Advances in stem cell research for the treatment of primary hypogonadism

Li, Lü; Papadopoulos, Vassilios

doi:10.1038/s41585-021-00480-2

Cited by 14 publications

(20 citation statements)

References 201 publications

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“…1 At the approximate age of 30 in humans, testosterone levels begin to decline at a rate of 0.4%-2% annually and can lead to testosterone deficiency, known as hypogonadism. [1][2][3] Due to the importance of testosterone in biological systems, hypogonadism is accompanied by a number of conditions, including decreased muscle mass, fat mass accumulation, mood changes, fatigue, metabolic syndrome, and others. 4 The first step in LC testosterone production involves the metabolism of cholesterol by the inner mitochondrial membrane enzyme cytochrome P450 side chain cleavage (CYP11A1).…”

Section: Introductionmentioning

confidence: 99%

“…Testosterone biosynthesis is essential for the development, function, and maintenance of the male reproductive system 1 . At the approximate age of 30 in humans, testosterone levels begin to decline at a rate of 0.4%–2% annually and can lead to testosterone deficiency, known as hypogonadism 1–3 . Due to the importance of testosterone in biological systems, hypogonadism is accompanied by a number of conditions, including decreased muscle mass, fat mass accumulation, mood changes, fatigue, metabolic syndrome, and others 4 …”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial dynamics, Leydig cell function, and age‐related testosterone deficiency

et al. 2022

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The mitochondrial translocator protein (18 kDa; TSPO) is a high-affinity cholesterol-binding protein that is an integral component of the cholesterol trafficking scaffold responsible for determining the rate of cholesterol import into the mitochondria for steroid biosynthesis. Previous studies have shown that TSPO declines in aging Leydig cells (LCs) and that its decline is associated with depressed circulating testosterone levels in aging rats. However, TSPO's role in the mechanistic decline in LC function is not fully understood. To address the role of TSPO depletion in LC function, we first examined mitochondrial quality in Tspo knockout mouse tumor MA-10 nG1 LCs compared to wild-type MA-10 cells. Tspo deletion caused a disruption in mitochondrial function and membrane dynamics. Increasing mitochondrial fusion via treatment with the mitochondrial fusion promoter M1 or by optic atrophy 1 (OPA1) overexpression resulted in the restoration of mitochondrial function and mitochondrial morphology as well as in steroid formation in TSPO-depleted nG1 LCs. LCs isolated from aged rats form less testosterone than LCs isolated from young rats. Treatment of aging LCs with M1 improved mitochondrial function and increased androgen formation, suggesting that aging LC dysfunction may stem from compromised mitochondrial dynamics caused by the age-dependent LC TSPO decline. These results, taken together, suggest that maintaining or enhancing mitochondrial fusion may provide therapeutic strategies to maintain or restore testosterone levels with aging.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial dynamics, Leydig cell function, and age‐related testosterone deficiency

et al. 2022

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“…It has been reported that the incidental risk of prostate cancer among other-based cancer surgery and androgen replacement therapy increases the risk of prostate cancer in these patients [32]. Meanwhile, targeted drug interventions and stem cells for aging have been reported in animal models, while the safety and efficacy of stem cell therapy need to be further confirmed in human LCs [33][34][35]. LIPUS is an appealing therapeutic option as it is a noninvasive treatment that has many advantages, including no risk of infection, no tissue damage and no known adverse reactions.…”

Section: Discussionmentioning

confidence: 99%

Low-Intensity Pulsed Ultrasound Alleviates Human Testicular Leydig Cell Senescence In Vitro

Han

Luo

et al. 2022

IJMS

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Aging has a significant negative impact on human testicular function; steroidogenesis is gradually impaired, and testosterone replacement therapy still has many risks. Low-intensity pulsed ultrasound (LIPUS) has been used as a novel non-invasive treatment for male erectile dysfunction and other fields, and has been shown to increase testosterone levels in animal models. Testosterone is synthesized and secreted by Leydig cells (LCs), and the serum testosterone level decreases after aging due to the LCs senescence. However, the effect of LIPUS on human senescent LCs has not been reported. In this study, human senescent LCs were isolated and stimulated with different energy intensities in vitro, and cell morphology, cell apoptosis, cell proliferation, cell senescence levels, lipid droplet number, testosterone and INSL3 secretion levels were tested and analyzed. Quantitative Polymerase Chain Reaction (QPCR) and Western Blot were performed to compare cell senescence characteristics and the expression profile of key pathways of testosterone secretion, and transcriptome analysis was performed to explore the signaling pathways of LCs alteration after LIPUS stimulation. It was safe and effective to stimulate LCs with the 75 mW/cm2 energy of LIPUS in vitro, which not only improved the senescence phenotype, but also effectively enhanced the secretory function of LCs in vitro, and increased the expression of key pathways of the testosterone synthesis pathway. These results suggest that LIPUS could be used as a novel treatment to human senescent LCs with decreased testosterone secretion levels in vitro.

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“…During gestation, fetal Leydig cells arise from mesenchymal precursors and produce high levels of testosterone before acquiring luteinizing hormone (LH) receptors (2,3). Testosterone production declines with the loss of the fetal Leydig cells, and then gradually increases to high levels with the development of adult Leydig cells from stem cells (2,3). Testosterone levels in men physiologically decrease at a rate of 0.4 to 2% per year starting at age 30 (4)(5)(6) The signal to produce testosterone initiates in the hypothalamus with the release of Gonadotropin-releasing hormone (GnRH) into the hypophyseal portal circulation (7).…”

Section: Introductionmentioning

confidence: 99%

Oral administration of VDAC1-derived small molecule peptides increases circulating testosterone levels in male rats

Martinez–Arguelles

Nedow²,

Gukasyan³

et al. 2023

Front. Endocrinol.

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Cholesterol is the precursor of all steroid hormones, and the entry of cholesterol into the mitochondria is the rate-limiting step of steroidogenesis. Voltage-dependent anion channel (VDAC1) is an outer mitochondrial protein part of a multiprotein complex that imports cholesterol. We previously reported that intratesticular administration of a 25 amino acid peptide blocking the interaction between 14-3-3ϵ with VDAC1 increased circulating levels of testosterone. This fusion peptide was composed of a HIV-1 transactivator of transcription (TAT) protein transduction domain cell-penetrating peptide, a glycine linker, and amino acids 159-172 of VDAC1 (TV159-172). Here, we describe the development of a family of small molecules that increase circulating testosterone levels after an oral administration. We first characterized an animal model where TV159-172 was delivered subcutaneously. This subcutaneous model allowed us to study the interactions between TV159-172 and the hypothalamus-pituitary-gonadal axis (HPG) and identify the biologically active core of TV159-172. The core consisted of the tetrapeptide RVTQ, which we used as a platform to design synthetic peptide derivatives that can be administered orally. We developed a second animal model to test various derivatives of RVTQ and found 11 active compounds. Dose-response experiments identified 4 synthetic peptides that robustly increased androgen levels in a specific manner. We selected RdVTQ as the leading VDAC1-core derivative and profiled the response across the lifespan of Brown-Norway rats. In summary, we present the development of a new class of therapeutics that act within the HPG axis to increase testosterone levels specifically. This new class of small molecules self-regulates, preventing abuse.

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Advances in stem cell research for the treatment of primary hypogonadism

Cited by 14 publications

References 201 publications

Mitochondrial dynamics, Leydig cell function, and age‐related testosterone deficiency

Mitochondrial dynamics, Leydig cell function, and age‐related testosterone deficiency

Low-Intensity Pulsed Ultrasound Alleviates Human Testicular Leydig Cell Senescence In Vitro

Oral administration of VDAC1-derived small molecule peptides increases circulating testosterone levels in male rats

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