The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism.
OBJECTIVE
Adult-onset idiopathic hypogonadotropic hypogonadism (AHH) is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men. This study aims to examine the etiology and long-term natural history of this disorder.


METHODS
Long-term follow up, including detailed clinical, biochemical, and genetic examinations, were performed and compared with those at diagnosis.


METHODS
Patients included 10 men with AHH [serum testosterone (T) <125 ng/dl].


METHODS
Overnight neuroendocrine studies, semen fluid analyses, and genetic screening were performed (KAL1, FGFR1, PROK2, PROKR2, NELF, TAC3, TACR3, and GNRH1) over a decade of longitudinal follow up.


RESULTS
Follow-up evaluations were conducted 10.6 +/- 5.9 yr after initial studies and revealed that the clinical characteristics and seminal fluid analyses of AHH men (body mass index, 28.8 +/- 4.1 vs. 27.0 +/- 4.3 kg/m(2); testicular volume, 18 +/- 6 vs. 19 +/- 6 ml) do not change over a decade with no spontaneous reversals. Several men exhibited some variability in their endogenous GnRH-induced LH secretory patterns, including emergence of endogenous pulsatility in three individuals. However, all remained hypogonadal (T < or =130 ng/dl). A single heterozygous DNA sequence change in PROKR2 (V317L) was identified, although this rare sequence variant did not prove to be functionally abnormal in vitro. Seven days of pulsatile GnRH therapy in this subject nearly normalized his serum T, supporting that the site of the defect is hypothalamic and not pituitary.


CONCLUSIONS
1) AHH in men appears to be a long-lasting condition. 2) Although minor changes in the abnormal pattern of endogenous GnRH-induced LH secretion occurred in some AHH patients, all remained frankly hypogonadal.
Dwyer
Andrew A
AA
Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit of Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Hayes
Frances J
FJ
Plummer
Lacey
L
Pitteloud
Nelly
N
Crowley
William F
WF
D000328:Adult; D017668:Age of Onset; D018450:Disease Progression; D005640:Follicle Stimulating Hormone / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D013737:Testis / Q000502:physiology; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome
D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone