Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes.
BACKGROUND
Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH. Accordingly, most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH, FSH, and testosterone (T) levels and achieving gametogenesis; some patients, however, show atypical responses. Interestingly, several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis.


OBJECTIVE
The aim of the study was to investigate whether the clinical, biochemical, or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis.


METHODS
We studied 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 yr.


METHODS
We conducted a retrospective study of response to GnRH at a Clinical Research Center.


METHODS
Physiological regimens of pulsatile s.c. GnRH were administered for at least 12 months. Dose-response studies using i.v. GnRH pulses assessed the pituitary LH response.


METHODS
We measured serum T, LH, FSH, and inhibin B levels, sperm in ejaculate, and determined the sequence of IHH-associated genes.


RESULTS
Twenty-six percent of subjects displayed atypical responses to GnRH: 1) 10 remained hypogonadotropic and hypogonadal, demonstrating pituitary and testicular defects; 2) eight achieved spermatogenesis and normal T but only with hypergonadotropism, indicating impaired testicular responsiveness to gonadotropins; and 3) five remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles, suggesting primary defects in spermatogenesis. Mutations were identified only in KAL1 across groups.


CONCLUSIONS
In addition to hypothalamic GnRH deficiency, IHH men can have primary pituitary and/or testicular defects, which are unmasked by GnRH replacement.
Sykiotis
Gerasimos P
GP
Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Hoang
Xuan-Huong
XH
Avbelj
Magdalena
M
Hayes
Frances J
FJ
Thambundit
Apisadaporn
A
Dwyer
Andrew
A
Au
Margaret
M
Plummer
Lacey
L
Crowley
William F
WF
Pitteloud
Nelly
N
D000328:Adult; D053713:Azoospermia / Q000235:genetics; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006062:Gonadotropins / Q000172:deficiency* / Q000235:genetics; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007031:Hypothalamus / Q000473:pathology*; D017436:Kallmann Syndrome / Q000150:complications / Q000235:genetics; D008297:Male; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D010902:Pituitary Gland / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000473:pathology*
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D009419:Nerve Tissue Proteins; D007987:Gonadotropin-Releasing Hormone; D004247:DNA
J Clin Endocrinol Metab. 2005 May;90(5):3122-7
15728198
J Clin Invest. 1996 Aug 15;98(4):1055-62
8770879
Endocrinology. 2008 Sep;149(9):4435-51
18499750
J Neurochem. 1988 Aug;51(2):624-33
3292705
Brain Res Mol Brain Res. 1989 Dec;6(4):311-26
2687610
Endocr Rev. 1998 Oct;19(5):521-39
9793755
Intern Med. 2005 Oct;44(10):1069-73
16293919
N Engl J Med. 1982 Nov 11;307(20):1237-41
6813732
Nat Rev Endocrinol. 2009 Oct;5(10):569-76
19707180
J Clin Endocrinol Metab. 2000 Feb;85(2):556-62
10690855
Dev Dyn. 1999 May;215(1):26-44
10340754
Endocrinology. 2008 Sep;149(9):4596-604
18499748
Histochem Cell Biol. 1998 Jul;110(1):57-62
9681690
Science. 1978 Nov 10;202(4368):631-3
100883
J Clin Invest. 1969 Nov;48(11):2046-56
4390462
J Clin Endocrinol Metab. 2002 Sep;87(9):4128-36
12213860
Genes Dev. 1998 Jun 1;12(11):1691-704
9620855
FEBS Lett. 1999 Nov 26;462(1-2):177-81
10580115
Clin Endocrinol (Oxf). 1999 Jun;50(6):695-701
10468940
Development. 1998 Dec;125(23):4835-40
9806931
Clin Endocrinol (Oxf). 2001 Aug;55(2):163-74
11531922
Intern Med. 1998 Oct;37(10):853-6
9840707
Anim Reprod Sci. 2005 Aug;88(1-2):95-113
15982835
Hum Genet. 1980;56(1):21-51
7203479
J Clin Endocrinol Metab. 1996 Dec;81(12):4388-95
8954047
J Clin Invest. 1974 Feb;53(2):408-15
11344554
Am J Physiol. 1988 May;254(5 Pt 1):E658-66
3129947
J Clin Endocrinol Metab. 1999 Oct;84(10):3563-9
10522996
J Biol Chem. 1994 Apr 29;269(17):12626-32
8175672
Neuroendocrinology. 2008;87(3):142-50
18063854
Acta Paediatr. 2007 May;96(5):611-6
17462053
J Clin Endocrinol Metab. 1973 Jun;36(6):1263-7
4574709
Development. 1998 Mar;125(6):1005-15
9463347
J Clin Endocrinol Metab. 2002 Jan;87(1):152-60
11788640
J Clin Endocrinol Metab. 1999 Mar;84(3):1028-36
10084591
Biochem Biophys Res Commun. 1997 Mar 6;232(1):173-7
9125125