Reversal of idiopathic hypogonadotropic hypogonadism.
BACKGROUND
Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy.


METHODS
We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued.


RESULTS
Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.


CONCLUSIONS
Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].).
Raivio
Taneli
T
Harvard Center for Reproductive Endocrine Sciences and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
Falardeau
John
J
Dwyer
Andrew
A
Quinton
Richard
R
Hayes
Frances J
FJ
Hughes
Virginia A
VA
Cole
Lindsay W
LW
Pearce
Simon H
SH
Lee
Hang
H
Boepple
Paul
P
Crowley
William F
WF
Pitteloud
Nelly
N
D000293:Adolescent; D000328:Adult; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005500:Follow-Up Studies; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000627:therapeutic use; D006062:Gonadotropins / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000151:congenital* / Q000188:drug therapy; D017436:Kallmann Syndrome / Q000097:blood / Q000188:drug therapy; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D011446:Prospective Studies; D011628:Puberty, Delayed; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics; D012075:Remission, Spontaneous; D013739:Testosterone / Q000097:blood* / Q000172:deficiency / Q000627:therapeutic use
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; D006062:Gonadotropins; C118688:KISS1R protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1