Development of biosimilaries and biosimilar growth hormone

In this article, an informative presentation was made about the development of biosimilar and biosimilar growth hormone in Europe and the Republic of Moldova following the selection and analysis of 37 bibliographic sources from the PubMed database and from specialized journals. Human growth hormone was approved by the EMA in 2006 as the world’s first biosimilar drug. Recombinant growth hormone therapy is currently approved for growth hormone deficiency, Turner syndrome, chronic kidney failure, in children/adolescents born young for gestational age and Prader-Willi syndrome. At the same time, biosimulation therapy is very expensive. In the Republic of Moldova but also in Eastern Europe, the accessibility of biological medicines is extremely low due to the lack of local or regional producers. Th e development of the biosimilar production branch, including the biosimilar growth hormone in the Republic of Moldova, will be an attractive and pharmacoeconomically advantageous option for the therapeutic arsenal.

Case Report: Human Recombinant Growth Hormone Therapy in a DSH Cat Presented With Dwarfism

A 6-month-old kitten, male, domestic shorthair cat was presented with dwarfism, ocular and nasal discharge, and Ascaris infestation. Congenital hyposomatotropism was diagnosed on the basis of serum level of insulin-like growth factor-1 (IGF-I). The cat was treated with human recombinant growth hormone for 9 weeks. After that, his liver enzymes became elevated, and the therapy was discontinued. His IGF-I levels were normal at the end of the therapy. Normal IGF-I was present 3 months after discontinuation of therapy with human recombinant growth hormone and even half a year after the discontinuation. All other comorbidities were addressed with the therapy. The cat is now the size of normal cats, living with the first author.

A 10-Year Perspective on the Utility of Three Adjuvants Often Used in IVF: Growth Hormone, Melatonin and DHEA

Since 2010, numerous studies reported from PIVET, a pioneer IVF facility established over 40 years ago, have explored the use of three adjuvants designed to improve laboratory and clinical outcomes in cases where a poor prognosis has been demonstrated. The adjuvants reported commenced with recombinant growth hormone (rGH), followed by dehydroepiandrosterone (DHEA) after developing a unique troche to avoid the first-pass effect and, subsequently, melatonin. The studies show that rGH is beneficial in the situation where women have poor-quality embryos in the setting of additional poor prognosis factors, such as advanced female age, a very low ovarian reserve, an insulin growth factor profile in the lowest quartile or recurrent implantation failure. The studies also imply that the adjuvants may actually reduce live birth productivity rates if used on women without poor prognosis factors; hence, further studies, which can now be better designed, should be undertaken to explore the notion of underlying adult growth hormone deficiency in some cases as well as the suggestion that DHEA can provide equivalent benefits in some poor prognosis settings. Melatonin showed no suggestive benefits in any of the studies and can be excluded from consideration in this context. Future studies should compare rGH and DHEA with a focus on those women who have poor embryo quality with additional poor prognosis factors. Such trials should be extended to 12 weeks to cover the entire period of oocyte activation.

The proteomic signature of recombinant Growth Hormone in recreational athletes

Objectives Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete’s sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. Methods Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomized into four groups, receiving one of three different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting four weeks prior to treatment, three weeks of treatment, and six weeks’ follow-up. A total of 749 serum samples was analyzed for 1,305 protein markers using the SOMAscan® proteomics platform. Results We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (e.g.: protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. Conclusion Our analysis suggests that hGH administration is impacting biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH associated proteins in the etiology of hGH related diseases and may indicate new risks that may be associated with hGH misuse.

Screening Sleep Abnormalities in Children with Prader–Willi Syndrome: Challenges in the Indian Scenario

There is a high prevalence of sleep-related breathing disorders in the form of obstructive and central sleep apnea as well as spontaneous oxygen desaturation in children with Prader–Willi syndrome (PWS). Most cases are asymptomatic and if untreated go on to develop unfavorable neurodevelopmental, cardiovascular, and cerebrovascular outcomes. Hence, sleep study or polysomnography (PSG) is recommended in all children at the time of diagnosis as well as with the development of certain risk factors including symptoms of sleep apnea, before and after initiation of recombinant growth hormone (rGH) therapy. The use of rGH in children with PWS has been shown to improve central sleep apnea but also shown to be associated with worsening of OSA. PSG is ideally performed in a sleep laboratory. Various types of PSG devices are available depending on the biological parameters that are desired to be monitored. Sleep disorders in children are distinct from those seen in adults and have different diagnostic scoring criteria necessitating a trained pediatric sleep specialist to analyze the PSG recording. Through the clinical case vignette of a 14-year-old girl with PWS, severe obesity, and sleep disordered breathing, this review aims to highlight the need, timing, types, analysis, and interpretation of sleep studies in infants and older children with PWS, particularly in relation to rGH therapy. There is a paucity of literature on sleep studies in children with PWS in the local setting. Thus this review also suggests the need for adapting the existing Western guidelines for PSG in Indian children with PWS.

Increased Testicular Insulin-like Growth Factor 1 is Associated with Gonadal Activation by Recombinant Growth Hormone in Immature Rats

To understand the mechanism of precocious sexual maturation following prepubertal growth hormone (GH) therapy, the effects of recombinant human GH (rhGH) on the kisspeptin-gonadotropin-releasing hormone-luteinizing hormone (GnRH-LH) system in the hypothalamus-pituitary axis, systemic and testicular insulin-like growth factor-1 (IGF1), spermatogenesis and Leydig cell steroidogenesis, and circulating testosterone levels were examined in immature rats. Following daily injection of rhGH (1 or 2 IU/kg) from postnatal day (PND) 21 to PND 23 or 30, testicular steroidogenic pathway genes and spermatogenesis marker genes mRNA levels, the number and size of HSD17B(+) Leydig cells, and blood testosterone levels in the rhGH rats were significantly higher than those of controls on PNDs 24 and 31. Hypothalamic Kiss1 and Gnrh1 mRNA in the rhGH rats were significantly higher than those in the controls on PND 24, indicating early activation of hypothalamic kisspeptin-GnRH neurons by rhGH. Hypothalamic Igf1 mRNA levels in rhGH rats were significantly higher than those in the controls on PND 24 but significantly lower than those in controls on PND 31. Testicular Igf1 mRNA levels were significantly higher in rhGH rats than in the controls on PNDs 24 and 31 whereas liver Igf1 mRNA levels and circulating IGF1 levels were not. In progenitor Leydig cells, rhGH significantly increased the Igf1 and steroidogenic pathway genes mRNA levels and the testosterone production. Therefore, local increases in testicular IGF1 might be an important mediator of gonadal activation via steroidogenic activation of Leydig cells in immature rats given rhGH.

Applying growth hormone as an adjuvant to correct poor prognosis outcomes in IVF: Study 1 compares melatonin

This retrospective study examines the influence of recombinant growth hormone (rGH) and melatonin adjuvants on oocyte numbers, embryo utilization and live births arising from 3637 autologous IVF±ICSI treatment cycles undertaken on 2376 women across ten years (2011-2020) within a pioneer Australian facility. Despite using an FSH-dosing algorithm enabling maximal doses up to 450 IU for women with reduced ovarian reserve, younger women had significantly higher mean numbers of oocytes recovered than older women ranging from 11.1 for women <35 years to 9.4 for women aged 35-39 years reducing to 6.5 for women aged 40-44 years and 4.0 for those aged ≥45 years (p<0.0001). Overall, the embryo utilization rate was 48.5% and live birth productivity rate was 35.4 % across all ages and neither rGH nor melatonin showed any benefit on these rates, in fact, those women with nil adjuvants showed the highest live birth rate per initiated cycle (42.0% overall: p<0.0001, and 55.3% for the youngest group: p<0.001). Embryo utilization was increased marginally by rGH in those women aged 40-44 years who had high ovarian reserve (p<0.05), but this benefit did not translate into any improvement in the live birth rate. Similarly, other factors known to cause a poor prognosis, including low IGF-1 profile, recurrent implantation failure, and low oocyte numbers at OPU, showed no improvement in embryo utilization nor in live births from the adjuvants. The relevance of embryo quality was examined on 1135 women whose residual embryos after a single fresh-embryo transfer failed to develop to a suitable grade for cryopreservation. From 1727 cycles such women often displayed an improved embryo utilization rate with rGH, but not with melatonin. Even so, live birth rates were not improved by either of the adjuvants.