Leydig Cell Aging and Hypogonadism

Discussion in 'Steroid Post Cycle Therapy and ASIH Treatment' started by Michael Scally MD, Feb 24, 2015.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    · Review changes in the steroidogenic enzymes of aging Leydig cells
    · Discusses effects of the redox environment on Leydig cell testosterone production.
    · Discusses ways to increase serum testosterone by stimulating the Leydig cells.

    Beattie MC, Adekola L, Papadopoulos V, Chen H, Zirkin BR. Leydig Cell Aging and Hypogonadism. Exp Gerontol. http://www.sciencedirect.com/science/article/pii/S0531556515000765

    Leydig cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of cellular changes have been identified in the steroidogenic pathway of aged Leydig cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum.

    Many of the changes in steroid formation that characterize aged Leydig cells can be elicited by the experimental alteration of the redox environment of young cells, suggesting that changes in the intracellular redox balance may cause reduced T production.

    Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction.

    Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis.

    Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children.

    There are promising new approaches to increase serum T by directly stimulating Leydig cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences.
  2. Mr.B66

    Mr.B66 Member AnabolicLab.com Supporter

    The article states that' there are promising new approaches to increase serum T' what would these promising new approaches be? Any studies or links available for reading?
  3. FockU

    FockU Member

    Sounds like hcg bud
    BirdieNumNum and Mr.B66 like this.
  4. Mr.B66

    Mr.B66 Member AnabolicLab.com Supporter

    I see ! I thought maybe there was some NEW form of treating low T
    Thanks bro!!!!
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Leydig Cells: Formation, Function and Regulation

    Herein we summarize important discoveries made over many years about Leydig cell function and regulation. During the fetal period, fetal Leydig cells produce the high levels of androgen (testosterone or androstenedione, depending upon the species) required for differentiation of male genitalia and brain masculinization. Androgen production declines with loss of these cells, reaching a nadir at postpartum. Testosterone then gradually increases to high levels with adult Leydig cell development from stem cells.

    In the adult, luteinizing hormone [LH] binding to Leydig cell LH receptors stimulates cAMP production, increasing the rate of cholesterol translocation into the mitochondria. Cholesterol is metabolized to pregnenolone by the CYP11A1 enzyme at the inner mitochondrial membrane, and pregnenolone to testosterone by mitochondria and smooth endoplasmic reticulum enzymes.

    Cholesterol translocation to the inner mitochondrial membrane is mediated by a protein complex formed at mitochondrial contact sites that consists of the cholesterol binding translocator protein [TSPO], voltage dependent anion channel [VDAC], and other mitochondrial and cytosolic proteins.

    Steroidogenic acute regulatory protein [STAR] acts at this complex to enhance cholesterol movement across the membranes and thus increase testosterone formation. The 14-3-3gamma and epsilon adaptor proteins serve as negative regulators of steroidogenesis, controlling the maximal amount of steroid formed. Decline in testosterone production occurs in many aging and young men, resulting in metabolic and quality-of-life changes.

    Testosterone replacement therapy is widely used to elevate serum testosterone levels in hypogonadal men. With knowledge gained of the mechanisms involved in testosterone formation, it also is conceivable to use pharmacological means to increase serum testosterone by Leydig cell stimulation.

    Zirkin BR, Papadopoulos V. Leydig Cells: Formation, Function and Regulation. Biology of reproduction 2018. Leydig Cells: Formation, Function and Regulation | Biology of Reproduction | Oxford Academic
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Chen F, Lu H, Chen P, et al. Acute Effects of the Translocator Protein (TSPO) Drug Ligand FGIN-1-27 on Serum testosterone and LH Levels in Male Sprague Dawley Rats. Biology of reproduction 2018. Acute Effects of the Translocator Protein (TSPO) Drug Ligand FGIN-1-27 on Serum Testosterone and LH Levels in Male Sprague Dawley Rats | Biology of Reproduction | Oxford Academic

    We reported that FGIN-1–27 (N, N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN), a synthetic ligand for translocator protein (TSPO, 18 kDa), increased serum testosterone levels in young and aged Brown Norway rats after its administration daily for 10 days.

    It is not known, however, how soon after treatment with FGIN serum testosterone rises, how long levels remain elevated after cessation of treatment, or whether the drug acts solely through TSPO.

    Adult Sprague Dawley male rats received a single ip dose of FGIN (1mg/kg BW). Serial blood samples were collected and serum testosterone and LH were assessed hourly throughout 24 hours.

    Testosterone concentration was maximal by 3 hours, remained significantly higher than the controls at 10 hours, and returned to the control level by 24 hours. Consistent with the in vivo study, culturing isolated Leydig cells with either FGIN (40μM) or LH (0.1ng/ml) resulted in significantly increased testosterone production by 30 mins, and the stimulatory effects persisted through 48 hours. At a very early (15 min) treatment time, however, FGIN significantly increased testosterone production but LH had not yet done so.

    Surprisingly, in vivo treatment with FGIN not only increased serum testosterone but also serum LH concentration, raising the possibility that FGIN may increase serum testosterone concentration by dual mechanisms.
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Rats] Effects of Pharmacologically Induced Leydig Cell testosterone Production on Intratesticular Testosterone and Spermatogenesis

    The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation.

    The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein-protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (18 kDa TSPO).

    We hypothesized that in contrast to TRT, the administration of the TSPO agonist FGIN-1-27, by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis.

    Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively.

    In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the GnRH antagonist cetrorelix.

    These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenousl.

    Chung J-Y, Brown S, Chen H, Liu J, Papadopoulos V, Zirkin B. Effects of Pharmacologically Induced Leydig Cell Testosterone Production on Intratesticular Testosterone and Spermatogenesis. Biology of Reproduction 2019. Effects of Pharmacologically Induced Leydig Cell Testosterone Production on Intratesticular Testosterone and Spermatogenesis
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  8. Sworder

    Sworder Member

    They say that the human body rids itself of the cells every 10 years or something like that. Does that apply to fat and muscle cells as well(Leydig and Sertoli?) Wouldn't killing the cells rid the cells of multiple nuclei which is responsible to my understanding for so called muscle memory?