GNRHR Mutations in a Woman with Idiopathic Hypogonadotropic Hypogonadism Highlight the Differential Sensitivity of Luteinizing Hormone and Follicle-Stimulating Hormone to Gonadotropin-Releasing Hormone
Abstract
Mutations in the GnRH receptor gene (GNRHR) are a cause of idiopathic hypogonadotropic hypogonadism. We describe a normosmic female subject with congenital idiopathic hypogonadotropic hypogonadism in whom treatment with pulsatile GnRH resulted in an unusual response. The subject not only required an increased dose of pulsatile GnRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously. Sequencing of the GNRHR coding sequence revealed compound heterozygous mutations leading to amino acid substitutions [N10K+Q11K] and P320L. The introduction of the P320L mutation into the GnRH receptor led to failure of detectable ligand binding and failure of stimulation of inositol phosphate production and gonadotropin subunit gene promoter activity in response to GnRH in transiently transfected cells. The [N10K+Q11K] mutation resulted in reduced binding of a GnRH agonist to 25% of the wild-type receptor. In addition, the EC(50) value for GnRH stimulation of inositol phosphate production was significantly increased, and the dose-response curves for stimulation of alpha gonadotropin subunit, LHbeta, and FSHbeta gene transcription by GnRH were similarly shifted to the right. Stimulation of FSHbeta gene transcription was more sensitive to GnRH than LHbeta for both wild-type and [N10K+Q11K] GnRH receptors, resulting in a greater loss of LHbeta stimulation than FSHbeta by the [N10K+Q11K] mutant at any given submaximal GnRH concentration. We propose that the mutations in the GnRH receptor result in a rightward shift of the dose-response curves of gonadotropin responses to pulsatile GnRH in the subject and unmask the differential sensitivities of LH and FSH to GnRH, resulting in low LH and estradiol levels despite appropriate FSH secretion and follicular growth.
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Some of these women suffer from multiple miscarriages, most often early in gestation.
“Some of these women suffer from multiple miscarriages, most often early in gestation.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [68]
Some women with IHH respond appropriately to gonadotropin supplementation and are able to carry a normal pregnancy, others are not.
“Work by Janet Hall’s lab provides important evidence that although some women with IHH respond appropriately to gonadotropin supplementation and are able to carry a normal pregnancy, others are not67,68.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [68]
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“Hypogonadotropic hypogonadism (HH), or secondary hypogonadism, results from reduced secretion of gonadotropins by gonadotropin-releasing hormone (GnRH), and reduced levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in lack of production of sex steroids.”
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“[Asn10Lys; Gln 11Lys] mutations resulted in reduced ligand binding and impaired intracellular signal transduction capacity (11).”
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“Additionally, an alternative variant at the same position results in binding defects (with GnRH), as shown in transiently transfected cells resulting in a total loss of function [18].”
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“Introduction The reproductive function and sexual maturation of human cells is regulated by hormones such as Gonadotropin-Releasin g Hormone (GnRH) or Luteinizing – hormone–releasing hormone (LHRH).[1] GnRH is a decapeptide isolated from hypothalamic cells.”
BackgroundNormal ovaries, inflammatory and non-neoplastic conditions
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Mutations of the Gonadotropin-Releasing Hormone Receptor Gene
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Mutations of the gonadotropin-releasing hormone receptor gene
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Self-citationGonadotropin-releasing hormone receptor mutation as a cause of pubertal delay
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“5 20 In summary, this case illustrates a genetically confirmed example of adolescent-onset IHH caused by compound heterozygous GNRHR variants.”
- Authors
- Meysing, A. U., Kanasaki, H., Bedecarrats, G. Y., Acierno, J. S., Conn, P. M., Martin, K. A., Seminara, S. B., Hall, J. E., Crowley, W. F., & Kaiser, U. B.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Meysing, Astrid U.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-07
- Volume
- 89
- Issue
- 7
- Pages
- 3189-3198
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2018909435
- Cited by
- 58
- References
- 40
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 1 · 2021: 4 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 2 · 2012: 6
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD19899, R01HD015788, R01HD043341, U54HD029164, U564 HD 28138, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- GnRH receptor, idiopathic hypogonadotropic hypogonadism, pulsatile GnRH therapy, luteinizing hormone, follicle-stimulating hormone, compound heterozygosity, inositol phosphate formation, dose-response shift, ovarian follicle development, female infertility, estradiol deficiency
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Cell Membrane, Cells, Cultured, DNA, Dose-Response Relationship, Drug, Estradiol, Female, Follicle Stimulating Hormone, Heterozygote, Humans, Hypogonadism, Inositol Phosphates, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Mutation, Receptors, LHRH, Case-Control Studies, Amino Acid Substitution, Luteinizing Hormone, beta Subunit, Follicle Stimulating Hormone, beta Subunit
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