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Schematic representation of FSH, FSH-CTP, and of the FSHβ-CTP-CGβ-α and FSHβ-CTP-LHβ-CTP-α analogues; A) FSH molecule; B) FSH-CTP with four additional O-linked glycosylations; C) dually active FSHβ-CTP-CGβ-α analogue. D) dually active FSHβ-CTP-LHβ-CTP-α analogue.
Source publication
Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in...
Context in source publication
Context 1
... analogues had comparable or improved biological activity in vivo compared to native FSH, half-lives were also improved presumably because O-linked glycosylation sites of the CTP reduced hepatic clearance rates [156][157][158]. Some analogues (Figure 2) presenting dual FSH and LH activities (FSHβ-CTP-CGβ-α and FSHβ-CTP-LHβ-CTP-α) increased serum estradiol, ovarian weight and the formation of corpora lutea when injected in sheep [158][159][160]. To date, no single-chain FSH or dually active gonadotropin analogue has reached the clinical phase of development. ...
Citations
... Treatments for male infertility include hormonal therapy where testosterone hormone is used, treatment of sexually transmitted infections, and medication to improve sperm production. 17 Surgical procedures are available to fix a varicocele or eliminate obstacles that could prevent sperm maturation, production, or ejaculation. 18 Technology for assisted reproduction, such as artificial insemination using donor sperm, intracytoplasmic sperm injection (ICSI), and in vitro fertilization (IVF) are other options for men affected with infertility. ...
... FSH is involved in regulating follicle development, 1 oogenesis, 2 and spermatogenesis. 3 It has also been linked to reproductive disorders such as polycystic ovary syndrome 4 and infertility. 5 Moreover, outside the reproductive system, FSH plays important roles in biological activities and is an important target for treating diseases. ...
The adenopituitary secretes follicle‐stimulating hormone (FSH), which plays a crucial role in regulating the growth, development, and reproductive functions of organisms. Investigating the process of FSH synthesis and secretion can offer valuable insights into potential areas of focus for reproductive research. Epidermal growth factor (EGF) is a significant paracrine/autocrine factor within the body, and studies have demonstrated its ability to stimulate FSH secretion in animals. However, the precise mechanisms that regulate this action are still poorly understood. In this research, in vivo and in vitro experiments showed that the activation of epidermal growth factor receptor (EGFR) by EGF induces the upregulation of miR‐27b‐3p and that miR‐27b‐3p targets and inhibits Foxo1 mRNA expression, resulting in increased FSH synthesis and secretion. In summary, this study elucidates the precise molecular mechanism through which EGF governs the synthesis and secretion of FSH via the EGFR/miR‐27b‐3p/FOXO1 pathway.
... More than 20 genes for congenital hypogonadotropic hypogonadism (CHH) have been identified, the most common of which are reported in Table 16.1. Patients with CHH generally respond well to gonadotropin replacement therapy, and the majority of them would regain sperm production and may proceed to natural conception [53]. However, genetic testing in such cases is recommended to explore the risks of disease inheritance to their offspring [13]. ...
Approximately one in twenty men have sperm counts low enough to impair fertility but little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or management strategies in infertile men. Many of these problems increase with age, leading to a growing population of men seeking help. To address this, there is a strong movement towards integrating male reproductive and sexual healthcare involving clinicians such as andrologists, urologists, endocrinologists and counselors. This book will emphasize this integrated approach to male reproductive and sexual health throughout the lifespan. Practical advice on how to perform both clinical and laboratory evaluations of infertile men is given, as well as a variety of methods for medically and surgically managing common issues. This text ties together the three major pillars of clinical andrology: clinical care, the andrology laboratory, and translational research.
... In this complex scenario, even less evidence is available on the best efficacy marker of FSH treatment in male idiopathic infertility. Several studies reported an average increase in sperm concentration in response to FSH administration [45], while in other studies, a reduction in sperm DNA fragmentation index emerged [13,46]. However, this latter parameter, which has recently been promoted as an additional in the latest WHO manual [47], is still far from being used in clinical practice, and data are limited to research settings. ...
Testis stimulation with follicle-stimulating hormone (FSH) is one of the empirical treatments proposed for male idiopathic infertility, although reliable markers to predict its efficacy are still lacking. This study aimed to identify parameters able to predict FSH efficacy in terms of pregnancy achievement. A real-world study was conducted, enrolling idiopathic infertile men treated with FSH 150IU three times weekly. Patients were treated until pregnancy achievement or for a maximum of two years and two visits were considered: V0 (baseline) and V1 (end of FSH treatment). Primary endpoints were the V1-V0 percentage change in sperm concentration, total sperm count, and total motile sperm number. In total, 48 pregnancies were recorded (27.7%) among 173 men (age 37.9 ± 6.2 years). All three endpoints increased after FSH administration, and only the V1-V0 percentage of sperm concentration significantly predicted pregnancy (p = 0.007). A V1-V0 sperm concentration of 30.8% predicted pregnancy, and the sperm concentration V1-V0 percentage (Y) required to obtain a pregnancy was predicted according to its baseline values (x): Y = 9.8433x2 − 203.67x + 958.29. A higher number of pregnancies was reached in men with baseline sperm concentration below 7.3 million/mL. Thus, the percentage of sperm concentration increasing after FSH administration could predict the treatment efficacy in terms of pregnancy. At the dosage used, the efficacy was significantly higher in patients with a starting sperm concentration < 7.3 mill/mL. Mathematical analyses identified a function able to predict the sperm concentration increase required to obtain a pregnancy in relation to the baseline sperm number.
... The Italian Society of Andrology and Sexual Medicine (SIAMS) recently suggested the use of FSH preparations to increase sperm concentration and motility in infertile normo-gonadotropic men with idiopathic OAT, with moderate evidence grading [8], although this is limited by the relatively high costs and off-label usage in some countries [9]. In hypogonadotropic hypogonadism the use of FSH is more easily recommended [10]. Beyond the well-known effects of FSH on male and female reproductive functions, and precisely because of its increasing usage in the treatment of infertility, the attention has recently focused on the extra-gonadal effects of FSH, along with the possible underlying mechanisms. ...
Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.
... Gonadotropin receptor allosteric modulation has been demonstrated to occur though heteromeric structures as well, which can deviate, amplify or suppress the hormone-dependent signaling. The different effects of those molecular interactions could find clinical applications to improve treatments of male and female infertility as well as gonadic disorders (94). For this purpose, new oral contraceptives with no side effects may provide useful tools to develop comfortable personalized treatments. ...
Gonadotropins regulate reproductive functions by binding to G protein-coupled receptors (FSHR and LHCGR) expressed in the gonads. They activate multiple, cell-specific signalling pathways, consisting of ligand-dependent intracellular events. Signalling cascades may be modulated by synthetic compounds which bind allosteric sites of FSHR and LHCGR or by membrane receptor interactions. Despite the hormone binding to the orthosteric site, allosteric ligands, and receptor heteromerizations may reshape intracellular signalling pattern. These molecules act as positive, negative, or neutral allosteric modulators, as well as non-competitive or inverse agonist ligands, providing a set of new compounds of a different nature and with unique pharmacological characteristics. Gonadotropin receptor allosteric modulation is gathering increasing interest from the scientific community and may be potentially exploited for clinical purposes. This review summarizes the current knowledge on gonadotropin receptor allosteric modulation and their potential, clinical use.
... Reseptor FSH yang menurun fungsinya secara langsung akan menghambat input FSH kedalam sel sertoli. 24,25 Konsentrasi FSH yang menurun kemudian akan menghambat pensinyalan untuk proses mitosis didalam sel sertoli yang akan menyebabkan proses spermatogoniogenesis terhambat. Penurunan konsentrasi FSH didalam sel sertoli juga menurunkan pensinyalan terhadap efek anti-apoptosis dan internalisasi FSHR yang dimediasi arrestin, hal ini akan menyebabkan proses apoptosis didalam sel sertoli meningkat sehingga terjadi kerusakan hingga kematian sel sertoli secara langsung yang dapat mengakibatkan organ testis menjadi atrofi. ...
... Penurunan konsentrasi FSH didalam sel sertoli juga menurunkan pensinyalan terhadap efek anti-apoptosis dan internalisasi FSHR yang dimediasi arrestin, hal ini akan menyebabkan proses apoptosis didalam sel sertoli meningkat sehingga terjadi kerusakan hingga kematian sel sertoli secara langsung yang dapat mengakibatkan organ testis menjadi atrofi. 24,25 Kerusakan sel sertoli secara sentral dimulai dari rusaknya sel-sel hipofisis di hypothalamus yang dimediasi reseptor AMDA dan NMDA di otak yang akan menghambat produksi GnRH, sehingga terjadi penurunan kadar gonadotropin baik LH atau FSH. 12,26 Hormon FSH berperan dalam proses spermatogenesis dengan cara menstimulasi sel sertoli, sehingga jika kadarnya menurun akan menyebabkan proses spermatogenesis menurun, akibatnya jumlah spermatozoa menurun. ...
The current modern era causes lifestyle changes, especially in urban communities, in terms of daily consumption patterns that tend to be accustomed to consuming fast food that contains many additional compounds. A compound commonly known as a food flavoring additive is monosodium glutamate (MSG), a sodium salt that is naturally produced from L-glutamic acid. Apart from its role in enhancing the taste of food, several studies have shown that MSG has toxic effects on human and animal tissues including the reproductive system which may cause infertility. Glutamate in MSG has a direct reaction effect at the cellular level, one of which forms free radicals and causes oxidative stress. The increase in free radicals in the body can cause damage to the organs of the body including the testes. Damage caused by MSG can also occur centrally in the hypothalamus so that it interferes with the hormonal and endocrine reproductive systems. Damage to pituitary cells will inhibit the production of gonadotropin-releasing hormone (GnRH), resulting in a decrease in gonadotropin levels, either luteinizing hormone (LH) or follicle stimulating hormone (FSH) produced by the pituitary gland. This article aims to discuss in detail how MSG affects male fertility.
... Regulation of spermatogenesis maintenance is the basic function of FSH in males. Sertoli cells, providing trophic, regulatory, and immunomodulatory factors for spermatogenesis [50], express FSH but not LH receptors [51]. Therefore, decreased FSH plasma levels may also account for structural disorders of the testes. ...
The development of the neuroendocrine system, including the hypothalamic–pituitary–gonadal (HPG) axis, is sensitive to environmental impacts during critical developmental periods. Maternal immune system activation by bacterial or viral infection may be one of the negative impacts. This study focused on the effect of systemic inflammation induced by lipopolysaccharides (LPS E. coli) on the HPG axis development in male rat offspring, corrected by the anti-inflammatory action of polyclonal IgG and monoclonal anti-interleukin (IL)-6 receptor antibodies (IL-6RmAbs). A single LPS exposure on the 12th embryonic day (ED) led to a decrease in the number of afferent synaptic inputs on gonadotropin-releasing, hormone-producing neurons in adult male offspring. LPS exposure on ED18 did not lead to such disruptions. Moreover, after the LPS injections on ED12, circulating follicle-stimulating hormone and sex steroid levels were reduced, and the gonadal structure was disrupted. A prenatal IL-6R blockade with IL-6RmAbs and polyclonal IgG reduced the negative effects of inflammation on fetal HPG axis development. Overall, the data obtained confirm the morphogenetic effect of inflammation on fetal HPG development and IL-6 involvement in these processes.
... The main hormonal treatment is represented by gonadotropins [42]. FSH treatment appears effective in men with hypogonadotropic hypogonadism [42,43], and with oligo/asthenozoospermia with normal FSH plasma levels [8]. Furthermore, it could be useful also to improve non-conventional semen parameters, such as DNA fragmentation. ...
Background:
Infertility, which is defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourses, affects about 15-20% of couples worldwide and a male factor is involved in about half of the cases. The development of assisted reproductive technology (ART) made it possible to conceive also to individuals affected from severe oligospermia or azoospermia. However, the impact of the male factor on embryo development, implantation, prevalence of chromosomal abnormalities, genetic and epigenetic alterations, and clinical and obstetric outcomes is still controversial.
Purpose:
This narrative review examines the indications, minimum access criteria, and outcomes by individual ART technique in relation to the male factor.
... Finally, although we did not detect follicle-stimulating hormone and luteinizing hormone receptors in testicular tissue, we detected testosterone, which is the product of follicle-stimulating hormone and luteinizing hormone acting on Sertoli cells and Leydig cells in testicular tissue, respectively (34)(35)(36)(37). We found that the seminal testosterone of the azoospermia group was significantly higher than that of the spermatozoa group. ...
Objective
Reproductive hormones are a traditional good method to evaluate spermatogenesis but might not accurately represent local spermatogenesis. To find a more accurate method, seminal reproductive hormones were studied.
Methods
A bidirectional cohort study was performed. A total of 126 infertile men from 2018 to 2019 were retrospectively analyzed. They were divided into nonobstructive azoospermia (NOA), oligozoospermia (OLZ) and normal (NOR) groups. A prospective study was conducted on patients in the NOA and OLZ groups for 2 years. Microscopic testicular sperm extraction was performed for NOA patients, who were divided into a focal spermatogenesis group (FS) and an idiopathic azoospermia group (IA). Drug treatment was for OLZ patients, who were divided into a valid group (VA) and an invalid group (IN). The differences in sperm parameters and reproductive hormones were compared. ANOSIM analysis was used between and within groups. Pearson correlation analysis, CO inertia analysis and Proctor’s analysis were for relationships. ROC curve for the specificity and sensitivity. Time series analysis was for the trends between hormones and time.
Results
The b-FSH, b-LH, s-T and ΔT in the NOA group were significantly higher than those in the OLZ and NOR groups. However, the s-FSH, s-E 2 , s-P, ΔFSH, ΔLH, ΔP and ΔE 2 were lower. Thirty-one NOA patients underwent MTSE, of whom 12 had sperm (FS) and 19 had no sperm (IA). The s-FSH and s-E 2 of the FS group were higher than those of the IA group. Twenty-six OLZ patients completed 30 days of treatment, of which 11 had an improved sperm count (VA) and 15 had no (IN). The ΔT of the VA group was higher than that of the IN group. After follow-up for 2 years, 18 patients’ results showed that b-FSH, b-LH and s-T were different over time, with delays of 19, 3 and -19 days. SC is closely related to pH, s-FSH, s-LH, s-E 2 , s-P, s-T, b-FSH, b-LH, ΔFSH, ΔLH, ΔP, ΔE 2 and ΔT. There were complex common trends and relationships between different kinds of hormones. s-FSH, s-LH, s-E 2 , s-P, s-T, b-FSH and b-LH were useful to judge spermatogenesis, of which s-T, b-FSH and b-LH were more sensitive. If s-T, b-FSH and b-LH reached 64.4, 9.4 and 4.7, respectively, their prediction performance was the strongest.
Conclusion
Seminal testosterone is sensitive for judging local spermatogenesis in nonobstructive azoospermia patients, which may be the direction of local spermatogenesis in nonobstructive azoospermia.
Clinical trial registration
http://www.chictr.org.cn/index.aspx , identifier ChiCTR2200060463.
