We are pleased to introduce the Andrology Special Issue “Gonadotropins and their receptors: State-of-the-art 2025” based on talks presented at the “ICGR-V - 5th International Conference on Gonadotropins and Receptors” held in Tours, France, in 2024. Consistent advancements were made in this field during the last 5 years, and we sought to cover the need for an expert update. Gonadotropins are essential to support reproduction and development, with in vitro, in vivo, and clinical studies expanding our knowledge of their evolution, biology, and therapeutic use. Scientists active in this field were gathered to provide a state-of-the-art from fundamental scientific advances to clinical perspectives. The Special Issue is opened by the review paper “Structural and evolutionary insights into the function of glycoprotein hormones and their receptors” from Hendrickson and Gong 1. Gonadotropin-receptor phylogeny was discussed in light of the existing knowledge of molecular structures obtained by X-ray crystallography and cryogenic electron microscopy. These data lead to hypothetical models for glycoprotein hormone-receptor binding, functionally relevant dimeric associations of receptors, and signal activation, in the metazoan neuroendocrine system. Ingram and Kumar provide a comparative review on storage and secretory pathways of gonadotropins in vertebrates 2. They described how multiple glycoprotein hormones require the differentiation of storage and release systems from the originator cell to maintain hormone functionality and support the physiological needs of the organism. These events are due to a luteinizing hormone beta subunit-specific heptapeptide sequence, which is absent in the follicle-stimulating hormone beta (FSHβ), and impacts the secretion mode. These issues were recently investigated in genetically manipulated mice. Altogether, this review explained how the separation of a distinct hypothalamus–pituitary–gonadal axis occurred in complex vertebrates, as an endocrine departure from redundant multihormonal signaling of basal vertebrates. Our understanding of the mechanisms of receptor folding was deepened by Ulloa-Aguirre et al. 3. The review provided an expert view on the cellular machinery directing the endoplasmic reticulum export of receptors, preventing aggregation and toxic accumulation of defective molecules. Mutations lead to misfolded receptors with altered intracellular trafficking, resulting in loss-of-function and clinically significant conditions, such as hypogonadism. Future therapeutic opportunities are discussed via a review of the studies on pharmacoperone drugs, which exhibit the ability to “correct” receptor misfolding due to protein conformational defects and potentially treat diseases due to these receptor perturbations. The existence of physiologically meaningful interactions between gonadotropin receptors is a debated topic discussed by Lazzaretti et al. 4. Molecular complexes involving multiple receptors are known as oligomers and challenge the common knowledge that gonadotropin receptors act only in the monomeric form. Although technical limitations prevent the detection of gonadotropin receptor oligomers in vivo, recent data support the formation of oligomers acting as allosteric modulators and/or biased agonists, with implications for human reproductive pathophysiology. In the last three decades, relevant insights into LH physiology were provided by several genetically modified mice. Lessons from these in vivo models were reviewed by Huhtaniemi 5. In particular, the LH receptor knockout mouse model has unveiled novel, and unexpected insights into gonadotropin hormone receptor function by crossing this line with distinct genetically modified models, such as mice expressing a constitutively active FSHR. These models have provided a comprehensive view on gonadotropin pathophysiology and contributed to explain cases of human hypogonadism. Gonadotropin production and release is under the hypothalamic control, where kisspeptin neurons regulate the pulsatile secretion of gonadotropin-releasing hormone. Malfunctioning of kisspeptin signaling negatively impacts gonadotropin physiology and leads to reproductive disorders in both males and females. Functional and pubertal disorders, as well as structural pathologies of hypothalamic origin were reviewed by Pierret et al. 6, who examined the potential use of kisspeptin as a hallmark of hypothalamic reproductive dysfunctions. Human chorionic gonadotropin (hCG) may be used to restore spermatogenesis in azoospermic males with hypogonadotropic hypogonadism. However, the use of this hormone as a drug to treat other forms of nonobstructive azoospermia is a debated matter reviewed by Esteves et al. 7. Authors discussed properties and effectiveness of currently available hCG therapeutic preparations in supporting spermatogenesis, indicating the main areas for future clinical research. Combined hCG and FSH therapy is a well-established treatment for patients with hypogonadotropic hypogonadism. Instead, the use of FSH in the context of idiopathic male factor infertility is debated due to variable and unpredictable effects. Graziani et al. 8 discussed the personalization of FSH therapy in male factor infertility, which should be adapted according to a patient's genetic profile and responsiveness to the hormone (pharmacogenetics). Creating a pathway to this personalized approach to treatment is discussed by the authors through the development of an algorithm potentially predicting the response to FSH treatment, considering FSHB and FSHR gene polymorphisms, clinical, biochemical, and cytological data. In summary, recent studies have provided new insights on the evolution and structure–function relationship of gonadotropins and their receptors, as well as on other key regulators of the hypothalamus–pituitary–gonadal axis. This Special Issue provided an expert and up-to-date overview on the most recent and significant advancements in the field of gonadotropin physiology and clinical use. This knowledge has the potential to provide the basis to improve current therapeutical approaches in treatment and management of both male and female infertility, including development of precision therapy. Livio Casarini conceptualized and drafted the manuscript. Frederic Jean-Alphonse, Clara Lazzaretti, and Aylin C. Hanyaloglu commented and edited the article. All the authors reviewed and approved the final version. This work did not receive any specific funding. The authors declare no conflicts of interest.
Casarini et al. (Wed,) studied this question.