A36-year-old man presents for evaluation of fatigue and decreased libido. Over the past six months, he has noted a progressive decline in his energy level, as well as in sexual function. He has few, if any, morning erections and is unable to sustain an erection to have intercourse. He has also noted a decreased frequency of shaving and a generalized darkening of his skin, despite a lack of sun exposure. He reports no heat or cold intolerance, headache, or change in vision.
He saw his primary care physician four months ago and had a random blood glucose concentration greater than 300 mg/dL on two occasions. He was counseled on a proper diet, taught how to monitor his glycemic control at home, and prescribed glipizide, 2.5 mg daily. With those interventions, he has noted a slight improvement in his diabetes with glucose concentrations of 100 to 250 mg/dL in the morning without any evidence of hypoglycemia.
Physical examination reveals normal vital signs. His skin is tanned without any tan lines. He has no goiter. His lungs are clear. He has no gynecomastia. His liver is palpable 2 cm below the costal margin, and his liver span is increased. Genitourinary examination reveals a normal phallus and testes.
His testosterone concentration is 180 ng/dL. Thus, you also order DXA to assess his risk of a fragility fracture.
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Which one of the following patterns of laboratory results (obtained at 8 AM) and radiographic findings best fit his diagnosis?
|ANSWER||LH,IU/L||CORTISOL,μg/DL||ESTRADIOL,PG/ML||PROLACTIN,NG/ML||LUMBAR SPINE Z SCORE|
AN EXPLANATION FOR A DECREASED LIBIDO:
A Case Study from ESAP™
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The answer is: D
This patient has hypogonadism secondary to hemochromatosis. Iron deposition in the liver, skin, and pancreatic islet cells accounts for his hepatomegaly, change in skin color, and recently developed diabetes mellitus. Interestingly, in men with hemochromatosis, sex hormone– binding globulin and estradiol levels are normal and gynecomastia is rare. In most affected men, secondary hypogonadism is the most common cause of gonadal failure. To a lesser extent, primary gonadal dysfunction (even concurrent with pituitary involvement) can occur. In cases of hypogonadism, subsequent to the loss of androgens, marked reductions in bone mineral density can be seen in both men and women. Interestingly, the gonadotropes are more predisposed to iron deposition than other cells. Thus, panhypopituitarism is rare, and secondary hypothyroidism or secondary adrenal insufficiency is not often encountered.
The pattern in Answer A is seen in patients with chronic liver disease. These findings are more likely to be seen in patients with alcohol-induced liver disease, although liver disease of any etiology can present with this biochemical profile. Alcohol can directly reduce androgen levels. In addition, any damage to hepatocyte function results in a reduction in estrogen degradation, thereby increasing circulating estradiol levels (some patients presenting with gynecomastia). Furthermore, high estrogen levels lead to a reduction in testosterone levels via negative feedback at the level of hypothalamus/pituitary. Despite low androgen levels, these individuals may not lose bone mass because of elevated serum estrogen levels.
The pattern in Answer B suggests hypogonadotropic hypogonadism that is secondary to hyperprolactinemia. Although both hemochromatosis (with pituitary involvement) and hyperprolactinemia present with low gonadotropins and testosterone levels, hemochromatosis is characterized by normal or even low prolactin levels (presumably due to damage to the lactotrophs from iron deposition).
The pattern in Answer C is typical for a man with hypergonadotropic hypogonadism due to primary testicular failure. Although primary hypogonadism can be seen in persons with hemochromatosis, it is less likely than a central etiology.
The pattern in Answer D is consistent with pituitary insufficiency. Concentrations of both androgens and estrogen are low because of low gonadotropin concentrations. In addition, affected persons have a blunted response to GnRH in terms of LH secretion and have reduced responses to compounds such as clomiphene citrate, which, via its estrogen-antagonist action, should increase gonadotropin secretion. The low bone density is a result of the hypogonadism that has probably been present for some time, and the normal 8 AM cortisol concentration reflects sparing of other anterior pituitary trophic hormones in the setting of hemochromatosis.
The pattern in Answer E also represents hypogonadotropic hypogonadism, although with concurrent adrenal insufficiency. In the face of cortisol deficiency, the finding of hyperglycemia (or lack of hypoglycemia after initiation of a sulfonylurea) would be less likely. Although panhypopituitarism is unlikely, so too is the increased bone mineral density. As noted, in men with hypogonadism, one would predict a reduced bone mass.
Treatment of the hemochromatosis has variable results. In some individuals, pituitary function can be restored with serial phlebotomy. The response is slow, and normalization of the hypothalamic-pituitary-gonadal axis may take months of treatment. In many patients, despite adequate control of iron balance, hypopituitarism persists and androgen replacement is needed.