The role of Kisspeptin and its analogue in the diagnosis and treatment of reproductive disorders in humans

Kisspeptin, a hypothalamic neuropeptide encoded by the KISS1 gene, is a key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, by stimulating pulsatile gonadotrophin releasing hormone (GnRH) secretion. Since 2005, there has been a huge body of work on the effects of exogenous kisspeptin administration on gonadotrophin responses in humans. These have demonstrated kisspeptin’s potential as a therapeutic agent in reproductive disorders and highlighted its potential as a diagnostic tool to probe hypothalamic GnRH neuronal function. The translational application of kisspeptin as a diagnostic and therapeutic tool in the field of reproductive endocrinology has been the focus of this research project. Firstly, I investigated kisspeptin’s ability to differentiate men with congenital hypogonadotrophic Hypogonadism (CHH) from healthy men compared to the currently available GnRH test. All circulating isoforms of kisspeptin have relatively short half-lives due to their rapid enzymatic degradation. Furthermore, repeated kisspeptin administration causes kisspeptin receptor desensitisation. Thus, a more stable, longer acting kisspeptin analogue would be an ideal candidate for use in the field of kisspeptin based therapeutics. MVT602 is one such agonist, and whilst it has shown promising results during application in men, its effects in women had not been previously explored. I thus investigated the effects of MVT602 on the gonadotrophin responses of healthy women in the follicular phase, and how these change after oestrogen pre-treatment. In the final study of this research project I compared the gonadotrophin responses elicited by both KP54 and MVT602 in women with the two commonest anovulatory disorders, namely Polycystic Ovarian Syndrome (PCOS) and Hypothalamic Amenorrhoea (HA). In summary, the results of this research project highlight the huge potential of KP54 and MVT602 to improve the diagnosis and treatment of patients with reproductive disorders, and also add to the existing body of work in the field of translational research for kisspeptin.Open Acces

Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with “red flag” features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa). Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH. Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured. Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB. Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54. Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%). Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating CHH in boys with delayed puberty (auROC 98.5%, 95.9-100%), than in adult men (auROC 93.9%, 87.2-100%). Conclusion: INSL3 better identifies CHH in adult men, whereas INB better identifies CHH in boys with delayed puberty

The effectiveness of transcranial magnetic stimulation for dysphagia in stroke patients: an umbrella review of systematic reviews and meta-analyses

Numerous studies have explored the use of repetitive Transcranial Magnetic Stimulation (rTMS) intervention in post-stroke dysphagia. The primary aim of this umbrella review was to appraise the methodological quality of systematic reviews (SRs), with and without meta-analyses (MAs), that synthesized the findings of randomized controlled trials (RCTs) exploring the effectiveness of rTMS in the management of dysphagia post-stroke. A secondary aim of was to evaluate the consistency and reliability of translational implications of rTMS for swallowing recovery after stroke across these SRs and MAs. We searched several databases from inception to the 14th of May 2023, to identify SRs and MAs that examined the effectiveness of rTMS in the management of dysphagia post-stroke. The methodological quality of the included studies was evaluated utilizing the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) instrument. To investigate the extent of literature overlap among the primary studies included in the SRs, the Graphical Overview of Evidence (GROOVE) was utilized. Of the 19 SRs that were identified, two studies received low quality ratings, while the rest (17) were rated with critically low quality based on the AMSTAR 2 rating. A high literature overlap across the SRs was observed. In all SRs and MAs reviewed, there was a consistent presence of at least some significant evidence supporting the effectiveness of rTMS in enhancing swallowing outcomes for individuals with dysphagia post-stroke, that is, all MAs reported at least a moderate overall effect in favor of rTMS (SMD range = [0.59, 6.23]). While rTMS shows promise for improving dysphagia post-stroke, the current evidence remains limited and inconclusive due to the methodological flaws observed in the published SRs and their respective MAs on the topic so far. Concerning the limitations of our study, language restrictions and methodological shortcomings may affect the generalizability of our findings

Patient and Public Involvement in Stroke and Aphasia Research: a Thematic Analysis

Research Objectives To explore the views of people who live with chronic stroke and aphasia on their potential involvement as research partners. Design Qualitative study: semi-structured interviews. Participatory research model with a Patient and Public Involvement (PPI) partner: a person with chronic stroke-induced aphasia. Setting On line interviews (zoom). Participants Inclusion criteria: (1) to have experienced a stroke, (2) to be in the chronic stage of stroke (> 6 months post-stroke) (3) to speak, understand, read, and write English post-stroke (4) to be socially active as confirmed from the case history (5) to have at least one academic qualification, and (6) to have had previous research experience, whether as students or as researchers. An additional inclusion criterion for PWA was to show evidence, from case history interviews, of mild-moderate chronic aphasia. Participants Eight people with chronic stroke, four with concomitant aphasia and four without. Interventions N/A. Main Outcome Measures A thematic analysis following Braun and Clarke 6-step framework. Implementation of outcomes on the International Classification of disability F framework. Results Inductive thematic analysis generated four themes: (1) the kinds of Restrictions that make involvement in research difficult, (2) the preferred levels and ways of Involvement during the research process, (3) the Support required for active and collaborative involvement, and (4) the Impact of their involvement and how it benefits the study's outcomes. Conclusions People living with chronic stroke and aphasia are willing to be involved in PPI stroke and aphasia studies, if researchers provide the necessary robust support environment. The findings provide new evidence about how patient partnership models can support people with chronic communication deficits to contribute meaningfully to co-produced research