ENDOC-ADRENAL GLANDS-CORTEX- HYPERCORTISOLISM

Question 1

The adrenal glands are ______________, which
differ in their development, structure, and function.

Answer 1

paired endocrine organs consisting of both cortex and medulla

Question 2

Beneath the capsule of the adrenal is the
_______________

Answer 2

narrow layer of zona glomerulosa

Question 3

. An equally narrow____________ abuts the medulla.

Answer 3

zona reticularis

Question 4

Intervening is the broad ___________, which makes up about 75% of the total cortex.

Answer 4

zona fasciculata

Question 5

The
adrenal cortex synthesizes three different types of steroids:

Answer 5

(1) glucocorticoids (principally
cortisol), which are synthesized primarily in the zona fasciculata and to a lesser degree in the
zona reticularis;

(2) mineralocorticoids, the most important being aldosterone, which is generated in the zona glomerulosa; and

(3) sex steroids (estrogens and androgens), which are
produced largely in the zona reticularis.

Question 6

The adrenal medulla is composed of_________
which synthesize and secrete catecholamines, mainly epinephrine.

Catecholamines have many
effects that allow rapid adaptations to changes in the environment.

Answer 6

chromaffin cells,

Question 7

glucocorticoids (principally
cortisol), which are synthesized primarily in the __________ and to a lesser degree in the
____________

Answer 7

zona fasciculata

zona reticularis;

So remember both in fasciulata and reticularis synthesized ang Glucocorticoids( Cortisol)

Question 8

mineralocorticoids, the most important being aldosterone, which is
generated in the_______________;

Answer 8

zona glomerulosa

Question 9

sex steroids (estrogens and androgens), which are
produced largely in the ____________

Answer 9

zona reticularis

Question 10

Diseases of the adrenal cortex can be conveniently divided into those associated with
_____________and those associated with _____________

Answer 10

hyperfunction

hypofunction.

Question 11

ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM)
Just as there are three basic types of corticosteroids elaborated by the adrenal cortex, so there
are three distinctive hyperadrenal syndromes:

Answer 11

(1) Cushing syndrome, characterized by an
excess of cortisol;

(2) hyperaldosteronism; and

(3) adrenogenital or virilizing syndromes caused
by an excess of androgens.

The clinical features of these syndromes overlap somewhat
because of the overlapping functions of some of the adrenal steroids

Question 12

Hypercortisolism (Cushing Syndrome)
Pathogenesis.
This disorder is

Answer 12

• caused by any condition that produces elevated glucocorticoid levels.

Question 13

Cushing syndrome can be broadly divided into ____________ and ____________

Answer 13

exogenous and endogenous causes.

Question 14

The vast majority of
cases of Cushing syndrome are the_____________. [66]

Answer 14

result of the administration of exogenous glucocorticoids
(“iatrogenic” Cushing syndrome

Question 15

The endogenous causes can, in turn, be divided into
those that are _____and _____ ( Table 24-8 ).

Answer 15

ACTH dependent and those that are ACTH independent

Question 16

Endogenous Causes of Cushing Syndrome

ACTH-DEPENDENT

Answer 16

1. Cushing disease (pituitary adenoma; rarely CRH-dependent pituitary hyperplasia)
2. Ectopic corticotropin syndrome (ACTH-secreting pulmonary smallcell
   carcinoma, bronchial carcinoid)

Question 17

Endogenous Causes of Cushing Syndrome

ACTH-INDEPENDENT

Answer 17

1. Adrenal adenoma
2. Adrenal carcinoma
3. Macronodular hyperplasia (ectopic expression of hormone
   receptors, including GIPR, LHR, vasopressin and serotonin
   receptors)
4. Primary pigmented nodular adrenal disease (PRKARIA and PDE11
   mutations)
5. McCune-Albright syndrome (GNAS mutations)

Question 18

ACTH, adrenocorticotropic hormone; GIPR, gastric inhibitory polypeptide receptor; LHR,
luteinizing hormone receptor; PRKAR1A, protein kinase A regulatory subunit 1α; PDE11,
phosphodiesterase 11A.
Note: These etiologies are responsible for endogenous Cushing syndrome. The most common
overall cause of Cushing syndrome is exogenous glucocorticoid administration (iatrogenic
Cushing syndrome).

Question 19

_____________ account for approximately 70% of cases of endogenous
hypercortisolism.

In recognition of Harvey Cushing, the neurosurgeon who first published the
full description of this syndrome, the pituitary form is referred to as Cushing disease. [67]

The disorder affects women about four times more frequently than men and occurs most frequently
in young adults

In the vast majority of cases it is **caused by an ACTH-producing pituitary **microadenoma; some corticotroph tumors qualify as macroadenomas (>10 mm).

Rarely, the anterior pituitary contains areas of corticotroph cell hyperplasia without a discrete adenoma.
Corticotroph cell hyperplasia may be primary or arise secondarily from excessive stimulation of
ACTH release by a hypothalamic corticotrophin-releasing hormone (CRH)–producing tumor.

Answer 19

ACTH-secreting pituitary adenomas

Question 20

The adrenal glands in individuals with Cushing disease are characterized by** _____________** (discussed later), caused by the elevated levels of ACTH. The
cortical hyperplasia, in turn, is responsible for hypercortisolism.

Answer 20

variable degrees
of nodular cortical hyperplasia

Question 21

_____________ by nonpituitary tumors accounts for about 10% of ACTH-dependent
Cushing syndrome.

In many instances the responsible tumor is a small-cell carcinoma of the
lung,althoughother neoplasms, including carcinoids, medullary carcinomas of the thyroid, and
islet cell tumors, have been associated with the syndrome.

Answer 21

Secretion of ectopic ACTH

Question 22

In addition to tumors that elaborate
ectopic ACTH, an occasional neuroendocrine neoplasm produces ectopic CRH, which, in turn,
causes ACTH secretion and hypercortisolism.

Question 23

As in the pituitary variant, the adrenal glands
undergo bilateral cortical hyperplasia, but the rapid downhill course of patients with these
cancers often cuts short the adrenal enlargement.

This variant of Cushing syndrome is more
common in men and usually occurs in the 40s and 50s.

Question 24

___________________** **are the
most common underlying causes for ACTH-independent Cushing syndrome.

The biochemical
sine qua non of ACTH-independent Cushing syndrome is elevated serum levels of cortisol with
low levels of ACTH.

Answer 24

Primary adrenal neoplasms , such as:

1. **adrenal adenoma (∼10%) **
2. and carcinoma (∼5%)

Question 25

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_** tend to **produce more marked hypercortisolism** than adenomas or hyperplasias. In instances of a unilateral neoplasm, the uninvolved adrenal cortex and the cortex in the opposite gland undergo atrophy because of suppression of ACTH secretion.

Answer 25

Cortical carcinomas

Question 26

The **overwhelming majority of hyperplastic adrenals** are \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ is uncommon.

Answer 26

ACTH dependent, and primary cortical hyperplasia (i.e., ACTH-independent hyperplasia)

Question 27

In\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_-- the **nodules are usually greater than 3 mm** in diameter. It is typically a **sporadic (nonsyndromic) condition observed in adults.** It is now known that, although the condition is ACTH independent, it is not entirely “**autonomous.**”

Answer 27

macronodular hyperplasia

Question 28

Specifically, cortisol production is regulated by **non-ACTH circulating hormones**, as a result of **ectopic overexpression of their corresponding receptors** in the adrenocortical cells. For example, overexpression of the receptors for gastric inhibitory peptide, LH, ADH, and serotonin are often found within the hyperplastic tissues. [68] The mechanism by which these receptors for non-ACTH hormones are overexpressed in adrenocortical tissues is, however, not known. A subset of macronodular hyperplasia arises in the setting of **McCune-Albright syndrome**, characterized by germline activating mutations in GNAS, which encodes a stimulatory Gsα ( Chapter 26 ). In addition, primary cortical hyperplasias may result from mutations in other genes that control intracellular levels of cAMP. These include the **PRKR1A gene** (see below) and the **phosphodiesterase 11A** **(PDE11A) gene.**

Question 29

The main lesions of Cushing syndrome are found in the __________ and \_\_\_\_\_\_\_\_\_\_

Answer 29

pituitary and adrenal glands.

Question 30

The pituitary shows changes regardless of the cause. The **most common alteratio**n, **resulting from high levels** of **endogenous or exogenous glucocorticoids,** is termed \_\_\_\_\_\_\_\_\_\_\_\_\_ In this condition the **normal granular, basophilic cytoplasm of the ACTHproducing cells in the anterior pituitary becomes homogeneous and paler.**

Answer 30

Crooke hyaline change.

Question 31

The pituitary shows changes regardless of the cause. The most common alteration, resulting from high levels of endogenous or exogenous glucocorticoids, is termed crooke syndrome. In this condition the** normal granular, basophilic cytoplasm of the ACTHproducing cells** in the anterior pituitary becomes homogeneous and paler. **This alteration is **the result of the \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 31

accumulation of intermediate keratin filaments in the cytoplasm.

Question 32

Depending on the **cause of the hypercortisolism** the adrenals have one of the following abnormalities:

Answer 32

(1) cortical atrophy, (2) diffuse hyperplasia, (3) macronodular or micronodular hyperplasia, and (4) an adenoma or carcinoma. In patients in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of the zonae fasciculata and reticularis by ACTH.

Question 33

The **zona glomerulosa** is of **normal thickness** in such cases, because **this portion of the cortex \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.** In contrast, in cases of endogenous hypercortisolism, the **adrenals either are hyperplastic or contain a cortical neoplasm.**

Answer 33

**functions** **independently of ACTH.** **"Remember: Accdg to Doc Domingo, Zona Glomerulosa is not stimulated by ACTH ( the only exception)**

Question 34

**\_\_\_\_\_\_\_\_\_\_\_ hyperplasia**is found in individuals with**ACTH-dependent Cushing syndrome**

Answer 34

**Diffuse**

Question 35

Both glands are enlarged, either subtly or markedly, weighing **up to 30 gm**. The **adrenal cortex**is**diffusely thickened**and**variably nodular**, although the**latter is not as pronounced as seen in cases of ACTH-independent nodular hyperplasia.**

Question 36

​Microscopically, the hyperplastic cortex demonstrates an expanded\_\_\_\_\_\_\_\_\_\_\_\_\_ **zona reticularis**, **comprising compact, eosinophilic cell**s, surrounded by an**outer zone of vacuolated “lipid-rich**” cells, resembling **those seen in the zona fasciculata**. **Any nodules present** are usually composed o**f vacuolated “lipid-rich” cell**s, which**accounts for the yellow color of diffusely hyperplastic glands**.

Answer 36

“lipid-poor”

Question 37

In contrast, in **macronodular hyperplas**i**a** the adrenals are **almost entirely replaced by** **prominent nodules of varying sizes (≤3 cm)**, which contain an \_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 37

admixture of lipid-poor and lipidrich cells.

Question 38

Unlike diffuse hyperplasia, the areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity. Micronodular hyperplasia is composed of 1- to 3-mm **darkly pigmented (brown to black) micronodules**, with **atrophic intervening areas** ( Fig. 24-42 ). The pigment is believed to be\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 38

lipofuscin, a wear-and-tear pigment

Question 39

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_causing Cushing syndrome **may be malignant or benign**.

Answer 39

Primary adrenocortical neoplasms

Question 40

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_as the source of cortisol are **not morphologically distinct from nonfunctioning adrenal neoplasms** (described later). **Both the benign and the malignant lesions are more common in women in their 30s to 50s.**

Answer 40

Functional adenomas or carcinomas of the adrenal cortex

Question 41

**\_\_\_\_\_\_\_\_\_\_\_\_\_ **are **yellow tumors** surrounded by **thin or well-developed capsules,** and most weigh less than 30 gm. Microscopically, they are composed of **cells that are similar to those encountered in the normal zona fasciculata**.

Answer 41

**Adrenocortical adenomas**

Question 42

The carcinomas associated with Cushing syndrome, by contrast, tend to be **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ than the adenomas.** These tumors are * *unencapsulated masses** frequently **exceeding 200 to 300 gm** in weight, having all of the * *anaplastic characteristics of cancer**, as will be detailed later.

Answer 42

**larger**

Question 43

With functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of the contralateral adrenal gland are **atrophic**, as a result of **suppression of endogenous ACTH by high cortisol levels.**

Question 44

Clinical Course. Developing slowly over time, Cushing syndrome can be quite **subtle in its early manifestations.**

Question 45

What is the early manifestation in Cushing's syndrome?

Answer 45

Early stages of the disorder may present with **hypertension and weight gain** ( Table 24-9 ).

Question 46

In Cushing's Disease with time the **more characteristic central pattern** of **adipose tissu**e deposition becomes apparent in the form of\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 46

* truncal obesity, * moon facies, * and accumulation of fat in the posterior neck and back** (buffalo hump).**

Question 47

Hypercortisolism causes **selective atrophy** of\_\_\_\_\_\_\_\_\_\_\_\_\_ resulting in **decreased muscle mass** and proximal limb weakness.

Answer 47

fast-twitch (type 2) myofibers,

Question 48

Explain the pathophysio of the clinical presentation in HYPERCORTICOLISM.

Answer 48

Glucocorticoids **induce** * *gluconeogenesis** and **inhibit the uptake of glucose by cells,** with **resultant hyperglycemia,** * *glucosuria** and** polydipsia (secondary diabetes)**. The **catabolic effects cause loss of collagen and resorption of bones.** Consequently the **skin is thin**,** fragile, and easily bruised ; wound** **healing is poor**; and **cutaneous striae are particularly common in the abdominal area** **Bone resorption** results in the **development of osteoporosis,** with **consequent backache** and **increased susceptibility to fractures**. Persons with Cushing syndrome are at **increased risk for a variety of infections**, because**glucocorticoids suppress the immune response.** Additional manifestations include **several mental disturbances,** including **mood swings**, **depression**, and **frank psychosis**, as well as **hirsutism and menstrual abnormalities.**

Question 49

Clinical Features of Cushing Syndrome

Answer 49

Obesity or weight gain 95%[\*] Facial plethora 90% Rounded face 90% Decreased libido 90% Thin skin 85% Decrease in linear growth in children 70–80% Menstrual irregularity 80% Hypertension 75% Hirsutism 75% Depression/emotional liability 70% Easy bruising 65% Glucose intolerance 60% Weakness 60% Osteopenia or fracture 50% Nephrolithiasis 50%

Question 50

Cushing syndrome is diagnosed in the laboratory with the following:

Answer 50

(1) the **24-hour urine freecortisol** concentration, which is increased, and (2) **loss of normal diurnal pattern of cortisol** secretion. Determining the cause of Cushing syndrome depends on the serum ACTH and measurement of urinary steroid excretion after administration of dexamethasone **(dexamethasone suppression test).**

Question 51

Cushing syndrome is diagnosed in the laboratory with the following: ## Footnote (1) the 24-hour urine freecortisol concentration, which is increased, and (2) loss of normal diurnal pattern of cortisol secretion. Determining the cause of Cushing syndrome depends on the serum ACTH and measurement of urinary steroid excretion after administration of dexamethasone (dexamethasone suppression test). The results of these tests **fall into three general patterns:**

Answer 51

**1**. In pituitary Cushing syndrome, the **most common form, ACTH levels are elevated** and cannot be **suppressed by the administration of a low dos**e of **dexamethasone**. Hence, there is no reduction in urinary excretion of 17-hydroxycorticosteroids. After higher doses of injected dexamethasone, however, the pituitary responds by reducing ACTH secretion, which is reflected by suppression of urinary steroid secretion. **2**. **Ectopic ACTH secretion** results in an **elevated level of ACTH,** but its secretion is completely insensitive to low or high doses of exogenous dexamethasone. **3.** When Cushing syndrome is caused by an **adrenal tumor**, the ACTH level is quite low because of feedback inhibition of the pituitary. As with ectopic ACTH secretion, both low-dose and high-dose dexamethasone fail to suppress cortisol excretion.