{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:31:49Z","timestamp":1760059909146,"version":"build-2065373602"},"reference-count":14,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient\u2019s total testosterone levels normalized (407\u2013424 ng\/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS.<\/jats:p>","DOI":"10.3390\/life15071151","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T13:59:11Z","timestamp":1753106351000},"page":"1151","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spontaneous Improvement of Hypogonadotropic Hypogonadism in a Patient with PCSK1 and HS6ST1 Mutations: A Case Report"],"prefix":"10.3390","volume":"15","author":[{"given":"Alanna","family":"Asgeirsson","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eujean","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0129-6783","authenticated-orcid":false,"given":"Vinicius","family":"Seidel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathew","family":"Shedd","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matheni","family":"Sathananthan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Arous","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Codorniz","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvana","family":"Giannelli","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Do","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wyut Yi","family":"Thin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arsenije","family":"Jelovac","sequence":"additional","affiliation":[{"name":"Providence Little Company of Mary Medical Center Torrance, Torrance, CA 4101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Loma Linda University Health Consortium, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref_1","first-page":"139","article-title":"Kallmann syndrome","volume":"17","author":"Hardelin","year":"2008","journal-title":"Eur. 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Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1210\/jc.2004-1361","article-title":"Reversible Kallman syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene","volume":"90","author":"Pitteloud","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1093\/hmg\/ddac172","article-title":"Convergent biological pathways underlying the Kallmann syndrome-linked genes HS6ST1 and FGFR1","volume":"31","author":"Moon","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1111\/cen.14182","article-title":"The ominous trio of PCSK1, CHD7 and PAX4: Normosmic hypogonadotropic hypogonadism with maturity-onset diabetes in a young man","volume":"92","author":"Cho","year":"2020","journal-title":"Clin. 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Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e14583","DOI":"10.1111\/and.14583","article-title":"Reversal of idiopathic hypogonadotropic hypogonadism in a Chinese male cohort","volume":"54","author":"Sun","year":"2022","journal-title":"Andrologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1210\/jc.2013-2809","article-title":"Reversal and relapse of hypogonadotropic hypogonadism: Resilience and fragility of the reproductive neuroendocrine system","volume":"99","author":"Sidhoum","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S2213-8587(24)00028-7","article-title":"Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: A cross-sectional study of six international referral centres","volume":"12","author":"Dwyer","year":"2024","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1210\/jc.2006-1216","article-title":"Antipuitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropoic hypogonadism","volume":"92","author":"Sinisi","year":"2007","journal-title":"J. Clin. Endocrinol. 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