A genetic basis for functional hypothalamic amenorrhea.
BACKGROUND
Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea.


METHODS
We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations.


RESULTS
Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q.


CONCLUSIONS
Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).
Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit and the Department of Medicine, Massachusetts General Hospital, Boston, USA.
Lisa M
LM
Caronia
Cecilia
C
Martin
Corrine K
CK
Welt
Gerasimos P
GP
Sykiotis
Richard
R
Quinton
Apisadaporn
A
Thambundit
Magdalena
M
Avbelj
Sadhana
S
Dhruvakumar
Lacey
L
Plummer
Virginia A
VA
Hughes
Stephanie B
SB
Seminara
Paul A
PA
Boepple
Yisrael
Y
Sidis
William F
WF
Crowley
Kathryn A
KA
Martin
Janet E
JE
Hall
Nelly
N
Pitteloud
D000568:Amenorrhea / Q000209:etiology / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007027:Hypothalamic Diseases / Q000150:complications / Q000235:genetics*; D007986:Luteinizing Hormone / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D017422:Sequence Analysis, DNA
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C470838:PROKR2 protein, human; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; D011966:Receptors, LHRH; D018000:Receptors, Peptide; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D051496:Receptor, Fibroblast Growth Factor, Type 1
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