IGF-I deficiency and enhanced insulin sensitivity due to a mutated growth hormone receptor gene in humans

Guevara‐Aguirre, Jaime; Torres, Carlos Duarte; Peña, Gabriela; Palacios, María G.; Bautista, Camila; Guevara, Alexandra; Gavilanes, Antonio W. D.

doi:10.1016/j.mce.2020.111044

Cited by 7 publications

(8 citation statements)

References 108 publications

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“…The significant clinical effect achieved in this trial, without side effects, and the significant and accelerating increases in TH density from week 12 to 24, can be explained clinically as prolonging anagen while also inducing anagen in involuted or non-productive telogen hair follicles. These clinical effects have been explained in the literature as HF regenerative and homeostatic physiological effects of activating HF stem cells via the Wnt/β-catenin signalling pathway, and by regulation and/or modulation of multiple cytokines, growth factors and hormone mediators, and likely relieving pressure on the HF [ 2 , [16] , [17] , [18] , 25 - 27 ] These mechanisms of action are similar to those observed in PRP scalp treatments which have been linked to multiple similar pathways [26] . Future research should focus on elucidating the main mechanisms of action to refine ALRV5XR delivery and applications in other ageing tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, several uncontrolled studies in women have reported improvements in hair growth [19] . Recombinant human insulin-like growth factor-I (rhIGF-I) treatment has induced the appearance of normal hair and recovery of hairline in subjects with growth hormone insensitivity and concomitant IGF deficiency [25] . Combination therapies of topical minoxidil with pharmaceuticals and supplements have been studied in women, showing no significant difference in TH density changes to those of minoxidil monotherapy [19] .…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of ALRV5XR in women with androgenetic alopecia or telogen effluvium: A randomised, double-blinded, placebo-controlled clinical trial

Feldman¹,

Fiebig²,

Piwko

et al. 2021

eClinicalMedicine

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Background Scalp hair loss (alopecia) in women is a common ageing and senescing condition. It usually presents as androgenetic alopecia (AGA) or telogen effluvium (TE) and often has pronounced psychological consequences. ALRV5XR is a novel treatment aiming to regenerate a normal hair phenotype by targeting multiple molecular pathways linked to hair growth promotion and hair follicle stem cell activation. The primary objectives of this 24-week trial were to evaluate the safety and efficacy of ALRV5XR in terminal hair (TH) regrowth in women with AGA or TE. Methods This randomised, double-blind, placebo-controlled trial was performed in a USA community clinic. Healthy women 18-65 years of age with AGA or TE of Ludwig classification I-II and Fitzpatrick skin type I-VI were enrolled. They were allocated in a 1:1 ratio into ALRV5XR or placebo treatment groups using a random number table. Masked dermatologist assessments, phototrichograms and blood samples were obtained at baseline, 12 and 24 weeks. Subjects were given a masked treatment regimen of oral capsules, shampoo, conditioner and follicle serum for daily administration. Main outcomes were absolute and per cent changes in TH density and response rates. The trial was registered with clinicaltrials.gov (NCT04450602) and is completed. Findings 46 subjects (23 ALRV5XR, 23 placebo) were enrolled between April 3 and October 20, 2018. Five subjects dropped out and two were non-compliant. Thirty-nine subjects completed the trial (18 ALRV5XR, 21 placebo). At 24 weeks, the absolute change in TH density improved by 30·1THs/cm 2 (95% CI: 15·1–45·1; p=0·0002), and the relative density increased by 19·7% (95% CI: 8·0%–31·4%; p=0·0016). The odds ratio for being a responder (≥0 change) was 2·7. Efficacy increased 133% from week 12 to 24. Efficacy outcomes were similar in AGA and TE subjects. 66·7% of the ALRV5XR group responded by regrowing 40THs/cm 2 or more hair. No adverse events were reported. Interpretation In women with AGA or TE, ALRV5XR treatment significantly increased hair regrowth without adverse events. ALRV5XR displayed a multi-fold improved efficacy and response rate when compared to published trials of standard therapy. Progressive acceleration of TH regrowth suggests regeneration of the structure and function of non-productive telogen follicles and prolonged treatment may restore a normal hair phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of ALRV5XR in women with androgenetic alopecia or telogen effluvium: A randomised, double-blinded, placebo-controlled clinical trial

Feldman¹,

Fiebig²,

Piwko

et al. 2021

eClinicalMedicine

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“…Still, for clinical purposes, such subclassification is useful, since the classical forms of these conditions, caused by a total functional loss of biological activity of the respective gene product, usually leads to such specific phenotype, that a candidate gene approach is warranted. Given the availability of recent reviews on these genetic disorders [27, 28, 161-164], we keep the descriptions of these conditions short.…”

Section: Conditions With Decreased Gh Sensitivitymentioning

confidence: 99%

“…Biochemically, GH secretion is increased and serum concentrations of IGF-I, IGFBP-3, and ALS are severely subnormal and do not respond to an IGFGT. The serum concentration of GHBP is usually decreased but can be normal or even elevated depending on the position of the genetic variant [27, 161].…”

Section: Conditions With Decreased Gh Sensitivitymentioning

confidence: 99%

Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

et al. 2021

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The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.

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“…Fifty-two percent of treated men with early stages of HL had a total hair regrowth response, and the odds ratio (OR) of finasteride vs. placebo was 1¢67 [7,19]. Interestingly, insulin-like growth factor-I (rhIGF-1) treatment induced the appearance of normal hair and recovery of hairline in IGF-1 deficient populations, thereby highlighting the wide range of molecules that act on the physiology of hair [22]. Combination therapies of topical minoxidil with finasteride, other pharmaceuticals and or supplements have been studied in randomised placebo-controlled trials (RCTs) in men.…”

Section: Added Value Of This Studymentioning

confidence: 99%

Safety and efficacy of ALRV5XR in men with androgenetic alopecia: A randomised, double-blinded, placebo-controlled clinical trial

Feldman¹,

Fiebig²,

Piwko

et al. 2021

EClinicalMedicine

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Background: Androgenetic alopecia (AGA) is the most common hair loss disorder seen in men. It can have an early onset but has also been associated with ageing and senescence. It often induces pronounced psychological impact. ALRV5XR, a new hair loss treatment herein evaluated, was designed to target multiple molecular pathways involved in hair growth and hair follicle stem cell biology. The main objectives of the study were the assessment of safety and efficacy profiles of ALRV5XR in men. Methods: This 24-week, parallel randomised, placebo-controlled, double-blinded clinical trial was performed in a USA community clinic. Healthy men (age 22À65) with AGA and belonging to the Hamilton-Norwood (HN) classification IÀVII and Fitzpatrick skin type (FST) IÀVI, were randomly allocated in a 1:1 ratio into ALRV5XR or placebo treatment groups. Dermatologist assessment, phototrichograms, and blood samples were obtained in a blinded fashion at baseline, 12 and 24 weeks. Subjects were given a masked treatment consisting of oral capsules, shampoo, conditioner, and follicle serum, which was intended for daily use. Efficacy was assessed via absolute and per cent changes in terminal hair (TH) density, and response rates. The trial was registered with clinicaltrials.gov (NCT04450589) and is completed. Findings: Forty-six subjects were enroled in the study, 23 allocated to the ALRV5XR treatment and 23 to the placebo group. Enrolment occurred from April 11 to October 23, 2018. Thirty-six subjects completed the trial (17 ALRV5XR, 19 placebo) and 11 subjects in each group were evaluable for TH outcomes. At 24 weeks, the absolute change in TH density improved by 21¢0 THs/cm 2 (95% CI: 9¢2À32¢8; p = 0¢0014), and the relative density increased by 16¢4% (95% CI: 7¢4%À25¢5%; p = 0¢0012). The odds ratio for being a responder ( 0 change) was 87¢4. TH density increased linearly and was not affected by HN, FST, ethnicity, age, or body mass index. All subjects in the ALRV5XR group responded to treatment while 81¢8% of the placebo group decreased TH density. ALRV5XR induced statistically significant changes in both decrease in vellus hair (VH) density as well as in concomitant increase of the TH/VH ratio when compared to placebo. ALRV5XR was well tolerated, and no adverse events were observed. Interpretation: ALRV5XR treatment resulted in clinically significant TH regrowth in men with AGA. Furthermore, it appeared to reverse the characteristic hair miniaturisation seen in this condition. When compared to results of published trials of standard therapy, ALRV5XR showed a multi-fold increase both in efficacy and in response rates. In addition, the continuance of TH regrowth from 12 to 24 weeks suggests that the normal structure and function of non-productive telogen follicles is restored and that a normal hair phenotype may be attained by extended ALRV5XR treatment. Funding: Arbor Life Labs.

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IGF-I deficiency and enhanced insulin sensitivity due to a mutated growth hormone receptor gene in humans

Cited by 7 publications

References 108 publications

Safety and efficacy of ALRV5XR in women with androgenetic alopecia or telogen effluvium: A randomised, double-blinded, placebo-controlled clinical trial

Safety and efficacy of ALRV5XR in women with androgenetic alopecia or telogen effluvium: A randomised, double-blinded, placebo-controlled clinical trial

Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

Safety and efficacy of ALRV5XR in men with androgenetic alopecia: A randomised, double-blinded, placebo-controlled clinical trial

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