[h=1]Testosterone-Induced Water Retention - How to Combat It[/h]
Connect the dots— a child’s game where a random-appearing collection of darkened circles on paper suddenly generates a favorite cartoon character or animal when the dots are connected by a pencil line in proper order. Innovation in science is a game of “connect the dots.” Clinical trials look primarily at outcome and results, while the real “sexiness” of research is finding out why and how, rather than what.
Bodybuilding represents the epitome of “what” science. For generations, a lore of training, nutrition, supplements and drugs has evolved from the combined experience of tens of thousands, maybe as many as a million bodybuilders— who have tried, tracked, studied and in some cases, suffered from being an “experiment of one” or “human guinea pigs,” as some refer to the iron culture. Only in the last decade or so has basic and abstract science come forward to attempt to determine the “why and how” of bodybuilding. Some scientists refer to bodybuilding lore as “broscience” in a condescending manner, perhaps to generate a YouTube persona, provide the gratification of self-grandeur or to resolve a deep-seated belief that they have always disappointed their father.
Unfortunately, there is very little direct research into bodybuilding, but related research can be applied if there is enough familiarity with the topic to recognize when seemingly disconnected findings are published. This paper may represent such an apocalyptic revelation. For the record, apocalypse is not a term of catastrophe or end times, but discovery as it translates to “lifting of the veil.”
Water Retention
One adverse effect of testosterone use and misuse is edema— particularly, dependent edema— a condition more common in older men.[SUP]1[/SUP] Edema means water retention, and dependent refers to water retention “toward the ground” like when you can see the imprint of your socks around your ankles after you take them off. This is a sign of fluid retention, often associated with elevated sodium and potassium in the serum (blood). A study looking at various doses of testosterone enanthate in older men revealed nearly half experienced leg edema in the groups provided with supraphysiologic testosterone (300 and 600 milligrams per week of testosterone enanthate).[SUP]2[/SUP]
Sodium and potassium are usually maintained in a balanced range through the actions of a multitude of hormones and chemokines that act primarily on the kidneys. Obviously, adequate water consumption plays a role as well, maintained by other hormones that stimulate thirst. Liver function also contributes, due to the osmotic (water-pulling) effect of various proteins produced by the blood, such as albumin. Hyperglycemia (elevated blood sugar) can factor in if it reaches pathologic concentrations, such as in type 1 diabetes, or perhaps following an extreme sugar binge.
Yet, many bodybuilders and lifters using anabolic-androgenic steroids (AAS), or men beginning testosterone replacement therapy (TRT), develop edema within a matter of days or weeks of beginning use, despite having previously been free of any such symptom. In TRT, dependent edema can lead to discontinuing treatment that is necessary to correct a hormonal deficiency that has direct consequences on metabolic health and even longevity. Certain gyms are filled with young men with transiently large, but doughy arms. Yet, what if this edema is not a significant adverse event that requires discontinuation of treatment (in the case of TRT), but a physiologic event that arises in men who generate an abnormal but treatable response to certain androgens? What if this treatment was not only safe and effective, but also may be instituted to treat a common condition that may pre-exist or develop over time eventually, regardless of exposure to or absence of TRT or AAS?
Regulating Blood Pressure
There is a responsive pathway that regulates blood pressure by increasing the reuptake of sodium from urine after it has been filtered from the blood. This causes sodium in the blood (serum) to go up, resulting in an increase in blood pressure and fluid retention. The pathway, CYP4A11 and CYP4F2, are enzyme systems in the liver, blood vessels and kidney cells that generate an active chemokine— a hormone-like messenger called 20-HETE.[SUP]3[/SUP] CYP4A11 and CYP4F2 convert arachadonic acid into 20-HETE using an enzyme called a monooxygenase.[SUP]4[/SUP]20-HETE generates numerous effects that cause an increase in both blood volume and resistance.[SUP]4[/SUP] This is like turning up the water flow on a garden hose and narrowing the opening. The water is discharged at a much greater pressure. This is great if you are pressure-washing your deck, but in your arteries and capillaries it causes damage and can lead to cardiovascular disease, organ damage and even death. An increase in blood pressure, alongside an increase in blood volume, causes extra “fluid” to be pushed from within blood vessels to the area between cells called the interstitial space. This is the beginning of one cause of androgen-associated edema.
To combat the effect of 20-HETE on the blood vessels requires a drug that antagonizes the CYP4A11 system, or competes with the enzyme to generate a non-harmful prostaglandin rather than 20-HETE. There are also antagonists to the 20-HETE receptor are in development. Unfortunately, none of these options are approved as of this time. However, the effect of 20-HETE on the kidneys can be managed using a common and inexpensive treatment. One possible strategy that may have value is increasing consumption of fish oil, as EPA and DHA (the omega-3 fatty acids) compete with arachadonic acid in the monooxygenase reaction. In test-tube studies, EPA and DHA in various concentrations reduced 20- HETE production by 15-65 percent.[SUP]5[/SUP]
Drawing Sodium Back Into the Bloodstream
When blood volume is too high, sodium is elevated or hypertension (high blood pressure) exists. Sodium is usually excreted from the blood and NOT reabsorbed from the urine— as it is one of the main determinants of how much “fluid” is in the blood. However, 20-HETE stimulates an increase in special transporters that draw sodium (and chloride) back into the bloodstream from the newly filtered urine. This may occur through 20-HETE’s stimulation of an enzyme that generates the hormone angiotensin II. These transporters, called NCC, have been shown to be more abundant and more active as well when levels of angiotensin II are elevated.[SUP]6[/SUP] Angiotensin II is a hormone that is created through multiple converting enzymes, and stimulates the release and action of aldosterone. The function of aldosterone is to retain sodium. However, as angiotensin II is generated locally in the kidneys when stimulated by 20-HETE, it is a direct link to the increase in NCC transporter activity. It has been reported in mouse models that were genetically altered to have the more blood pressure-prone form of the human CYP4A11 gene that NCC transporters increased by 50 percent.[SUP]3[/SUP]
Treating mice (and likely humans) with increased NCC activity, potentially due to increased 20-HETE production, is achieved by simple mechanisms. As stated earlier, inhibiting CYP4A11 or 20-HETE receptor antagonists will likely enter the pharmaceutical arsenal in the future.[SUP]3[/SUP]However, for now, established and inexpensive drugs and even supplements may offer much of the same benefits. Fish oil, sesamin, low sodium and a low-carb diet may be helpful.[SUP]4[/SUP] There are blood pressure drugs that work by acting directly upon the NCC to block sodium reuptake, as well as drugs that inhibit the production of angiotensin II (e.g., captopril, lisinopril, enalapril) or block angiotensin II’s action at its receptor (e.g., losartan). Another option is the diuretic hydrochlorothiazide (Dyazide), which acts directly on the NCC transporter. Given the prevalence of edema in older men started on TRT in the high-normal range or greater, it may be prudent to monitor their blood pressure frequently, or even consider administering an ACE inhibitor or losartan if their blood pressure is already in the prehypertensive range.
AAS Use and Edema
Now, the only thing lacking is the connection to AAS use, and what drugs may be most relevant to causing edema. AAS-associated edema is common among those using testosterone esters or oral AAS that aromatize easily, and rarely associated with DHT-based AAS such as stanozolol (aka Winstrol) or mesterolone (aka Proviron). One would then think that the estrogenic metabolites are causing the puffiness, and Winstrol and Proviron are cutting drugs that provide a hard, dry physique. Yet, it appears that DHT is the main culprit in AAS-associated edema, and estrogens get a pass this time.[SUP]7[/SUP] This may be relevant when choosing treatment modality in TRT, as topical agents have been shown to increase serum DHT over twice what was seen with injected testosterone.[SUP]8[/SUP]
CYP4A11 and CYP4F2 are androgen regulated in mice and men. Increased androgen signaling results in an increase in CYP4F2, directly leading to an increase in 20-HETE in the kidneys’ microcirculation.[SUP]4,5,7,9[/SUP] This leads to many questions, of course, as this is a novel area of investigation. Is there an increase in blood pressure in men using predominantly DHT-derived AAS cycles (e.g., Winstrol)? Does the use of an aromatase inhibitor increase the risk of an elevation in blood pressure in AAS users of testosterone or aromatizable AAS, or men on TRT? Does suppressing estrogen via an aromatase inhibitor increase risk, or does adding an aromatizable AAS to a cycle decrease risk? Why are drugs such as Winstrol and Proviron “hardening” AAS— are they metabolized differently or generate a different response? Would a 5-alpha reductase drug reduce androgen-associated hypertension?
The purpose of this article is to make the reader aware of the presence of androgen-associated hypertension, so that he will be better prepared to make an informed decision about the choice of illicit AAS use and another relevant risk. For men on TRT or seeking treatment, as well as AAS users, blood pressure should be monitored throughout the exposure to the drug(s). Some individuals are more prone to this adverse effect due to one’s specific CYP4A11 or CYP4F2 gene.[SUP]10[/SUP] If one’s blood pressure increases, or is already high, then appropriate conversations should be initiated with one’s personal physician. Hypertension is known as one of the “silent killers,” as it can be without symptoms— but it also causes vascular and organ damage over time that can result in greatly impaired health, or even death.
References:
1. Chahla EJ, Hayek ME, et al. Testosterone replacement therapy and cardiovascular risk factors modification. Aging Male 2011;14:83-90.
2. Bhasin S, Woodhouse L, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678-88.
3. Savas Ü, Wei S, et al. 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent hypertension in human cytochrome P450 (CYP) 4A11 transgenic mice: normalization of blood pressure by sodium restriction, hydrochlorothiazide, or blockade of the type 1 angiotensin ii receptor. J Biol Chem 2016;291:16904-19.
4. Wu CC, Gupta T, et al. 20-HETE and blood pressure regulation: clinical implications. Cardiol Rev 2014;22:1-12.
5. Harmon SD, Fang X, et al. Oxygenation of omega-3 fatty acids by human cytochrome P450 4F3B: effect on 20-hydroxyeicosatetraenoic acid production. Prostaglandins Leukot Essent Fatty Acids 2006;75:169-77.
6. Rojas-Vega L, Gamba G. Mini-review: regulation of the renal NaCl cotransporter by hormones. Am J Physiol Renal Physiol 2016;310:F10-4.
7. Singh H, Schwartzman ML. Renal vascular cytochrome P450-derived eicosanoids in androgen-induced hypertension. Pharmacol Rep 2008;60:29-37.
8. Borst SE, Shuster JJ, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med 2014 Nov 27;12:211(16 pp).
9. Liu X, Wu J, et al. Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice. Gene 2012;505:352–359.
10. Jiang Y, Hou J, et al. T8590C polymorphism of CYP4A11 is a risk factor for hypertension: a meta-analysis. Chin Med J 2014;127:2382-5.
Connect the dots— a child’s game where a random-appearing collection of darkened circles on paper suddenly generates a favorite cartoon character or animal when the dots are connected by a pencil line in proper order. Innovation in science is a game of “connect the dots.” Clinical trials look primarily at outcome and results, while the real “sexiness” of research is finding out why and how, rather than what.
Bodybuilding represents the epitome of “what” science. For generations, a lore of training, nutrition, supplements and drugs has evolved from the combined experience of tens of thousands, maybe as many as a million bodybuilders— who have tried, tracked, studied and in some cases, suffered from being an “experiment of one” or “human guinea pigs,” as some refer to the iron culture. Only in the last decade or so has basic and abstract science come forward to attempt to determine the “why and how” of bodybuilding. Some scientists refer to bodybuilding lore as “broscience” in a condescending manner, perhaps to generate a YouTube persona, provide the gratification of self-grandeur or to resolve a deep-seated belief that they have always disappointed their father.
Unfortunately, there is very little direct research into bodybuilding, but related research can be applied if there is enough familiarity with the topic to recognize when seemingly disconnected findings are published. This paper may represent such an apocalyptic revelation. For the record, apocalypse is not a term of catastrophe or end times, but discovery as it translates to “lifting of the veil.”
Water Retention
One adverse effect of testosterone use and misuse is edema— particularly, dependent edema— a condition more common in older men.[SUP]1[/SUP] Edema means water retention, and dependent refers to water retention “toward the ground” like when you can see the imprint of your socks around your ankles after you take them off. This is a sign of fluid retention, often associated with elevated sodium and potassium in the serum (blood). A study looking at various doses of testosterone enanthate in older men revealed nearly half experienced leg edema in the groups provided with supraphysiologic testosterone (300 and 600 milligrams per week of testosterone enanthate).[SUP]2[/SUP]
Sodium and potassium are usually maintained in a balanced range through the actions of a multitude of hormones and chemokines that act primarily on the kidneys. Obviously, adequate water consumption plays a role as well, maintained by other hormones that stimulate thirst. Liver function also contributes, due to the osmotic (water-pulling) effect of various proteins produced by the blood, such as albumin. Hyperglycemia (elevated blood sugar) can factor in if it reaches pathologic concentrations, such as in type 1 diabetes, or perhaps following an extreme sugar binge.
Yet, many bodybuilders and lifters using anabolic-androgenic steroids (AAS), or men beginning testosterone replacement therapy (TRT), develop edema within a matter of days or weeks of beginning use, despite having previously been free of any such symptom. In TRT, dependent edema can lead to discontinuing treatment that is necessary to correct a hormonal deficiency that has direct consequences on metabolic health and even longevity. Certain gyms are filled with young men with transiently large, but doughy arms. Yet, what if this edema is not a significant adverse event that requires discontinuation of treatment (in the case of TRT), but a physiologic event that arises in men who generate an abnormal but treatable response to certain androgens? What if this treatment was not only safe and effective, but also may be instituted to treat a common condition that may pre-exist or develop over time eventually, regardless of exposure to or absence of TRT or AAS?
Regulating Blood Pressure
There is a responsive pathway that regulates blood pressure by increasing the reuptake of sodium from urine after it has been filtered from the blood. This causes sodium in the blood (serum) to go up, resulting in an increase in blood pressure and fluid retention. The pathway, CYP4A11 and CYP4F2, are enzyme systems in the liver, blood vessels and kidney cells that generate an active chemokine— a hormone-like messenger called 20-HETE.[SUP]3[/SUP] CYP4A11 and CYP4F2 convert arachadonic acid into 20-HETE using an enzyme called a monooxygenase.[SUP]4[/SUP]20-HETE generates numerous effects that cause an increase in both blood volume and resistance.[SUP]4[/SUP] This is like turning up the water flow on a garden hose and narrowing the opening. The water is discharged at a much greater pressure. This is great if you are pressure-washing your deck, but in your arteries and capillaries it causes damage and can lead to cardiovascular disease, organ damage and even death. An increase in blood pressure, alongside an increase in blood volume, causes extra “fluid” to be pushed from within blood vessels to the area between cells called the interstitial space. This is the beginning of one cause of androgen-associated edema.
To combat the effect of 20-HETE on the blood vessels requires a drug that antagonizes the CYP4A11 system, or competes with the enzyme to generate a non-harmful prostaglandin rather than 20-HETE. There are also antagonists to the 20-HETE receptor are in development. Unfortunately, none of these options are approved as of this time. However, the effect of 20-HETE on the kidneys can be managed using a common and inexpensive treatment. One possible strategy that may have value is increasing consumption of fish oil, as EPA and DHA (the omega-3 fatty acids) compete with arachadonic acid in the monooxygenase reaction. In test-tube studies, EPA and DHA in various concentrations reduced 20- HETE production by 15-65 percent.[SUP]5[/SUP]
Drawing Sodium Back Into the Bloodstream
When blood volume is too high, sodium is elevated or hypertension (high blood pressure) exists. Sodium is usually excreted from the blood and NOT reabsorbed from the urine— as it is one of the main determinants of how much “fluid” is in the blood. However, 20-HETE stimulates an increase in special transporters that draw sodium (and chloride) back into the bloodstream from the newly filtered urine. This may occur through 20-HETE’s stimulation of an enzyme that generates the hormone angiotensin II. These transporters, called NCC, have been shown to be more abundant and more active as well when levels of angiotensin II are elevated.[SUP]6[/SUP] Angiotensin II is a hormone that is created through multiple converting enzymes, and stimulates the release and action of aldosterone. The function of aldosterone is to retain sodium. However, as angiotensin II is generated locally in the kidneys when stimulated by 20-HETE, it is a direct link to the increase in NCC transporter activity. It has been reported in mouse models that were genetically altered to have the more blood pressure-prone form of the human CYP4A11 gene that NCC transporters increased by 50 percent.[SUP]3[/SUP]
Treating mice (and likely humans) with increased NCC activity, potentially due to increased 20-HETE production, is achieved by simple mechanisms. As stated earlier, inhibiting CYP4A11 or 20-HETE receptor antagonists will likely enter the pharmaceutical arsenal in the future.[SUP]3[/SUP]However, for now, established and inexpensive drugs and even supplements may offer much of the same benefits. Fish oil, sesamin, low sodium and a low-carb diet may be helpful.[SUP]4[/SUP] There are blood pressure drugs that work by acting directly upon the NCC to block sodium reuptake, as well as drugs that inhibit the production of angiotensin II (e.g., captopril, lisinopril, enalapril) or block angiotensin II’s action at its receptor (e.g., losartan). Another option is the diuretic hydrochlorothiazide (Dyazide), which acts directly on the NCC transporter. Given the prevalence of edema in older men started on TRT in the high-normal range or greater, it may be prudent to monitor their blood pressure frequently, or even consider administering an ACE inhibitor or losartan if their blood pressure is already in the prehypertensive range.
AAS Use and Edema
Now, the only thing lacking is the connection to AAS use, and what drugs may be most relevant to causing edema. AAS-associated edema is common among those using testosterone esters or oral AAS that aromatize easily, and rarely associated with DHT-based AAS such as stanozolol (aka Winstrol) or mesterolone (aka Proviron). One would then think that the estrogenic metabolites are causing the puffiness, and Winstrol and Proviron are cutting drugs that provide a hard, dry physique. Yet, it appears that DHT is the main culprit in AAS-associated edema, and estrogens get a pass this time.[SUP]7[/SUP] This may be relevant when choosing treatment modality in TRT, as topical agents have been shown to increase serum DHT over twice what was seen with injected testosterone.[SUP]8[/SUP]
CYP4A11 and CYP4F2 are androgen regulated in mice and men. Increased androgen signaling results in an increase in CYP4F2, directly leading to an increase in 20-HETE in the kidneys’ microcirculation.[SUP]4,5,7,9[/SUP] This leads to many questions, of course, as this is a novel area of investigation. Is there an increase in blood pressure in men using predominantly DHT-derived AAS cycles (e.g., Winstrol)? Does the use of an aromatase inhibitor increase the risk of an elevation in blood pressure in AAS users of testosterone or aromatizable AAS, or men on TRT? Does suppressing estrogen via an aromatase inhibitor increase risk, or does adding an aromatizable AAS to a cycle decrease risk? Why are drugs such as Winstrol and Proviron “hardening” AAS— are they metabolized differently or generate a different response? Would a 5-alpha reductase drug reduce androgen-associated hypertension?
The purpose of this article is to make the reader aware of the presence of androgen-associated hypertension, so that he will be better prepared to make an informed decision about the choice of illicit AAS use and another relevant risk. For men on TRT or seeking treatment, as well as AAS users, blood pressure should be monitored throughout the exposure to the drug(s). Some individuals are more prone to this adverse effect due to one’s specific CYP4A11 or CYP4F2 gene.[SUP]10[/SUP] If one’s blood pressure increases, or is already high, then appropriate conversations should be initiated with one’s personal physician. Hypertension is known as one of the “silent killers,” as it can be without symptoms— but it also causes vascular and organ damage over time that can result in greatly impaired health, or even death.
References:
1. Chahla EJ, Hayek ME, et al. Testosterone replacement therapy and cardiovascular risk factors modification. Aging Male 2011;14:83-90.
2. Bhasin S, Woodhouse L, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678-88.
3. Savas Ü, Wei S, et al. 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent hypertension in human cytochrome P450 (CYP) 4A11 transgenic mice: normalization of blood pressure by sodium restriction, hydrochlorothiazide, or blockade of the type 1 angiotensin ii receptor. J Biol Chem 2016;291:16904-19.
4. Wu CC, Gupta T, et al. 20-HETE and blood pressure regulation: clinical implications. Cardiol Rev 2014;22:1-12.
5. Harmon SD, Fang X, et al. Oxygenation of omega-3 fatty acids by human cytochrome P450 4F3B: effect on 20-hydroxyeicosatetraenoic acid production. Prostaglandins Leukot Essent Fatty Acids 2006;75:169-77.
6. Rojas-Vega L, Gamba G. Mini-review: regulation of the renal NaCl cotransporter by hormones. Am J Physiol Renal Physiol 2016;310:F10-4.
7. Singh H, Schwartzman ML. Renal vascular cytochrome P450-derived eicosanoids in androgen-induced hypertension. Pharmacol Rep 2008;60:29-37.
8. Borst SE, Shuster JJ, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med 2014 Nov 27;12:211(16 pp).
9. Liu X, Wu J, et al. Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice. Gene 2012;505:352–359.
10. Jiang Y, Hou J, et al. T8590C polymorphism of CYP4A11 is a risk factor for hypertension: a meta-analysis. Chin Med J 2014;127:2382-5.
