The influence of the pharmaceutical industry on the development of gonadotrophins and ovarian stimulation protocols in assisted reproductive technologies

IntroductionThis review examines the evolution of gonadotrophins in ovarian stimulation (OS) protocols for assisted reproductive techniques (ART). Since the advent of in vitro fertilisation (IVF) in the late 1970s, the pharmaceutical industry has played a pivotal role in advancing gonadotrophin production, improving drug purity and optimising delivery methods. Despite significant progress, questions remain about the robustness of the evidence supporting the use of different gonadotrophins and the impact of industry-driven research on clinical practice. The review critically examines the evolution, evidence and future directions of gonadotrophin use in ART.MethodsA comprehensive literature search was carried out in multiple databases to select articles/reviews on historical developments, manufacturing and analytical techniques, regulatory frameworks and clinical trials undertaken to assess gonadotrophin production, formulation processes and their integration into clinical practice. The analysis included mainly evidence from pharmaceutical sponsored randomised controlled trials (RCTs) as well as single arm, registration or post approval studies. Studies on new molecular entities were reviewed. Systematic reviews and meta-analyses, national registries were consulted. Laboratory developments, regulatory challenges, economic constraints, were considered.ResultsOver the past four decades, ART has seen remarkable improvements, including increased live birth rates in women of advanced ovarian age, reduced multiple births, and the advent of patient-friendly pen devices. Innovations such as recombinant FSH (rFSH) and biosimilars have expanded treatment options. However, the high cost of drug development as well as the complexity of the ART process have contributed to underpowered trials and reliance on meta-analyses, which often fail to account for confounding factors.DiscussionWhile gonadotrophins have been shown to be effective for OS, unresolved issues, such as the role of supplementing LH activity in OS protocols, highlight the need for more robust trials. Collaboration between stakeholders is essential to standardise trial designs, define key outcomes and minimise bias. Emerging technologies, including AI and genetic testing, offer opportunities to refine embryo assessment and implantation outcomes, thus improving trial design. A renewed focus on rigorous, transparent trials and interdisciplinary collaboration is essential to advance patient care and address unmet challenges in ART treatment. Beyond gonadotrophins, alternative therapeutic avenues to improve oocyte competence and implantation success warrant exploration

The influence of the pharmaceutical industry on the development of gonadotrophins and ovarian stimulation protocols in assisted reproductive technologies

Introduction: This review examines the evolution of gonadotrophins in ovarian stimulation (OS) protocols for assisted reproductive techniques (ART). Since the advent of in vitro fertilisation (IVF) in the late 1970s, the pharmaceutical industry has played a pivotal role in advancing gonadotrophin production, improving drug purity and optimising delivery methods. Despite significant progress, questions remain about the robustness of the evidence supporting the use of different gonadotrophins and the impact of industry-driven research on clinical practice. The review critically examines the evolution, evidence and future directions of gonadotrophin use in ART. Methods: A comprehensive literature search was carried out in multiple databases to select articles/reviews on historical developments, manufacturing and analytical techniques, regulatory frameworks and clinical trials undertaken to assess gonadotrophin production, formulation processes and their integration into clinical practice. The analysis included mainly evidence from pharmaceutical sponsored randomised controlled trials (RCTs) as well as single arm, registration or post approval studies. Studies on new molecular entities were reviewed. Systematic reviews and meta-analyses, national registries were consulted. Laboratory developments, regulatory challenges, economic constraints, were considered. Results: Over the past four decades, ART has seen remarkable improvements, including increased live birth rates in women of advanced ovarian age, reduced multiple births, and the advent of patient-friendly pen devices. Innovations such as recombinant FSH (rFSH) and biosimilars have expanded treatment options. However, the high cost of drug development as well as the complexity of the ART process have contributed to underpowered trials and reliance on meta-analyses, which often fail to account for confounding factors. Discussion: While gonadotrophins have been shown to be effective for OS, unresolved issues, such as the role of supplementing LH activity in OS protocols, highlight the need for more robust trials. Collaboration between stakeholders is essential to standardise trial designs, define key outcomes and minimise bias. Emerging technologies, including AI and genetic testing, offer opportunities to refine embryo assessment and implantation outcomes, thus improving trial design. A renewed focus on rigorous, transparent trials and interdisciplinary collaboration is essential to advance patient care and address unmet challenges in ART treatment. Beyond gonadotrophins, alternative therapeutic avenues to improve oocyte competence and implantation success warrant exploration

Biological versus chronological ovarian age:implications for assisted reproductive technology

<p>Abstract</p> <p>Background</p> <p>Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment.</p> <p>Methods</p> <p>Literature searches supplemented with the authors' knowledge.</p> <p>Results</p> <p>Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells.</p> <p>Conclusion</p> <p>Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.</p