Subclinical Hypercortisolism: An Important, Unrecognized Dysfunction

Abstract

While Cushing syndrome is rare, but well-recognized, subclinical hypercortisolism (defined as excessive cortisol secretion without the classic manifestations of Cushing syndrome) is significantly more common. Subclinical hypercortisolism contributes to several chronic diseases, such as diabetes, osteoporosis, sarcopenia and hypertension. The incidence increases with age and correlates with body load of environmental toxins such as bisphenol A (BPA). This editorial discusses prevalence, contribution to disease, causes, diagnosis, and intervention.

Introduction

Subclinical hypercortisolism (SH) is defined as excessive cortisol secretion without the classic manifestations of clinically overt Cushing syndrome, e.g., indications of catabolic excess such as central muscle weakness, adipose tissue redistribution, skin fragility, and unusual infections. SH significantly increases risk of bone fragility, sarcopenia, depression, type 2 diabetes, resistant hypertension, cardiovascular events, and mortality. However, it has been described as “hidden hypercortisolism” since it is typically asymptomatic. It is usually identified incidentally in patients—discovered when an adrenal mass (adrenal incidentaloma) is found during an imaging procedure for an unrelated disorder.¹

SH differs from Cushing syndrome in numerous ways (some noted below) and Cushing syndrome itself is considered to be a rare disease. In contrast, SH is not rare. Adrenal incidentalomas are thought to be present in up to 7% of individuals above 60 years of age and 10% over age 70.² SH is estimated to be present in 0.8–2% of the elderly population (>60 years), an estimate derived from data showing that AI are present in 3% of 50-year-old patients, and that the prevalence of SH when AI are present ranges between 5% and 30%. Incidence increases with age. Higher prevalence, up to 10%, is seen in elders with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility.³

Besides patients with AI, SH has been found to be more prevalent than expected in some populations at risk: patients with poorly controlled or complicated hypertension and/or diabetes or with iatrogenic bone fragility. SH has also been found in patients with incidentally discovered pituitary tumors. In these individuals, prevalence of SH is ~5%.³

AI are discovered on 1% to 10% of abdominal imaging studies. They are often not given clinical follow-up, either because many health care providers do not understand the importance of screening for adrenal hormone excess, and/or because they were considered unimportant at a time when another nonadrenal issue was the focus.⁴

Etiology/Pathogenesis

After synthesis and secretion, glucocorticoids (GC) are metabolized to their active forms in peripheral tissues and interact with glucocorticoid receptors (GR). So tissue exposure to GC involves not only the amount secreted, but the degree of 11β-hydroxysteroid dehydrogenase type 1 activity (11βHSD1), also known as cortisone reductase, and GR genetic variants.³

11BHSD enzyme Activity

The NADPH-dependent enzyme 11βHSD1 is highly expressed in the liver, adipose tissue, and the central nervous system, where it reduces cortisone to the active hormone, cortisol, which binds to GR.

In studies of animals and patients with adrenal incidentalomas, overexpression or overstimulation of 11βHSD1, and thus GC reactivation in peripheral tissues, is a major determinant of excess cortisol secretion.

Factors involved in humoral immune responses, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), stimulate 11βHSD1, which results in an increase in the local concentration of cortisol in the liver and promotes metabolic disorders such as glucose intolerance and/or abnormal lipid metabolism. In postmenopausal subjects, increased 11βHSD1 activity (evaluated by the urinary free cortisol/urinary free cortisone ratio) was found to be directly associated with increased risk of trabecular bone fragility, type 2 diabetes, and hypertension.³

Genomic Causes

Overall, the presence of a potential genomic cause has been found in about 40% of patients with SH. In about 60% of patients, possible genetic alterations have not yet been identified. Epigenetic mechanisms, such as stress, disrupted circadian rhythms, and endocrine-disrupting environmental toxin exposure, are thought to play a role.³

Glucocorticoid receptor gene polymorphisms

GR polymorphisms associated with decreased GC sensitivity include the ER22/23EK polymorphism and the GR-9Beta (rs6198 or A3669G) polymorphism and are associated with lower risk of AI and the adverse effects of SH. The ER22/23EK polymorphism, found in 2% of the general population, results in a healthier metabolic profile, which includes lower total cholesterol levels, lower fasting insulin levels, increased insulin sensitivity, lower risk of type 2 diabetes, and in elders, of developing dementia. The GR-9Beta polymorphism, which has an 8% prevalence in the general population, is associated with a decreased risk of obesity in women and decreased total cholesterol and increased HDL cholesterol levels.³

GR polymorphisms associated with increased GC sensitivity include the BclI polymorphism (rs41423247) and the sensitizing N363S (rs6195) polymorphism and increase risk of AI and SH.⁵ The BclI polymorphism (rs41423247) is reported in 25% of the general population, is linked to higher body mass index, higher waist circumference, higher fasting glucose and insulin levels in men, and in a large Caucasian population, the presence of major depression. The sensitizing N363S (rs6195) polymorphism, found in 2.3% of the general population, is linked to significantly higher body mass index and higher risk of hypertension. In postmenopausal women, even those not found to have cortisol excess, the N363S GR single nucleotide polymorphism was directly associated with increased risk of type 2 diabetes, hypertension and bone fragility.³

HSD11B1 polymorphisms have been found to predict bone mineral density changes and fracture risk in postmenopausal women without clinically apparent hypercortisolism. In a large study (n = 452) of patients evaluated for osteoporosis, genetic polymorphisms in 11BHSD1 correlated with postdexamethasone suppression testⁱ cortisol levels and bone mineral density. In a sample of 72 patients with AI, the presence of vertebral fracture increased 5-fold in the presence of either SH or what has been called “the GC-sensitizing haplotype” (i.e., homozygous BclI and heterozygous N363S polymorphism).³

On the basis of these data, it is conceivable that not only in the general population, but also in patients with SH, the presence of a more active 11BHSD1 and GR polymorphisms that increase GR sensitivity can significantly increase GC exposure, so the same amount of GC secretion could result in profoundly different GC-related chronic consequences. In Cushing syndrome, the huge amount of GC secreted overcomes the cortisol-inactivating activity exerted by 11BHSD2 (the enzyme that converts active cortisol to inactive cortisone and is inhibited by Glycyrrhiza glabra, i.e., licorice root), overpowering the impact of 11BHSD1 and GR polymorphisms. In SH, increased levels of 11BHSD1 activity and GR polymorphisms that increase sensitivity combine to significantly affect GC exposure. In support of this, 11BHSD2 activity is directly associated with cortisol secretion in AI patients, but not in those with Cushing syndrome.

The Armadillo Repeat Gene

The armadillo repeat, a repetitive amino acid sequence of about 40 residues in length found in many proteins, is involved in protein– protein interactions, the maintenance of tissue integrity, and tumorigenesis. Mutations at the armadillo repeat containing 5 gene (ARMC5) are thought to decrease the expression of steroidogenic enzymes whose chronic inhibition could induce the growth of the adrenal masses and consequent cortisol hypersecretion. In patients with adrenal SH, prevalence of ARMC5 mutations is ~ 11%. This could be one factor involved in the slow progression and late development of SH that occurs in elders as the adrenals enlarge.⁶

Aberrant G protein-coupled Receptors

Numerous aberrant G protein-coupled receptors, whose activation by their specific ligands stimulates cortisol biosynthesis, have also been implicated in the pathogenesis of cortisol overproduction, including those for gastric inhibitory polypeptide, vasopressin, angiotensin type 1, luteinizing hormone/human chorionic gonadotropin, serotonin and glucagon. These aberrant receptors have been identified in as many as 50% of patients with unilateral adenomas associated with SH.³

Medical Disorders

SH may also be promoted by medical disorders in which the hypothalamus–pituitary–adrenal (HPA) axis is chronically overly activated, such as alcoholism, renal failure, poorly controlled diabetes, and neuropsychiatric disorders—all of which promote “functional hypercortisolism.”³

Circadian Dysregulation

Circadian dysregulation and stress act on the hypothalamus, leading to the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), which stimulate the secretion of the adrenocorticotrophic hormone (ACTH) from the anterior pituitary. In the adrenal cortex, ACTH binds to the melanocortin 2 receptor (MC2R), activating production of cyclic adenosine monophosphate and leading to a phosphorylation cascade involving different cytochrome P450 enzymes and 11BHSD to form cortisol.³

Stress

Stressful conditions in early life have been found to cause permanent changes in pituitary and/or adrenal levels in adult life, suggesting that conditions of chronic stress can alter HPA axis activity and cause autonomous (independent of gonadotropin-releasing hormone) pituitary ACTH secretion. This hypothesis has been confirmed in a mouse model in which mice stressed in early life developed an autonomous pituitary ACTH secretion with GC excess that persisted after resolution of the stressful period and was biochemically confirmed by high ACTH and levels of corticosterone (the primary adrenal corticosteroid in laboratory mice) and clinically confirmed by significant increase in body weight and fasting plasma glucose levels.³

The link between ACTH-dependent hypercortisolism and stressful conditions has also been studied in patients with type 2 diabetes, who have been shown to have increased risk of hypercortisolism and AI. Chronic hyperglycemia increases production of reactive oxygen species and oxidative stress, which may impair GR function and promote GC resistance in the HPA axis. The resulting chronic hypercortisolism, due to impaired glucose metabolism, may increase the production of reactive oxygen species and perpetuate a vicious cycle. Chronic HPA axis activation and ACTH hypersecretion continually stimulate cortisol-producing cells in the adrenal cortex, thus potentially leading to hyperplasia and/or development of an AI.

Bisphenol A (BPA)

Exposure to endocrine-disrupting environmental toxins, especially bisphenol A (BPA), may be a significant cause of adrenal hypertrophy/adrenal incidentaloma⁷ whose adverse impact can be ameliorated by simple dietary and lifestyle changes. “Every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP’s 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target…”⁸

BPA’s AI-promoting potential has been demonstrated in animal studies. When BPA-containing food (25 mg BPA/kg diet) was given to pregnant rats until the end of pregnancy, adrenal gland weight was increased in both male and female offspring.⁹

A study published in the February 2021 issue of Endocrine investigated the effects of BPA on incidence of SH (non-functional adrenal incidentaloma [NFAI]).⁷ Serum BPA levels were compared in 50 patients diagnosed with NFAI and 50 controls, healthy individuals without adrenal mass or adrenal pathology. Age, gender, and body mass index (BMI) were similar. Patients with possible confounding factors were excluded. These included diabetes, thyroid dysfunction, acute or chronic infection, malignancy, coronary artery disease, renal failure, liver failure, pregnancy, a history of drug use affecting adrenal function, insulin resistance, use of antidepressants, antipsychotics or antiepileptics, use of alcohol or smoking, or a history of rheumatic disease. All patients diagnosed with AI were evaluated with endocrine tests for 3 adrenal hyperfunction forms, which included subclinical Cushing syndrome (SH), pheochromocytoma, and primary hyperaldosteronism. This is a particularly significant correlation considering that several of the indications for exclusion are themselves indicative of either or both SH and BPA, so the results understate the impact of BPA.

Mean serum BPA levels were 7.06 ng/ml in NFAI patients and 4.79 ng/ml in controls. Fasting plasma glucose (99.1 mg/dl), insulin (12.6 μIU/ml), and HOMA-IR (homeostasis model assessment of insulin resistance) (3.08) were all higher in the NFAI group than in the control group (89.3 mg/dl, 9.9 μIU/ml, 2.19, respectively). HOMA-IR values showed 58% of NFAI patients were insulin resistant. According to logistic regression in univariate analysis, elevated serum BPA level increased adenoma risk 1.23-fold.

Participants in both groups were asked about their consumption of canned meals, plastic-packaged food, beverages in cans, beverages in plastic, water in plastic containers, microwave meals, meals at restaurants, fast food consumption and frequency. No significant difference was found between patient and control groups, which may indicate that the degree of 11βHSD1 activity and GR genetic variants increase susceptibility to SH.

Eker et al.⁷ note that the study was conducted in an area where factories related to oil refinery and the defense industry are prevalent, so they hypothesized that BPA exposure may also be occurring through ways they could not measure, such as breathing contaminated air. BPA may be present in dust particles, and dust inhalation is recognized as an important and potentially more damaging route of exposure since airborne BPA absorption by the lungs bypasses the intestines and liver.¹⁰ More than 1 million pounds of BPA are released into the environment every year. According to the Environmental Protection Agency’s Toxics Release Inventory, of the 72 factories reporting BPA emissions, the largest sources are in Ohio, Indiana, and Texas.¹¹

In “Update on the Health effects of Bisphenol A: overwhelming Evidence of Harm,” highly respected researcher, Dr. Frederick vom Saal writes, “Based on an integration of the academic investigator studies and data from the FDA’s guideline study, a majority of the independent academic investigators concluded that the FDA’s acceptable daily intake (safe) dose of BPA should be 20 000-fold lower than the current estimated ‘safe’ dose.” Adrenal hyperplasia is listed among the ADRs reported in animal experiments and human epidemiological studies, along with obesity, impaired glucose tolerance, type 2 diabetes, hypertension, and cardiovascular disease.¹²

Clinical Manifestations

The physiological imbalances caused by SH are surprisingly diverse and contribute to many chronic diseases.

Bone fragility

SH adversely affects bone density and quality.

• GC excess causes reduced bone formation due to impairment of osteoblasts and osteocyte function. GC reduce osteoblastogenesis by directing mesenchymal stem cells’ differentiation into adipocytes rather than osteoblasts.

• GC also induce osteocyte apoptosis and osteycytes’ production of sclerostin and Dickkopf-related protein 1 (Dkk-1), which impairs osteoblast function by inhibiting Wnt signaling.

• Cortisol excess induces differentiation and maturation of osteoclasts by increasing the expression of the macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor kappa-B ligand (RANK-L), while also decreasing the expression of its soluble decoy receptor, osteoprotegerin, in stromal and osteoblastic cells.

• GC inhibit the release of gonadotropins, affecting estrogen and testosterone production.

• GC plays a role in the inhibition of the production of growth hormone and insulin-like growth factor, important stimulators of osteoblasts.

• GC lessen the intestinal capacity to absorb calcium and inhibit calcium reabsorption by the renal tubule.

About 4% of patients with osteoporosis have a slight cortisol excess, which is a significant cause of bone loss. However, when looking specifically at vertebral fractures, subclinical hypercortisolism occurs in up to 82.4%.¹³ A multicenter, retrospective study conducted in Italy evaluated bone mineral density, bone quality and the prevalence of vertebral fractures in 194 healthy controls compared to 287 patients with AI, 85 of whom were found to have SH. All of the 287 patients with adrenal incidentalomas had lower bone mineral density at the lumbar spine (affected first because it is an area rich in trabecular bone, which is far more metabolically active than cortical bone) than the healthy controls. In the 85 people with subclinical hypercortisolism, the odds ratio (OR) for having had a vertebral fracture was 7.27 regardless of age, bone mineral density, menopausal status, or gender.^14,15

The same research group conducted another multicenter study, this time a prospective study that looked at study participants’ spinal deformity index (SDI), a marker of bone microarchitecture and bone quality, and then at the number of vertebral fractures that had already occurred in these individuals when the study began and after a further 12 and 24 months. Those who had subclinical hypercortisolism had an OR of 12.26. Surprisingly, this significant increase in risk for vertebral fractures is comparable to that reported in Cushing’s syndrome.¹⁶

A possible reason the increased risk for vertebral fracture is so high in individuals with SH is that the condition is asymptomatic. It’s likely to have been present for quite a while before it’s finally diagnosed.¹⁷ In as many as 4% of patients with apparently primary osteoporosis, the cause is estimated to be SH.¹⁸

Resistant Hypertension

Mechanisms include increased activity of the renin-angiotensin system via increased hepatic production of angiotensinogen and increased vascular reactivity via increased production of endothelin-1, a vasoconstrictor that is the natural counterpart of the vasodilator nitric oxide.¹⁹

At diagnosis, ~ 58–64% of patients with SH have cortisol-induced resistant hypertension.

Cardiovascular Disease

SH promotes a prothrombotic state both by activation of the coagulation system and inhibition of fibrinolysis. Typical hemostatic alterations in SH are a rise in factor VIII, fibrinogen and von Willebrand factor levels, along with shortening of the activated partial thromboplastin time, an increase in the number of platelets, thromboxane B2 and thrombin–antithrombin complexes.

Attention has been focused on von Willebrand factor because GCs modulate von Willebrand factor gene transcription, which has been found to be higher in adrenal SH compared to controls. Patients with SH also have higher levels of protein C, protein S and thrombomodulin, disturbances in the endogenous anticoagulation system that could be protective responses to a prothrombotic state.³

Patients with AI and SH have higher risk of cardiovascular events, including coronary artery disease, myocardial infarction, stroke, transient ischemic attack, and heart failure, as well as mortality compared to patients with nonsecreting AI and controls. Even individuals with supposedly “non-functioning” AI, which do secrete low levels of GCs, have been shown to be at increased risk for hypertension, hyperlipidemia, and cardiovascular events. In addition, chronic intima-media thickness has been shown to correlate with cortisol levels after DST in individuals with SH compared to age-matched healthy subjects. SH increases risk of thromboembolic events via its prothrombotic effects on hemostasis.⁴

Type 2 Diabetes

Excessive glucocorticoid levels cause beta-cell dysfunction by binding to glucocorticoid receptors in pancreatic beta-cells, which impairs glucose uptake and metabolism and reduces insulin sensitivity. GCs cause insulin resistance mainly by impairing glucose transporter migration to the cell surface. Insulin secretion increases but cannot compensate for the significant alteration in insulin receptor signaling in the liver and peripheral tissues.

One-third of patients with SH are estimated to suffer from type 2 diabetes.³

Sarcopenia

GC excess promotes type 2 muscle fiber atrophy via anti-anabolic and catabolic actions.³ Anti-anabolic mechanisms include:

• Inhibition of the mammalian target of rapamycin (mTOR), the central controller of muscle protein synthesis

• decreased amino acid uptake by muscle

• inhibition of insulin-like growth factor 1 secretion

• inhibition of myogenin, a transcription factor essential for myogenesis and repair

Stimulation of myostatin, a myokine that suppresses skeletal muscle growth and may lessen insulin sensitivity, loss of myostatin in mouse models improves insulin sensitivity.²⁰

An increasing number of studies are showing SH promotes sarcopenia. Two recent examples: A comparison of appendicular skeletal muscle mass (ASM) and fat mass between 21 patients with SH (12 women and 9 men) and 224 controls (67 women and 157 men) with nonfunctioning adrenal incidentaloma (NFAI) using bioelectrical impedance analysis and serum cortisol levels after the overnight 1-mg dexamethasone suppression test (DST) found that ASM was 6.2% lower in women with SH compared with those with NFAI, but not men. In women with SH, compared with women with NFAI, ASM of the lower limb was 6.8% lower.²¹

In a group of 227 patients with adrenal adenomas, 20 were diagnosed with Cushing syndrome, 76 with SH, and 131 with non-functioning adrenal tumor (NFAT). Median age was 56 years (range: 18-89), and 67% were women. Individuals with CS, SH, and NFAT had significantly more visceral fat (odds ratio (OR): 2.2, 2.0, and 1.8) and less skeletal muscle area (OR: 0.01, 0.31, and 0.3), respectively. For every 1 μg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3, and mean total skeletal muscle area decreased by 2.2 cm².²²

Diagnosis

Formal diagnosis of SH is challenging since the definition of the condition is still evolving and standard passive laboratory measures have poor sensitivity/specificity²³

Virtually all guidelines recommend use of the 1 mg overnight dexamethasone suppression test (DST), but the cutoff for cortisol levels after DST is still being debated. European guidelines suggest cortisol levels after DST between 1.9 and 5.0 μg/dL or >5.0 μg/dL as diagnostics for either “possible autonomous cortisol secretion” or “confirmed autonomous cortisol secretion,” respectively. Other experts suggest the use of DST with a cutoff of 1.8 μg/dL.

In the standard dose version of this test, 1mg of dexamethasone is given orally at 11 PM and a serum cortisol level is checked the next morning at 8 AM. A cortisol level of less than 1.8mg/dL is a normal response (i.e., the patients cortisol is suppressed as expected) and has a low false negative rate (<2%). However, false positives have been reported in up to 40% of patients, so confirmatory testing is needed with positive results.

Part of the problem with diagnostic guidelines is that cortisol secretion is a continuum from completely normal to abnormally increased levels, and it is highly variable in the same individual. For this reason, Favero, et al.¹ suggest that evaluating the degree of cortisol secretion should be conducted by considering cortisol levels after 1 mg-DST as a continuous variable, rather than a binary diagnostic. To partially meet this need, some guidelines distinguish different cut-offs of cortisol levels after 1 mg-DST with cortisol levels between 50 and 138 nmol/L (1.9-5.0 μg/dL) or above 138 nmol/L (>5.0 μg/dL) indicating either “possible autonomous cortisol secretion” or “confirmed autonomous cortisol secretion,” respectively.

In the low dose dexamethasone suppression test, a dose of 0.5 mg is taken orally every 6 hours starting at 6 AM with the last dose at midnight. Cortisol is then measured the next morning at 8 AM and the same cutoff value of 1.8 mg/dL has been shown to have an excellent sensitivity and a specificity of 98%. Certain drugs, such as phenytoin, phenobarbital, and rifampin increase the clearance rate of dexamethasone, resulting in false positives during the dexamethasone suppression test.

A 24-hour urine collection for free cortisol can be used as a confirmatory test when the dexamethasone suppression test is positive. However, if kidney function is poor (low estimated glomerular filtration rate [eGFR]), urinary cortisol excretion will be decreased and may appear normal even in the presence of excessive cortisol production.

Once initial testing confirms the presence of excess cortisol, basal morning plasma ACTH level should be measured. A suppressed ACTH is suggestive of adrenal pathology, while an elevated ACTH level in the presence of SH (ACTH levels above 20 pg/mL without stimulation or 30 pg/mL after a CRH stimulation test) may indicate the primary lesion is in the pituitary³

Recently, an androgen steroid profile including 11-deoxycortisol, 11-deoxy-corticosterone and corticosterone has been suggested to be as accurate as the dexamethasone suppression test in identifying SH in patients with AI. This is because AI with biochemically demonstrated SH has very different steroid secretions than those seen in Cushing’s syndrome. In addition, ACTH levels are directly associated with DHEA and androstenedione levels in AI patients. A recent study of the steroid profile in patients with SH found significantly decreased levels of DHEA and androstenedione, thought to be due to cortisol suppression of ACTH leading to decreased stimulation of the adrenal cortex, and low androgen production.³,²⁴

To exclude SH, baseline serum dehydroepiandrosterone sulfate (DHEAS) level was measured and overnight 1 mg of dexamethasone suppression test (DST) was performed. Low DHEAS reflects chronic suppression of ACTH secretion. One mg dexamethasone was administered orally between 11 PM and 12 PM, and blood samples were taken for serum cortisol levels the next morning between 8 AM and 9 AM. The value of 1.8 mcg/dl (50 nmol/l) was chosen as cutoff, and autonomous cortisol production was excluded in patients whose serum cortisol was below 1.8 mcg/dl.

To exclude pheochromocytoma, a rare benign type of adrenal tumor that grows on chromaffin cells in the adrenal medulla, 24-h urinary fractionated metanephrines and vanillylmandelic acid levels are measured. (Pheochromocytoma/Paraganglioma) If clinical suspicion was low in patients with normal results, no further tests were performed. In patients with high clinical suspicion (episodes of hypertension, palpitations, headaches), a urine sample was collected during the spell and the test was repeated. If normal, diagnosis of pheochromocytoma was excluded.

In patients with adrenal incidentaloma with hypertension, plasma aldosterone (ng/dl) / renin (ng/ml/hour) ratio was examined to exclude primary aldosteronism. If the ratio was below 20, no further tests were run. If greater than 20, confirmation tests were performed.

Treatment

Unfortunately, understanding and recognition of subclinical hypercorticolism is at an early stage and controlled studies are few. Little has been published other than surgical intervention.

While we cannot document effective non-surgical interventions, obviously addressing controllable causes is appropriate. The most obvious approach is to decrease body load of BPA. This can be done through avoidance and by supporting glucuronidation, the primary pathway for bisphenol detoxification.²⁵ While detoxification of bisphenols is fast, exposure is widespread, and avoidance requires substantial vigilance. All bisphenols should be avoided since they cause similar dysfunction. Unfortunately, the term BPA-free often means other bisphenols have been substituted. While the research on the toxicity of these substitutes is scant compared to that for BPA, it clearly shows these are toxic as well.

Figure 1.

Adrenocortical steroidogenic pathway⁸

Abbreviations: ACTH, adrenocorticotrophic hormone; AVP, arginine vasopressin; CRH, corticotrophin-releasing hormone.

Figure 2.

Physiological Dysfunctions Found in Subclinical Hypercortisolism³

Abbreviations: mHC, mild hypercortisolism; OB, osteoblast; OCL, osteoclast; OC, osteocytes; PPRγ2, peroxisome proliferator-activated receptor γ2; C/EBP, CCAAT/ enhancer binding protein family; M-CSF, macrophage stimulating factor; RANK-L, receptor activator of nuclear factor kappa B ligand; 11BHSD1, 11β hydroxysteroid dehydrogenase type 1; HSP-90, heat shock protein 90; AIItype1AR, angiotensin II; type 1A receptors; MR, mineralocorticoid receptor; vWF, von Willebrand factor; APTT, activated partial thromboplastin time; IMT, intima-media thickness; CV, cardiovascular; GR, glucocorticoid receptor; VLDL, very-low-density lipoprotein; FFA, free fatty acid; GLUT, glucose transporter; IRS1, insulin receptor substrate-1; PKB, protein kinase B; PI3K, phosphatidylinositol-3 kinase; AA, amino acid; IGF-1, insulin growth factor 1; mTOR, mammalian target of rapamycin (mTOR); MF, muscle fibers; MuRF1, muscle-ring finger protein-1; FOX-3a, forkhead box O3a; SNP, single nucleotide polymorphism; γIFN, γ-interferon; IL2, interleukin 2; TNFβ, tumor necrosis factor β; Ab, antibodies.

Figure 3.

Impact of Excessive Cortisol on Bone Metabolism³

Figure 4.

Glucocorticoid Excess Impairs Skeletal Muscle³

Abbreviations: IGF-1 (insulin-like growth factor 1) 11HSD1 (11 beta-Hydroxysteroid dehydrogenase type 1), MuRF1 (muscle-ring finger protein-1), FOXO3a (human protein encoded by the FOXO3 gene) atrogin-1 (muscle-specific protein induced in catabolic states).

Biographies

Lara Pizzorno, MDiv, MA, LMT, is the lead author of Healthy Bones, Healthy You and a prolific writer on bone health.

Joseph Pizzorno, ND, Editor in Chief, IMCJ; co-author, Textbook of Natural Medicine; Founding President, Bastyr University; Chair, Board of Directors, Institute for Functional Medicine.