pseudopuberty with early secondary sexual characteristics.
• In girls, it may cause ambiguous genitalia, virilization, or adrenogenital syndrome.
• Common causes include congenital adrenal hyperplasia and adrenal tumors.