Type-IIx
Well-known Member
Learning about the gut histamine/androgen connection surprised me, so I thought I'd share what I learned about androgens and acid reflux and peptic ulcer, as it is not discussed often. If anyone has any useful information including anecdotes on what's worked for them with respect to AAS-induced acid reflux or peptic ulcer, please share!
Gastric mucosal susceptibility and ulcerogenic effects
acid reflux; peptic ulcer
Androgens are ulcerogenic and enhance the susceptibility of gastric mucosa to the peptic action of gastric juice [1]. Estrogens are protective: females appear to be protected against both gastric hypersecretion and peptic ulcers in those periods in their lives when circulating estrogens are high [1].
Pronounced sex difference in acid reflux and peptic ulcer
The sex difference in the male rat excreting lesser free histamine than the female is ascribed to the sex-related efficiency in the male for metabolic inactivation of histamine via methylation as the principal catabolic pathway [2]... Testosterone increases the proportion of methylhistamine in urine [2]. The female kidney, most pronounced in pregnancy, forms more histamine, and in pregnancy, the activity of histidine decarboxylase (histamine formation capacity of tissues, especially kidney and fetal tissue) is markedly increased [2].
Estrogen provokes a dose- and time- dependent increase in histamine excretion. Progesterone does not alter histamine excretion. Testosterone provokes a striking dose- and time- dependent decrease in histamine excretion. Testosterone virtually abolishes kidney histidine decarboxylase activity.
Histamine and the gut
Histamine serves a function in gastric acid secretion via the H₂ receptors (H₂R). H₂R antagonists potently inhibit acid (HCl) secretion [3].
Gastric mucosa is markedly rich in histamine, and there is a selective accumulation of histamine related to acid secretory cells. Gastric acid secretion is strongly stimulated by histamine and a number of methyl histamine analogs, including n(Me)histamine, n'n'dimethyl histamine, and 4-(Me)histamine [3].
- cimetidine antagonizes histamine by competitive inhibition of H₂ receptors (H₂R) located in gastric parietal cells ⇒ ↓gastric acid secretion & volume & acidity
Histamine interacts with other stimuli of gastric acid secretion: there is potentiation in the parietal cell between histamine, acetylcholine, and gastrin [3]. Other stimuli of gut acid secretion include: food, caffeine, distension, vagal, and other cholinergic agents [3].
Relevant organs
Gastric (stomach) muscle contracts with H₁R stimulation & relaxes with H₂R stimulation
- Gastric emptying is unaffected by H₂R antagonists
Pylorus:
- Histamine has unclear effects on, but does affect, phasic contractions of the pyloric sphincter (frequency, amplitude, duration) via neural & myogenic H₁R
Intestine:
- Ileal contraction with histamine is a classic H₁ effect
Gallbladder:
- H₁R mediate gallbladder contraction by histamine; H₂R mediate gallbladder relaxation
...Blockade of H₂R augments the response to [hormonal agents], suggesting that histamine may modify the response to this class of agents [including androgens?]
[3]
Cimetidine ✖
Tagamet
- cimetidine antagonizes AR by cytosolic binding & inhibits gastric acid secretion
- antagonizes H2 histamine receptor-mediated gastric acid secretory response
- stimulates plasma prolactin
Also:
- binds cytochrome P-450 as a type II ligand, inhibiting its function, causing reduced metabolism of exogenous pharmacological agents (via cyt. P-450)
- alters hepatic metabolism of estrogens (↓2- & 16α- hydroxylation of E₂
- alters hepatic metabolism of androgens (↓formation of polar metabolites [hydroxylated derivatives], producing a marked increase in 3-androstenediol, the fully reduced androgen)
- ↓6β-, 7α-, and 16α- hydroxylation of T (20, 21) [4]
Ranitidine, Famotidine, Nizatidine ✓
Zantac, Pepcid, Axid
Ranitidine and famotidine (2d gen. H₂R antagonists) do not affect cytochrome P-450 metabolism, androgen nor estrogen metabolism [4].
Nizatidine did not antagonize AR, had a less potent and consistent effect on plasma prolactin increase.
______________________________
References:
[1] Kowalewski, K., Schier, J. F., & Chmura, G. (1970). Effect of Sex Hormones on Gastric Secretion and on Gastric Mucosa in Oophorectomized Histamine Stimulated Rats. Digestion, 3(1), 13–19. doi:10.1159/000196983
[2] HENNINGSSON, S. S. G., & ROSENGREN, E. (1972). Alterations of histamine metabolism after injections of sex hormones in mice. British Journal of Pharmacology, 44(3), 517–526. doi:10.1111/j.1476-5381.1972.tb07288.x
[3] Hirschowitz, B. I. (1985). Histamine and the Gut. Allergy and Asthma Proceedings, 6(1), 21–27. doi:10.2500/108
854185779048942
[4] Galbraith, R. A., & Jellinck, P. H. (1989). Differential effects of cimetidine, ranitidine and famotidine on the hepatic metabolism of estrogen and testosterone in male rats. Biochemical Pharmacology, 38(12), 2046–2049. doi:10.1016/0006-2952(89)90507-8
Gastric mucosal susceptibility and ulcerogenic effects
acid reflux; peptic ulcer
Androgens are ulcerogenic and enhance the susceptibility of gastric mucosa to the peptic action of gastric juice [1]. Estrogens are protective: females appear to be protected against both gastric hypersecretion and peptic ulcers in those periods in their lives when circulating estrogens are high [1].
Pronounced sex difference in acid reflux and peptic ulcer
The sex difference in the male rat excreting lesser free histamine than the female is ascribed to the sex-related efficiency in the male for metabolic inactivation of histamine via methylation as the principal catabolic pathway [2]... Testosterone increases the proportion of methylhistamine in urine [2]. The female kidney, most pronounced in pregnancy, forms more histamine, and in pregnancy, the activity of histidine decarboxylase (histamine formation capacity of tissues, especially kidney and fetal tissue) is markedly increased [2].
Estrogen provokes a dose- and time- dependent increase in histamine excretion. Progesterone does not alter histamine excretion. Testosterone provokes a striking dose- and time- dependent decrease in histamine excretion. Testosterone virtually abolishes kidney histidine decarboxylase activity.
Histamine and the gut
Histamine serves a function in gastric acid secretion via the H₂ receptors (H₂R). H₂R antagonists potently inhibit acid (HCl) secretion [3].
Gastric mucosa is markedly rich in histamine, and there is a selective accumulation of histamine related to acid secretory cells. Gastric acid secretion is strongly stimulated by histamine and a number of methyl histamine analogs, including n(Me)histamine, n'n'dimethyl histamine, and 4-(Me)histamine [3].
- cimetidine antagonizes histamine by competitive inhibition of H₂ receptors (H₂R) located in gastric parietal cells ⇒ ↓gastric acid secretion & volume & acidity
Histamine interacts with other stimuli of gastric acid secretion: there is potentiation in the parietal cell between histamine, acetylcholine, and gastrin [3]. Other stimuli of gut acid secretion include: food, caffeine, distension, vagal, and other cholinergic agents [3].
Relevant organs
Gastric (stomach) muscle contracts with H₁R stimulation & relaxes with H₂R stimulation
- Gastric emptying is unaffected by H₂R antagonists
Pylorus:
- Histamine has unclear effects on, but does affect, phasic contractions of the pyloric sphincter (frequency, amplitude, duration) via neural & myogenic H₁R
Intestine:
- Ileal contraction with histamine is a classic H₁ effect
Gallbladder:
- H₁R mediate gallbladder contraction by histamine; H₂R mediate gallbladder relaxation
...Blockade of H₂R augments the response to [hormonal agents], suggesting that histamine may modify the response to this class of agents [including androgens?]
[3]
Cimetidine ✖
Tagamet
- cimetidine antagonizes AR by cytosolic binding & inhibits gastric acid secretion
- antagonizes H2 histamine receptor-mediated gastric acid secretory response
- stimulates plasma prolactin
Also:
- binds cytochrome P-450 as a type II ligand, inhibiting its function, causing reduced metabolism of exogenous pharmacological agents (via cyt. P-450)
- alters hepatic metabolism of estrogens (↓2- & 16α- hydroxylation of E₂
- alters hepatic metabolism of androgens (↓formation of polar metabolites [hydroxylated derivatives], producing a marked increase in 3-androstenediol, the fully reduced androgen)
- ↓6β-, 7α-, and 16α- hydroxylation of T (20, 21) [4]
Ranitidine, Famotidine, Nizatidine ✓
Zantac, Pepcid, Axid
Ranitidine and famotidine (2d gen. H₂R antagonists) do not affect cytochrome P-450 metabolism, androgen nor estrogen metabolism [4].
Nizatidine did not antagonize AR, had a less potent and consistent effect on plasma prolactin increase.
______________________________
References:
[1] Kowalewski, K., Schier, J. F., & Chmura, G. (1970). Effect of Sex Hormones on Gastric Secretion and on Gastric Mucosa in Oophorectomized Histamine Stimulated Rats. Digestion, 3(1), 13–19. doi:10.1159/000196983
[2] HENNINGSSON, S. S. G., & ROSENGREN, E. (1972). Alterations of histamine metabolism after injections of sex hormones in mice. British Journal of Pharmacology, 44(3), 517–526. doi:10.1111/j.1476-5381.1972.tb07288.x
[3] Hirschowitz, B. I. (1985). Histamine and the Gut. Allergy and Asthma Proceedings, 6(1), 21–27. doi:10.2500/108
854185779048942
[4] Galbraith, R. A., & Jellinck, P. H. (1989). Differential effects of cimetidine, ranitidine and famotidine on the hepatic metabolism of estrogen and testosterone in male rats. Biochemical Pharmacology, 38(12), 2046–2049. doi:10.1016/0006-2952(89)90507-8
Ive even asked for an alternative sleep medication that doesnt work through the histamine pathway but they dont have any suggestions....
