13.1 MedicineII_Endocrinology (Adrenals)_ 2014A

August 16, 2012

Principles of Endocrinology & Adrenal Gland 1.

2. 3. 4. 5. 6. 7.

Outline Endocrinology a. Endocrine System b. In Relation to Physiologic Processes c. Hormones d. Pathologic Mechanisms of Endocrine Disease e. Approach to Endocrine Diseases Diseases of the Adrenal Gland a. Renin-Angiotensin-Aldosterone Axis b. Steroid Hormone Synthesis, Metabolism, and Action Adrenal Excess a. Glucocorticoid Excess b. Mineralocorticoid Excess Adrenal Mass a. Incidentalinomas b. Adrenocortical Carcinoma Pheochromocytoma and Parangangliomas Adrenal Insufficiency a. Primary vs Secondary b. Acute vs Chronic Congenital Adrenal Hyperplasia

NOTE FROM THE TRANSERS: Hi classmates! Malabo at mahirap talaga intindihin iyong recording ni Dr. Ramos so di namin masasabing kumpleto iyong nalagay naming recordings dito sa trans but rest assured, we tried our bestest to put whatever we could understand from the recording…  Note from Editor: The tables and figures in the appendix are included in the lecture but are placed in the appendix because they do not fit in the columns. Sir mostly just read the contents of the tables and figures but pay more attention to the Algorithms for Management. “Sir’s ppt notes” are notes from his powerpoint lecture. Some are from Harrison’s, the others are from journal articles, guidelines, and other internet references.

ENDOCRINOLOGY 

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Managing patients with endocrine disorders is a fascinating and continuing challenge. The variety of disorders encountered, the range of presentation from the subtle to the gross, and from the stereotype to the atypical, are excitements met in every clinic. Added to this is the almost unparalleled capacity to transform patient’s lives for the better. o Example, somebody who is having cachexia because of hyperthyroidism. In a just a few weeks of treatment they will be up and about just like normal. Most hormone disorders are amenable to effective treatment. Endocrinology is the study of hormones – the site and control of their synthesis and secretions; their blood born effects on distant organs and the disorders of hormone production and response constitute the basis of endocrinology – something that you will never find in other specialties.

[Harrison’s]  The term endocrine was coined to contrast the actions of hormones secreted internally (endocrine) with those excreted externally (exocrine).

Endocrine System

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Associated to hormones related to glands/tissues that bind to receptors in other tissues where they affect a specific physiologic process Endocrine glands communicate broadly with other organs to the nervous system, hormones, cytokines and growth factors Example: o Hypothalamic releasing factors – influence the pituitary glands o Peripheral nervous system – affects the adrenal medulla Closely related to immune system Example: o Adrenal hormones are immunosuppressant Examples would be prednisone and hydrocortisone acetate in treatment of immune diseases. o Cytokines and interleukins influence function of the pituitary, adrenal, thyroid and gonads  Autoimmune thyroid disease  Type I Diabetes Mellitus  Addison’s disease  Lymphocytic Hypophysitis

[Harrison’s]  Common endocrine diseases such as autoimmune thyroid disease and Tyoe 1 DM are caused by dysregulation of immune surveillance and tolerance. Less common disease such as polyglandular failure, Addison’s disease, and lymphocytic hypophysitis also have immunologic basis.

Endocrinology in Relation to Physiologic Processes The endocrine system is also related to physiologic processes, not just simply related to the glands. Hormones are related to: Cardiovascular system  BP maintenance  Intravascular volume  Peripheral Resistance  Ex: Catecholamines, Angiotensin II, Endothelins and Nitric oxide – involved in dynamic changes of vascular tone in addition to their multiple roles in other tissues.  Heart – Atrial Natriuretic Peptide o Causes diuresis in patients who are having congestive heart failure. Its action is not directly to the heart, but to the kidneys. Kidneys  Ex: Erythropoeitin - stimulates erythropoiesis in bone marrow; involved in Renin-Angiotensin Axis, and the primary target organ of PTH, Mineralocorticoids and Vasopressin GIT

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Ex: Peptide hormones, Cholecystokinins, Ghrelin, Gastrin, Secretin, Vacoactive Intestinal Peptide (VIP) Adipose Tissue  Ex: Leptin – acts centrally to control appetite [Harrison’s]  Carcinoid and islet tumors can secrete excessive amount of these hormones, leading to specific clinical syndromes.  Characterization of hormone receptors frequently reveals unexpected relationships to factors in nonendocrine disciplines.  The growth hormone and leptin receptors, for example are members of cytokine receptors. The GPCRs, which mediate the actions of many peptide hormones, are used in many physiologic processes, including vision, smell and neurotransmission.

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Evaluation and treatment of Endocrine disorders requires understanding of hormone secretion, hormone action and principles of feedback control Hormones are either: bound or unbound to proteins Many hormones circulate in association with binding proteins to provide a hormonal reservoir to prevent otherwise rapid degradation of unbound hormones, to restrict hormone access to certain sites and to modulate the unbound hormone concentration o Ex: Total T4 Unbound hormones (active) are available to interact with receptors eliciting a biological response Unbound hormones have so much to do with controlling the overall hormonal function o Ex: FT4 (free thyroxine) o The unbound hormones are the free T4. They are active and interact with the receptors, not like the bound hormones included in the total T4. In the clinics, we don’t just rely on the test of total T4, we look for the free hormones because these are the ones that are active. They make the difference in the control of thyroid tissue.

[Harrison’s]  Short term pertubations in binding proteins change the free hormone concentration, which in turn induces compensatory adaptations of the feedback loops. Exception is when SHBG (sex-hormone binding globulin) decreases in women because of insulin resistance or androgen excess, the unbound testosterone is increased leading to hirsutism. It does not result in an adequate compensatory feedback correction because estrogen is the primary regulator of the reproductive axis.

Organization of the Endocrine System Chu, Chua, Claveria

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Table 1. Organs and glands and their associated hormones Orga Hormones n Hypothalamus Production of ADH, oxytocin, releasing hormones (TRH, CRH, GHRH, GnRH), and somatostatin Pituitary gland Anterior: ACTH, TSH, GH, PRL, FSH, LH, and MSH Posterior: release of ADH and oxytocin Pineal gland Melatonin Thyroid gland T4, T3, calcitonin Parathyroid PTH glands Heart Atrial natriuretic peptide (ANP) Adrenal glands Medulla: Epinephrine, Norepinephrine Cortex: Cortisol, aldosterone, androgens Kidney Erythropoietin (EPO), calcitriol, renin Fat Leptin Thymus Thymopoietin Digestive tract Gastrin, secretin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP), motilin Pancreatic Insulin, glucagon, somatostatin islets Testes Androgens, inhibin Ovaries Estrogen, progestins, inhibin, relaxin

Hormones Receptor for Hormones 

General principles of hormone receptor interaction. o Hormones bind to receptors with specificity o Receptors numbers may vary greatly in different target tissues  Ex. ACTH in Adrenal – produces cortisol  The receptor numbers vary greatly in different target tissues. Like insulin, it can affect other areas aside from the muscle. It’s the same with the thyroid hormone because it affects every part of our body.

[Harrison’s]  ACTH and FSH receptors are located almost exclusively in the adrenal cortex, and FSH receptors are found predominantly in the gonads. In contrast, insulin and thyroid receptors are widely distributed, reflecting the need for metabolic responses in all tissues.

2 types 1. Membrane receptors o Bind peptide catecholamines

hormones

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Relevant to the bigger peptide hormones and catecholamines. Examples are the releasing hormones in the hypothalamus and in the pituitary.

Table 2. Membrane Signaling Pathways

Receptor

Families

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to distinguish hyperparathyroidism secondary from hypocalcaemia of malignancy.

2. Nuclear Receptors o Classified according to the nature of the Ligands. o They may reside in the cytoplasm or in the nucleus o May cross talk with membrane receptors o Cross each activity with the membrane receptors o These are non-specific. [Harrison’s]  Nuclear receptors bind small molecules that can diffuse across the cell membrane, such as steroids and vitamin D.  Though all nuclear receptors ultimately act to increase or decrease gene transcription, some (glucocorticoid receptors) reside in the cytoplasm, whereas others (thyroid hormone receptors) are always located in the nucleus.  The hormone-binding domains are more variable providing great diversity in the array of small molecules that bind to different nuclear receptors. With few exceptions, hormone binding is highly specific for a single type of nuclear receptor. Examples are the glucocorticoid and mineralocorticoid receptors. Because the MR also binds glucocorticoids with high affinity, an enzyme (11-hydroxysteroid dehydrogenase) in renal tubular cells inactivates glucocorticoids, allowing selective responses to mineralocorticoids such as aldosterone.  In Cushing’s syndrome, there is glucocorticoid excess and the degradation pathway becomes saturated, allowing excessive cortisol levels to exert mineralocorticoid effects (sodium retention, potassium wasting)  Another example is the estrogen receptors. The lack of specificity provides an opportunity to synthesize remarkable series of clinically useful antagonists and selective estrogen response modulators.

[Harrison’s]  There is minimal overlap of glycoprotein hormone binding. For example, TSH binds with high specificity to TSH receptors but interacts with LH or the FSH receptors. Very high levels of hCG during pregnancy stimulate the TSH receptor and increase thyroid hormone levels, resulting in a compensatory decrease in TSH levels.  High levels of an IGF-II precursor produced by certain tumors can cause hypoglycemia, partly because of binding of insulin and IGF-I receptors. High concentrations of insulin also bind to the IGF-I receptor, accounting for some manifestations in severe insulin resistance.  Cross talk is seen with PTH and parathyroid hormone-related peptide (PTHrP), which is expressed at high levels during development and by a variety of tumors. Both bind to a single PTH receptor expressed in bone and kidney. Hypocalcaemia and hypophosphatemia therefore may result from either hormone, making it difficult Chu, Chua, Claveria

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Receptor Signaling:

Figure 1. Membrane receptor signaling. Mitogenactivated protein kinase (MAPK), Protein kinase A

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and C (PKA, PKC), Transforming growth factor (TGF). (Nice to know)

Figure 2. Nuclear receptor signaling. Estrogen (ER); androgen (AR); progesterone (PR); glucocorticoid (GR); thyroid hormone (TR); vitamin D (VDR); retinoic acid (RAR); peroxisome proliferator activated (PPAR); steroidogenic factor-1 (SF-1); dosage-sensitive sex-reversal, adrenal hypoplasia congenital, x-chromosome (DAX); hepatic nuclear factor 4 (HNF4). The homodimer and heterodimer nuclear receptors have specific ligands. Orphan receptors don’t have specific ligands. [Harrison’s]  Orphan receptors are classified as such because their ligands have not been identified.

Physiologic Functions of Hormones 

Growth and differentiation o Short stature – may be caused by GH deficiency, hypothyroidism, Cushing’s syndrome, precocious puberty, malnutrition, chronic illness or genetic abnormalities that affect the epiphyseal plates. 

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Sex steroids lead to epiphyseal closure. Delaying exposure to high levels of sex steroids may enhance efficacy of GH treatment. [Harrison’s]

Increased growth – GH, IGF and Thyroid hormones stimulate growth

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Maintenance of homeostasis o Hypoglycemia: Glucagon, Epinephrine, GH, Cortisol Somebody who is starving will not die of starvation initially because your counterregulatory hormones will come into play. o Stress One would be able to keep up with stress because of catecholamines inherent in us. Chu, Chua, Claveria

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Free Water Clearance: controlled by Vasopressin (ADH), Cortisol, Thyroid hormone In relation to diuresis, this can also be affected by vasopressin. Cortisol and thyroid hormone can also affect water clearance in the distal tubule. o

[Harrison’s] Though virtually all hormones affect homeostasis, the most important among them are the following: 1. Thyroid hormone – controls about 25% of basal metabolism in most tissues 2. Cortisol – exerts a permissive action for many hormones in addition to its own direct effects 3. PTH – regulates calcium and phosphorous levels 4. Vasopressin – regulates serum osmolality by controlling renal free-water clearance 5. Mineralocorticoids – control vascular volume and serum electrolyte concentrations 6. Insulin – maintains euglycemia in the fed and fasted states.  If hypoglycemia develops (usually from insulin administration or sulfonylureas), an orchestrated counterregulatory response occurs – glucagon and epinephrine rapidly stimulate glycogenolysis and gluconeogenesis, whereas GH and cortisol act over several hours to raise glucose and antagonize insulin action.  Cortisol and thyroid hormones are also important for facilitating renal tubular responses to vasopressin.

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Reproduction o Sex determination during fetal development o Sexual maturation during puberty o Conception, pregnancy, lactation and child rearing o Cessation of reproductive capability o Relevant from the period of development until menopausal period.

Nature of Hormones 5 Major Classes 1. Amino Acid Derivatives Dopamine, Catecholamine and Thyroid Hormone 2. Small Neuropeptide - GRH, TRH, Somatostatin and Vasopressin 3. Large proteins - Insulin, LH, PTH 4. Steroid Hormones - Cortisone and Estrogen 5. Vitamin Derivatives - Vitamin A and Vitamin D [Harrison’s]  A variety of peptide growth factors, most of which act locally, share actions with hormones. As a rule, amino acid derivatives and peptide hormones interact with cell-surface membrane receptors. Steroids, thyroid hormones, vitamin D, and retinoids are lipid-soluble and interact with intracellular nuclear receptors.

Hormone Synthesis and Processing Page 4 of 29

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Classic Pathway of Gene expression of peptide hormone and receptor synthesis: Transcription  mRNA  Protein  Post translational protein processing, intracellular setting, membrane integration or secretion

Hormone Synthesis  Many hormones are embedded within larger precursor polypeptides (prohormones) – adding an additional level of regulatory control  Ex: o Proopiomelanocortin (POMC) – ACTH and MSH o Proglucagon – Glucagon o Proinsulin – Insulin o ProPTH – PTH  Prohormone conversion is also for certain steroids o Testosterone  dihydrotestosterone  Somebody who has a normal level of testosterone doesn’t necessarily have a normal level of dihydrotestosterone. That’s why you have to go to the more specific, more active hormone that would be more relevant in determining the actual action of the hormone of the receptor. o Thyroid hormone T4  T3  Both from the thyroid gland, but it is known that T4 that is secreted in abundance is just a prohormone that is eventually converted to the active T3. In hyperthyroidism, T4 is normal, and TSH is below normal, you look for T3 in this situation. Because T4 is just a prohormone, it may be normal, but if you detect T3, it may tell you that there is a problem of hyperthyroidism.  Steroid synthesis is based on modification of its precursor cholesterol – always the precursor  Synthesis of testosterone, estradiol, cortisol and vitamin D are a result of regulated enzymatic steps [Harison’s] 

Multiple enzymatic steps are required for synthesis of testosterone, estradiol, cortisol, and vitamin D. This large number of synthetic steps predisposes to multiple genetic and acquired disorders of steroidogenesis.

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As in giving T4 and T3, glucocorticoids and dexamethasone

Half-life of T4 is about a week; T3 has a half-life of 3 days. The glucocorticoids would be useful for 6 hours and dexamethasone lasts for 72 hours. One has to know the differences in half-life for you to know to recommend the dosaging of these hormones. [Harrison’s]  FT4 has a half life of 7 days. Consequently, > 1 month is required to reach a new steady state, but single daily doses are sufficient to achieve constant hormone levels. T3 has a half-life of 1 day, and must be administered 2 to 3 times a day.  Synthetic glucocorticoids (dexamethasone) with longer half-lives have a greater suppression of hypothalamic-pituitary-adrenal axis (HPA).  Short half-life of PTH allows the use of intraoperative PTH determinations to confirm successful removal of an adenoma. This is particularly valuable diagnostically in multicentric disease or parathyroid hyperplasia, as occurs with MEN or renal insufficiency.

Stimulus for Hormone Secretion 1. 2. 3.  

Releasing Factor (ex. TRH on TSH) – like the peptides in the hypothalamus and the pituitary Neural Signal Outright diffusion into the circulation from synthesis (e.g. steroid hormone) Hormone transport and degradation decide the rapidity with which a hormonal signal decays. Example: o Evanescent - Somatostatin – It’s very hard to follow the level due to its rapid decay in the circulation. Its short half life allows its o

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concentrations and actions to be controlled locally. [Harrison’s] Longer Lived - TSH – highly specific for the thyroid gland. Half-life accounts for relatively constant serum levels even though TSH is secreted in discrete pulses. [Harrison’s]

Short half lives - ACTH, GH, Prolactin, PTH and LH

There will always be a variation depending on the particular hormone that we encounter.

Feedback Control

Transport and Degradation  The circulating level of a hormone is determined by the rate of secretion and its circulating half life o Half-life determines physiologic hormone replacement Chu, Chua, Claveria

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Hormonal Rhythms  

Figure 3. Feedback regulation of endocrine axes. Negative feedback - more common in hormones  Examples o TRH, TSH; CRH, ACTH; Gonadal steroids LH, GnRH LH; IGF on GHRH o Calcium feedback and PTH o Glucose inhibition of insulin secretion o Leptin feedback on the hypothalamus Whenever we talk about hormones, we always relate to the feedback. That’s why when we analyze the hormones we always do a paired testing. So if you test TSH, as much as possible you also test TRH and T4. If you pick up an abnormal level of calcium, you look at the PTH. Positive feedback  Examples o Estrogen mediated stimulation of the midcycle LH surge – Only example that can give this picture. Depending on the timing of ovulation and menstruation you can see the estrogen variation.

Local Regulatory System Paracrine Regulation  Factors released by 1 cell that act on adjacent cell in the same tissue  E.g. Somatostatin (Delta cells) inhibiting insulin in Beta Cells Autocrine Regulation  Action of a factor on the same cell from which it is produced  E.g. IGF acts on many cells that it produces including chondrocytes, breast epithelium and gonadal cells Chu, Chua, Claveria

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The Feedback regulatory systems are superimposed on hormonal rhythms that are used for adaption to the environment Ex: o Seasonal/periodic changes relevant to menstruation o Light-dark cycle – pituitary hormones  Ex. Circadian rhythm, melatonin from pineal gland  Melatonin – for sleeping  Problems in sleeping, especially in the young, are mostly due to over-playing of computer games. The light consumes the melatonin as they play the game. The longer they are exposed to the light from the computer that would affect the hormone melatonin. o Sleep – insulin resistance, food cravings and hypertension  You are not able to get a good sleep; you will find problems with sugar.  Ghrelin – the hormone related to food cravings. As you stay up in the night, you have unusual craving for food. You have to anticipate that. Just drink water or else you gain a lot of weight. o Stress o Meals

[Harrison’s]  The HPA axis, for example, exhibits characteristic peaks of ACTH and cortisol production in the early morning, with a nadir during the night.  In Cushing’s syndrome, there is an abnormally increased midnight cortisol level and morning cortisol levels are similar to normal individuals. The HPA axis is more susceptible to suppression by glucocorticoids administered at night as they blunt the early morning rise of ACTH.  Other endocrine rhythms occur on a more rapid time scale. Many peptide hormones are secreted in discrete bursts every few hours. LH and FSH secretion are exquisitely sensitive to GnRH pulse frequency. Intermittent pulses of GnRH are required to maintain pituitary sensitivity, whereas continuous exposure to GnRH causes pituitary gonadotrope desensitization. This feature of the hypothalamicpituitarygonadotrope axis forms the basis for using long-acting GnRH agonists to treat central precocious puberty or to decrease testosterone levels in the management of prostate cancer.

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To address hormonal fluctuation, integrated markers are used to determine hormonal levels o 24 hour urine collection for cortisol, HbA1c and IGF o Paired hormone studies are also necessary  Serum Calcium  PTH

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FT4  TSH

Because of the circadian rhythm of cortisol secretion, it’s best to take a 24-hour urine collection of the total amount of cortisol being secreted. HbA1C is now used to monitor blood glucose control for three months. Fasting blood sugar is not necessarily the only way to monitor sugar problems. HbA1c can also help you with that, and the same with IGF.

Pathologic Mechanisms of Endocrine Diseases Table 3. Causes of Endocrine Dysfunction. Among the autoimmune diseases, the more common would be Hashimoto’s thyroiditis. Among Asians, Type 2 DM would be more common, unlike the Caucasians where Type 1 DM would be more common. Among hormone resistance, the more common are the postreceptor Type 2 DM and leptin resistance.

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Tumor cells – not completely resistant to feedback, as evidenced by ACTH suppression by higher doses of dexamethasone (high-dose dexamethasone test). [Harrison’s] Hypofunction – hormone deficiency  Hashimoto’s thyroiditis and Type 1 DM  Mutations, autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration can cause hormone deficiency. [Harrison’s]

Hormone Resistance  Defective hormone action in the presence of increased hormonal levels  E.g. Insulin resistance in Type II DM, Leptin resistance in Obesity, GH resistance in Catabolic states o Functional resistance involves receptor

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downregulation and postreceptor desensitization of signaling pathways; functional forms of resistance are generally reversible. [Harrison’s] Most are due to inherited defects in transmembrane receptors, nuclear receptors, or the pathways that transduce receptor signals. [Harrison’s]

Approach to Endocrine Diseases History  Exposure to drugs, knowledge of disease prevalence, signs and symptoms  Steroids – autoimmune diseases such as lupus, Graves’ ophthalmopathy. These are the conditions wherein the steroid can affect the endocrine system.  Locally, we have more goiters compared to other countries due to iodine deficiency. Physical Examination  Direct examination of Thyroid or Gonads  Look at the more obvious areas like the thyroid, hyperactivity, hyperfunction or hypoactivity, hypofunction. Examine the gonads and check if there is hyponagonadism. Testicles would feel gelatinous. What is characteristic among the males is that they will not have any response or pain even if you crush the testes. Laboratory testing of hormone levels and dynamics  In situations wherein you would have levels that are not significantly abnormal then you have this dynamic testing. Again, when you test it should be paired testing.

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1. Basal hormone testing o Component endocrine axis are addressed simultaneously

Hyperfunction – hormone excess 

Cushing’s inhibition

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feedback

Table 4. Basal Hormone Testing and Associated Disorders Page 7 of 29

Hormone 1 Low testosterone Low testosterone

Hormone 2 High LH Low LH

High TSH

Low FT4

Low TSH

High FT4

Low ACTH

High cortisol

Disorder Primary gonadal disorder Hypothalamic pituitary disorder (Higher center problem) Primary hypothyroidism (Low FT4 naturally will be sensed by your pituitary that’s why it will show an increase in TSH) Primary hyperthyroidism (High FT4 will naturally switch off the pituitary and TSH will be low) Hyperfunctioning adrenal adenoma (The same with taking steroids such as prednisone, dexamethasone, hydrocortisone acetate will also switch off your pituitary causing low ACTH levels)

Paired testing helps you in determining the nature of the disorder. [Harrison’s]  Low TSH is most often caused by thyrotoxicosis.  Because TSH is a sensitive indicator of thyroid function, it is generally recommended as a first line test for thyroid disorders.  Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or ganulomatous diseases.  Radiologic imaging tests, such as CT scan, MRI, thyroid scan, and ultrasound, are also used for the diagnosis of endocrine disorders. However, these tests are generally employed only after a hormonal abnormality has been established by biochemical testing.  Most hormones measurements are based on plasma and serum samples. However, urinary hormone determinations remain useful for the evaluation of some conditions. Urinary collections over 24h provide an integrated assessment of the hormone or metabolite production.  A 24-h urine free cortisol measurement largely reflects the amount of unbound cortisol, providing a reasonable index of biologically active hormone.

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Baseline hormones of pathologic symptoms may not be obvious or sometimes overlap with normal range

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In this circumstance, dynamic testing is useful. There are a multitude of dynamic endocrine tests, but all are based on principles of feedback regulation, and most responses can be remembered based on the pathways that govern endocrine axes. [Harrison’s]

a) Suppression test:  For endocrine hyperfunction  Dexamethasone Suppression Test in Cushing’s syndrome  Overnight dexamethasone test for patients who are obese and alcoholic. b) Stimulatory test:  For endocrine hypofunction  ACTH stimulatory test You have low cortisol levels and you would like to know if it’s really an adrenal insufficiency then you do an ACTH stimulatory test.  CRH and GHRH to test for pituitary hormone reserves – utilized in the same way  Insulin induced hypoglycemia also evokes pituitary ACTH and GH responses A very efficient test to determine adrenal insufficiency is to do an insulin-induced hypoglycemia. Give the patient insulin. If hypoglycemia is present, check the levels of cortisol or growth hormone.  Pituitary ACTH to test for adrenal reserve and GH response See Appendix for “Table 322-3. Examples of Prevalent Endocrine and Metabolic Disorders in the Adult.”

DISORDERS OF THE ADRENAL GLAND

2. Dynamic Testing

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Figure 4. Adrenal Gland Anatomy - suprarenal, on top of the kidney. Figure 6. Regulation of the HPA (hypothalamuspituitary-adrenal) axis.

Figure 5. Adrenal Gland Histology. The adrenal gland has a cortex and medulla. The adrenal cortex is divided into zona glomerulosa which synthesizes mineralocorticoid (mainly aldosterone), zona fasciculata which synthesizes corticosteroid (11-deoxycorticosterone, corticosterone, and cortisol), zona reticularis which synthesizes sex steroids (estrogen and androgen – dehydroepiandrosterone/ DHEA, DHEA sulfate, and androstenedione). Adrenal medulla synthesizes catecholamines (epinephrine).

[Harrison’s]  Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitaryadrenal (HPA) axis, whereas mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system. Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary.  Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress. CRH stimulates the cleavage of the 241–amino acid polypeptide proopiomelanocortin (POMC) by pituitary-specific prohormone convertase, yielding adrenocorticotropic hormone (ACTH).  ACTH is released by the corticotrope cells of the anterior pituitary and acts as the pivotal regulator of cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis. The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm under the control of the hypothalamus, specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes.

(Physiologic Cortisol) Circadian Rhythym- In the morning, cortisol is high which energizes us. What energizes us? GH and cortisol. During the night, opposite occurs: cortisol is low, ACTH is high. Treatment is patterned according to this difference. [Harrisons] Circulating cortisol concentrations drop under the rhythm-adjusted mean (MESOR) in the early evening hours, with nadir levels around midnight and a rise in the early morning hours; peak levels are observed 8:30 A.M. (acrophase).

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Renin-Angiotensin-Aldosterone Axis

Figure 8. ACTH stimulation is required for the initiation

Figure 7. RAA Axis. Kidney secretes renin, which converts angiotensinogen to angiotensin I, which is then converted to angiotensin II by ACE. Angiotensin II stimulates aldosterone release. [Harrison’s]  Mineralocorticoid production is controlled by the RAA regulatory cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor), resulting in increased aldosterone production and vasoconstriction. Aldosterone enhances sodium retention and potassium excretion, and increases the arterial perfusion pressure, which in turn regulates renin release.  Because mineralocorticoid synthesis is primarily under the control of the RAA system, hypothalamicpituitary damage does not significantly impact the capacity of the adrenal to synthesize aldosterone.  Similar to the HPA axis, the assessment of the RAA system can be used for diagnostic purposes. If mineralocorticoid excess is present, there is a counter-regulatory downregulation of plasma renin. Conversely, in mineralocorticoid deficiency, plasma renin is markedly increased. Physiologically, oral or IV sodium loading results in suppression of aldosterone, a response that is attenuated or absent in patients with autonomous mineralocorticoid excess.

Steroid Hormone Synthesis, Metabolism, and Action Nice to know:

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of steroidogenesis. The ACTH receptor MC2R (melanocortin 2 receptor) interacts with the MC2Raccessory protein MRAP, and the complex is transported to the adrenocortical cell membrane, where it binds to ACTH. ACTH stimulation generates cyclic AMP (cAMP), which upregulates the protein kinase A (PKA) signaling pathway. PKA activation impacts steroidogenesis in three distinct ways: (1) increases the import of cholesterol esters; (2) increases the activity of hormone- sensitive lipase, which cleaves cholesterol esters to cholesterol for import into the mitochondrion; and (3) increases the availability and phosphorylation of CREB (cAMP response element binding), a transcription factor that enhances transcription of CYP11A1 and other enzymes required for glucocorticoid synthesis. [Harrison’s]

ADRENAL EXCESS Glucocorticoid Excess     

Cushing’s Syndrome Result from chronic exposure to excess glucocorticoids Caused by corticotrope pituitary microadenoma often only a few mm in diameter Ectopic ACTH production caused by occult carcinoid tumor: Lung, thymus, pancreas. The term Cushing's disease refers specifically to Cushing's syndrome caused by a pituitary corticotrope adenoma.

Classification: 1. ACTH-dependent e.g., pituitary corticotrope adenoma (more common), ectopic secretion of ACTH by nonpituitary tumor (rarest!) 2. ACTH-independent e.g., adrenocortical adenoma (uncommon), adrenocortical carcinoma, nodular adrenal hyperplasia Prevalence: pituitary corticotrope adenoma > adrenocortical adenoma > ectopic secretion of ACTH by nonpituitary tumor.

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3. Iatrogenic – the most common among the three e.g., administration of exogenous glucocorticoids to treat various inflammatory conditions Pituitary gland is only 4 cm. For it to be amplified by the tumor, it has to be quite small. Before it gets bigger, there are usually lots of symptoms already. Easy to pick them up because you get them in the hormonal secretions. When the tumor gets so big, above 1 cm, it will produce hemianopsia. Ectopic sources are supposedly found in those who have lung tumor and tumor in the thyroid and pancreas.

Clinical Manifestation The name “Cushing’s” refers to the surgeon who first performed operation on the pituitary. See Appendix for “Table1. Overlapping conditions and clinical features of Cushing’s syndrome.”

Figure 9. Cushing’s Syndrome. Once corrected, symptoms of Cushing’s like buffalo hump, proximal muscle weakness will disappear once you give right amount of treatment. Chu, Chua, Claveria

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Diagnosis To verify, perform any of these tests: I. Daily urinary cortisol excretion  During the entire day. The mean rate of cortisol secretion in normal adults is 9.9+2.7 mg/24 hours  In a patient thought likely to have Cushing’s syndrome, cortisol should be measured in two, and preferably three, consecutive 24-hour urine specimens collected on an outpatient basis.  Excretion of creatinine (a 70-kg person excretes about 1 g per day) should be measured to determine the completeness of the collection: the amount should vary by no more than 10 percent from day to day.  The result of an incomplete collection cannot be corrected by expressing cortisol excretion as a function of creatinine excretion, because cortisol is excreted episodically, whereas creatinine excretion is relatively constant.  If the creatinine content of two specimens does not agree within 10 percent, at least two more collections should be obtained. Sir’s ppt notes: The determination of 24-hour excretion of cortisol in urine is now the most direct and reliable practical index of cortisol secretion. The reason is that plasma concentrations of corticotropin and cortisol rise and fall episodically, not only in normal subjects but also in most patients with Cushing’s disease or the ectopic corticotropin syndrome. The measurement of 24-hour excretion of cortisol in urine integrates the plasma free cortisol concentrations during the entire day. The mean (±SD) rate of cortisol secretion in normal adults is 9.9±2.7 mg per 24 hours (27±7.5 mmol per 24 hours), about 12 to 40 mg (33 to 110 nmol) of which is filtered by the kidney and excreted in urine as unmetabolized cortisol (usually called urinary free cortisol). In many assays of urinary cortisol, the upper limit of normal is 90 to 100 mg (250 to 275 nmol) per 24 hours, indicating that the assay is not specific. If cortisol excretion is consistently elevated, the patient has increased cortisol secretion associated with Cushing’s syndrome, pseudo– Cushing’s syndrome, or major stress, such as from trauma or infection; cortisol secretion is not usually increased by obesity. In a patient thought likely to have Cushing’s syndrome, cortisol should be measured in two, and preferably three, consecutive 24-hour urine specimens collected on an outpatient basis. Multiple measurements are needed because even intelligent and carefully instructed patients can make mistakes (such as not discarding the urine voided when the first day’s collection begins). Cortisol excretion in patients with Cushing’s syndrome may vary from day to day and can be frankly cyclical, so multiple values indicate the constancy of cortisol secretion, which is important for interpreting subsequent test results.

II. Dexamethasone suppression test

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A. Two-day, low-dose dexamethasone suppression test (0.5mg every 6 hours for 8 doses) o Urinary cortisol values >10mg (>28 mmol) per 24 hours or urinary 17hydroxycorticosteroid values >2.5mg (>6.9 mmol) per 24 hours indicate the presence of Cushing’s syndrome Done to know the cause. Why dexamethasone? Because of its high steroid contents which are able to suppress levels of nonpathologic conditions. It cannot suppress someone who has Cushing’s syndrome. After this, do a test for ACTH for the pituitary. You have to know if it’s high from the start. If it’s high, then you consider ACTHindependent Cushing’s, either ectopic or endotopic. Sir’s ppt notes: The standard suppression tests designed to identify patients with Cushing’s syndrome are the two-day, lowdose dexamethasone suppression test (0.5 mg every six hours for eight doses) and the overnight dexamethasone suppression test (1 mg at 11 p.m. or midnight). In the two-day test, urinary cortisol values greater than 10 mg (>28 mmol) per 24 hours or urinary 17-hydroxycorticosteroid values greater than 2.5 mg (>6.9 mmol) per 24 hours indicate the presence of Cushing’s syndrome, as do 8 a.m. plasma cortisol values greater than 5 mg per deciliter (>138 nmol per liter) in the overnight test. Dexamethasone is a substitute for endogenous cortisol in suppressing the secretion of corticotropin; the dosages used are three to four times the normal replacement dosage. If cortisol secretion is normal, dexamethasone suppression is almost always normal; if cortisol secretion is only marginally increased, dexamethasone suppression may be only marginally abnormal; and if cortisol secretion is unequivocally increased, the lack of suppressibility with low-dose dexamethasone adds no useful information. These two tests are useful for confirming a diagnosis of Cushing’s syndrome, but they should be reserved primarily for patients with mildly increased urinary cortisol excretion and those thought to have pseudo–Cushing’s syndrome. Measuring plasma dexamethasone at the conclusion of the test can clarify otherwise confusing results caused by noncompliance, individual variability in dexamethasone metabolism, or the effects of drugs on steroid metabolism. Patients who are acutely ill may have decreased suppressibility of plasma cortisol. However, a normal result of either of these two tests excludes the possibility of Cushing’s syndrome.

B. Overnight dexamethasone suppression test (1mg at 11p.m. or midnight)  8 a.m. plasma cortisol values >5mg per decilitre (>138 nmol/L) III. Late-night salivary cortisol  Healthy individuals: serum cortisol begins to rise at 0300-0400 h, peak at 0700-0900 h, and then falls for the rest of the day to very low Chu, Chua, Claveria

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levels when the person is unstressed and asleep at midnight 92-100% sensitivity and a 93-100% specificity HOW? Collect a saliva sample on two separate evenings between 2300 and 2400 h. Saliva is collected either by passive drooling into a plastic tube or by placing a cotton pledget in the mouth and chewing for 1-2 min. Salivary testing is what’s being done now.

Sir’s ppt notes: The loss of circadian rhythm with absence of a latenight cortisol nadir is a consistent biochemical abnormality in patients with Cushing’s syndrome. This difference in physiology forms the basis for measurement of a midnight serum or late-night salivary cortisol. Biologically active free cortisol in the blood is in equilibrium with cortisol in the saliva, and the concentration of salivary cortisol does not appear to be affected by the rate of saliva production. Furthermore, an increase in blood cortisol is reflected by a change in the salivary cortisol concentration within a few minutes. Various methods have been used to measure cortisol in the saliva, resulting in different reference ranges and yielding differences in sensitivity and specificity. The best-validated assays used in the United States to measure salivary cortisol are an ELISA and an assay performed by LC-MS/MS. When these two assay techniques are used, normal subjects usually have salivary cortisol levels at bedtime, or between 2300 and 2400 h, of less than 145 ng/dl (4 nmol/liter). Using a variety of assays and diagnostic criteria, investigators from different countries have reported that late-night salivary cortisol levels yield a 92–100% sensitivity and a 93–100% specificity for the diagnosis of Cushing’s syndrome. Overall, the evidence in adults suggests that the accuracy of this test is similar to that of UFC. This easily performed, noninvasive test has been used in children to differentiate patients with Cushing’s syndrome from those with simple obesity. Investigators have reported high sensitivity (100%) and specificity (95.2%) for Cushing’s syndrome in this setting. The influence of gender, age, and coexisting medical conditions on the late-night salivary cortisol concentrations has not been fully characterized. It is important to note that the circadian rhythm is blunted in many patients with depressive illness and in shift workers and may be absent in the critically ill. Other populations may have a high percentage of false-positive results. For example, in a study of men aged 60 yr or older, Liu et al. reported that 20% of all participants and 40% of diabetic hypertensive subjects had at least one elevated late-night salivary cortisol measurement. Using the upper reference range of each assay as the cutoff point, Baid et al. measured bed- time salivary cortisol levels in a large number of obese subjects and found a specificity of only 85% when they used a RIA technique, but a better specificity of 92% when tandem mass spectrometry was used. Most clinicians using the late-night salivary cortisol test ask patients to collect a saliva sample on two separate evenings between 2300 and 2400 h. Saliva is collected either by passive drooling into a plastic tube or by placing a cotton pledget (salivette) in the mouth and chewing for 1–2 min. The sample is stable at room or Page 12 of 29

refrigerator temperature for several weeks and can be mailed to a reference laboratory. Reports show good correlation between salivary and simultaneous serum cortisol values in healthy volunteers. When samples were obtained at the same sitting, those collected using the salivette device had lower cortisol concentrations than those collected from passive drooling, but they correlated better with total and free serum cortisol levels. Several factors that affect the salivary cortisol test should be considered when evaluating the results. The salivary glands express 11�-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts the biologically active cortisol to inactive cortisone. It is theoretically possible that individuals using licorice or chewing tobacco (both of which contain the 11 β -hydroxysteroid dehydrogenase type 2 inhibitor glycyrrhizic acid) may have a falsely elevated late-night salivary cortisol. Patients who smoke cigarettes also have been shown to have higher late-night salivary cortisol measurements than do nonsmokers. Although the duration of this effect is not known, it seems prudent to avoid cigarette smoking on the day of collection. Direct contamination of the salivette by steroid-containing lotion or oral gels also may result in false-positive results. Because the test assumes a nadir of cortisol in the late evening, it may not be appropriate for shift workers or those with variable bedtimes, and the timing of the collection should be adjusted to the time of sleeping for those with bedtimes consistently long after midnight. Similarly, nocturnal salivary cortisols may be transiently abnormal in individuals crossing widely different time zones. Finally, stress immediately before the collection also may increase salivary cortisol physiologically; therefore, ideally, samples should be collected on a quiet evening at home. Theoretically, contamination with blood might increase salivary cortisol levels. Although Kivlighan et al. reported that minor to moderate blood leakage as a result of vigorous tooth brushing had no effect on salivary cortisol values, the possible effect of gingivitis or oral sores or injury is not known.

Figure 10. Algorithim for Management of the Patient with Suspected Cushing’s Syndrome. CHR, corticotropin-releasing hormone; DEX, dexamethasone.

Treatment

Figure 10. Endonasal endoscopic approach to the sella.

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Treatment of choice: selective removal of the pituitary corticotrope tumor (transsphenoidal approach)easy to perform, patient can be sent home after 3-5 days

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Metastasized, glucocorticoid-producing carcinomas: long-term anti-glucocorticoid drug treatment, can also be subjected to radiation Tx Ectopic ACTH syndrome, in which the tumor cannot be located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is appropriate

Medical Treatment:  Metyrapone (500mg/tid, max dose 6 g) o MOA: inhibits cortisol synthesis at the level of 11-hydroxylase  Ketoconazole (200mg/tid, max dose 1200 mg) o MOA: inhibits the early steps of steroidogenesis 

After surgery, 1.) HPA axis will remain suppressed, 2.) Hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery. Depending on degree and duration of cortisol excess, the HPA axis may require many months or even years to resume normal function. (Because of the circadian rhythm, you should dose high in the morning and none at night.)

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Figure 11. Therapeutic Approaches to Patients with the Three Major Causes of Cushing’s Syndrome and Approximate Rates of Success

Mineralocorticoid Excess See Appendix for “Table Mineralocorticoid Excess.”

342-3.

Causes

of

Sir’s ppt notes [Harrison’s]: The most common cause of mineralocorticoid excess is primary hyperaldosteronism, reflecting excess production of aldosterone by the adrenal zona glomerulosa. Bilateral micronodular hyperplasia is somewhat more common than unilateral adrenal adenomas (Table 342-3). Bilateral adrenal hyperplasia is usually micronodular but can also contain larger nodules that might be mistaken for a unilateral adenoma. In rare instances, primary hyperaldosteronism is caused by an adrenocortical carcinoma. Carcinomas should be considered in younger patients and in those with larger tumors, as benign aldosterone-producing adenomas usually measure