.gif "IP Gear")
- Joined
- Jan 15, 2012
- Messages
- 2,902
I was having a discussion with ChatGPT about the effects of using steroids while using HMG for fertility, and it suggested that high doses of testosterone could hinder the effects. The first reason suggested was due to suppression of LH/FSH, but then I pointed out that those would already be suppressed by the HMG usage. At which point it suggested that nevertheless the presence of supraphysiological testosterone levels could disrupt the intratesticular environment, and when I asked how, it said that sertoli cell sensitivity could decrease in response. I'll past the answer below. Would be interested in any of your guys thoughts on if this seems plausible. Seems to me like ChatGPT is sort of spit balling here.
___________
Leydig and Sertoli cells play key roles in testosterone production and spermatogenesis, respectively, and both cell types have specific receptors that are sensitive to hormones like androgens (testosterone and related compounds), LH, and FSH. Here’s an overview of how these receptors work and what is known about potential downregulation or desensitization effects due to androgens:
Leydig Cells and Receptor Sensitivity
Leydig cells, located in the interstitial space of the testes, are primarily responsible for producing testosterone in response to LH stimulation. Here’s how receptor sensitivity and potential desensitization might work:
1. LH Receptors on Leydig Cells:
LH binds to LH receptors on Leydig cells, stimulating the production of testosterone. The sensitivity of Leydig cells to LH can be modulated by testosterone levels.
When systemic testosterone levels are very high, the negative feedback loop through the hypothalamus and pituitary can reduce the natural demand for LH. Although exogenous LH from HMG bypasses this loop, persistently high androgen levels might reduce Leydig cells’ sensitivity to LH over time, as they have less need to respond when external androgens are available.
2. Androgen Receptor (AR) on Leydig Cells:
Leydig cells also have androgen receptors. High levels of testosterone or other androgens can lead to downregulation of these receptors. When androgen receptors are saturated or exposed to high levels of androgens chronically, the cell may reduce the number of receptors or their sensitivity as a regulatory measure, which can blunt the effects of LH on testosterone production.
Sertoli Cells and Receptor Sensitivity
Sertoli cells, located within the seminiferous tubules, support and nurture developing sperm cells. They rely on both FSH and testosterone (via androgen receptors) to function optimally. Here’s how androgen exposure affects these cells:
1. FSH Receptors on Sertoli Cells:
FSH binds to its receptor on Sertoli cells and stimulates spermatogenesis. FSH receptor expression can be affected by testosterone levels. In some cases, high testosterone can reduce the number of FSH receptors or affect their sensitivity, potentially reducing FSH’s effectiveness in promoting sperm maturation.
Studies have shown that FSH receptor expression and activity may fluctuate based on androgen levels, with extremely high testosterone sometimes interfering with optimal FSH signaling.
2. Androgen Receptor (AR) on Sertoli Cells:
Sertoli cells also have androgen receptors, which are essential for spermatogenesis. Testosterone binds to these receptors to aid in sperm maturation and the function of Sertoli cells.
Chronic exposure to high levels of exogenous androgens can downregulate androgen receptors, potentially leading to diminished Sertoli cell response. Downregulation of androgen receptors means that even when testosterone is present, the cells might not respond as robustly, potentially impairing sperm maturation.
Mechanisms of Downregulation
Receptor downregulation typically occurs through one or more of the following mechanisms:
Decreased Receptor Expression: High levels of ligands (such as testosterone) can reduce gene expression of receptors, leading to fewer available receptors on the cell surface.
Receptor Internalization and Degradation: When receptors are constantly bound by high levels of a hormone, the cell may internalize and degrade them, removing them from the cell surface and reducing the cell’s sensitivity.
Negative Feedback Regulation: Cells have internal feedback mechanisms that detect excessive signaling and can initiate pathways to desensitize the receptor, making it less responsive to stimulation.
Practical Implications for Fertility
The potential downregulation of androgen receptors on Sertoli and Leydig cells, due to high systemic testosterone, can blunt the effects of LH and FSH. In fertility protocols, this is why HMG and HCG are carefully balanced to provide a controlled amount of LH and FSH directly, avoiding excess androgens that could impair receptor function on these critical cells.
In summary, while androgens like testosterone are crucial for both Leydig and Sertoli cell function, excessive systemic levels may desensitize or downregulate androgen and FSH receptors, potentially impairing the natural processes of testosterone production and spermatogenesis.
___________
Leydig and Sertoli cells play key roles in testosterone production and spermatogenesis, respectively, and both cell types have specific receptors that are sensitive to hormones like androgens (testosterone and related compounds), LH, and FSH. Here’s an overview of how these receptors work and what is known about potential downregulation or desensitization effects due to androgens:
Leydig Cells and Receptor Sensitivity
Leydig cells, located in the interstitial space of the testes, are primarily responsible for producing testosterone in response to LH stimulation. Here’s how receptor sensitivity and potential desensitization might work:
1. LH Receptors on Leydig Cells:
LH binds to LH receptors on Leydig cells, stimulating the production of testosterone. The sensitivity of Leydig cells to LH can be modulated by testosterone levels.
When systemic testosterone levels are very high, the negative feedback loop through the hypothalamus and pituitary can reduce the natural demand for LH. Although exogenous LH from HMG bypasses this loop, persistently high androgen levels might reduce Leydig cells’ sensitivity to LH over time, as they have less need to respond when external androgens are available.
2. Androgen Receptor (AR) on Leydig Cells:
Leydig cells also have androgen receptors. High levels of testosterone or other androgens can lead to downregulation of these receptors. When androgen receptors are saturated or exposed to high levels of androgens chronically, the cell may reduce the number of receptors or their sensitivity as a regulatory measure, which can blunt the effects of LH on testosterone production.
Sertoli Cells and Receptor Sensitivity
Sertoli cells, located within the seminiferous tubules, support and nurture developing sperm cells. They rely on both FSH and testosterone (via androgen receptors) to function optimally. Here’s how androgen exposure affects these cells:
1. FSH Receptors on Sertoli Cells:
FSH binds to its receptor on Sertoli cells and stimulates spermatogenesis. FSH receptor expression can be affected by testosterone levels. In some cases, high testosterone can reduce the number of FSH receptors or affect their sensitivity, potentially reducing FSH’s effectiveness in promoting sperm maturation.
Studies have shown that FSH receptor expression and activity may fluctuate based on androgen levels, with extremely high testosterone sometimes interfering with optimal FSH signaling.
2. Androgen Receptor (AR) on Sertoli Cells:
Sertoli cells also have androgen receptors, which are essential for spermatogenesis. Testosterone binds to these receptors to aid in sperm maturation and the function of Sertoli cells.
Chronic exposure to high levels of exogenous androgens can downregulate androgen receptors, potentially leading to diminished Sertoli cell response. Downregulation of androgen receptors means that even when testosterone is present, the cells might not respond as robustly, potentially impairing sperm maturation.
Mechanisms of Downregulation
Receptor downregulation typically occurs through one or more of the following mechanisms:
Decreased Receptor Expression: High levels of ligands (such as testosterone) can reduce gene expression of receptors, leading to fewer available receptors on the cell surface.
Receptor Internalization and Degradation: When receptors are constantly bound by high levels of a hormone, the cell may internalize and degrade them, removing them from the cell surface and reducing the cell’s sensitivity.
Negative Feedback Regulation: Cells have internal feedback mechanisms that detect excessive signaling and can initiate pathways to desensitize the receptor, making it less responsive to stimulation.
Practical Implications for Fertility
The potential downregulation of androgen receptors on Sertoli and Leydig cells, due to high systemic testosterone, can blunt the effects of LH and FSH. In fertility protocols, this is why HMG and HCG are carefully balanced to provide a controlled amount of LH and FSH directly, avoiding excess androgens that could impair receptor function on these critical cells.
In summary, while androgens like testosterone are crucial for both Leydig and Sertoli cell function, excessive systemic levels may desensitize or downregulate androgen and FSH receptors, potentially impairing the natural processes of testosterone production and spermatogenesis.
