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Novel Drugs for Infertility Treatment in 2022

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 13891

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Prof. Dr. Thomas D'Hooghe

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Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium
Interests: obstetrics; gynaecology; endometriosis
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Dear Colleagues,

In recent years, new drugs for infertility treatment have been developed and made available to patients and physicians. Some of these drugs have been newly developed, whereas others have been on the market for a while but have been found to be potentially effective and safe for infertility treatment. These drugs have a specific (bio)chemical structure, which is related to a number of activities in vitro and in vivo using research in animal models. However, the key relevant outcome is to understand how the drug biochemical structure is translated into biological activity in the human body, and how the drug dose and related pharmacokinetics, pharmacodynamics and metabolism affect the efficiency, effectiveness and safety of these drugs in humans.

This Special Issue of the International Journal of Molecular Sciences invites authors to submit original research or review papers providing new information regarding medicinal products intended for human infertility treatment, more specifically on the relationship between drug biochemical/molecular structure and dose, in vitro activity and biopotency in animal and in vitro models. In addition, within the scope of this issue are papers focusing on the molecular action of infertility drugs containing FSH, LH, HCG, progesterone or other compounds, taking into account the clinical relevance of this molecular action. Finally, we also welcome papers clarifying if and how genetic polymorphisms affect fertility and the response to infertility treatment.

Prof. Dr. Thomas D'Hooghe
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

infertility
drug biochemical structure
human infertility treatment
molecular structure
infertility drugs

Published Papers (6 papers)

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Research

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21 pages, 1738 KiB

Open AccessArticle

Biological Assay to Determine Gonadotropin Potency: From In Vivo to In Vitro Sustainable Method

by Francesco Nevelli, Angelo Palmese, Ralf Gleixner, Flavio Peroglio, Cosimo-Walter D’Acunto, Aurora Dadone, Thomas D’Hooghe and Monica Lispi

Int. J. Mol. Sci. 2023, 24(9), 8040; https://doi.org/10.3390/ijms24098040 - 28 Apr 2023

Cited by 3 | Viewed by 1975

Abstract

Various preparations of follicle-stimulating hormone (FSH) are commercially available; however, they differ in glycoforms composition and purity owing to their respective sources. Additional chemical/physical changes can also be introduced during manufacturing and can impact their biological activity (biopotency), which is routinely assessed using an in vivo bioassay (Steelman–Pohley). This study aimed to determine whether an in vitro bioassay could assess biopotency by distinguishing between r-hFSH chemical/physical variants with similar ability to the in vivo bioassay. The specific activity (units of biological activity per mg of product) of variants of r-hFSH generated through enrichment (acidic/basic), stress (oxidative/acidic pH) and enzymatic treatment (desialylation and desialylation/degalactosylation) was compared using the in vivo and in vitro bioassays. The in vitro bioassay reliably detected potential chemical/physical modifications in r-hFSH variants that may impact biopotency. Overall, the methods demonstrated a comparable ability to detect changes in specific activities due to chemical/physical differences in r-hFSH variants. These data indicate that the in vitro bioassay is suitable to replace the in vivo bioassay. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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16 pages, 3813 KiB

Open AccessArticle

Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats

by Xingfa Han, Xue Xia, Weihao Chen, Fengyan Meng, Xiaohan Cao, Guixian Bu, Tian Gan, Xiaogang Du, Qiuxia Liang and Xianyin Zeng

Int. J. Mol. Sci. 2023, 24(8), 6914; https://doi.org/10.3390/ijms24086914 - 7 Apr 2023

Viewed by 1362

Abstract

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin α subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence <VRTTSDGGYSFKY> within the betaglycan-binding epitope on human inhibin α subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INHα13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INHα13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INHα13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17β-estradiol concentrations. In summary, active immunization against INHα13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INHα13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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18 pages, 1568 KiB

Open AccessArticle

Comparative Assessment of the Structural Features of Originator Recombinant Human Follitropin Alfa Versus Recombinant Human Follitropin Alfa Biosimilar Preparations Approved in Non-European Regions

by Lucio Manzi, Nunzio Sepe, Walter Migliaccio, Ludovica Lanzoni, Luisa Iozzino, Fabrizia D’Angelo, Lucia Colarusso, Susana Montenegro, Angelo Palmese, Thomas D’Hooghe, Alfredo Ulloa-Aguirre, Yulia Koloda and Monica Lispi

Int. J. Mol. Sci. 2022, 23(12), 6762; https://doi.org/10.3390/ijms23126762 - 17 Jun 2022

Cited by 4 | Viewed by 3615

Abstract

Although the full primary structures of the alfa and beta subunits of reference r-hFSH-alfa and its biosimilars are identical, cell context-dependent differences in the expressing cell lines and manufacturing process can lead to variations in glycosylation profiles. In the present study, we compared the structural features of reference r-hFSH-alfa with those of five biosimilar preparations approved in different global regions outside Europe (Primapur^®, Jin Sai Heng^®, Follitrope^®, Folisurge^®, and Corneumon^®) with respect to glycosylation, macro- and microheterogeneity, and other post-translational modifications and higher order structure. The mean proportion of N-glycosylation-site occupancy was highest in reference r-hFSH-alfa, decreasing sequentially in Primapur, Jin Sai Heng, Corneumon, Follisurge and Follitrope, respectively. The level of antennarity showed slightly higher complexity in Corneumon, Primapur and Follitrope versus reference r-hFSH-alfa, whereas Jin Sai Heng and Folisurge were aligned with reference r-hFSH-alfa across all N-glycosylation sites. Sialylation level was higher in Corneumon and Follitrope, but small differences were detected in other biosimilar preparations compared with reference r-hFSH-alfa. Jin Sai Heng showed higher levels of N-glyconeuramic acid than the other preparations. Minor differences in oxidation levels were seen among the different products. Therefore, in summary, we identified var ious differences in N-glycosylation occupancy, antennarity, sialylation and oxidation between reference r-hFSH-alfa and the biosimilar preparations analyzed. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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Review

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14 pages, 1415 KiB

Open AccessReview

Gonadotropin Activity during Early Folliculogenesis and Implications for Polycystic Ovarian Syndrome and Premature Ovarian Insufficiency: A Narrative Review

by Salvatore Longobardi, Francesca Gioia Klinger, Wenjing Zheng, Maria Rosaria Campitiello, Thomas D’Hooghe and Antonio La Marca

Int. J. Mol. Sci. 2024, 25(14), 7520; https://doi.org/10.3390/ijms25147520 (registering DOI) - 9 Jul 2024

Viewed by 306

Abstract

Female fertility depends on the ovarian reserve of follicles, which is determined at birth. Primordial follicle development and oocyte maturation are regulated by multiple factors and pathways and classified into gonadotropin-independent and gonadotropin-dependent phases, according to the response to gonadotropins. Folliculogenesis has always been considered to be gonadotropin-dependent only from the antral stage, but evidence from the literature highlights the role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) during early folliculogenesis with a potential role in the progression of the pool of primordial follicles. Hormonal and molecular pathway alterations during the very earliest stages of folliculogenesis may be the root cause of anovulation in polycystic ovary syndrome (PCOS) and in PCOS-like phenotypes related to antiepileptic treatment. Excessive induction of primordial follicle activation can also lead to premature ovarian insufficiency (POI), a condition characterized by menopause in women before 40 years of age. Future treatments aiming to suppress initial recruitment or prevent the growth of resting follicles could help in prolonging female fertility, especially in women with PCOS or POI. This review will briefly introduce the impact of gonadotropins on early folliculogenesis. We will discuss the influence of LH on ovarian reserve and its potential role in PCOS and POI infertility. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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19 pages, 1797 KiB

Open AccessReview

Follicle-Stimulating Hormone Biological Products: Does Potency Predict Clinical Efficacy?

by Monica Lispi, Peter Humaidan, George R. Bousfield, Thomas D’Hooghe and Alfredo Ulloa-Aguirre

Int. J. Mol. Sci. 2023, 24(10), 9020; https://doi.org/10.3390/ijms24109020 - 19 May 2023

Cited by 3 | Viewed by 3687

Abstract

Follicle-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. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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29 pages, 2091 KiB

Open AccessReview

Mass Spectrometry-Based Untargeted Approaches to Reveal Diagnostic Signatures of Male Infertility in Seminal Plasma: A New Laboratory Perspective for the Clinical Management of Infertility?

by Mariaimmacolata Preianò, Serena Correnti, Tahreem Arshad Butt, Giuseppe Viglietto, Rocco Savino and Rosa Terracciano

Int. J. Mol. Sci. 2023, 24(5), 4429; https://doi.org/10.3390/ijms24054429 - 23 Feb 2023

Cited by 4 | Viewed by 2056

Abstract

Male infertility has been recognized as a global health problem. Semen analysis, although considered the golden standard, may not provide a confident male infertility diagnosis alone. Hence, there is the urgent request for an innovative and reliable platform to detect biomarkers of infertility. The rapid expansion of mass spectrometry (MS) technology in the field of the ‘omics’ disciplines, has incredibly proved the great potential of MS-based diagnostic tests to revolutionize the future of pathology, microbiology and laboratory medicine. Despite the increasing success in the microbiology area, MS-biomarkers of male infertility currently remain a proteomic challenge. In order to address this issue, this review encompasses proteomics investigations by untargeted approaches with a special focus on experimental designs and strategies (bottom-up and top-down) for seminal fluid proteome profiling. The studies reported here witness the efforts of the scientific community to address these investigations aimed at the discovery of MS-biomarkers of male infertility. Proteomics untargeted approaches, depending on the study design, might provide a great plethora of biomarkers not only for a male infertility diagnosis, but also to address a new MS-biomarkers classification of infertility subtypes. From the early detection to the evaluation of infertility grade, new MS-derived biomarkers might also predict long-term outcomes and clinical management of infertility. Full article

(This article belongs to the Special Issue Novel Drugs for Infertility Treatment in 2022)

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