Steroidogenesis of Corticosteroids, Genetic Mutation, and Endocrine Disruption Leading to Adrenal Insufficiency

Abstract

Steroidogenesis, the process by which steroids are synthesized, involves a complex cascade of enzymatic reactions that ultimately produce hormones, such as cortisol and aldosterone. Cortisol is a steroid hormone that plays a critical role in the regulation of various physiological processes, including metabolism, immune response, and stress response. Aldosterone is responsible for blood pressure and water balance. The biosynthesis of cortisol and aldosterone occurs primarily in the adrenal cortex and is processed by a series of enzymatic reactions that convert cholesterol into cortisol and aldosterone. Enzymes include CYP11A1, 3β-hydroxysteroid dehydrogenase 2, CYP11B1, CYP11B2, CYP17A1, and 21-hydroxylase. Mutations or defects in these enzymes can lead to impaired cortisol and aldosterone biosynthesis, thereby resulting in various disorders such as congenital adrenal hyperplasia, adrenal hypoplasia congenita, and familial glucocorticoid deficiency. Endocrine disruptors, such as phthalates, bisphenols, and pesticides, affect adrenal cortex development or steroidogenesis, thereby causing adrenal cortex dysfunction. Understanding the complex process of steroidogenesis involved in cortisol and aldosterone biosynthesis can provide crucial insights into the pathophysiology of adrenal disorders and inform the development of targeted therapies to alleviate the associated symptoms.

1. Introduction

Corticosteroids are a class of steroid hormones that play critical roles in various physiological processes in the body. They are synthesized through a complex process known as steroidogenesis. Corticosteroids belong to two main subclasses: glucocorticoids and mineralocorticoids, each with distinct functions and regulation. Glucocorticoids primarily regulate metabolism, immune responses, and stress responses, while mineralocorticoids are mainly involved in maintaining electrolyte balance and fluid homeostasis. In this chapter, we will focus on the steroidogenesis of corticosteroids, with an emphasis on glucocorticoid and mineralocorticoid biosynthesis.

2. Adrenal corticosteroid biosynthesis and regulation

2.1 Adrenal cortex anatomy

The adrenal gland is essentially divided into two endocrine glands, composed of two structures of different embryonic origin and function, namely the outer cortex and inner medulla (Figure 1). The adrenal medulla is an extension of the sympathetic nervous system and consists of irregularly arranged chromaffin cells. The adrenal medulla is not the subject of the current chapter. The adult adrenal cortex is histologically and functionally divided into three distinct zones, each controlled by unique hormonal signals. The outer zona glomerulosa (zG) synthesizes aldosterone, a mineralocorticoid hormone that regulates sodium retention and blood vessel volume, thereby controlling blood pressure. The middle zona fasciculata (zF) synthesizes glucocorticoids (cortisol in humans or corticosterone in rodents), which play a key role in glucose metabolism, immune responses, and stress responses. The innermost zona reticularis (zR) is responsible for the biosynthesis and secretion of androgens [1]. The adrenal is covered by a layer of capsule. Controversy has sometimes surrounded the existence of mouse and rat zR zones, but its presence can be clearly documented based on morphological criteria. However, it is worth noting that the thickness of this zone can vary significantly among different mouse strains [2].

Figure 1.

Illustration of adrenal glands. The adrenal gland comprises an inner medulla and an outer adrenal cortex. The cortex is covered by a thin cellular capsule. The adrenal cortex has three classical zones, the zG (zona glomerulosa) which is under capsule, zF (zona fasciculata) which exists between zG and zR (zona reticularis), and zR which is innermost of the adrenal cortex, showing distinct morphology.

According to immunohistochemistry, some researchers have described the presence of an intermediate zone or undifferentiated zone between zG and zF in rats and mice. This zone does not express corticosteroid-specific enzymes such as cytochrome P450 aldosterone synthase (CYP11B2) in the zG and cytochrome P450 11β-hydroxylase (CYP11B1) in the zF [3, 4, 5].

The foetal human adrenal gland primarily consists of a specialized foetal zone that synthesizes precursor steroids, which can be converted to oestrogen by the placenta. This foetal zone is surrounded by definitive tissue. After birth, the foetal zone rapidly “involutes” or disappears and is replaced by the expanding definitive zone [6]. Recent evidence suggests that the developing mouse adrenal cortex may mainly comprise a foetal zone. The residue of this zone forms the so-called X zone around day 10 postpartum, following its replacement by definitive tissue around birth [7]. Cells of the mouse X zone appear highly basophilic [7].

This book chapter primarily focuses on zG and zF zones, dealing with the biosynthesis of corticosteroids, including cortisol/corticosterone and aldosterone.

2.2 Adrenal development

The development of the adrenal gland is a complex and fascinating process that begins during early embryonic development. The adrenal gland is a unique endocrine organ located on top of the kidneys and plays a key role in regulating various physiological processes in the body. During early embryonic development, the adrenal gland arises from two distinct regions: the adrenal cortex and the adrenal medulla. These two regions have different embryological origins and functions. The adrenal cortex originates from the mesoderm [8], while the adrenal medulla develops from neural crest cells (see review [9]). This book chapter focuses on adrenal cortex development. The development of the adrenal gland can be divided into several stages, each characterized by specific cellular and molecular events. The first stage is known as the specification stage, during which the precursor cells are specified to become adrenal cortex, called the anlage of the adrenal cortex, which is first identified at 3–4 weeks of gestation in humans, due to a condensation of the coelomic epithelium. The next stage is the proliferation and differentiation stage, where the precursor cells undergo rapid proliferation and begin to differentiate into the specific cell types of the adrenal gland and migrate to the superior end of the mesonephros, and the adrenal gland is first recognizable at 4–6 weeks of gestation in humans. In the adrenal cortex, different zones start to form (called foetal zone and definitive zone) at 8–10 weeks of gestation. By late gestation, the foetal adrenal gland starts to develop into the early form of the adult adrenal cortex and the morphology of zG and zF appears. Then, the foetal zone declines and disappears during the first three postnatal months. Finally, the final adult zonal pattern is established and stabilized between 10 and 20 years of age [8].

Although there may be variations in developmental milestones and timing between different species, the overall processes of adrenocortical development in rats and mice are similar to those in humans [4, 10]. Several researchers have reported that the precursors of steroidogenic tissues first appear in mouse and rat embryos as transcription factor steroidogenic factor 1 (SF-1, also called nuclear receptor family 5 member A1, NR5A1)-positive adrenogenital primordium at approximately E8.5-E9.5 in mice and E11.5 in rats [4, 10, 11]. This adrenogenital primordium separates into distinct adrenal and gonadal primordia around E10.5-E11.5 in mice and E12.5 to E14.5 in rats. Medullary precursor cells migrate into the adrenal primordium around E12.5 in mice and E15 in rats. Subsequently, the adrenal gland becomes encapsulated around E14.5 in mice and E16.5 in rats [4, 10, 11].

In rats and mice, zonation of the adrenal cortex begins in late gestation [4, 10, 11]. Besides, the mouse adrenal cortex also has an X zone [4, 10, 11], which exists in the innermost region of the cortex surrounding the medulla. The X zone first appears around 10 days after birth and reaches its maximum volume in males during the weaning period. It degenerates during puberty in males under the action of androgens. However, in female mice, the X zone reaches its maximum size at around 3 months of age and gradually degenerates with age or rapidly during the first pregnancy under the influence of oestrogens [7, 12, 13]. The function of the X zone remains unclear, but it is believed to be equivalent to the foetal zone found in human adrenal glands [14].

As the adrenal gland continues to develop, it undergoes morphological changes and establishes functional connections with other organs. One significant interaction occurs between the adrenal cortex and the placenta during foetal development [12]. The foetal adrenal cortex produces precursor steroids that can be converted into oestrogens by enzymes in the placenta, contributing to the hormonal balance in the developing foetus [12].

The final stage of adrenal gland development is the maturation stage, during which the adrenal gland acquires its final structure and function. This process involves the refinement of hormone production, establishment of innervation, and vascularization of the organ. Additionally, the adrenal gland undergoes changes in response to various physiological and pathological stimuli throughout life.

2.3 Steroidogenesis of corticosteroids

Due to the specific structures of adrenal cortex, each adrenal cortex zone secretes distinct steroid hormones, including corticosteroids. Figure 2 provides an illustration of the steroidogenic pathway within each zone of the human adrenal cortex. These pathways have distinct proteins (or enzymes) for the stepwise conversion from precursor cholesterol into aldosterone (mineralocorticoid) in the zG, cortisol (glucocorticoid) in the zF, and androgens in the zR.

Figure 2.

Pathways of steroidogenesis in the adrenal cortex. Cholesterol is shuttled into inner membrane of the mitochondrion, when it is processed variously to produce different steroidogenic products including glucocorticoids (cortisol in humans), mineralocorticoids (aldosterone) and adrenal androgens. zG, zona glomerulosa; zF, zona fasciculata; zR, zona reticularis; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate. Red color represents aldosterone synthesis; green color represents cortisol or corticosterone synthesis; blue color represents adrenal androgen synthesis.

The synthesis of corticosteroids starts with cholesterol, a precursor molecule that serves as the backbone for steroid hormone biosynthesis. In the adrenal cortex cells, cholesterol is present in free form or in esterified form [15]. Cholesterol in adrenal cortex cells is obtained from both dietary intake via several receptors and transporters, including scavenger receptor member B 1 (SCARB1), also called high-density lipoprotein receptor [16, 17] and low-density lipoprotein receptor (LDLR), and de novo synthesis within the body [13].

Once inside the adrenal cortex cells, cholesterol undergoes a series of enzymatic reactions to convert it into corticosteroids. These reactions take place in different cellular compartments, including the mitochondria and the smooth endoplasmic reticulum. Each step of corticosteroid biosynthesis is catalyzed by specific enzymes expressed in a tissue-specific manner.

The first step in the biosynthesis of corticosteroids is the conversion of cholesterol to pregnenolone. This reaction is catalyzed by the enzyme cytochrome P450 cholesterol side-chain cleavage (CYP11A1). It occurs in the inner mitochondrial membrane and involves the cleavage of the side chain of cholesterol. Transportation of cholesterol to the inner mitochondrial membrane is the initial and limiting step for the biosynthesis of all corticosteroids [15]. Although the underlying mechanisms responsible for the transportation remain unclear, it is thought that the steroidogenic acute regulatory protein (STAR) plays a critical role in this cholesterol transport [18]. When cholesterol reaches CYP11A1, it carries out several steps of hydroxylation and side-chain cleavage of cholesterol to form pregnenolone, which is assisted by cofactors adrenodoxin and the enzyme adrenodoxin reductase [19].

Pregnenolone serves as the precursor for the biosynthesis of both glucocorticoids and mineralocorticoids. Because different zone cells contain distinct other steroidogenic enzymes, they biosynthesize distinct corticosteroids.

In the zG cells, the conversion of pregnenolone to progesterone is mediated by enzymes 3β-hydroxysteroid dehydrogenase/Δ^5–4 isomerase 2 (3β-HSD2), and then progesterone is further into 11-deoxycorticosterone and corticosterone after enzymatic reactions catalysis by cytochrome P450 21-hydroxylase (CYP21A2) and CYP11B1, respectively. In the last step, CYP11B2 catalyzes aldosterone biosynthesis [20].

In the zF cells, the smooth endoplasm reticulum contains cytochrome P450 17α-hydroxylase/17–20-lyase (CYP17A1), which converts pregnenolone into 17α-hydroxypregnenolone. CYP17A1 catalyzes two steps of reaction, including 17α-hydroxylation, which requires coenzyme cytochrome P450 reductase (POR), and 17–20-lysis, which requires cytochrome b5 (b5). The 17α-hydroxypregnenolone is converted to 17α-hydroxyprogesterone by 3β-HSD2. After that, 17α-hydroxyprogesterone is further converted to 11-deoxycortisol and cortisol after the catalysis of CYP21A2 and CYP11B1. Interestingly, the rat and mouse adrenal cortex do not express CYP17A1, therefore, only glucocorticoid corticosterone is formed.

The next crucial step in cortisol level control is cortisol metabolism. This process is regulated by two enzymes, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Both enzymes are expressed in the adrenal cortex [1, 21, 22]. 11β-HSD1 is responsible for the activation of biologically inert cortisone to active cortisol [23], while 11β-HSD2 does the opposite reaction, catalyzing the conversion of cortisol to cortisone [22, 24]. 11β-HSD2 selectively oxidizes the 11β-hydroxy group of cortisol/corticosterone to a ketone, resulting in cortisol inactivation. This step plays a significant role in maintaining the appropriate balance between cortisol and its inactive form, cortisone, as it prevents the excessive buildup of cortisol in tissues with high expression of 11β-HSD2.

Once biosynthesized, mineralocorticoids like aldosterone and glucocorticoids like cortisol are released into the bloodstream. Cortisol binds to corticosteroid-binding globulin (CBG) or albumin that circulates it throughout the body. Cortisol can then reach its target tissues, where it exerts its effects by binding to the intracellular glucocorticoid receptor (NR3C1) and thereby modulating target gene expression.

2.4 Regulation of aldosterone synthesis

The biosynthesis of aldosterone is tightly regulated to maintain electrolyte balance and fluid homeostasis in the body. Several factors, including hormonal, enzymatic, and physiological mechanisms, contribute to the regulation of aldosterone biosynthesis. The renin-angiotensin-aldosterone system (RAAS) is a key hormonal pathway that regulates aldosterone biosynthesis. When blood pressure decreases or sodium levels are low, the juxtaglomerular cells in the kidneys release an enzyme called renin into the bloodstream. Renin acts on its substrate angiotensinogen, which is produced by the liver, to convert it into angiotensin I. Angiotensin I is then converted into angiotensin II by the action of an enzyme called angiotensin-converting enzyme, predominantly found in the lungs. Angiotensin II acts as a potent stimulator of aldosterone biosynthesis by binding to the angiotensin II type 1 receptor (AT1 receptor) on the cells of the adrenal cortex. Activation of the AT1 receptor triggers a series of intracellular signaling events that lead to increased aldosterone production. The key enzyme of aldosterone biosynthesis within the adrenal cortex is the enzyme CYP11B2.

In addition to the RAAS, other hormonal systems can also influence aldosterone biosynthesis. For example, plasma potassium levels directly stimulate aldosterone release. Hyperkalaemia (high potassium levels) stimulates aldosterone biosynthesis and secretion, while hypokalaemia (low potassium levels) inhibits it. Potassium exerts its effect through depolarization of the zG cells, leading to increased calcium influx and subsequent activation of various signaling pathways involved in aldosterone production.

Atrial natriuretic peptide and brain natriuretic peptide, which are released by specialized cells in the heart, also play a role in regulating aldosterone biosynthesis. Atrial natriuretic peptide and brain natriuretic peptide act as inhibitors of the RAAS, opposing the effects of angiotensin II. They promote diuresis and natriuresis, lowering blood pressure, and counteracting the stimulatory effects of angiotensin II on aldosterone release.

The physiological state of the body also influences aldosterone biosynthesis. Physical factors such as blood volume, blood pressure, and body position can affect aldosterone production. For instance, in conditions of low blood volume or blood pressure, baroreceptors detect these changes and stimulate the release of aldosterone to promote sodium and water retention, thereby increasing blood volume and pressure.

Various genetic and molecular mechanisms also contribute to aldosterone biosynthesis regulation. The expression of key enzymes involved in aldosterone biosynthesis, such as CYP11B2, is regulated by different transcription factors and signaling pathways, such as calcium/calmodulin-dependent protein kinase pathway after the rapid intracellular elevation of calcium [25]. Mutations or alterations in these regulatory mechanisms can lead to dysregulation of aldosterone biosynthesis and result in disorders such as primary aldosteronism.

2.5 Regulation of cortisol/corticosterone biosynthesis

The biosynthesis and release of cortisol/corticosterone are tightly regulated by various mechanisms to maintain physiological homeostasis. Several factors, including hormonal, neural, and physiological mechanisms, contribute to the regulation of cortisol biosynthesis. The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the regulation of cortisol biosynthesis. The hypothalamus releases corticotropin-releasing hormone (CRH) in response to various internal and external stressors. CRH stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then acts on the adrenal cortex, specifically the zF, to stimulate the biosynthesis and secretion of cortisol. ACTH binds to melanocortin two receptors (MC2R) on the zF cells, initiating a signaling cascade that leads to increases in intracellular cyclic adenosine monophosphate (cAMP) levels. This, in turn, activates several enzymes involved in cortisol biosynthesis, such as CYP11A1. The release of CRH from the hypothalamus and ACTH from the pituitary gland is subject to a complex feedback system to regulate cortisol production. High levels of cortisol inhibit the release of CRH and ACTH, thereby reducing further cortisol biosynthesis. Conversely, low cortisol levels stimulate the release of CRH and ACTH, leading to increased cortisol production. The negative feedback regulation of cortisol is also influenced by other factors, such as the circadian rhythm. Cortisol levels follow a diurnal pattern, with the highest levels occurring in the early morning and the lowest levels during sleep. The regulation of this circadian rhythm involves the interaction between the suprachiasmatic nucleus in the brain, the pineal gland, and the HPA axis.

Another important regulator of cortisol biosynthesis is the NR3C1. Once synthesized, cortisol binds to NR3C1 in target tissues, resulting in negative feedback on the HPA axis. The binding of cortisol to NR3C1 inhibits the release of CRH and ACTH, thereby reducing cortisol biosynthesis and secretion.

Apart from the hormonal regulation, other factors influence cortisol biosynthesis. Stress, both physical and psychological, can trigger an increase in cortisol production. Stress-related signals, such as pain, injury, or emotional distress, activate the HPA axis [26, 27, 28] and lead to the release of cortisol to help the body cope with the stressor.

Cortisol biosynthesis is also influenced by various physiological factors. Blood glucose levels, for example, can impact cortisol production. Low blood glucose levels stimulate the release of CRH and ACTH, leading to increased cortisol biosynthesis and release. The immune system and inflammation can also influence cortisol levels, as cytokines and other inflammatory mediators can regulate HPA axis activity.

Overall, the biosynthesis and release of cortisol are tightly regulated by a complex interplay of hormonal, neural, and physiological mechanisms. Various factors, including the HPA axis, circadian rhythm, stress, and immune system function, contribute to maintaining appropriate cortisol levels and ensuring proper physiological responses to stress and metabolic demands. The biosynthesis of corticosteroids, especially glucocorticoids, is tightly regulated through complex feedback mechanisms involving the HPA axis. The HPA axis acts as a central control system, controlling the release of hormones involved in corticosteroid biosynthesis and regulating the body’s response to stress.

3. Adrenal cortex diseases related with gene mutations

3.1 Congenital adrenal hyperplasia (CAH)

CAH (Table 1) is a group of autosomal recessive genetic disorders characterized by the enzymatic defects in the biosynthesis of cortisol, a vital hormone produced by the adrenal glands [29, 30, 31]. This condition affects the adrenal cortex, leading to impaired production of cortisol, along with other hormones such as aldosterone and adrenal androgens, because the resulting ACTH excess stimulates adrenal cortex growth through adrenocortical cell proliferation [32]. CAH is primarily caused by mutations in genes involved in steroid hormone biosynthesis, particularly the CYP21A2 gene [32], referred as 21-hydroxylase deficiency [33].

Empty cell	Disorder	Gene	OMIM
Defects of corticosteroid steroidogenesis (congenital adrenal hyperplasia, CAH)	Congenital lipoid adrenal hyperplasia (LCAH)	STAR	201710
	P450 side chain cleavage syndrome (CAH)	CYP11A1	118485
	3β-hydroxysteroid dehydrogenase deficiency (CAH)	HSD3B2	201810
	21-hydroxylase deficiency (CAH)	CYP21A2	201910
	11β-hydroxylase deficiency (CAH)	CYP11B1	202010
	17-hydroxylase deficiency (CAH)	CYP17A1	202110
	P450 oxidoreductase deficiency (CAH)	POR	613571
	Steroidogenic factor 1 deficiency	NR5A1	184757
	Corticosterone methyl oxidase type II deficiency	CYP11B2	124080
Adrenal hypoplasia congenita (AHC)	X-linked adrenal hypoplasia congenita (AHC)	NR0B1	300200
	Steroidogenic factor 1 deficiency	NR5A1	184757
Familial glucocorticoid deficiency (FGD)	Familial glucocorticoid deficiency (FGD)	MC2R; MRAP	202200; 607398

Table 1.

Reported monogenetic causes of primary adrenal insufficiency and associated phenotype in humans.

The CYP21A2 gene provides instructions for producing an enzyme known as cytochrome 21-hydroxylase, which plays a crucial role in the biosynthesis of cortisol and aldosterone [34]. In CAH, mutations in this gene result in reduced or absent 21-hydroxylase activity, leading to a block in cortisol biosynthesis. As a compensatory mechanism, the pituitary gland produces increased amounts of ACTH to stimulate the adrenal glands to produce cortisol precursors. However, due to the enzymatic deficiency, these precursors accumulate and are diverted to the production of androgens, resulting in excessive adrenal androgen release [35, 36, 37, 38].

The severity of CAH can vary depending on the specific mutation in the CYP21A2 gene. The classic form of CAH is the most severe and is further classified into two types: salt-wasting CAH and non-salt-wasting CAH. Salt-wasting CAH, accounting for around 75% of cases, is characterized by a deficiency of both cortisol and aldosterone, leading to electrolyte imbalances and potentially life-threatening salt loss. Non-salt-wasting CAH involves only cortisol deficiency, with aldosterone levels remaining normal, leading to milder symptoms [32].

In addition to the CYP21A2 gene variants, there are other rare forms of CAH caused by mutations in genes such as CYP11B1 [39, 40], referred as 11β-hydroxylase deficiency [41, 42], and HSD3B2 [32, 43, 44], referred as 3β-hydroxysteroid dehydrogenase deficiency, which encode other enzymes involved in steroid biosynthesis. These forms of CAH are associated with different enzyme deficiencies and result in distinct clinical presentations.

CYP11B1 mutation refers to a genetic alteration in the CYP11B1 gene [39, 40] which encodes the enzyme 11β-hydroxylase [41, 42]. This enzyme is crucial for the biosynthesis of cortisol and aldosterone, two important adrenal steroid hormones. Mutations in the CYP11B1 gene can reduce or completely abolish the activity of 11β-hydroxylase, resulting in disrupted cortisol and aldosterone biosynthesis. As a result, there is an accumulation of precursor molecules, such as 17-hydroxyprogesterone and progesterone, which can be converted into adrenal androgens. The symptoms and severity of 11β-hydroxylase deficiency can vary depending on the specific mutation and the residual enzyme activity. Common symptoms include excessive production of adrenal androgens, leading to varying degrees of genital ambiguity in females, early-onset pubic hair growth in both males and females, and menstrual irregularities [41, 42, 45, 46, 47, 48, 49].

HSD3B2 mutation refers to a genetic alteration in the HSD3B2 gene, which encodes the enzyme 3β-HSD2 [43]. This enzyme plays a crucial role in the conversion of pregnenolone to progesterone in the adrenal cortex. Mutations in the HSD3B2 gene can lead to reduced or absent activity of the 3β-HSD2, resulting in impaired production of cortisol and aldosterone. This deficiency can cause an imbalance in the adrenal hormone pathway, leading to elevated levels of precursor hormones such as pregnenolone and progesterone [32, 43, 44]. The symptoms and severity of 3β-HSD2 deficiency can vary depending on the specific mutation and the residual enzyme activity. Individuals with this form of CAH may experience symptoms such as salt-wasting, ambiguous genitalia in females, adrenal crises, and abnormal growth.

CYP11B2 mutation refers to a genetic alteration in the CYP11B2 gene, which encodes an enzyme called aldosterone biosynthesis [50]. This enzyme is responsible for the final step in the biosynthesis of aldosterone, a mineralocorticoid hormone produced in the adrenal cortex. Mutations in the CYP11B2 gene can lead to aldosterone synthase deficiency, which is a rare form of CAH known as corticosterone methyl oxidase type II deficiency (CMO-II) [50, 51, 52]. This deficiency affects the production of aldosterone, resulting in insufficient levels of this hormone. Aldosterone is important for regulating sodium and potassium balance in the body, as well as maintaining blood pressure. Consequently, individuals with CMO-II may experience symptoms associated with mineralocorticoid deficiency, such as salt-wasting and electrolyte imbalances. Additionally, reduced aldosterone levels may lead to excess production of precursor hormones, leading to an imbalance in the adrenal hormone pathway.

One specific form of CAH is known as STAR deficiency. STAR deficiency is a rare autosomal recessive disorder caused by mutations in the STAR gene [44, 53]. This gene provides instructions for producing the STAR, which plays a crucial role in transporting cholesterol into the mitochondria of adrenal cells. Cholesterol is a key precursor in the biosynthesis of cortisol and other steroid hormones. In individuals with STAR deficiency, the impaired function of the STAR protein prevents cholesterol from being transported effectively into the mitochondria. As a result, cortisol production is severely reduced or absent. The adrenal glands attempt to compensate by increasing ACTH secretion, leading to adrenal hyperplasia as they try to produce more cortisol precursors, leading to the accumulation of lipid droplets, which is also referred as congenital lipoid adrenal hyperplasia (CLAH). However, since the precursors cannot be converted into cortisol, they are eventually diverted towards the production of adrenal androgens, which can lead to symptoms such as early puberty and virilization in females. The clinical presentation of STAR deficiency varies depending on the severity of the mutation. Severe forms typically present in infancy with life-threatening adrenal crisis and salt-wasting due to the deficiency of aldosterone, in addition to cortisol deficiency. Milder forms may present later in childhood or even adulthood, and may not have significant salt-wasting or adrenal crisis [54, 55, 56, 57, 58].

CYP11A1 deficiency (also referred as P450 side chain cleavage syndrome) is a rare genetic disorder that falls under the umbrella term of CAH. Unlike most forms of CAH, which are caused by specific enzyme deficiencies in the adrenal steroidogenic pathway, CYP11A1 deficiency results in a defect in the first and rate-limiting step of steroid hormone biosynthesis. Defects in the CYP11A1 gene disrupt this conversion, leading to impaired production of cortisol, aldosterone, and other adrenal steroid hormones [15, 59]. The clinical presentation of CYP11A1 deficiency can vary widely depending on the severity of the mutation and the residual activity of the enzyme. In some cases, individuals with CYP11A1 deficiency can present with ambiguous genitalia at birth, similar to other forms of CAH [15, 59]. However, unlike other forms of CAH, the deficiency in CYP11A1 affects the entire adrenal steroidogenesis pathway, resulting in low levels of cortisol, aldosterone, and adrenal androgens. This can cause salt-wasting, adrenal crises, and potentially life-threatening complications in infancy [15, 59].

CYP17A1 is an enzyme that plays a key role in the steroid hormone synthesis pathway. Mutations or variants in the CYP17A1 gene can result in various forms of CAH, also known as 17α-hydroxylase deficiency [53, 60, 61]. This condition affects the adrenal glands’ ability to produce cortisol and adrenal androgens, leading to a disruption in the biosynthesis of these hormones [53, 60, 61]. The severity of 17α-hydroxylase deficiency can vary depending on the nature of the mutation. In some cases, individuals with this condition may have ambiguous genitalia at birth due to impaired production of adrenal androgens. This can affect sexual development, causing individuals assigned female at birth to undergo masculinization during puberty. In addition, the reduction in cortisol production may result in adrenal insufficiency, leading to symptoms such as fatigue, weakness, and electrolyte imbalances [53, 60, 61]. In individuals with 17α-hydroxylase deficiency, the lack of cortisol feedback to the pituitary gland causes an increase in ACTH production. This stimulates the adrenal glands to produce more precursor hormones that are subsequently shunted to the production of mineralocorticoids, specifically aldosterone. The elevated levels of aldosterone can lead to hypertension and contribute to potassium wasting and low renin levels [53, 60, 61].

POR (P450 oxidoreductase) is an enzyme that plays a crucial role in the function of several other enzymes (CYP17A1 and CYP21A2) involved in steroid hormone biosynthesis, including those responsible for cortisol and aldosterone production. Mutations in the POR gene can lead to a specific form of CAH known as P450 oxidoreductase deficiency [43, 62]. P450 oxidoreductase deficiency affects multiple enzymatic reactions related to steroid hormone synthesis. The POR gene mutations can impair the activity and stability of the P450 oxidoreductase enzyme, leading to disruptions in various steps of the adrenal steroidogenesis pathway. Patients with P450 oxidoreductase deficiency may present with a wide range of symptoms and varying degrees of hormone deficiencies. The clinical presentation can include symptoms of cortisol deficiency such as fatigue, low blood sugar, and poor growth. Additionally, some individuals may exhibit mineralocorticoid deficiency symptoms such as salt-wasting, hyponatraemia (low sodium levels), and hyperkalaemia. One distinctive feature of P450 oxidoreductase deficiency is that it affects both the adrenal cortex and the gonads, leading to abnormalities in reproductive development. In males, this can manifest as undervirilization or ambiguous genitalia at birth, while in females, it can lead to primary amenorrhea or incomplete sexual development during puberty [63]. These features distinguish P450 oxidoreductase deficiency from other forms of CAH.

Management of CAH involves lifelong hormone replacement therapy to replace cortisol and potentially aldosterone, balancing hormone levels and preventing adrenal crises. Additional treatments may be required to manage the physical and hormonal aspects of the condition, particularly in individuals with the classic form of CAH. Close monitoring by a multidisciplinary medical team is essential to optimize treatment and quality of life for individuals with CAH.

3.2 Adrenal hypoplasia congenita (AHC)

AHC (Table 1) is a rare genetic disorder characterized by hypoplasia or absence of the adrenal glands. This condition affects the production of cortisol and, in some cases, aldosterone, leading to adrenal insufficiency. AHC can be classified into two main types: X-linked AHC (also known as AHC type 1) and autosomal recessive AHC (AHC type 2). AHC type 1 is caused by mutations in the NR0B1 (nuclear receptor family 0 member b1) gene (also called DAX1, dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) [32], while AHC type 2 is caused by mutations in the SF-1 gene (also known as NR5A1) [64]. These genes play essential roles in the development and function of the adrenal glands.

The presentation and severity of AHC can vary among individuals depending on the specific gene mutation and its impact on adrenal development [65]. Males with X-linked AHC usually have more severe symptoms, including dehydration, vomiting, low blood sugar, and adrenal crises in infancy [66, 67, 68]. In contrast, females may have milder symptoms due to random X-inactivation and can present with primary amenorrhea and delayed sexual development during puberty [66, 67, 68].

In autosomal recessive AHC, both males and females can be affected, and the severity of symptoms can vary. Symptoms typically include adrenal insufficiency-related manifestations such as fatigue, weakness, poor weight gain, and low blood pressure.

Therefore, AHC is a rare genetic disorder characterized by underdeveloped or absent adrenal glands, resulting in cortisol and possibly aldosterone deficiency. The two main types, X-linked AHC and autosomal recessive AHC are caused by mutations in specific genes involved in adrenal gland development and function.

3.3 Familial glucocorticoid deficiency (FGD)

FGD, also known as primary glucocorticoid resistance or autosomal recessive pseudohyperaldosteronism, is a rare genetic disorder characterized by the inability of the body to respond properly to cortisol, resulting in adrenal insufficiency [69]. FGD is typically caused by mutations in MC2R. Mutations in the MC2R gene can disrupt the normal functioning of the MC2R protein, resulting in an impaired response to ACTH and subsequent cortisol deficiency [70, 71, 72]. FGD is also caused by mutations in the MRAP (melanocortin 2 receptor accessory protein) gene [73, 74], which is required for proper function and transport of the MC2R protein to the cell membrane location [32]. Mrap^−/− knockout mice have been found to mimic the human FGD phenotype [73, 75]. Individuals with FGD typically present with symptoms of adrenal insufficiency, including fatigue, weakness, hypoglycaemia, poor weight gain, and potentially life-threatening adrenal crises [32]. In some cases, mineralocorticoid deficiency may also occur, leading to electrolyte imbalances and salt-wasting.

Diagnosis of FGD involves hormone testing to evaluate cortisol and ACTH levels. Genetic testing can confirm the presence of mutations in the MC2R gene or other relevant genes associated with ACTH signaling.

4. Corticosteroid-disrupting endocrine disruptors

Many endocrine disruptors, including perfluoroalkylated and polyfluoroalkylated substances (PFAS), phthalates, polybrominated diphenyl ethers (PBDEs), and insecticides, interfere with the adrenal cortex endocrine system.

4.1 Polyfluoroalkylated substances (PFAS)

PFAS are a group of synthetic chemicals that are characterized by the presence of fluorinated carbon chains [76, 77]. These compounds have gained significant attention due to their widespread use in various industrial and consumer products, as well as their persistence in the environment and potential adverse health effects [76, 77]. PFAS have unique properties, including water and oil repelling, heat resistance, and chemical stability, which make them useful in a wide range of applications. They have been used in the production of non-stick cookware, water-resistant textiles, firefighting foams, paper and packaging materials, and many other products [76, 77]. One of the concerning aspects of PFAS is their persistence in the environment [76, 77]. These compounds do not readily break down and can remain in the environment for long periods of time. As a result, they have been detected in various environmental compartments, including air, soil, water, and wildlife. Studies have highlighted potential health impacts associated with PFAS exposure [76, 77]. Using human adrenocortical carcinoma cells HAC15, it was found that two most widely used PFAS, perfluorooctanoic acid (PFOA, C8) and perfluorooctane sulfonate (PFOS, C8S), can significantly upregulated CYP11B2 expression by several times and increased aldosterone secretion via stimulating reactive oxygen species production [78]. Oral PFOS exposure to adult Sprague-Dawley male rats for 28 days downregulated the expression of corticotropin-releasing factor 1 receptor (Crf1r) in the pituitary gland and Nr3c1 in the pituitary gland, thereby leading to the reduction of corticosterone biosynthesis [79]. Using human adrenocortical carcinoma cells H295R cells, it was found that PFOS at 200 μM can significantly upregulate MC2R, CYP11B1 and CYP11B2 expression, thereby increasing cortisol and aldosterone secretion [80]. Some PFAS are potent inhibitors of human 11β-HSD2. The inhibitory potency of PFAS depends on the carbon chain length and sulfur atoms. PFAS significantly inhibited human 11β-HSD2 with a potency as C10 (half-maximal inhibitory concentration, IC₅₀, 9.19 μM) > C11 (15.09 μM) > C12 (18.43 μM) > C9 (20.93 μM) > C13 (124 μM) > C14 (147.3 μM) > other C4-C7 carboxylic acids and C8S > C7S = C10S > other sulphonic acids [81, 82]. PFOS and PFOA also inhibit human 11β-HSD1 activity with IC₅₀ values of 7.56 μM and 37.61 μM, respectively, while perfluorobutanesulfonic acid and perfluorohexyanesulfonic sulphonic acid do not inhibit the enzyme activity at 250 μM [83].

4.2 Phthalates

Phthalates, also known as phthalate esters, are a group of industrial chemicals primarily used as plasticizers [84]. They are commonly added to plastics to make them more flexible, durable, and transparent. Phthalates can be found in various products such as vinyl flooring, adhesives, coatings, medical devices, toys, cosmetics, and personal care products. Phthalates are not chemically bound to the plastics they are added to, which means they can easily leach out over time and be released into the environment or come into contact with humans through product use. As a result, there has been growing concern about their potential health effects. Studies have suggested that certain phthalates may have endocrine-disrupting properties, meaning they can interfere with the normal function of hormones in the body. One of their targets is the adrenal cortex. They have been shown to have adverse effects on the development and function of the adrenal cortex, which produces glucocorticoids and mineralocorticoids. Studies have demonstrated that exposure to phthalates during critical periods of adrenal gland development can lead to alterations in adrenal structure and function.

Phthalates have been implicated in disturbances of mineralocorticoid biosynthesis. Animal studies have demonstrated that exposure to certain phthalates, such as the most widely used phthalate di-(2-ethylhexyl) phthalate (DEHP), can affect the RAAS, resulting in changes in aldosterone levels and electrolyte balance [85]. Rat studies have shown that prenatal exposure to certain phthalates, such as the most widely used phthalate DEHP can disrupt adrenal development, leading to changes in adrenal size and reduction of aldosterone in adult offspring [86]. A second exposure in the adult rat male offspring when they are exposed in utero to low levels of DEHP can markedly reduce serum aldosterone levels, possibly via downregulation for the expression of potassium channel Kcnk5 and the retinoid-X receptors Rxra and Rxrb [87]. This could be due to the epigenetic regulation of genes related to adrenal cortex steroidogenesis [88]. Although in utero exposure to DEHP at the highest dose (750 mg/kg) does not affect corticosterone levels of adult male offspring [86], other more potent phthalates such as di-pentyl phthalate can reduce aldosterone and corticosterone and ACTH levels after in utero exposure, although aldosterone is most sensitive to DPeP exposure (at 10 mg/kg) [89]. Di-pentyl phthalate disrupts corticosteroid biosynthesis mostly by downregulating the expression of Agtr1a, Mc2r, Scarb1, Cyp11a1, Hsd3b1, Cyp21, Cyp11b1, Cyp11b2, Nr5a1, and Nr4a2, possibly via inducing reactive oxygen species production [89].

The effects of phthalates on glucocorticoids and mineralocorticoid biosynthesis in puberty and adults may depend on doses and phthalate types. Rat studies have reported decreased levels of corticosterone, following di-butyl phthalate and DEHP exposure, suggesting a disruption in the function of the HPA axis [90]. Bis (2-butoxyethyl) phthalate exposure to male rats in puberty (from day 35 to 56 postpartum) also reduces serum corticosterone and aldosterone level without affecting ACTH, possibly via downregulating the expression of steroidogenesis-related genes (Scarb1, Star, Cyp11a1, Cyp21, Cyp11b1, Cyp11b2, Nr5a1, Nr4a1, and Nr4a2) by inducing reactive oxygen species [91]. In contrast, other studies have shown increased glucocorticoid and ACTH levels after exposure to DEHP in rats at 20 and 40 days of age, indicating an activation of the stress response [92]. These effects on glucocorticoid levels may be linked to alterations in the expression and activity of enzymes involved in glucocorticoid metabolism, such as 11β-HSD2 [93, 94]. Some phthalates with di-propyl phthalate, dibutyl phthalate, and di-cyclohexyl phthalate also weakly inhibit human 11β-HSD2 activity [94]. Although DEHP does not inhibit human 11β-HSD2 while its metabolite mono-diethylhexyl phthalate can moderately inhibit this enzyme activity [93, 94].

It is important to note that the specific effects of phthalates on adrenal cortex development and function may vary depending on the type of phthalate, exposure levels, timing, and duration of exposure. Furthermore, these effects may differ between animal models and humans. Studies in human populations regarding the associations between phthalate exposure and adrenal cortex function are limited and often rely on indirect measurements of hormone levels or urinary metabolites. The Hokkaido Study with 202 mother-infant pairs showed that maternal urinary DEHP metabolites were negatively correlated with cord serum cortisol and cortisone levels, indicating that corticosteroid synthesis in the adrenal cortex of infants is reduced [95]. Overall, evidence suggests that phthalate exposure can disrupt adrenal cortex development and function, affecting both glucocorticoid and mineralocorticoid hormone systems.

4.3 Polybrominated diphenyl ethers (PBDEs)

PBDEs are a class of flame retardants that have been widely used in various consumer products, including electronics, textiles, plastics, and furniture. PBDEs can persist in the environment and bioaccumulate in organisms. Some studies suggest that certain PBDEs may contribute to disruptions in adrenal cortex steroidogenesis. 4-Bromodiphenyl ether (BDE3), the PBDE’s photodegraded metabolite increases serum aldosterone and corticosterone levels at 200 mg/kg without affecting adrenocorticotropic hormone level after male rats are exposed to this chemical from the age of day 35 to 56. The mechanism possibly is related with the upregulation of Cyp11b1, Scarb1, Star, Cyp11b2, Cyp21, and Nr5a1 expression by decreasing the phosphorylation of AMP-activated protein kinase and increasing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha (PGC-1α) and phosphorylated cyclic AMP-responsive element-binding protein [96]. Two PBDEs, 2-OH-BDE85 and 2-OH-BDE47 at a micromolar concentration induce transcriptional changes associated with endoplasmic reticulum stress and the unfolded protein response, which possibly impairs the adrenocortical secretory function in human H295R cells [97]. However, the exact mechanisms through which PBDEs may interfere with adrenal cortex steroidogenesis are still being investigated. Furthermore, the specific effects may vary depending on the type of PBDE compound, the dose and duration of exposure, and individual factors such as age and overall health. Some PBDEs also inhibit 11β-HSD2. BDE-47 and BDE-153 potently inhibit human 11β-HSD2, with IC₅₀ values of 11.97, and 4.41 μM, respectively, while BDE-3 and BDE-47 inhibit rat 11β-HSD2 with IC₅₀ values of 12.42 and 5.95 μM [98]. However, all these PBDEs do not affect human and rat 11β-HSD1 activity [98].

4.4 Bisphenols

Bisphenols are a group of chemical compounds used in the production of various consumer products, including plastics and epoxy resins. One of the most well-known bisphenols is bisphenol A (BPA) [99]. The potential effects of bisphenols on adrenal cortex steroidogenesis, which is the synthesis of steroid hormones in the adrenal glands, have raised concerns due to their classification as endocrine disruptors. Bisphenols, including BPA, have been shown to interfere with hormonal signaling pathways and affect the function of hormone receptors. Adrenal cortex steroidogenesis can be influenced by bisphenols through several mechanisms. When offspring is in utero exposed to BPA (25 mg BPA/kg food pellet) via diet from gestational day 7 to 19, BPA increases adrenal gland weight, increases plasma corticosterone levels in both sexes, and upregulates the expression of Star and Cyp11a1 [100]. Adult male Wister rats exposed to BPA (10 mg/kg) for 14 days have an increase in corticosterone synthesis possibly via inducing reactive oxygen species since antioxidant melatonin can antagonize it [101]. In mouse Y1 adrenal cortex cells, treatment with low doses of BPA (10–1000 nM) increases the Cyp11a1 transcription, thereby increasing corticosterone production through the JNK/c-Jun signaling pathway [102]. In the human adrenal H295R cell line, BPA increases cell number and protein levels of proliferating cell nuclear antigen, a universal marker of cell proliferation, cyclin D1 and D2, key proliferation factors, as well as Shh and its key transcriptional regulator Gli1 possibly via activating oestrogen receptor β [103].

Bisphenols may also affect adrenal steroidogenesis by interacting with enzymes involved in hormone production. For example, studies have suggested that bisphenols can inhibit enzymes such as 11β-HSD2 [104]. Bisphenols show inhibitory potency against human 11β-HSD2, depending on its structure, being bisphenol FL > bisphenol AP > bisphenol Z > bisphenol B > bisphenol C > bisphenol AF > BPA [104]. Halogenated bisphenols also potently inhibit human 11β-HSD2 activity [105].

Case-control study also shows that the maternal BPA levels are positively correlated with the serum cortisol levels in female infants [106]. A cross-sectional relationship between BPA exposure and cortisol among peripubertal boys in Canada shows that BPA concentrations were associated with a 16% decrease in serum cortisol levels [107].

4.5 Organotin

Organotin compounds are a group of chemicals that contain tin and carbon atoms bonded together [108]. They have been used in a variety of industrial and consumer applications, including as stabilizers in plastics, fungicides, and as antifouling agents in paints for boats and ships. However, their use has been restricted or banned in many countries due to their widespread environmental persistence and toxicity [109]. The relationship between organotin compounds and adrenal cortex steroidogenesis, the process involving the production of steroid hormones in the adrenal glands, has been the subject of research. While there is limited information specifically on this topic, some studies suggest that certain organotin compounds may disrupt adrenal cortex steroidogenesis by interfering with the function of enzymes involved in hormone production. Exposure of adult male Sprague Dawley rats to triphenyltin (0, 0.5, 1, and 2 mg/kg) from age of 56 days to 86 days decreases serum corticosterone levels without affecting aldosterone and ACTH levels possibly by downregulating the expression of Scarb1, Star, Cyp11a1, Hsd3b, Cyp21, Cyp11b1, and Hsd11b1 while up-regulating the expression of At1, Nr4a2, and Hsd11b2 [110]. Triphenyltin in vitro also inhibits corticosteroid secretion by inducing ROS production in H295R cells [110]. Young male rats exposed to 0, 0.5, 1, or 2 mg/kg/day triphenyltin for 18 days also have lower corticosterone and ACTH levels, possibly due to the suppression of adrenal cortex development due to the reduced expression of transcription factor genes (Nr4a1, Nr4a2, Nr4a3, and Ppard) [111]. Female rats exposed to tributyltin have also high CRH and low ACTH expression and increased plasma corticosterone levels [112]. Triphenyltin and tributyltin, also inhibit human 11β-HSD2 activity with IC₅₀ of 3.3 and 16.5 μM [113]. This disruption can lead to alterations in the production and regulation of hormones such as cortisol, aldosterone, and adrenal androgens. However, it’s important to note that the available research on the effects of organotin compounds on adrenal cortex steroidogenesis is still limited and further studies are needed to better understand the specific mechanisms and potential health impacts.

4.6 Pesticides

The potential effects of various types of pesticides, such as insecticides, fungicides, and biocides, on adrenal cortex steroidogenesis have been a subject of scientific investigation. Research has indicated that certain pesticides may have the potential to disrupt adrenal cortex steroidogenesis. These chemicals are known as endocrine disruptors, as they can interfere with the normal functioning of hormones in the body. The specific mechanisms through which pesticides disrupt adrenal function can vary depending on the individual compound and its mode of action. Insecticides, for example, have been shown to impact adrenal cortex steroidogenesis by directly affecting key enzymes involved in hormone synthesis.

3-Methylsulphonyl-DDE (3-MeSO2-DDE) is a derivative of DDE (dichlorodiphenyldichloroethylene), which is a metabolite of the pesticide DDT (dichlorodiphenyltrichloroethane) [114]. 3-MeSO2-DDE is formed in the human body through the metabolism of DDE. Foetal mice in utero exposure to 3-MeSO2-DDE have mitochondrial degeneration and vacuolation in foetal adrenal cortex cells and dysfunction of corticosteroid steroidogenesis [115]. 1,1-Dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p′-DDE) is a chemical compound that is derived from the pesticide DDT [116, 117]. It is formed through the breakdown of DDT in the environment or in the human body. p,p′-DDE is a persistent organic pollutant and has been widely detected in the environment, including in soil, water, and food sources [116, 117]. p,p′-DDE exposure (50 and 100 mg/kg) in utero to rats inhibits corticosteroid steroidogenesis in the foetal adrenal cortex [118].

Cis-bifenthrin is a synthetic pyrethroid insecticide commonly used for pest control in residential, agricultural, and public health settings [119]. Pyrethroids, including cis-bifenthrin, act on the nervous systems of insects, leading to paralysis and death [120]. Cis-bifenthrin inhibits cortisol and aldosterone biosynthesis via cAMP signaling cascade in human adrenocortical H295R cells [119].

Lindane is an organochlorine pesticide that has been widely used in the past for insect control, particularly against lice and scabies [121]. Research investigating the effects of lindane on H295R cells has indicated that it can disrupt adrenal steroidogenesis. Specifically, lindane has been shown to interfere with the synthesis and regulation of adrenal hormones, including cortisol. Lindane’s mechanism of action involves interference with the enzymes involved in steroid hormone synthesis and STAR expression [122].

Triadimefon is a fungicide that belongs to the class of triazole compounds. It is commonly used in agriculture and horticulture to control fungal diseases in crops and ornamental plants [123, 124]. After in-utero exposure to triadimefon (0, 25, 50, and 100 mg/kg/day) for 10 days from gestational day 12 to 21, male foetal rat’s zF thickness is reduced and serum aldosterone, corticosterone, and ACTH levels are reduced possibly via downregulating the expression of Agtr1, Mc2r, Star, Cyp11b1, Cyp11b2, Igf1, and Nr5a1 after activating the reactive oxygen species through reducing the expression of antioxidant Sod2, Gpx1, and Cat [125]. Triadimefon also inhibits human and rodent 11β-HSD1 activity [126].

5. Conclusion

The steroidogenesis of corticosteroids plays a critical role in regulating various physiological processes in the body, including immune function, metabolism, and stress response. Genetic mutations in genes involved in adrenal cortex steroidogenesis can disrupt the synthesis and regulation of cortisol, aldosterone, and adrenal androgens, resulting in adrenal insufficiency and related symptoms. CAH represents a group of genetic disorders characterized by enzyme deficiencies that impair adrenal steroidogenesis. These deficiencies can lead to a range of clinical presentations and hormonal imbalances, depending on the specific gene mutations involved. Other disorders such as AHC and FGD are also due to the mutation of some critical genes in the adrenal cortex. In addition to genetic mutations, endocrine-disrupting compounds, such as certain pesticides, fungicides, biocides, and bisphenols, can interfere with adrenal cortex steroidogenesis. These chemicals disrupt the normal function of hormones, hormone receptors, and enzyme activity, thereby impacting the synthesis and regulation of corticosteroids. The resulting endocrine disruption can contribute to adrenal insufficiency and associated health effects. Understanding the interplay between genetic mutations, endocrine disruption, and adrenal insufficiency is crucial for diagnosis, management, and prevention of related health conditions. Genetic testing, hormone monitoring, and tailored hormone replacement therapies are often employed in the management of adrenal insufficiency. Additionally, awareness of potential exposure to endocrine-disrupting compounds and adopting safety measures can help to minimize health risks. Further research is needed to explore the mechanisms by which genetic mutations and endocrine-disrupting compounds impact adrenal cortex steroidogenesis, as well as their long-term consequences on overall health. This knowledge will enable the development of strategies to mitigate the effects of these factors and improve patient outcomes.

Author contribution

Y.S. and R.S.G wrote the chapter and R.S.G. edited the chapter.

Declaration

The authors declare no conflict of interest.

Abbreviations

11β-HSD1	11β-hydroxysteroid dehydrogenase 1
11β-HSD2	11β-hydroxysteroid dehydrogenase 2
3β-HSD2	3β-hydroxysteroid dehydrogenase/Δ^5,4-isomerase 2
ACTH	adrenocorticotropic hormone
AHC	adrenal hypoplasia congenita
ANP	atrial natriuretic peptide
AT1	angiotensin II type 1 receptor
B5	cytochrome b5
CAH	congenital adrenal hyperplasia
CMO-II	corticosterone methyl oxidase type II deficiency
cAMP	cyclic adenosine monophosphate
CBG	corticosteroid-binding globulin
CLAH	congenital lipoid adrenal hyperplasia
Crf1r	corticotropin-releasing factor 1 receptor
CRH	corticotropin-releasing hormone
CYP11A1	cytochrome P450 cholesterol side chain cleavage
CYP11B1	cytochrome P450 11β-hydroxylase
CYP11B2	cytochrome P450 aldosterone synthase
CYP17A1	cytochrome P450 17α-hydroxylase/17–20-lyase
CYP21A2	cytochrome P450 21-hydroxylase 2
DAX1	dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1
DHEA	dehydroepiandrosterone
DEHP	di-(2-ethylhexyl) phthalate
DPeP	di-n-pentyl phthalate
FGD	familial glucocorticoid deficiency
HPA	hypothalamic-pituitary-adrenal axis
IC50	half maximal inhibitory concentration
Kcnk5	potassium channel 5
LDLR	low-density lipoprotein receptor
NR0B1	nuclear receptor family 0 member b1
NR3C1	glucocorticoid receptor
NR5A1	nuclear receptor family 5 member A1
MC2R	melanocortin 2 receptor
MRAP	melanocortin 2 receptor accessory protein
PBDE	polybrominated diphenyl ether
PFAS	perfluoroalkylated and polyfluoroalkylated substances
PFOA	perfluorooctanoic acid
PFOS	perfluorooctane sulfonate
PGC-1α	peroxisome proliferator-activated receptor-γcoactivator 1α
POR	P450 oxidoreductase
RAAS	renin-angiotensin-aldosterone system
Rxra	retinoid-X receptor α
Rxra	retinoid-X receptor β
SCARB1	scavenger receptor member BI
SF-1	steroidogenic factor 1
STAR	steroidogenic acute regulatory protein
zF	zona fasciculata
zG	zona glomerulosa
zR	zona reticularis