{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:02:58Z","timestamp":1792141378570,"version":"4.4.0"},"reference-count":31,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>This work aimed to determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A retrospective study was conducted (1980-2020) examining olfaction (Kallmann syndrome [KS] vs normosmic IHH [nHH]), baseline testicular volume (absent vs partial puberty), neuroendocrine profiling (pulsatile vs apulsatile luteinizing hormone [LH] secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In total, 242 men (KS: n = 131 [54%], nHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (P &amp;lt; .001) and were more likely to have undetectable LH (P &amp;lt; .001). Logistic regression showed partial puberty as a statistically significant predictor of pulsatile LH secretion (R2 = 0.71, P &amp;lt; .001, OR: 10.8; 95% CI, 3.6-38.6). Serum LH of 2.10 IU\/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204 of 242 IHH men with ES data available revealed 36 of 204 (18%) men carried protein-truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (P &amp;lt; .001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (P = .002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Partial puberty and LH greater than or equal to 2.10 IU\/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac615","type":"journal-article","created":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T08:10:42Z","timestamp":1666339842000},"page":"897-908","source":"Crossref","is-referenced-by-count":19,"title":["Reproductive Phenotypes and Genotypes in Men With IHH"],"prefix":"10.1210","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7023-6794","authenticated-orcid":false,"given":"Andrew A","family":"Dwyer","sequence":"first","affiliation":[{"name":"William F. 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Connell School of Nursing, Boston College , Chestnut Hill, Massachusetts 02467 , USA"},{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital\u2014Harvard Center for Reproductive Medicine, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"},{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B","family":"Seminara","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital\u2014Harvard Center for Reproductive Medicine, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"},{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6008-5585","authenticated-orcid":false,"given":"Ravikumar","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital\u2014Harvard Center for Reproductive Medicine, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"},{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital , Boston, Massachusetts 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"issue":"2","key":"2023052516431017100_dgac615-B1","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1210\/er.2018-00116","article-title":"Clinical management of congenital hypogonadotropic hypogonadism","volume":"40","author":"Young","year":"2019","journal-title":"Endocr Rev"},{"issue":"9","key":"2023052516431017100_dgac615-B2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism\u2014pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"2023052516431017100_dgac615-B3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00439-020-02147-1","article-title":"Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease","volume":"140","author":"Cangiano","year":"2021","journal-title":"Hum Genet"},{"issue":"5","key":"2023052516431017100_dgac615-B4","doi-asserted-by":"crossref","first-page":"E943","DOI":"10.1210\/jc.2012-4116","article-title":"Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes","volume":"98","author":"Costa-Barbosa","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2023052516431017100_dgac615-B5","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1210\/jc.2002-020518","article-title":"Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism","volume":"87","author":"Pitteloud","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2023052516431017100_dgac615-B6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1210\/jcem.87.1.8131","article-title":"The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism","volume":"87","author":"Pitteloud","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2023052516431017100_dgac615-B7","first-page":"4388","article-title":"The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human","volume":"81","author":"Waldstreicher","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2023052516431017100_dgac615-B8","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/0031-9384(84)90269-5","article-title":"Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function","volume":"32","author":"Doty","year":"1984","journal-title":"Physiol Behav"},{"issue":"1","key":"2023052516431017100_dgac615-B9","doi-asserted-by":"crossref","first-page":"E136","DOI":"10.1210\/jc.2011-2041","article-title":"Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications","volume":"97","author":"Lewkowitz-Shpuntoff","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2023052516431017100_dgac615-B10","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1172\/JCI107454","article-title":"Episodic luteinizing hormone secretion in man. 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