Format

Send to

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2013 Feb;98(2):E206-16. doi: 10.1210/jc.2012-3294. Epub 2013 Jan 22.

Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism.

Author information

  • 1Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Reproductive Endocrine Sciences Center, Harvard Medical School, Boston, MA 02114, USA.

Abstract

CONTEXT:

Isolated hypogonadotropic hypogonadism (IHH) is caused by defective GnRH secretion or action resulting in absent or incomplete pubertal development and infertility. Most women with IHH ovulate with physiological GnRH replacement, implicating GnRH deficiency as the etiology. However, a subset does not respond normally, suggesting the presence of defects at the pituitary or ovary.

OBJECTIVES:

The objective of the study was to unmask pituitary or ovarian defects in IHH women using a physiological regimen of GnRH replacement, relating these responses to genes known to cause IHH.

DESIGN, SETTING, AND SUBJECTS:

This study is a retrospective analysis of 37 IHH women treated with iv pulsatile GnRH (75 ng/kg per bolus).

MAIN OUTCOME MEASURES:

Serum gonadotropin and sex steroid levels were measured, and 14 genes implicated in IHH were sequenced.

RESULTS:

During their first cycle of GnRH replacement, normal cycles were recreated in 60% (22 of 37) of IHH women. Thirty percent of women (12 of 37) demonstrated an attenuated gonadotropin response, indicating pituitary resistance, and 10% (3 of 37) exhibited an exaggerated FSH response, consistent with ovarian resistance. Mutations in CHD7, FGFR1, KAL1, TAC3, and TACR3 were documented in IHH women with normal cycles, whereas mutations were identified in GNRHR, PROKR2, and FGFR1 in those with pituitary resistance. Women with ovarian resistance were mutation negative.

CONCLUSIONS:

Although physiological replacement with GnRH recreates normal menstrual cycle dynamics in most IHH women, hypogonadotropic responses in the first week of treatment identify a subset of women with pituitary dysfunction, only some of whom have mutations in GNRHR. IHH women with hypergonadotropic responses to GnRH replacement, consistent with an additional ovarian defect, did not have mutations in genes known to cause IHH, similar to our findings in a subset of IHH men with evidence of an additional testicular defect.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00383656.

PMID:
23341491
PMCID:
PMC3565114
DOI:
10.1210/jc.2012-3294
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon Icon for PubMed Central
    Loading ...
    Support Center