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By Frederik Joelving

NEW YORK (Reuters Health) - Although it's rare, adult-onset idiopathic hypogonadotropic hypogonadism (AHH) in men appears to be a permanent condition.

Metabolism.

The condition was first described in 10 men in 1997 by Dr. William Crowley of Harvard Medical School in Boston and colleagues. Its diagnosis is based on a series of criteria, including completed puberty, clinical symptoms of hypogonadism, serum testosterone levels of less than 130 ng/dL, and the absence of predisposing anatomical or functional factors.

"We have now followed these guys for over a decade, and none of them reversed themselves," said Dr. Crowley, who also heads the Reproductive Endocrine Unit at Massachusetts General Hospital in Boston. "We think there is a genetic component, in at least some of them."

He said many men are being over-treated for so-called "low testosterone" today, but AHH is different.

"Those patients whose testosterone is under 100 and remains there over several months definitely need to be treated with testosterone. This is in sharp distinction to most people who are getting treated today," Dr. Crowley told Reuters Health.

The mean age of the 10 men in the new study, seven of whom were in the 1997 study, was about 50 years. All had received hormone therapy and had stopped taking it up to eight weeks before follow-up, an average of 10.6 years after their initial evaluation.

Mean luteinizing hormone (LH) levels at follow-up did not differ significantly from baseline (3.9 IU/L vs. 2.3 IU/L; p=0.2), and testosterone levels had remained lower than 130 ng/dL in all men (mean, 58 ng/dL).

Taken as a group, none of the men's biochemical parameters had changed. Of those who could deliver an ejaculate, one had a normal sperm count; the rest were azoospermic or oligospermic.

These findings indicate AHH is a lasting condition, the researchers note. In contrast, congenital idiopathic hypogonadotropic hypogonadism is reversible, just as women with functional hypothalamic amenorrhea often recover.

In genetic studies, the researchers found a potentially novel single-nucleotide polymorphism in one man. This patient had a heterozygous mutation in PROKR2, a gene involved in the development of the hypothalamus, that was not present in a control group of 192 ethnically matched men.

Three men reported delayed puberty, though all had completed sexual maturation by their late teens.

"Although AHH is considered an acquired disorder, this subtle history of a somewhat delayed puberty in several AHH men suggests the possibility of an underlying preexisting, mild defect of (gonadotropin-releasing hormone) ontogeny," the researchers write. "This hypothesis is now supported by the identification of heterozygous PROKR2, GNRHR, and FGF8 variants, all of which are genetic loci impacting on the ontogeny of GnRH neuronal development."

They conclude that although AHH is a very rare form of hypogonadotropic hypogonadism, "it is important in that it not only remains one of the few medically treatable forms of male infertility but may well provide future biological lessons about the ontogeny of the GnRH neuronal network."

J Clin Endocrinol Metab 2010.

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