hemochromatosis vs high ACTH

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A 43 y/o male presents with fatiguability, dry mouth, and impotence. Physical exam reveals mild hepatosplenomegaly and atrophic testes. His fasting blood glucose is 252 mg/dL. His urine is positive for glucose but negative for ketones and protein. He also says he developed a "strange tan" despite spending almost all his time indoors. What's wrong with him?

How do we know that this is a presentation of hemochromatosis and not high ACTH? I feel like high ACTH would explain for his atrophic testes, his blood glucose, as well as his skin discoloration.

The only organ that responds to ACTH is the adrenal cortex (specifically the fasiculata and reticulata). Hyperpigmentation is due to alpha-MSH production from POMC. None of the products of POMC act on the testis. None of the products of POMC act on the liver. High cortisol can induce insulin resistance and hyperglycemia.

Hemochromatosis can explain the skin, liver, gonad, and endocrine findings. Cushing disease or ectopic ACTH can only explain the skin and endocrine findings.

So high ACTH will increase production of the androgens --> estrogens by peripheral conversion and that would cause reduced libido/impotence/gynecomastia but would NOT cause testicular atrophy. Is that correct?

What is the mechanism by which hemochromatosis would cause testicular atrophy?

Originally Posted by johndoe3344

A 43 y/o male presents with fatiguability, dry mouth, and impotence. Physical exam reveals mild hepatosplenomegaly and atrophic testes. His fasting blood glucose is 252 mg/dL. His urine is positive for glucose but negative for ketones and protein. He also says he developed a "strange tan" despite spending almost all his time indoors. What's wrong with him?

How do we know that this is a presentation of hemochromatosis and not high ACTH? I feel like high ACTH would explain for his atrophic testes, his blood glucose, as well as his skin discoloration.

High ACTH due to adrenal insufficiency would not cause hyperglycemia or hepstosplenomegaly with atrophic testes.
High ACTH due to its hyperproduction in pituitary or ectopically would cause features of Cushing symptoms: weight gain, specific fat distribution, strii, hypertension.
I remember that atrophic testes are one of the remarkable features of hemochromatosis due to iron deposition there, as well as in skin (tan), liver, spleen (hepatosplenomegaly), pancreas (hyperglycemia, malabsorption)

Iron can produce free radicals that means damage and fibrosis

Originally Posted by johndoe3344

So high ACTH will increase production of the androgens --> estrogens by peripheral conversion and that would cause reduced libido/impotence/gynecomastia but would NOT cause testicular atrophy. Is that correct?

Hmm, I think I was wrong. I can see that working. Maybe not via aromatization to estrogen, but excess testosterone production from adrenal DHEA/androsteindione in the testicles could feedback on the hypothalamus and decrease LH/FSH leading to atrophy. However you still wouldn't have hepatosplenomegaly in Cuhsing's disease.

What is the mechanism by which hemochromatosis would cause testicular atrophy?

I think it's the same mechanism as with the hyperpigmentation, restrictive cardiomyopathy, and diabetes mellitus. The iron deposits in the testicular tissue. Excess free radicals production results in fibrosis.

Originally Posted by ijn

Hmm, I think I was wrong. I can see that working. Maybe not via aromatization to estrogen, but excess testosterone production from adrenal DHEA/androsteindione in the testicles could feedback on the hypothalamus and decrease LH/FSH leading to atrophy. However you still wouldn't have hepatosplenomegaly in Cuhsing's disease.

The thing is, though, on medscape and wikipedia and other random google sites I looked at, none of them lists testicular atrophy as a symptom. The other things, yes, but not atrophy. Not sure why...

Because this mechanism seems to be similar to the mechanism by which exogenous steroids would lead to testicular atrophy.

Correct me if i'm wrong, I always thought that androgens excess from adrenals would cause testosteron conversion more to DHT than to estrogens, that's why in adrenogenital syndrome girls may have ambiguos genitalia. Though I found that due to androgen excess some part of it can be converted to estrogens and cause precocious puberty and dysmenorrhea in girls, it still seems to me that adrenals are not so great source of estrogens in men.
Testosterone excess has negative feedback only on LH and GnRH, FSH is under inhibin and estradiol control.

Originally Posted by Convalaria

Correct me if i'm wrong, I always thought that androgens excess from adrenals would cause testosteron conversion more to DHT than to estrogens, that's why in adrenogenital syndrome girls may have ambiguos genitalia. Though I found that due to androgen excess some part of it can be converted to estrogens and cause precocious puberty and dysmenorrhea in girls, it still seems to me that adrenals are not so great source of estrogens in men.

The predominant source of estrogen in men is by peripheral conversion, not the adrenals.

Originally Posted by Convalaria

Testosterone excess has negative feedback only on LH and GnRH, FSH is under inhibin and estradiol control.

I'm pretty sure GnRH activates FSH as well... otherwise, what's the mechanism by which exogenous steroid would lead to testicular atrophy?

Originally Posted by johndoe3344

The thing is, though, on medscape and wikipedia and other random google sites I looked at, none of them lists testicular atrophy as a symptom. The other things, yes, but not atrophy. Not sure why...

Because this mechanism seems to be similar to the mechanism by which exogenous steroids would lead to testicular atrophy.

I use Goljan RR that says about atrophy of testes and ovaries as well

Originally Posted by Convalaria

I use Goljan RR that says about atrophy of testes and ovaries as well

Okay that makes sense, then. Thanks for the clarification

So with regard to the original question, then, I guess in summary the only thing that ACTH can't cause would be the hepatosplenomegaly. Tricky...

Originally Posted by johndoe3344

The predominant source of estrogen in men is by peripheral conversion, not the adrenals.



I'm pretty sure GnRH activates FSH as well... otherwise, what's the mechanism by which exogenous steroid would lead to testicular atrophy?

I meant adrenals as indirect source of estrogens.

Concerning atrophy: iron deposition in pituitary and iron deposition in gonads both cause atrophy

Originally Posted by johndoe3344

Okay that makes sense, then. Thanks for the clarification

So with regard to the original question, then, I guess in summary the only thing that ACTH can't cause would be the hepatosplenomegaly. Tricky...

I still can't see how ACTH can cause dry mouth and impotence with atrophic testes in males adrenal androgens play minor role and even ACTH overproduction with cosequent increase in adrenal androgens wouldn't cause it.

Originally Posted by Convalaria

I still can't see how ACTH can cause dry mouth and impotence with atrophic testes in males adrenal androgens play minor role and even ACTH overproduction with cosequent increase in adrenal androgens wouldn't cause it.

Plasma testosterone levels were suppressed in 6 of 8 mature male patients with Cushing's disease, all of whom complained of loss of libido and decreased sexual potency. Gonadotrophin levels, both under basal conditions and in response to LH-RH, were generally normal. The testicular response to stimulation with hCG was brisk in the 2 patients examined. Oestradiol levels were slightly elevated in 2 patients and prolactin levels were normal in all patients. Thus, male patients with Cushing's disease demonstrated normal gonadotrophin levels in the presence of suppressed testosterone, or, viewed from a slightly different prospect, low testosterone levels despite normal gonadotrophins.

I can also see how hypercortisolism -> glucose -> impotence, but atrophic testes?...

Perhaps there's a weird cortisol -> reduced GnRH release from Hyth feedback loop... similar to how stress / cortisol will produce amenorrhea.