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Azione delle Gonadotropine sulle cellule target e relativa azione farmacologica nell'infertilità maschile: è tempo per l'azienda farmaceutica di cogliere la sfida?
No full textL'infertilità maschile è responsabile del 50% delle cause di infertilità di coppia. Tuttavia, viene trattata raramente con terapie mirate, poiché la riproduzione assistita può offrire una possibile soluzione. Questo PhD-industriale ha avuto l'obiettivo di sviluppare un business-case sul trattamento dell'infertilità maschile grazie alla collaborazione tra Merck KGaA e l'Università di Modena e Reggio Emilia. Il progetto si è basato su più line di ricerca: i) studiare il meccanismo di azione delle gonadotropine su cellule/organi target utilizzando modelli in-vitro per identificare il trattamento più efficace; ii) identificare endpoint clinici oggettivi e misurabili; iii) valutare l'efficacia clinica di LH e HCG in pazienti affetti da ipogonadismo ipogonadotropo (Ipo-Ipo);
Lo studio in-vitro dell'induzione di steroidi con gonadotropina corionica umana (hCG) nella linea mLTC1 mediante LC-MS/MS (Fanelli F et al 2022) ha dimostrato che l'hCG è in grado di stimolare la sintesi di DHT attraverso entrambi i pathway cellulari noti, canonico e backdoor. Ulteriori analisi volte a valutare la differenza dell'azione di LH e hCG sulle cellule di Leydig sono state eseguite nella linea cellulare mLTC1, dimostrando che LH e hCG attivano diversamente l'espressione dei geni steroidogenici, riflettendo una steroidogenesi ormone-mediata. In particolare l'hCG sovraregola l’espressione del gene Hsd13b3, mentre Hsd3b6 e 2, così come Srd5a2, sono sovraregolati dall'LH. Entrambe le gonadotropine sovraregolano l'espressione di Srd5a1, mentre solo la stimolazione delle cellulare con LH ha generato una sovraregolazione di Akr1c13, 14 e 20 (Kruskal Wallis, p <0,05, n = 4; Hprt1 usato come controllo). Questi ultimi dati non sono stati ancora pubblicati.
L’analisi retrospettiva di dati clinici pubblicati ha mostrato che il trattamento con FSH migliora la frammentazione del DNA spermatico (sDF) nei pazienti con infertilità idiopatica. Inoltre, i livelli di testosterone (T) dopo il trattamento hanno mostrato una correlazione negativa con la riduzione del sDFI, suggerendo una potenziale azione sinergica tra i compartimenti interstiziali e tubulari testicolari (Lispi et al 2022) e candidando il T come un potenziale biomarker dell’efficacia del trattamento con FSH.
Lo studio “Farmacodinamica e sicurezza dell’ormone luteinizzante umano ricombinante in pazienti maschi con ipogonadismo ipogonadotropo” (EudraCT 2019-004677-12 ), attualmente in corso, ha lo scopo di valutare se la somministrazione di LH potrebbe essere più efficace dell’hCG nella stimolazione della steroidogenesis in casi di deficienza di attività dell’LH. L'ipotesi statistica è la non inferiorità della dose più alta di LH usata rispetto all'hCG. Endpoint primario: livelli sierici di testosterone valutati mediante LC-MS/MS. Dosi crescenti di hCG e LH vengono somministrati ogni due settimane per ottenere una curva dose-risposta dei livelli di T. Dati preliminari hanno dimostrato che LH non è in grado di aumentare sufficientemente il T.
In ultimo, sono stata in grado di finalizzare il "Business case sull'infertilità maschile". I dati forniti da questo PhD hanno mostrato un alto potenziale dell’uso delle gonadotropine per il trattamento di pazienti con ipogonadismo ipogonadotropo e con infertilità maschile idiopatica. FSH e hCG mostrano un potenziale di investimento per l’azienda che potrebbe così ampliare il portfolio prodotti. I dati generati hanno anche mostrato un potenziale beneficio clinico dell’LH che dovrebbe essere ulteriormente esplorato. Il lavoro di ricerca di base ha generato nuove evidenze sul modo d’azione delle gonadotropine, ampliando le conoscenze sulla spermatogenesi e sulla steroidogenesi nell’uomo e fornendo nuove opportunità terapeutiche per il trattamento dell’infertilità maschile.Male infertility is one of the most relevant scientific topics in reproduction, the male factor being responsible of 50% of causes of couple infertility. However, male infertility is rarely treated since assisted reproduction is successful in many cases. This industrial PhD had the objective to build a business case on male infertility treatment thanks to the collaboration between Merck KGaA and Modena & Reggio Emilia University on three main projects: i) to understand thoroughly gonadotropin mechanism of action on target cells/organs using in-vitro models, aimed at identifying the most efficient treatment of the male-factor; ii) to identify objective, assessable, clinical endpoints; iii) to evaluate the clinical efficacy of LH and HCG in patients with hypogonadotropic hypogonadism (HH). Finally, iv) Merck built a business case aimed at evaluating the profitability of entering this therapeutic area, beyond the case of HH, by developing appropriate therapies based on the market potential and unmet medical needs.
In-vitro exploration of the human chorionic gonadotropin (hCG) induction of steroid secretion in the mouse cell line mLTC1 by LC-MS/MS (Fanelli F et al 2022) demonstrated that hCG is able to massively stimulate steroid production via both the canonical and backdoor pathway of DHT synthesis. Additional analysis aimed at assessing difference of LH and hCG action on Leydig cells were performed in mLTC1 cells, showing that LH and hCG differently impact the expression of steroidogenic genes, reflecting hormone-specificity. In particular, digital droplet PCR analysis revealed that hCG upregulates the Hsd13b3 gene, while Hsd3b6 and 2, as well as Srd5a2, are upregulated by LH. Both gonadotropins increased the expression of Srd5a1, while only treatment with LH resulted in Akr1c13, 14 and 20 upregulation (Kruskal Wallis test, p<0.05, n=4) (manuscript in preparation).
Retrospective post hoc analysis of published data provided evidence that FSH improves sperm DNA fragmentation (sDF) in idiopathic male patients. Moreover, testosterone l(T) evels after treatment are negatively correlated with sDF decrease, suggesting a potential synergic action between the interstitial and tubular testicular compartments (Lispi et al 2022) and electing T as potential biomarker of FSH action.
The ongoing clinical study “Pharmacodynamics and safety of human recombinant LH in HH men” aims at assessing whether LH supplementation could be more efficient than hCG to stimulate steroidogenesis in those cases where LH activity is required (EudraCT 2019-004677-12). The statistical hypothesis is non-inferiority of the highest LH dose employed compared to hCG. Primary endpoint is serum T levels evaluated by LC-MS/MS. Increasing dosages of hCG and LH are administered at two-week intervals to obtain dose-response curves of stimulated serum T levels. Preliminary data demonstrated that LH alone is not able to sufficiently increase T.
Finally, I was able to finalize the “Male Infertility Business Case” for Company discussion and decision. The data generated in this PhD project showed high potential for gonadotropin use to treat HH and idiopathic male infertility. FSH and hCG are target molecules on which the Company could invest to expand indications. Meanwhile, the potential clinical benefit of LH should be further explored. The basic research work done here is providing novel evidence on the mode of action of gonadotropins on target cells. This will expand the knowledge on spermatogenesis and steroidogenesis regulation, providing new treatment approaches of male infertility
Comparison between follitropin-delta and follitropin-alfa for ovarian stimulation in context of ART is only scientifically sound and clinically relevant if individualization of starting dose is allowed in both arms!
No full textFollicle-Stimulating Hormone Biological Products: Does Potency Predict Clinical Efficacy?
Get PDFFollicle-stimulating hormone (FSH), together with luteinizing hormone (LH) and human chorionic gonadotropin (hCG), plays a fundamental role in human reproduction. The discovery of FSH and other gonadotropins was a defining moment in our understanding of reproduction and led to the development of many treatments for infertility. In this regard, exogenous FSH has been used to treat infertility in women for decades. Today, several recombinant and highly purified urinary forms of FSH are used in medically assisted reproduction (MAR). However, differences in the macro- and micro-heterogeneity of FSH result in a variety of FSH glycoforms, with glycoform composition determining the bioactivity (or potency), pharmacokinetic/pharmacodynamic (PK/PD) profiles, and clinical efficacy of the different forms of FSH. This review illustrates how the structural heterogeneity of FSH glycoforms affects the biological activity of human FSH products, and why potency does not predict effects in humans in terms of PK, PD, and clinical response
Cost-effectiveness analysis of recombinant human follicle-stimulating hormone alfa(r-hFSH) and urinary highly purified menopausal gonadotropin (hMG) based on data from a large German registry
Get PDFThis was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German in vitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (€17,938 vs. €20,054), two (€18,251 vs. €20,437), and three (€18,473 vs. €20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles
Testosterone Serum Levels Are Related to Sperm DNA Fragmentation Index Reduction after FSH Administration in Males with Idiopathic Infertility
Get PDFPurpose: Although a robust physiological rationale supports follicle stimulating hormone (FSH) use in male idiopathic infertility, useful biomarkers to evaluate its efficacy are not available. Thus, the primary aim of the study was to evaluate if testosterone serum levels are related to sperm DNA fragmentation (sDF) index change after FSH administration. The secondary aim was to confirm sDF index validity as a biomarker of FSH administration effectiveness in male idiopathic infertility. Methods: A retrospective, post-hoc re-analysis was performed on prospectively collected raw data of clinical trials in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported. Results: Three trials were included, accounting for 251 patients. The comprehensive analysis confirmed FSH’s beneficial effect on spermatogenesis detected in each trial. Indeed, an overall significant sDF decrease (p < 0.001) of 20.2% of baseline value was detected. Although sDF resulted to be unrelated to testosterone serum levels at baseline, a significant correlation was highlighted after three months of FSH treatment (p = 0.002). Moreover, testosterone serum levels and patients’ age significantly correlated with sDF (p = 0.006). Dividing the cohort into responders/not responders to FSH treatment according to sDF change, the FSH effectiveness in terms of sDF improvement was related to testosterone and male age (p = 0.003). Conclusion: Exogenous FSH administration in male idiopathic infertility is efficient in reducing sDF basal levels by about 20%. In terms of sDF reduction, 59.2% of the patients treated were FSH-responders. After three months of FSH administration, a significant inverse correlation between sDF and testosterone was detected, suggesting an association between the FSH-administration-related sDF improvement and testosterone serum levels increase. These observations lead to the hypothesis that FSH may promote communications or interactions between Sertoli cells and Leydig cells
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Letter to the editor in response to ‘A real-world study of ART in France (REOLA) comparing a biosimilar rFSH against the originator according to rFSH starting dose’ by P. Barrière, S. Hamamah, E. Arbo, C. Avril, B. Salle, J.-L. Pouly, et al. (J Gynecol Obstet Hum Reprod. 2023;52(1):102510)
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