Addisons as an underlying primary disorder

[Cryptochid]

Does anyone have experience with Addisons? with hypogonadism being secondary. Any thoughts? Maybe easier to read through the hyperlink

http://www.pathology.vcu.edu/educati...enal/Index.htmADRENAL PATHOLOGY LECTURE
Adrenal Overview and Pathologies | Adrenal Medulla & Paraganglia

Anatomy and Physiology

The adrenal gland weighs approximately 4-5gm. It has two components:

Cortex--Secretes steroids (mesoderm of argental ridge)
Outer-most zona glomerulosa
Intermediate fasciculata--10-15% of cortex
Innermost Reticularis (clear cells)--80% of cortex
Dark compact cells--10% of cortex
Medulla--secretes neuropeptides (Neural crest)
Images of Adrenal Gland

Normal gland gross image--This figure shows a section from a freshly obtained adrenal gland. Notice that the endocrine portion is reddish brown in color, whereas the surrounding fat is yellow.

Normal adrenal Gross from glass slide--very low power

Microscopic Image--notice the reticularis and glomerulosa layers. The fasciculata would be the zone in between these two layers.

Adrenal Cortex
Glomerulosa synthesizes mineralocorticoids (aldosterone)
Fasciculata and reticularis are a functional unit that secrete glucocorticoids and sex steroids
Main glucocorticoid is cortisol
Main androgen is testosterone
ACTH is a 39 amino acid peptide that controls secretion of glucocorticoids and sex steroids
It derives from a longer peptide termed proopiomelanocortin (POMC)
In ACTH, hypersecretion hyperplasia of fasciculata and reticularis are seen
Bronchogenic carcinomas and other neoplasms may secrete ACTH-like substances
Corticotropic releasing factor (CRF), synthesized in the hypothalamus, induces secretion of ACTH by Anterior Pituitary
Pituitary-Adrenal Axis

Adrenal steroid hormone secretion is regulated by adrenocorticotrohic hormone (ACTH) which is a 39-amino acid peptide
Hypothalamic corticotropin-releasing hormone (CRH) is a 41-amino acid peptide that stimulates corticotroph secretion of ACTH in a pulsatile manner
CRH secretion is regulated by the CNS input with a 24-hour cycle
This results in a circadian rhythm in plasma cortisol levels.
Cortisol is the major glucocorticoid produced by the adrenal cortex
Physiologic concentrations are necessary for the normal function of all cells in the body
The basal secretory rate is 10 to 30 mg per day, but may increase 10-fold during physical stress
These hormone levels are highest in the early morning hours
The negative feedback control by cortisol appears to be at both hypothalamic and pituitary levels
Mineralocorticoids are controlled by potassium and angiotensin levels
A newly described 26KD glycoprotein has been found in the pituitary and serum that also controls electrolytes
Clinical considerations

Many clinical symptoms of adrenal pathology result from abnormalities of adrenal steroids.

Cortisol

Increases protein breakdown, nitrogen excretion, hepatic gluconeogenesis, extracellular fluid, appetite, fat deposition in the upper body, chance of infection
Decreases Leukocyte adhesion and diapedesis, inflammation, bacterial lysis in leukocytes, numbers of T-cells, and inhibits migration of water into cells
Aldosterone
Major regulator of extracellular fluid
Major regulator of potassium metabolism
Excess aldosterone results in sodium retention, loss of potassium, expansion of extracellular fluid compartment, and hypertension
Decreased aldosterone results in contraction of extracellular fluid and potassium retention
Testosterone
Accentuates male characteristics and suppresses female characteristics

Pathology of the Adrenal
There are four major types of adrenal pathologies

Disorders that decrease output of steroids
Adrenal Hypoplasia
Anencephalic type--may have adrenal agenesis
Cytomegalic type--not from cytomegalovirus. Large eosinophilic cells, may be X-linked
Disorders that increase output of steroids
Hyperplasia or neoplasia
Developmental anomalies--Adrenocortical Hyperplasias are the most significant since all cause steroid secretion abnormalities, inducing Adrenogenital Syndromes
Ectopic adrenal--accessory adrenal (cortex) can be found from diaphragm to pelvis in the retroperitoneum (Medulla can also be found if near celiac ganglion).
May be seen in hernial sacs (Marchand rests)
These may give origin to neoplasms or undergo hyperplasia
Lesions with no hormonal function defect
Inflammation or infection
Images of Adrenal Rest

Low power adrenal rest

High power adrenal rest--Notice that the tissue is identical to normal adrenal. This adrenal rest was found incidentally in a hernia sac.

Clinical Workup in Hypofunction of Adrenal

If cortisol levels at 0800 hrs are <10mcg/dL and the 24hr urinary free cortisol is < 50 mcg then the following stimulation tests are warranted:
Cosyntropin stimulation test
Metyrapone stimulation test
Insulin induced hypoglycemia (a subnormal level of glucocorticoid response reveals hypothalamic-pituitary deficiency)Skin pigmentation, high ACTH and low response to cosyntropin reveals a primary adrenal failure
ACTH levels
Primary features

Loss of Cortex--autoimmune, bacterial, hemorrhage, amyloidosis, sarcoidosis, Hemochromatosis, metastatic disease, surgical ablation.
Metabolic Failure--Congenital adrenal hyperplasia, drug induced inhibition of adrenocortical function
Secondary features

Hypothalamic/pituitary diseaseNeoplasm, infection
Hypothalamic/pituitary suppression--long term steroid administration
Addison's Disease

Primary: due to adrenal insufficiency. Should be suspected when there is marked skin pigmentation due to high ACTH levels.
Secondary: Pituitary or hypothalamic Insufficiency (no skin pigmentation).
Addison's disease is rare.

Causes of Primary Addison's
Autoimmune--most cases of Additions show anti-adrenal Antibodies 60-75%
Two types exist
Type I Addison's--defect in suppressor cells--hypoparathyroidism, mucocutaneous candidiasis
Type II Schmidt's syndrome Addison's--autoimmune thyroid disease--insulin dependent diabetes, no Candidiasis or PTH deficiency. Associated with HLA-A1 and HLA-B8 haplotype.
TB--25% of cases
Other causes--Histoplasmosis, amyloid, sarcoid, mets
Clinical

Insidious, progressive weakness, fatigue, anorexia, nausea & vomiting, weight loss, hypotension, hyperpigmentation in skin and oral mucosa due to >ACTH and POMC precursor.

Pathology
There may be a lymphocytic infiltrate or a "burned out" fibrotic appearance. Medulla is untouched. In TB and other diseases, evidence for these is usually apparent.

Lab
Sodium, chloride, bicarbonate, glucose, cortisol, and 17-keto and 17-hydrocorticoids fall late in the disease. Potassium increases due to aldosterone deficiency.

Primary Acute Adrenal Insufficiency
Precipitated by stress in a patient with Addison's Precipitated by withdrawal of steroids in an adrenalectomized patient
In patients with acute bilateral hemorrhagic necrosis of adrenals
Acute Hemorrhagic Necrosis of Adrenals

Waterhouse-Friderichsen syndrome. In adults usually due to bacteremia. Newborns due to perinatal trauma.
Bacterial often due to meningococcemia, less commonly Staph, pneumococcus, or Haemophilus.

Clinical
DIC (disseminated intravascular coagulation) with multiple petechiae, diffuse hemorrhages in various tissues. Shock often occurs. Death may occur in 24 hrs. Shock in these cases is a combination of toxemia and decrease or loss of steroids.

Pathology
Hemorrhagic necrosis, some islands of tissue spared. Hemorrhage starts in reticularis.

Secondary Adrenocortical Insufficiency
Any pathologic condition that results in decreased ACTH--metastatic disease, autoimmunity, infection, chronic use of glucocorticoids

Clinical
No skin pigmentation, symptoms related to decreased cortisol and sex steroidsAldosterone normalACTH levels are diagnosticACTH therapy corrects the deficiency
Adrenals may be very small
Hyperadrenal Syndromes

Cushing's Aldosteronism Conn's Syndrome
Adrenogenital Syndrome
Cushing's Syndrome (Adrenal or Steroid Therapy)
Clinical pathology

A 24 hr urinary free cortisol levels assay is very good screening testA normal level makes Cushing’s unlikelyObtain at least two ACTH baseline levelsHypercortisolism with very low levels of ACTH are consistent with adrenal-dependent Cushing’s. Hypercortisolism and moderately high ACTH levels suggest pituitary-dependent Cushing’sHypercortisolism and very high ACTH levels suggest ectopic-dependent (tumor i.e., lung Ca) Cushing’s
Early diagnosis essential before cardiovascular changes are irreversible
Features
HypertensionGlucose intolerancediabetes--20% of casesCentripetal obesity--moon facies, buffalo hump, abdominal striaeIn men, oss of libido, impotence, oligospermia
In women, hirsutism, amenorrhea, osteoporosis
Types

Pituitary (ACTH-dependent Cushing’s)
Diffuse cortical hyperplasia with or without nodularity60% of cases of Cushing's are due to Cushing's DiseaseMost secondary to pituitary adenoma, some are hypothalamic in origin (these cases are associated with high ACTH
Dexamethasone therapy induces a drop of cortisol and urinary 17-ketosteroids (diagnostic)
Adrenal neoplasm:
Adenoma and carcinoma (carcinoma more frequent in children) Cushing's Disease--20-25% of casesFunctioning neoplasm, usually adenoma in adultsCancer results in severe Cushing'sContralateral gland atrophic due to ACTH
ACTH low, dexamethasone resistant
Ectopic production of ACTH or CRH
Diffuse cortical hyperplasia10-15% casesbronchogenic cancer in 60% of non endocrine tumorsThymoma 15%Pancreatic cancer 10%Adrenals undergo hyperplasia
Cortisol excretion not blocked by steroids
Diffuse cortical hyperplasia with or without nodularity. Microadenomatous dysplasia (small pigmented nodules)
Iatrogenic--bilateral adrenal atrophy may be present
Pathology of Cushing's
Pituitary
Crooke's hyalin degeneration of basophilic cells in anterior pituitaryhyalin composed of intermediate filaments
Pituitary Cushing's--adenoma composed of corticotrophs
In adrenals
Bilateral hyperplasia, cortex widened at expense of lipid-poor reticularisAdrenal cortical neoplasm Nodular hyperplasia- more often seen in pituitary type of Cushing's If iatrogenic, atrophy
Diagnosis of carcinoma may be difficult; some characteristics are
Large tumors with necrosis and fibrous bands
nuclear anaplasia and mitoses
Cushing's SyndromeUsually due to adrenal adenoma. Female to male ratio 3:1.Images of Cortical Adenoma

Gross Image of Cortical Adenoma--cross section of an adrenal adenoma in a fresh state Low Power Microscopic Image--cortical adenoma at 1X magnification

High Power Microscopic Image--cortical adenoma at 10X magnification

Nelsons Syndrome
Corticotropic pituitary adenomas that have been adrenalectomized due to refractory pituitary lesions,. Patients have intense pigmentation due to >ACTH.

Primary Hyperaldosteronism (Low Renin)
Termed Conn's syndrome. Elevated aldosterone with resulting neuromuscular symptoms, renal sodium retention and potassium wasting (hypokalemia and hypokalemic alkalosis) in patients with a cortical adenoma.

Main causes
Adreno-cortical adenomas--50-90% of cases2cm in diameter, bright yellow, nonencapsulatedLipid-layden clear cells and compact cellsHyperplasia of zona glomerulosa (congenital hyperaldosteronism)Rare cases are suppressed by corticosteroids
Carcinomas very rarely causative
Clinical

In the absence of complicating Heart Failure, edema is usually not present in these cases.

Secondary Hyperaldosteronism
Secretion of aldosterone as a response to increased levels of renin-angiotensin.

Causes
Renal ischemia (renal artery stenosis and malignant nephrosclerosis) Any edematous state ( i.e. Nephrotic syndrome) Barter's syndrome: juxtaglomerular-cell hyperplasia
Renin producing neoplasms.
Adrenal Virilism and Congenital Adrenal Hyperplasia
Adrenal virilism is readily recognizable in females, not in males until advanced.

Causes
Androgen secreting adenoma, usually larger than those associated with Cushing's syndrome and are frequently very hyperpigmented. More often associated with masculinization than feminization. Carcinoma: Rare.
Associated with a congenital metabolic error. Depending on the site in the metabolic pathway that is altered:
Pure virilization Salt wasting
Mixed
The most common is due to a 21- hydroxylase deficiency- clitoral enlargement fused labio-scrotal folds (internal reproductive organs appear normal). In males it manifests as cryptorchidism and hypospadias. 65% have aldosterone abnormalities (salt wasting -low sodium and hyperkalemia).Requires treatment or death may ensue 2 weeks after birth.

Mixed type may result in early virilization and 21-hydroxylase deficiency (3% of European Jews)

HLA associations
HLA Bw 60 -salt wasting type HLA Bw 51 -virilization HLA Bw 14,DR1- Mixed
Next most common is an 11-Hydroxylase deficiency:
Not HLA associated
More common in Moroccan Jews11-deoxycortisol is not converted to cortisol,accumulated precursors are converted into androgensIn addition deoxycorticosterone is not converted into corticosterone causing hypertension and hypokalemiaIn 17-hydroxylase deficiency there is a diminished secretion of glucocorticoids and sex steroidsThe precursors are therefore converted into aldosterone causing aldosteronismThe deficiency in androgens leads to pseudohermaphroditism in these cases
Untreated females have sexual infantilism
Pathology
Adrenals are very enlarged and have a cerebriform aspect. Microscopically they exhibit nodular hyperplasia. In desmolase deficiency (crucial for testosterone synthesis), there is extensive cell vacuolization, as well as cholesterol clefts and giant cells.

Most of these syndromes respond to corticosteroid replacement therapy, but the genital malformations must be corrected surgically.

Non-functional cortical neoplasms
Non-functioning adenomas are found in up to 2% of adult autopsies. Bronchogenic carcinomas often metastasize to adrenal. Some adrenal non-steroid secreting primary carcinomas may grow to large masses. Metastasis are via adrenal vein, to lung and other viscera, rarely to bone.Other lesions

Cysts, some of which are parasitic. Adrenal myelolipoma (fat and hemopoietic cells).

Adrenocortical Carcinoma
Adrenocortical carcinoma is rare (about 2 per million population). Functionally active tumors may be as frequent as 96% of cases and is usually a combined endocrine malfunction that includes virilism and Cushing's syndrome. These tumors tend to be large (>12cm) in diameter. Malignancy is diagnosed when mytoses are >5/high-power field (hpf) or if there is vascular invasion. These lesions are also composed of very pleomorphic cells but this criterion cannot alone support the diagnosis of malignancy. The following images 5-7a show a case of adrenal-cortical cancer.Images of Adrenal Cortical Carcinoma

Cat Scan--this computerized tomography shows the large adrenal tumor labeled AT
Gross Image--notice the variegated appearance of the cut surface with areas of hemorrhage

Microscopic, low power--notice that the tumor emulates the normal adrenal trabecular pattern
Microscopic Higher power

Digital Legends for Labs
Lab 1 Images
1-3 | 4-5 | 7-9 | 10-11 | 12-13 | 14-17 | 18-19 | 20-22
Lab 2 Images
1-4 | 5-6 | 7-8 | 9-11 | 12-14 | 15-16 | 17-18 | 19-20

Home

Medical II

[love_en]

When I saw the doctor earlier this year, I actually suspected Addison's disease due to the fatigue and weakness. Thanks to this board, I also asked to have my testosterone level checked. If you remember the post with my bloodwork results, my cortisol ended up at the top of the reference range and the ACTH stimulation test came back negative. That was a relief for me. Because hypogonadism will make you wish for death, Addison's disease can kill you.

I have heard of people who have suffered physical damage to the pituitary developing multiple hormonal deficiencies. The scary part is the pituitary is easily damaged by a hard bump to the head.

[Cryptochid]

Originally Posted by love_en

When I saw the doctor earlier this year, I actually suspected Addison's disease due to the fatigue and weakness. Thanks to this board, I also asked to have my testosterone level checked. If you remember the post with my bloodwork results, my cortisol ended up at the top of the reference range and the ACTH stimulation test came back negative. That was a relief for me. Because hypogonadism will make you wish for death, Addison's disease can kill you.

I have heard of people who have suffered physical damage to the pituitary developing multiple hormonal deficiencies. The scary part is the pituitary is easily damaged by a hard bump to the head.

Thx Love_en

Just doing tat research has promted me to further investigate a ACTH test as it doesnt appear conclusive in plasma.

To much history with signs and symptoms, including hypoglyceamia, hyperpigmentation and hospitalization requiring saline administration

[love_en]

Hypoglycemia, pigmentation and dehydration are all signs of adrenal insufficiency. For you, an ACTH test is definitely indicated. Also, you mentioned IBS, the symptoms of that closely resemble adrenal insufficiency. A plasma cortisol test by itself does not indicate much. From what I understand, your cortisol levels should more than double 1 hour after injection of ACTH. So if your base reading is say 15, your post injection should be 30+. I still doubt my test as well, because following that guideline, my post injection cortisol should have been 50+.

I always had orthostatic hypotension, or loss of blood pressure upon standing. However, the testosterone is helpng that . After all, it does induce retention of water and salt. I am curious to see my morning cortisol levels now that I am on testosterone. Hypogonadism can cause the adrenals to increase output to compensate for the lack of androgens. But high cortisol levels can suppress testosterone production. It is a case of chicken or egg coming first. I do not care, because for the first time, I am feeling well.

[dano79]

I find this very interesting. I was diagnosed with an adrenal insuficency six years ago. I had not energy and was always feeling sick. Bloodwork showed abnormal levels of ACTH and medical scans of my adrenal glands showed that they had shrunk.

I was put on low doses of prednisone for over a year. My adrenal levels returned to normal, and the gland returned to normal size.

After the treatment (about a year) I noticed my testicles had began to atropy and sufferd from loss of libido, energy, etc. I have always wondered if these two things were related. My adrenal functions are still normal today. Maybe fixing one system, broke another.

[frankwhardy]

Hi Dano,

At the time of your diagnosis, by "abnormal levels of ACTH" do you mean that your ACTH level was too high? If so, did you see any areas of hyperpigmentation, like your face being too red, for example? And how was your cortisol level? I'm working with an endocrinologist right now to see if adrenal insufficiency might be part of my problem. Thanks,
Frank

[love_en]

The pigmentation caused by high ACTH looks like a dark tan. This appears even in areas not exposed to sun. Corticosteroids such as prednisone can cause the pituitary to shut down. If you were on the usual 4-5mg dose of prednisone, I do not think that would be enough to suppress LH and FSH. Your low T might just be coincidence. Or a pituitary that is malfuctioning.

[1cc]

Originally Posted by love_en

I always had orthostatic hypotension, or loss of blood pressure upon standing. However, the testosterone is helpng that . After all, it does induce retention of water and salt.

I also have Adrenal problems and I never drink water without mixing in 1/2 teaspoon salt. After drinking salted water in the morning (or any other time), I feel a major energy boost. A lot of the symptoms of Adrenal Insufficiency are caused more by the lack of salt and dehydration than the low cortisol.

[stat1951]

Originally Posted by dano79

I find this very interesting. I was diagnosed with an adrenal insuficency six years ago. I had not energy and was always feeling sick. Bloodwork showed abnormal levels of ACTH and medical scans of my adrenal glands showed that they had shrunk.

I was put on low doses of prednisone for over a year. My adrenal levels returned to normal, and the gland returned to normal size.

After the treatment (about a year) I noticed my testicles had began to atropy and sufferd from loss of libido, energy, etc. I have always wondered if these two things were related. My adrenal functions are still normal today. Maybe fixing one system, broke another.

Hypercortisolism - whether from your own internal overproduction or via excessive / prolonged external administration can very definitely cause a state of hypogonadism (as I know only way too well). I can post a number of links if you;d like me to look them up, but here's one specific one from Cleveland Clinic (one of their top Endocrinologists):

http://www.clevelandclinicmeded.com/...pogonadism.htm

Conditions Associated with Causing Male Hypogonadism

* Aging
* Chronic illness
o Diabetes
o Acquired immunodeficiency syndrome (AIDS)
o Chronic renal failure
o Rheumatoid arthritis
* Cancer cachexia
* Corticosteroid use

Of course that latter item refers to cortisol in the body and would refer to either the use of artificial cortisol prednisone, etc.) or excess production of cortisol by the body itself.

Additional, Doctor C makes mention of elevated cortisol level causing hypogonadism in one of hor protocol papers (if my memory serves me right).

So..... ya' never know. Fixing one system may have very well led to the malfunction of another system!

Larry

[love_en]

If that were so, there would never be a need for fludrocortisone in cases of Addison's. Salt loading simply masks the true issue of mineralcorticoid deficiency. I suspect many of my health problems had some connection to my T deficiency. Orthostatic hypotension is no longer a problem with adequate levels of T.