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MuscleChemistry
Food for thought!
Exogenously administered Growth Hormone leads to feminized secretory pattern and altered steroid metabolism
Men and women release growth hormone (GH) in patterns unique to their sex. Adult men secrete growth hormone in pulsatile pattern with well pronounced peaks of plasma growth hormone occurring approximately every 3.5 hours followed by periods without measurable growth hormone (GH off-time) lasting about two hours.
In contrast, adult females have a more frequent growth hormone release which results in near-continuous presence of GH in plasma.
These adult patterns of GH release are set during the first month of life by exposure to gonadal steroids, which program the hypothalamus and its regulation of pituitary GH secretion to behave in sexually distinct ways at the onset of puberty and during adulthood [SUP]1[/SUP].
This difference in pattern has significant consequence primarily determined by the "off time" or period when no detectable GH is present in males or is elevated in females. This "off time", a period when there is no (or very low) growth hormone present is required for the expression of male-specific liver enzymes, such as cytochrome P450 (CYP) 2C11 [SUP]2[/SUP]. Without this off time those liver enzymes needed to metabolize male hormones do not get expressed to a significant degree. The reason for this failure appears to primarily result from the fact that the intracellular pathway STAT5b responsible for the synthesis of these enzymes needs time off. If it doesn't get time off it fails to reset.
The following image will serve to give a quick understanding. Growth Hormone is a molecule that may be visualized as a peg which lands on a receptor where it flips a switch and sets things in motion. One of the things it sets in motion is an intracellular pathway known as signal transducer and activator of transcription 5b (STAT5b). This protein once activated moves to the cell nucleus and initiates the transcription of end product proteins such as liver enzymes. It then is deactivated returns to the receptor and is reactivated to again mediate transcription.
When a pulse of growth hormone activates growth hormone receptors it does so with a strong enough punch that STAT5b undergoes multiple rounds of activity during this single pulse. When a non-pulsatile more feminine continuous growth hormone "bleed" activates growth hormone receptors STAT5b activity is not as vigorous and this activity or mediating cycle is terminated more quickly.
When exogenous growth hormone is administered in a way that causes prolonged elevation of plasma growth hormone the GH pulse induced expression of male specific liver genes is reduced and if long enough completely abolished. While the expression of female specific genes is significantly induced [SUP]3[/SUP].
This can primarily be attributed to the failure to give STAT5b an "off time" which reduces its activation and partially desensitizes it to growth hormone [SUP]4[/SUP].
The time period required to reset the STAT5b pathway after a GH pulse is two to three hours [SUP]5,6[/SUP].
What does a reduction in STAT5b imply?
In male mice STAT5b deficiency leads to loss of the male-specific liver enzymes and loss of both puberty and adult male body growth pattern. In fact loss of STAT5b resulted in a substantial decrease in the expression of about 90% of male-specific liver genes [SUP]7,8[/SUP]. In females STAT5b gene disruption has only a modest effect on body growth rate and liver gene expression.
STAT5b disruption is associated with lower circulating IGF-I levels, elevated plasma GH, increased expression of prolactin receptor [SUP]9-11[/SUP] and lower body growth rates [SUP]12[/SUP].
Treatment of exogenous GH treatment given in pulsatile fashion restores the expression of sex-dependent liver enzymes that are normally present in normal males. Exogenous GH pulses also stimulate body weight gain in males [SUP]7,13[/SUP]. All of this underscores the requirement of STAT5b for both liver gene expression and body growth.
Which liver enzymes are effected and how does this contribute to "toxicity" ?
There is an entire class of liver enzymes known as Cytochrome P450. Within this general class are male and female specific forms. These enzymes metabolize steroids, fatty acids, lipophilic drugs (i.e. dissolve in fats), environmental chemicals and pollutants.
The creation of these enzymes is induced by various factors including growth hormone. Growth hormone regulates the expression of these Cytochrome genes in a sex-dependent manner. Pulsation of growth hormone secretion (a masculine pattern) results in creation of the male Cytochrome P450 isoforms while continuous growth hormone secretion (a feminine pattern) results in creation of the female Cytochrome P450 isoforms.
The metabolism of foreign chemicals by Cytochrome P450 enzymes frequently results in successful detoxification of irritants however, the actions of P450 enzymes can also generate toxic metabolites that contribute to increased risks of cancer, birth defects, and other toxic effects [SUP]14[/SUP].
Furthermore expression of many P450 enzymes is often induced by accumulation of a substrate. For example, liver concentrations of the female liver enzyme may be induced by a specific drug or hormone which must be metabolized. This may lead to a cascade of other liver enzymes expressing themselves in response to this activity [SUP]14[/SUP].
Finally these enzymes often act on various substrates including saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D3 derivatives, retinoids, and uroporphyrinogens. When they act on these subtrates they may effect an oxidative, peroxidative or reductive change into small molecules which results in a new array of chemical structures [SUP]14[/SUP].
The proper understanding of these things is simply the following. It is important to both liver and overall health to take steps to reduce imbalances in this entire class of enzymes and to the extent that imbalances do occur there may be consequences that at the very least require correction.
Specific Examples
The female P450 isoform CYP3A4 can be thought of as having a role in estradiol homeostasis. Specifically it hydroxylates estradiol at the 2, 4 and 16 alpha positions. It also catablyzes 6 beta-hydroxylation of testosterone which is converts to estradiol by the action of aromatase. This activity is welcome for mammary gland development and lactation if you are a female. But if you are a male with a lot of substrate in the form of testosterone you don't want this enzyme to be active [SUP]15[/SUP].
Yet patients suffering from acromegaly and men who are given continuous forms of GH treatment end up with greatly upregulated expression of this female liver enzyme[SUP]16,17[/SUP]. This female liver enzyme is supressed by intermittent pulsatile GH [SUP]18[/SUP].
The female P450 isoform CYP3A4 also metabolizes other steroids such as cortisol as well which is converted more rapidly in women then men [SUP]19[/SUP].
Many of the male P450 isoforms have roles in testosterone metabolism such as CYP2C11 which hydroxylases testosterone and converts testosterone to androstenedione for use in resynthesis. This activity is lost when a female pattern of GH release is instituted.
The female GH release profile stimulates the full expression of testosterone 5 alpha reductase activity [SUP]20,21[/SUP]. In men with the substrate testosterone this female GH release profile can lead to a substantial conversion of testosterone to Dihydrotestosterone (DHT).
It is also thought that certain environmental triggers and food additives can trigger autoimmune diseases for those genetically predisposed. Alterations in GH release profile brought about by environmental factors make middle aged women more susceptible then men to such triggers as MSG and Aspartame in invoking auto-immune hepatitis [SUP]22[/SUP].
The full treatment of this topic is beyond the scope of this review. This section was meant to underscore the fact that imbalances are created in ways not often considered. Health and a reduction in toxicity require countermeasures which could include the use of compounds such as the Arginine/Lysine combination to reduce cortisol or Sodium Glucuronate to bind and eliminate the byproducts of P450 enzymal activity. Of course another beneficial method would be to optimize sex specific GH release patterns rather then eliminate them.
References:
1 - Chowen JA, Frago LM, Argente J, The regulation of GH secretion by sex steroids. Eur J Endocrinol 151(Suppl 3):U95–U100 (2004)
2 - Waxman DJ, Pampori NA, Ram PA, Agrawal AK, Shapiro BH, Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450, Proc Natl Acad Sci USA 88:6868–6872 (1991)
3 - Thangavel C, Garcia MC, Shapiro BH, Intrinsic sex differences determine expression of growth hormone-regulated female cytochrome P450s, Mol Cell Endocrinol 220:31–39 (2004)
4 - Waxman DJ, Ram PA, Park SH Choi HK, Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein, Proposed role as an intracellular regulator of male-specific liver gene transcription, J Biol Chem 270:13262–13270 (1995)
5 - Gebert CA, Park SH, Waxman DJ, Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation, Mol Endocrinol 11:400–414 (1997)
6 - Ji S, Frank SJ, Messina JL, Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation, J Biol Chem 277:28384–28393 (2002)
7 - Holloway MG, Laz EV, Waxman DJ Co-dependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on STAT5b and HNF4-alpha, Mol Endocrinol 20:647–660 (2006)
8 - Clodfelter K, Holloway MG, Hodor P, Park S-H, Ray WJ, Waxman DJ, Sex-dependent liver gene expression is extensive and largely dependent upon STAT5b: STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis, Mol Endocrinol 20:1333–1351 (2006)
9 - Norstedt G, Palmiter R, Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver, Cell 36:805–812(1984)
10 - Kelly PA, The growth hormone/prolactin receptor family, Recent Prog Horm Res. 48:123–164 1993
11 - Noshiro M, Negishi M, Pretranslational Regulation of Sex-dependent Testosterone Hydroxylases by Growth Hormone in Mouse Liver, J Biol Chem 261:15923–15927 (1986)
12 - Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW, Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression, Proc Natl Acad Sci USA 94:7239–7244 (1997)
13 - Davey HW, Park SH, Grattan DR, McLachlan MJ, Waxman DJ, STAT5b-deficient mice are growth hormone pulse-resistant, Role of STAT5b in sex-specific liver p450 expression, J Biol Chem 274:35331–35336 (1999)
14 - Nebert Daniel W, Russell David W, Clinical importance of the cytochromes P450, THE LANCET • Vol 360 • October 12, 2002
15 - Yu AM, Fukamachi K, Krausz KW, Cheung C, Gonzalez FJ, Potential role for human cytochrome P450 3A4 in estradiol homeostasis, Endocrinology 146:2911–2919 (2005)
16 - Watkins PB, Turgeon DK, Jaffe CA, Ho PJ, Barkan AL, Pulsation frequency of growth hormone may mediate gender differences in CYP3A activity in man, Clin Res 41:132 (1993)
17 - Jaffe CA, Turgeon DK, Lown K, Demott-Friberg R, Watkins PB, Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans, Am J Physiol Endocrinol Metab 283:E1008–E1015 (2002)
18 - Dhir RN, Dworakowski W, Tangavel C, Shapiro BH, Sexual dimorphic regulation of hepatic isoforms of human cytochrome P450 by growth hormone, J Pharmacol Exp Ther 316:87–94 (2006)
19 - Inagaki K, Inagaki M, Kataoka T, Sekido I, Gill MA, Nishida M, A wide interindividual variability of urinary 6ß-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition, Ther Drug Monit 24:722–727 (2002)
20 - Shapiro BH, Agrawal AK, Pampori NA, Gender differences in drug metabolism regulated by growth hormone, Int J Biochem Cell Biol 1995;27:9–20
21 - Pampon NA, Shapiro BH, Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile, Endocrinology 1999;140:1245–1254
22 - Prandota, Joseph, Possible Pathomechanism of Autoimmune Hepatitis, American Journal of Therapeutics 10, 51–57 (2003)
Exogenously administered Growth Hormone leads to feminized secretory pattern and altered steroid metabolism
Men and women release growth hormone (GH) in patterns unique to their sex. Adult men secrete growth hormone in pulsatile pattern with well pronounced peaks of plasma growth hormone occurring approximately every 3.5 hours followed by periods without measurable growth hormone (GH off-time) lasting about two hours.
In contrast, adult females have a more frequent growth hormone release which results in near-continuous presence of GH in plasma.
These adult patterns of GH release are set during the first month of life by exposure to gonadal steroids, which program the hypothalamus and its regulation of pituitary GH secretion to behave in sexually distinct ways at the onset of puberty and during adulthood [SUP]1[/SUP].
This difference in pattern has significant consequence primarily determined by the "off time" or period when no detectable GH is present in males or is elevated in females. This "off time", a period when there is no (or very low) growth hormone present is required for the expression of male-specific liver enzymes, such as cytochrome P450 (CYP) 2C11 [SUP]2[/SUP]. Without this off time those liver enzymes needed to metabolize male hormones do not get expressed to a significant degree. The reason for this failure appears to primarily result from the fact that the intracellular pathway STAT5b responsible for the synthesis of these enzymes needs time off. If it doesn't get time off it fails to reset.
The following image will serve to give a quick understanding. Growth Hormone is a molecule that may be visualized as a peg which lands on a receptor where it flips a switch and sets things in motion. One of the things it sets in motion is an intracellular pathway known as signal transducer and activator of transcription 5b (STAT5b). This protein once activated moves to the cell nucleus and initiates the transcription of end product proteins such as liver enzymes. It then is deactivated returns to the receptor and is reactivated to again mediate transcription.
When a pulse of growth hormone activates growth hormone receptors it does so with a strong enough punch that STAT5b undergoes multiple rounds of activity during this single pulse. When a non-pulsatile more feminine continuous growth hormone "bleed" activates growth hormone receptors STAT5b activity is not as vigorous and this activity or mediating cycle is terminated more quickly.
When exogenous growth hormone is administered in a way that causes prolonged elevation of plasma growth hormone the GH pulse induced expression of male specific liver genes is reduced and if long enough completely abolished. While the expression of female specific genes is significantly induced [SUP]3[/SUP].
This can primarily be attributed to the failure to give STAT5b an "off time" which reduces its activation and partially desensitizes it to growth hormone [SUP]4[/SUP].
The time period required to reset the STAT5b pathway after a GH pulse is two to three hours [SUP]5,6[/SUP].
What does a reduction in STAT5b imply?
In male mice STAT5b deficiency leads to loss of the male-specific liver enzymes and loss of both puberty and adult male body growth pattern. In fact loss of STAT5b resulted in a substantial decrease in the expression of about 90% of male-specific liver genes [SUP]7,8[/SUP]. In females STAT5b gene disruption has only a modest effect on body growth rate and liver gene expression.
STAT5b disruption is associated with lower circulating IGF-I levels, elevated plasma GH, increased expression of prolactin receptor [SUP]9-11[/SUP] and lower body growth rates [SUP]12[/SUP].
Treatment of exogenous GH treatment given in pulsatile fashion restores the expression of sex-dependent liver enzymes that are normally present in normal males. Exogenous GH pulses also stimulate body weight gain in males [SUP]7,13[/SUP]. All of this underscores the requirement of STAT5b for both liver gene expression and body growth.
Which liver enzymes are effected and how does this contribute to "toxicity" ?
There is an entire class of liver enzymes known as Cytochrome P450. Within this general class are male and female specific forms. These enzymes metabolize steroids, fatty acids, lipophilic drugs (i.e. dissolve in fats), environmental chemicals and pollutants.
The creation of these enzymes is induced by various factors including growth hormone. Growth hormone regulates the expression of these Cytochrome genes in a sex-dependent manner. Pulsation of growth hormone secretion (a masculine pattern) results in creation of the male Cytochrome P450 isoforms while continuous growth hormone secretion (a feminine pattern) results in creation of the female Cytochrome P450 isoforms.
The metabolism of foreign chemicals by Cytochrome P450 enzymes frequently results in successful detoxification of irritants however, the actions of P450 enzymes can also generate toxic metabolites that contribute to increased risks of cancer, birth defects, and other toxic effects [SUP]14[/SUP].
Furthermore expression of many P450 enzymes is often induced by accumulation of a substrate. For example, liver concentrations of the female liver enzyme may be induced by a specific drug or hormone which must be metabolized. This may lead to a cascade of other liver enzymes expressing themselves in response to this activity [SUP]14[/SUP].
Finally these enzymes often act on various substrates including saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D3 derivatives, retinoids, and uroporphyrinogens. When they act on these subtrates they may effect an oxidative, peroxidative or reductive change into small molecules which results in a new array of chemical structures [SUP]14[/SUP].
The proper understanding of these things is simply the following. It is important to both liver and overall health to take steps to reduce imbalances in this entire class of enzymes and to the extent that imbalances do occur there may be consequences that at the very least require correction.
Specific Examples
The female P450 isoform CYP3A4 can be thought of as having a role in estradiol homeostasis. Specifically it hydroxylates estradiol at the 2, 4 and 16 alpha positions. It also catablyzes 6 beta-hydroxylation of testosterone which is converts to estradiol by the action of aromatase. This activity is welcome for mammary gland development and lactation if you are a female. But if you are a male with a lot of substrate in the form of testosterone you don't want this enzyme to be active [SUP]15[/SUP].
Yet patients suffering from acromegaly and men who are given continuous forms of GH treatment end up with greatly upregulated expression of this female liver enzyme[SUP]16,17[/SUP]. This female liver enzyme is supressed by intermittent pulsatile GH [SUP]18[/SUP].
The female P450 isoform CYP3A4 also metabolizes other steroids such as cortisol as well which is converted more rapidly in women then men [SUP]19[/SUP].
Many of the male P450 isoforms have roles in testosterone metabolism such as CYP2C11 which hydroxylases testosterone and converts testosterone to androstenedione for use in resynthesis. This activity is lost when a female pattern of GH release is instituted.
The female GH release profile stimulates the full expression of testosterone 5 alpha reductase activity [SUP]20,21[/SUP]. In men with the substrate testosterone this female GH release profile can lead to a substantial conversion of testosterone to Dihydrotestosterone (DHT).
It is also thought that certain environmental triggers and food additives can trigger autoimmune diseases for those genetically predisposed. Alterations in GH release profile brought about by environmental factors make middle aged women more susceptible then men to such triggers as MSG and Aspartame in invoking auto-immune hepatitis [SUP]22[/SUP].
The full treatment of this topic is beyond the scope of this review. This section was meant to underscore the fact that imbalances are created in ways not often considered. Health and a reduction in toxicity require countermeasures which could include the use of compounds such as the Arginine/Lysine combination to reduce cortisol or Sodium Glucuronate to bind and eliminate the byproducts of P450 enzymal activity. Of course another beneficial method would be to optimize sex specific GH release patterns rather then eliminate them.
References:
1 - Chowen JA, Frago LM, Argente J, The regulation of GH secretion by sex steroids. Eur J Endocrinol 151(Suppl 3):U95–U100 (2004)
2 - Waxman DJ, Pampori NA, Ram PA, Agrawal AK, Shapiro BH, Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450, Proc Natl Acad Sci USA 88:6868–6872 (1991)
3 - Thangavel C, Garcia MC, Shapiro BH, Intrinsic sex differences determine expression of growth hormone-regulated female cytochrome P450s, Mol Cell Endocrinol 220:31–39 (2004)
4 - Waxman DJ, Ram PA, Park SH Choi HK, Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein, Proposed role as an intracellular regulator of male-specific liver gene transcription, J Biol Chem 270:13262–13270 (1995)
5 - Gebert CA, Park SH, Waxman DJ, Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation, Mol Endocrinol 11:400–414 (1997)
6 - Ji S, Frank SJ, Messina JL, Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation, J Biol Chem 277:28384–28393 (2002)
7 - Holloway MG, Laz EV, Waxman DJ Co-dependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on STAT5b and HNF4-alpha, Mol Endocrinol 20:647–660 (2006)
8 - Clodfelter K, Holloway MG, Hodor P, Park S-H, Ray WJ, Waxman DJ, Sex-dependent liver gene expression is extensive and largely dependent upon STAT5b: STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis, Mol Endocrinol 20:1333–1351 (2006)
9 - Norstedt G, Palmiter R, Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver, Cell 36:805–812(1984)
10 - Kelly PA, The growth hormone/prolactin receptor family, Recent Prog Horm Res. 48:123–164 1993
11 - Noshiro M, Negishi M, Pretranslational Regulation of Sex-dependent Testosterone Hydroxylases by Growth Hormone in Mouse Liver, J Biol Chem 261:15923–15927 (1986)
12 - Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW, Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression, Proc Natl Acad Sci USA 94:7239–7244 (1997)
13 - Davey HW, Park SH, Grattan DR, McLachlan MJ, Waxman DJ, STAT5b-deficient mice are growth hormone pulse-resistant, Role of STAT5b in sex-specific liver p450 expression, J Biol Chem 274:35331–35336 (1999)
14 - Nebert Daniel W, Russell David W, Clinical importance of the cytochromes P450, THE LANCET • Vol 360 • October 12, 2002
15 - Yu AM, Fukamachi K, Krausz KW, Cheung C, Gonzalez FJ, Potential role for human cytochrome P450 3A4 in estradiol homeostasis, Endocrinology 146:2911–2919 (2005)
16 - Watkins PB, Turgeon DK, Jaffe CA, Ho PJ, Barkan AL, Pulsation frequency of growth hormone may mediate gender differences in CYP3A activity in man, Clin Res 41:132 (1993)
17 - Jaffe CA, Turgeon DK, Lown K, Demott-Friberg R, Watkins PB, Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans, Am J Physiol Endocrinol Metab 283:E1008–E1015 (2002)
18 - Dhir RN, Dworakowski W, Tangavel C, Shapiro BH, Sexual dimorphic regulation of hepatic isoforms of human cytochrome P450 by growth hormone, J Pharmacol Exp Ther 316:87–94 (2006)
19 - Inagaki K, Inagaki M, Kataoka T, Sekido I, Gill MA, Nishida M, A wide interindividual variability of urinary 6ß-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition, Ther Drug Monit 24:722–727 (2002)
20 - Shapiro BH, Agrawal AK, Pampori NA, Gender differences in drug metabolism regulated by growth hormone, Int J Biochem Cell Biol 1995;27:9–20
21 - Pampon NA, Shapiro BH, Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile, Endocrinology 1999;140:1245–1254
22 - Prandota, Joseph, Possible Pathomechanism of Autoimmune Hepatitis, American Journal of Therapeutics 10, 51–57 (2003)
