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Arachidonic Acid’s Role in Stress and Shock

Also see:
Resuscitation: Benefits of ATP, Glucose, and Sodium
Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution
Sunburn, PUFA, Prostaglandins, and Aspirin
Phospholipases, PUFA, and Inflammation
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Toxicity of Stored PUFA
PUFA – Accumulation and Aging
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
Fish Oil Toxicity
Estrogen’s Role in Asthma
PUFA Decrease Cellular Energy Production
Benefits of Aspirin
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
Unsaturated Fats and Lung Function

“In adults, prostaglandins are known to be involved in many of the harmful effects of inflammation. They are formed from the polyunsaturated fats, linoleic acid and arachidonic acid, which we are unable to synthesize ourselves, so the adult’s exposure to the prostaglandins is influenced by diet.” -Ray Peat, PhD

“The remarkable resistance of “essential fatty acid deficient” animals to shock (Cook, et al., 1981; Li et al., 1990; Autore, et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive reactions of shock. The cellular changes that occur in shock–calcium retention, leakiness, reduced energy production–are seen in aging and the degenerative diseases; the stress hormones and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old age is the reduced ability to tolerate stress and to recover from injuries…” -Ray Peat, PhD

Adv Shock Res. 1981;6:83-91.
Implications for thromboxane A2 in the pathogenesis of endotoxic shock.
Wise WC, Cook JA, Halushka PV.
During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.

J Clin Invest. 1980 Jan;65(1):227-30.
Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency.
Cook JA, Wise WC, Halushka PV.
The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A(2), in endotoxic shock was investigated in rats. Plasma thromboxane A(2) was determined by radioimmunoassay of its stable metabolite thromboxane B(2). After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B(2) levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054+/-524 pg/ml (n = 8), within 30 min to 2,071+/-429 at 60 min, and decreased to 1,119+/-319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146+/-33 pg/ml in normal controls (n = 5) to 2,161+/-606 pg/ml 30 min after endotoxin (n = 5). In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B(2). Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg), a thromboxane antagonist, reduced mortality from endotoxic shock at 24 h from 100% in control rats to only 50% (P < 0.01). The results suggest that endotoxin induces increased synthesis of thromboxane A(2) that may contribute to the pathogenesis of endotoxic shock.

Adv Shock Res. 1981;6:93-105.
Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock.
Cook JA, Wise WC, Knapp DR, Halushka PV.
Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats.Treatment of EFAD rats with the fatty acid docosahexaenoic acid, a non-prostaglandin and thromboxane precursor, (100 mg, IP) produced significantly less (less than 0.01) mortality than ethyl-arachidonate-treated groups (ie, 40% vs 100%). The arachidonate metabolite, thromboxane B2 (TxB2), increased from nondetectable plasma levels (less than 200 pg/ml) to 2285 +/- 449 pg/ml (N = 10) at 30 min and remained elevated for 180 minutes after endotoxin administration in nondeficient rats. However, plasma TxB2 was not detectable in endotoxin-treated EFAD rats and was only slightly elevated in groups supplemented with docosahexaenoic acid (273 +/- 104 pg/ml, N = 6) after 30 minutes. In ethyl arachidonate (100 mg, IP) supplemented EFAD rats, plasma TxB2 rose to 873 +/- 204 pg/ml (N = 8), 30 min after endotoxin. Pretreatment of the ethyl-arachidonate-supplemented EFAD group with a specific thromboxane synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (30 mg/kg, IV), significantly reduced mortality 100% to 50% (P less than 0.05) from endotoxic shock. These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.

Circ Shock. 1990 Jun;31(2):159-70.
Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability.
Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.
Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats (47 +/- 2% vs. 54 +/- 1% respectively, P less than 0.01). Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3. Infusion of LTC4 (4 micrograms/kg/min) in normal rats induced a rise in HCT from 44 +/- 1% to 51 +/- 1% (P less than 0.01), which was greater (P less than 0.05) than the rise induced by LTC3 (47 +/- 1% to 49 +/- 1%). The results showing that EFAD rats are resistant to endotoxin-induced increases in HCT and vascular permeability raise the possibility that this may, in part, be a result of preferential LTC3 production that is less potent than LTC4.

Journal of Applied Physiology August 1989 vol. 67 no. 2 811-816
Essential fatty acid-deficient rats are resistant to oleic acid-induced pulmonary injury
H. A. Ball, J. A. Cook, K. M. Spicer, W. C. Wise, and P. V. Halushka
Because leukotrienes and prostaglandins are inflammatory mediators derived from arachidonic acid, their potential role in oleic acid-induced lung injury was evaluated in control and in essential fatty acid-deficient (EFAD) rats depleted of arachidonic acid substrate. In control rats, oleic acid (0.06 ml/kg iv) increased the pulmonary permeability index (measured by scintigraphy) from -10 +/- 13 x 10(-6) s-1 to 217 +/- 20 x 10(-6) s-1 and 118 +/- 13 x 10(-6) s-1 at 5 and 50 min (P less than 0.05), respectively. It also caused arterial hypoxemia at 30 min (P less than 0.05). Compared with saline controls, oleic acid increased bronchoalveolar lavage fluid levels of immunoreactive (i) LTC4/D4, iLTB4, (P less than 0.01), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) (P less than 0.05). In EFAD rats, oleic acid failed to significantly increase the lung permeability index at 5 and 50 min. In contrast to control rats, oleic acid failed to cause hypoxemia in the EFAD rats. Bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha after oleic acid in EFAD rats were lower compared with oleic acid controls, whereas iLTC4/D4 in the oleic acid EFAD group was not decreased. Treatment with intraperitoneal ethyl arachidonate (400 mg over 2 wk) reversed the resistance of EFAD rats such that the pulmonary edema (P less than 0.05) was evident after oleic acid. This latter group also manifested a significant (P less than 0.05) rise in the bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha. These results suggest that arachidonic acid metabolites contribute to oleic acid-induced pulmonary permeability.

INTENSIVE CARE MEDICINE Volume 12, Number 3, 116-126
Role of thromboxane, prostaglandins and leukotrienes in endotoxic and septic shock
H. A. Ball, J. A. Cook, W. C. Wise and P. V. Halushka
Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB2 and 6-keto-PGF1 in a large number of species. A smaller, delayed and more prolonged increase in TxB2 and 6-keto-PGF1 are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA2 exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB2 and 6-keo-PGF1 concentrations in patients with septic shock, and elevated LTD4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.

Am J Vet Res. 2008 Feb;69(2):199-207.
Roles of thromboxane A2 and 5-hydroxytryptamine in endotoxin-induced digital vasoconstriction in horses.
Menzies-Gow NJ, Sepulveda MF, Bailey SR, Cunningham FM, Elliott J.
OBJECTIVE:
To evaluate the roles of 5-hydroxytryptamine (5-HT), thromboxane A2 (TxA2), and platelet-activating factor (PAF) in endotoxin-induced digital hypoperfusion in horses.
ANIMALS:
6 healthy adult Thoroughbreds.
PROCEDURES:
Horses were treated with IV administration of saline (0.9% NaCl) solution (control treatment) or the 5-HT 1B/D selective antagonist, GR55562 (0.3 mg/kg), prior to tryptamine infusion (1.6 microg/kg/min for 30 minutes) to establish an effective GR55562 dose. In a crossover study, horses were treated with IV administration of saline solution (control treatment), aspirin (4 mg/kg, 2 hours or 4 days before lipopolysaccharide [LPS] infusion), GR55562 (0.3 mg/kg), the PAF antagonist WEB2086 (3 mg/kg), or aspirin plus GR55562 prior to LPS infusion (30 ng/kg for 30 minutes). Digital blood flow was measured by use of Doppler ultrasonography. Concomitant measurements of hoof wall and coronary band surface temperatures were made. Serial blood samples were collected and plasma 5-HT and TxA2 concentrations determined.
RESULTS:
GR55562 abolished tryptamine-induced digital hypoperfusion. Neither WEB2086 nor GR55562 affected LPS-induced alterations in digital perfusion or plasma mediator concentrations. Aspirin given 2 hours before LPS administration abolished the increase in plasma TxA2 concentration and significantly attenuated LPS-induced digital hypoperfusion. Aspirin given 4 days before LPS significantly attenuated the increase in plasma TxA2 concentration and digital hypothermia. Aspirin plus GR55562 had a greater effect on LPS-induced digital hypothermia than aspirin alone.
CONCLUSIONS AND CLINICAL RELEVANCE:
Thromboxane A2 and 5-HT played a role in mediating LPS-induced digital hypoperfusion in horses. Platelet-activating factor appeared unimportant in mediating LPS-induced 5-HT or TxA2 release or digital hypoperfusion.

Prostaglandins, Leukotrienes and Medicine Volume 11, Issue 2, June 1983, Pages 179–188
Protective effects of thromboxane A2 on endotoxin shock
Sumio Fukumoto, Kenzo Tanaka
To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(l-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1α levels in the venous blood. In the untreated shock group, micrathrombi were observed in 64 % of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic.

Am J Physiol. 1989 Oct;257(4 Pt 2):H1192-9.
Lung injury caused by cobra venom factor is reduced in rats raised on an essential fatty acid-deficient diet.
Morganroth ML, Schoeneich SO, Till GO, Pickett W, Ward PA.
Arachidonate metabolites appear to be involved in lung injury caused by cobra venom factor (CVF)-induced complement and polymorphonuclear leukocyte (PMN) activation. These studies were designed to assess the effects of a dietary-induced deficiency of arachidonic acid on CVF-induced lung injury. Rats raised on an essential fatty acid-deficient (EFAD) diet exhibited the expected changes in fatty acid composition including decreased plasma levels of arachidonic acid and increased levels of 5,8,11-eicosatrienoic acid. In intact rats raised on the EFAD diet, CVF-induced lung injury was attenuated. When blood and excised lungs from rats raised on the normal diet were used, CVF caused pulmonary vascular constriction and acute lung injury, as evidenced by increased 125I-labeled bovine serum albumin accumulation in lung parenchyma and alveolar lavage fluid. The CVF-induced pulmonary artery pressor response and lung injury were reduced when blood perfusate or blood perfusate and excised lungs were obtained from rats raised on the EFAD diet. The pulmonary vascular constriction and lung injury were not attenuated when the blood perfusate was obtained from rats raised on the normal diet, irrespective of whether the excised lungs were obtained from rats raised on the normal or EFAD diet. PMNs obtained from rats raised on the EFAD diet demonstrated decreased superoxide production as well as impaired random migration and chemotaxis in vitro. In contrast, beta-glucuronidase release was quantitatively similar to PMNs from control rats. These data indicate that the EFAD diet-induced attenuation of CVF-induced pulmonary hypertension and acute lung injury is due to defective effector cells in blood rather than modified pulmonary target tissue.

Kidney Int. 1992 May;41(5):1245-53.
Essential fatty acid deficiency normalizes function and histology in rat nephrotoxic nephritis.
Takahashi K, Kato T, Schreiner GF, Ebert J, Badr KF.
The central lipid abnormality in essential fatty acid deficiency (EFAD) is the lack of availability of arachidonic acid. To examine the role of total eicosanoid’s biosyntheses in the pathology and pathophysiology of glomerulonephritis, EFAD was induced in weanling rats, which were then subjected to antiglomerular basement membrane antibody (NTS)-induced injury in adulthood. Glomerular dynamics (as assessed by micropuncture), quantitative histology, and eicosanoid generation rates were measured at two hours and two weeks post-NTS, and compared to those of standard diet-fed (STD) controls. Two hours post-NTS, and despite the occurrence of proteinuria in both EFAD and STD animals, glomerular dynamics were essentially normal in EFAD rats, whereas STD animals had reduced values for glomerular filtration rate (GFR) and renal plasma flow rate (RPF). At two weeks, severe histologic changes were observed in STD animals including mesangial and stalk hypercellularity, moderate sclerosis, and interstitial nephritis, coupled with heavy proteinuria and reduced GFR and RPF. In dramatic contrast, EFAD rats displayed totally normal glomerular structures and functions. In parallel, glomerular generation rates of prostaglandin E2 and thromboxane A2 were suppressed markedly in EFAD rats. Thus, EFAD confers complete protection against the histopathologic and functional sequelae of immune-initiated injury in the glomerulus. The data suggest that the initial wave of complement-induced neutrophil infiltration (with resultant proteinuria) is not sufficient to perpetuate injury into the more destructive chronic phases. The results provide strong impetus for the design of more specific interventional therapies targeting the various enzymes and products of arachidonic acid metabolism in the attempts to control glomerular inflammation.

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By Team FPS – April 3, 2012

Protective Carbon Dioxide, Exercise, and Performance

Also see:
Protective Altitude
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Lactate Paradox: High Altitude and Exercise
Carbohydrate Lowers Exercise Induced Stress
Exercise Induced Menstrual Disorders
Aspirin and Exercise
Bicarbonate For Strength Athletes: 25g of Baking Soda Up Your Squat (+27%) & Bench Press (+6%) Within 60 Min
How Measuring My Urine pH Got Me to Love Working Out Again

1026140808a

EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY AND OCCUPATIONAL PHYSIOLOGY
Volume 57, Number 1, 45-48, DOI: 10.1007/BF00691236
Induced metabolic alkalosis and its effects on 400-m racing time
Jo Goldfinch, Lars Mc Naughton and Peter Davies
Six trained male athletes who competed regularly in 400 metre races, were studied under control, alkalotic (NaHCO3) and placebo (CaCO3) conditions to study the effect of induced metabolic alkalosis on 400 m racing time. Pre and post exercise blood samples in the three conditions were analysed for pH, bicarbonate and base excess. Following ingestion of NaHCO3, pre-exercise pH, bicarbonate and base excess levels were significantly higher than either control or placebo conditions. In the alkalotic condition the subjects ran significantly (p<0.005) faster (1.52 s) than either the control of placebo conditions. The post-exercise pH, bicarbonate and base excess levels were all lower in the alkalotic condition than in the others. The results suggest that NaHCO3 can be used as an effective ergogenic aid and support the speculation that the increased extracellular buffering afforded by NaHCO3 ingestion facilitated efflux of H+ from the working tissues, thus decreasing intracellular pH and hence offsetting fatigue.

J Strength Cond Res. 2014 May;28(5):1358-66. doi: 10.1519/JSC.0000000000000277.
The effect of sodium bicarbonate ingestion on back squat and bench press exercise to failure.
Duncan MJ, Weldon A, Price MJ.
Duncan, MJ, Weldon, A, and Price, MJ. The effect of sodium bicarbonate ingestion on back squat and bench press exercise to failure. J Strength Cond Res 28(5): 1358-1366, 2014-This study examined the acute effects of NaHCO3 ingestion on repetitions to failure and rating of perceived exertion in the back squat and bench press in trained men. Eight resistance-trained men took part in this double-blind, randomized crossover experimental study whereby they ingested NaHCO3 (0.3 g·kg body mass) or placebo (sodium chloride NaCl: 0.045 g·kg body mass) solution 60 minutes before completing a bout of resistance exercise (3 sets of bench press and back squat exercise to failure at an intensity of 80% 1 repetition maximum). Experimental conditions were separated by at least 48 hours. Participants completed more repetitions to failure in the back squat after NaHCO3 ingestion (p = 0.04) but not for bench press (p = 0.679). Mean ± SD of total repetitions was 31.3 ± 15.3 and 24.6 ± 16.2 for back squat and 28.7 ± 12.2 and 26.7 ± 10.2 for bench press in NaHCO3 and placebo conditions, respectively. Repetitions to failure decreased as set increased for the back squat and bench press (p = 0.001, both). Rating of perceived exertion significantly increased with set for the back squat and bench press (p = 0.002, both). There was no significant change in blood lactate across time or between conditions. There were however treatment × time interactions for blood pH (p = 0.014) and blood HCO3 concentration (p = 0.001). After ingestion, blood pH and HCO3 (p = 0.008) concentrations were greater for the NaHCO3 condition compared with the placebo condition (p < 0.001). The results of this study suggest that sodium bicarbonate ingestion can enhance resistance exercise performance using a repetition to failure protocol in the first exercise in a resistance exercise session.

J Sports Sci. 1992 Oct;10(5):415-23.
Bicarbonate ingestion: effects of dosage on 60 s cycle ergometry.
McNaughton LR.
Nine healthy male subjects who were all participating in athletic events volunteered to take part in this study, the aim of which was to determine whether there are specific dosages of sodium bicarbonate (HCO3-) that are useful as an ergogenic aid as far as anaerobic performance times are concerned. A control, placebo (CaCO3 500 mg kg-1) and five dosages of bicarbonate (100, 200, 300, 400 and 500 mg kg-1) were used. The anaerobic test consisted of pedalling a Repco Exertech cycle ergometer for 1 min during which total work (kJ) and peak power (W) were measured. The subjects completed more work in the 200 (P < 0.05), 300, 400 and 500 mg kg-1 (P < 0.005) trials with most work being undertaken in the 300 mg kg-1 trial (41.9 kJ min-1). Peak power was not significantly different from the control until the 300 mg kg-1 dose, and there were no further changes from this with increasing doses of HCO3-. The highest level of peak power achieved was 1295 +/- 72.8 W at the 300 mg kg-1 dosage. Blood pH indicated that after ingestion of all but the 100 mg kg-1 dose, a state of alkalosis was achieved (P < 0.005), and this was also indicated by changes in base excess. Bicarbonate levels increased post-ingestion in all but the 100 mg kg-1 dose, with these changes reflecting the changes that occurred in the work output. Blood lactate (BLa) levels increased post-exercise (P < 0.0001). The BLa level during ingestion of 200mg kg-1 does was higher than the control, placebo, or 100 mg kg-1 dose (P<0.05), and this was also true for the three remaining doses (P<0.01). In conclusion, it is suggested that the optimal dose of bicarbonate for anaerobic performance of 1 min is 300mg kg-1. Further doses showed no greater increase in work and there was increased gastrointestinal disturbance.

Int J Sports Med. 2010 Nov;31(11):797-802. Epub 2010 Aug 11.
Metabolic alkalosis, recovery and sprint performance.
Siegler JC, McNaughton LR, Midgley AW, Keatley S, Hillman A.
Pre-exercise alkalosis and an active recovery improve the physiological state of recovery through slightly different mechanisms (e. g. directly increasing extracellular bicarbonate (HCO3 (-)) vs. increasing blood flow), and combining the two conditions may provide even greater influence on blood acid-base recovery from high-intensity exercise. Nine subjects completed four trials (Placebo Active ( PLAC A), sodium bicarbonate (NaHCO3) Active ( BICARB A), Placebo Passive ( PLAC P) and NaHCO3 Passive ( BICARB P)), each consisting of three, 30-s maximal efforts with a three min recovery between each effort. Pre-exercisealkalosis was evident in both NaHCO3 conditions, as pH and HCO3 (-) were significantly higher than both Placebo conditions (pH: 7.46 ± 0.04 vs. 7.39 ± 0.02; HCO3 (-): 28.8 ± 1.9 vs. 23.2 ± 1.4  mmol·L (-1); p<0.001). In terms of performance, significant interactions were observed for average speed (p<0.05), with higher speeds evident in the BICARB A condition (3.9 ± 0.3 vs. 3.7 ± 0.4  m·s (-1)). Total distance covered was different (p=0.05), with post hoc differences evident between the BICARB A and PLAC P conditions (368 ± 33 vs. 364 ± 35 m). These data suggest that successive 30-s high intensity performance may be improved when coupled with NaHCO3 supplementation.

Int J Sports Med. 2008 Jul;29(7):545-51. Epub 2007 Nov 14.
Pre-exercise alkalosis and acid-base recovery.
Siegler JC, Keatley S, Midgley AW, Nevill AM, McNaughton LR.
The aim of this study was to observe the influence of pre-exercise sodium bicarbonate (NaHCO3) ingestion and varying recovery modes on acid-base recovery from a single bout of supramaximal exercise. Nine male subjects completed four separate, randomized cycle ergometer exercise trials to volitional fatigue at 120% maximum power output, under the following conditions: 0.3 g.kg(-1) BW NaHCO3 ingestion with passive recovery (BICARB P), 0.3 g.kg (-1) BW NaHCO3 ingestion with active recovery (BICARB A), placebo ingestion with passive recovery (PLAC P) and placebo ingestion with active recovery (PLAC A). Capillary blood samples were obtained every minute for 15 min during recovery. Significant main effects for pH were observed for time (F = 42.1, p < 0.001), intervention (BICARB and PLAC) (F = 1117.3, p < 0.001) and recovery condition (F = 150.0, p < 0.001), as the BICARB condition reduced acid-base perturbation. Significant interaction effects were observed between conditions (BICARB and PLAC) for active and passive recovery modes (F = 29.1, p < 0.001) as the active recovery facilitated H+ removal better than the passive condition. Pre-exercise alkalosis attenuates blood acid-base perturbations from supramaximal exercise to exhaustion, regardless of whether the recovery mode is active or passive. These findings suggest that individuals may benefit from introducing a pre-exercise alkalotic condition while including passive recovery during high-intensity training protocols.

Int J Sports Med. 2008 Jun;29(6):519-23. Epub 2007 Nov 14.
Sodium bicarbonate improves swimming performance.
Lindh AM, Peyrebrune MC, Ingham SA, Bailey DM, Folland JP.
Sodium bicarbonate ingestion has been shown to improve performance in single-bout, high intensity events, probably due to an increase in buffering capacity, but its influence on single-bout swimming performance has not been investigated. The effects of sodium bicarbonate supplementation on 200 m freestyle swimming performance were investigated in elite male competitors. Following a randomised, double blind counterbalanced design, 9 swimmers completed maximal effort swims on 3 separate occasions: a control trial (C); after ingestion of sodium bicarbonate (SB: NaHCO3 300 mg . kg (-1) body mass); and after ingestion of a placebo (P: CaCO3 200 mg . kg (-1) body mass). The SB and P agents were packed in gelatine capsules and ingested 90 – 60 min prior to each 200 m swim. Mean 200 m performance times were significantly faster for SB than C or P (1 : 52.2 +/- 4.7; 1 : 53.7 +/- 3.8; 1 : 54.0 +/- 3.6 min : ss; p < 0.05). Base excess, pH and blood bicarbonate were all elevated pre-exercise in the SB compared to C and P trials (p < 0.05). Post-200 m blood lactate concentrations were significantly higher following the SB trial compared with P and C (p < 0.05). It was concluded that SB supplementation can improve 200 m freestyle performance time in elite male competitors, most likely by increasing buffering capacity.

J Strength Cond Res. 2010 Nov;24(11):3105-11.
Sodium bicarbonate ingestion and repeated swim sprint performance.
Siegler JC, Gleadall-Siddall DO.
The purpose of the present investigation was to observe the ergogenic potential of 0.3 g·kg-1 of sodium bicarbonate (NaHCO3) in competitive, nonelite swimmers using a repeated swim sprint design that eliminated the technical component of turning. Six male (181.2 ± 7.2 cm; 80.3 ± 11.9 kg; 50.8 ± 5.5 ml·kg-1·min-1 VO2max) and 8 female (168.8 ± 5.6 cm; 75.3 ± 10.1 kg; 38.8 ± 2.6 ml·kg-1·min-1 VO2max) swimmers completed 2 trial conditions (NaHCO3 [BICARB] and NaCl placebo [PLAC]) implemented in a randomized (counterbalanced), single blind manner, each separated by 1 week. Swimmers were paired according to ability and completed 8, 25-m front crawl maximal effort sprints each separated by 5 seconds. Blood acid-base status was assessed preingestion, pre, and postswim via capillary finger sticks, and total swim time was calculated as a performance measure. Total swim time was significantly decreased in the BICARB compared to PLAC condition (p = 0.04), with the BICARB condition resulting in a 2% decrease in total swim time compared to the PLAC condition (159.4 ± 25.4 vs. 163.2 ± 25.6 seconds; mean difference = 4.4 seconds; 95% confidence interval = 8.7-0.1). Blood analysis revealed significantly elevated blood buffering potential preswim (pH: BICARB = 7.48 ± 0.01, PLAC = 7.41 ± 0.01) along with a significant decrease in extracellular K+ (BICARB = 4.0 ± 0.1 mmol·L-1, PLAC = 4.6 ± 0.1 mmol·L-1). The findings suggest that 0.3 g·kg-1 NaHCO3 ingested 2.5 hours before exercise enhances the blood buffering potential and may positively influence swim performance.

J Strength Cond Res. 2010 Jan;24(1):103-8.
Sodium bicarbonate ingestion and boxing performance.
Siegler JC, Hirscher K.
Boxing is a sport that consists of multiple high-intensity bouts separated by minimal recovery time and may benefit from a pre-exercise alkalotic state. The purpose of this study was to observe the ergogenic potential of sodium bicarbonate (NaHCO3) ingestion on boxing performance. Ten amateur boxers volunteered to participate in 2 competitive sparring bouts. The boxers were prematched for weight and boxing ability and consumed either 0.3 g.kg(-1) body weight (BW) of NaHCO3 (BICARB) or 0.045 g.kg(-1) BW of NaCl placebo (PLAC) mixed in diluted low calorie-flavored cordial. The sparring bouts consisted of four 3-minute rounds, each separated by 1-minute seated recovery. Blood acid-base (pH, bicarbonate [HCO3(-)], base excess [BE]), and performance (rates of perceived exertion [RPE], heart rate [HR] [HR(ave) and HR(max)], total punches landed successfully) profiles were analyzed before (where applicable) and after sparring. The results indicated a significant interaction effect for HCO3(-) (p < or = 0.001) and BE (p < 0.001), but not for pH (p = 0.48). Post hoc analysis revealed higher presparring HCO3(-) and BE for the BICARB condition, but no differences between the BICARB and PLAC conditions postsparring. There was a significant increase in punches landed during the BICARB condition (p < 0.001); however, no significant interaction effects for HRave (p = 0.15), HRmax (p = 0.32), or RPE (p = 0.38). The metabolic alkalosis induced by the NaHCO3 loading elevated before and after sparring blood buffering capacity. In practical application, the findings suggest that a standard NaHCO3 loading dose (0.3 g.kg(-1)) improves punch efficacy during 4 rounds of sparring performance.

Eur J Appl Physiol Occup Physiol. 1988;58(1-2):171-4.
Sodium bicarbonate ingestion improves performance in interval swimming.
Gao JP, Costill DL, Horswill CA, Park SH.
In an effort to determine the effects of bicarbonate (NaHCO3) ingestion on exercise performance, ten male college swimmers were studied during five different trials. Each trial consisted of five 91.4 m (100-yd) front crawl swims with a two-minute rest interval between each bout. The trials consisted of two NaHCO3 treatments, two placebo trials and one test with no-drink. One hour before the onset of swimming, the subjects were given 300 ml of citric acid flavored solution containing either 17 mmol of NaCl (placebo) or 2.9 mmol of NaHCO3.kg-1 body weight (experimental), or received no drink (no-drink). Performance times for each 91.4 m swim were recorded. Blood samples were obtained before and one hr after treatment, two min after warmup, and two min after the final 91.4 m sprint. Blood pH, lactate, standard bicarbonate (SBC) and base excess (BE) were measured. No differences were found for performance or the blood measurements between the placebo and no-drink trials. Bicarbonate feedings, on the other hand, produced a significant (P less than 0.05) improvement in performance on the fourth and fifth swimming sprints. Blood lactate, pH, SBC and BE were significantly higher (P less than 0.05) at post-exercise in NaHCO3 treatments. These data are in agreement with previous findings that during repeated bouts of exercise pre-exercise administration of NaHCO3 improves performance, possibly by facilitating the efflux of hydrogen ions from working muscles and thereby delaying the onset of fatigue.

Journal of Sports Sciences Volume 13, Issue 5, 1995
The effect of sodium bicarbonate ingestion on 1500‐m racing time
S.R. Birda, J. Wiles & J. Robbins
Twelve athletes, all of whom regularly participated in middle‐ or long‐distance running races at club to national standard, competed in simulated 1500‐m races under three conditions: following ingestion of 300 mg sodium bicarbonate per kg of body mass (B); following ingestion of a placebo (100 mg sodium chloride per kg of body mass and 200 mg calcium carbonate per kg of body mass) (P); and following ingestion of neither (C). A double‐blind protocol was used between the B and P trials. Each condition was replicated so that the athletes competed in six races. Ten of the athletes completed all the races. The athletes’ average times for trials B, P and C were 253.9, 256.8 and 258.0 s, respectively. The data were analysed using a two‐way ANOVA with replicates and Tukey tests. This revealed a difference between trial B and trials P and C (P < 0.05), but no difference between trials P and C. These findings, therefore, indicate that sodium bicarbonate can have an ergogenic effect upon 1500‐m running.

Journal of Sports Science and Medicine (2009) 8, 45 – 50
EFFECTS OF SODIUM BICARBONATE INGESTION ON SWIM PERFORMANCE IN YOUTH ATHLETES
Adam Zajac, Jaroslaw Cholewa, Stanislaw Poprzecki, Zbigniew Waskiewicz and Jozef Langfort
The purpose of this study was to evaluate the effect of oral administration of sodium bicarbonate (300 mg·kg-1 b.w.) on swim performance in competitive, (training experience of 6.6 ± 0.6 years) youth, (15.1 ± 0.6 years) male swimmers. The subjects completed a test trial, in a double blind fashion, on separate days, consisting of 4 x 50m front crawl swims with a 1st minute passive rest interval twice, on two occasions: after ingestion of bicarbonate or placebo, 72 hours apart, at the same time of the day. Blood samples were drawn from the finger tip three times during each trial; upon arrival to the laboratory, 60 min after ingestion of placebo or the sodium bicarbonate solution and after the 4 x 50m test, during the 1st min of recovery. Plasma lactate concentration, blood pH, standard bicarbonate and base excess were evaluated. The total time of the 4 x 50 m test trial improved from 1.54.28 to 1.52.85s, while statistically significant changes in swimming speed were recorded only during the first 50m sprint (1.92 vs. 1.97 m·s-1, p < 0.05). Resting blood concentration of HCO-3 increased following the ingestion of sodium bicarbonate from 25.13 to 28.49 mM (p < 0.05). Sodium bicarbonate intake had a statistically significant effect on resting blood pH (7.33 vs. 7.41, p < .05) as well as on post exercise plasma lactate concentration (11.27 vs. 13.06 mM, p < 0.05)). Collectively, these data demonstrate that the ingestion of sodium bicarbonate in youth athletes is an effective buffer during high intensity interval swimming and suggest that such a procedure can be used in youth athletes to increase training intensity as well as swimming performance in competition at distances from 50 to 200 m.

J Appl Physiol. 1997 Aug;83(2):333-7.
Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery.
Verbitsky O, Mizrahi J, Levin M, Isakov E.
The influence of acute ingestion of NaHCO3 on fatigue and recovery of the quadriceps femoris muscle after exercise was studied in six healthy male subjects. A bicycle ergometer was used for exercising under three loading conditions: test A, load corresponding to maximal oxygen consumption; test B, load in test A + 17%; test C, load in test B but performed 1 h after acute ingestion of NaHCO3. Functional electrical stimulation (FES) was applied to provoke isometric contraction of the quadriceps femoris. The resulting knee torque was monitored during fatigue (2-min chronic FES) and recovery (10-s FES every 10 min, for 40 min). Quadriceps torques were higher in the presence of NaHCO3 (P < 0.05): with NaHCO3 the peak, residual, and recovery (after 40 min) normalized torques were, respectively, 0.68 +/- 0.05 (SD), 0.58 +/- 0.05, and 0.73 +/- 0.05; without NaHCO3 the values were 0.45 +/- 0.04, 0.30 +/- 0.06, and 0.63 +/- 0.06. The increased torques obtained after acute ingestion of NaHCO3 indicate the possible existence of improved nonoxidative glycolysis in isometric contraction, resulting in reduced fatigue and enhanced recovery.

Med Sci Sports Exerc. 1983;15(4):277-80.
Effect of acute induced metabolic alkalosis on 800-m racing time.
Wilkes D, Gledhill N, Smyth R.
Six trained middle-distance runners wer studied under alkalotic (NaHCO3 ingestion), placebo (CaCO3 ingestion), and control conditions to determine the effect of an acute induced metabolic alkalosis on time to run an 800-m race. Pre-exercise, following NaHCO3 ingestion, pH and standard [HCO3-] were significantly higher. In the alkalotic condition, subjects ran faster (2.9 s) and the corresponding post-exercise values for blood [lactate] and extracellular H+ were higher than in the control and placebo conditions, suggesting an increased anaerobic energy contribution. These results support the speculation that the increase in extracellular buffering following NaHCO3 ingestion facilitated H+ efflux from the cells of working muscle, thereby delaying the decrease in intracellular pH and postponing fatigue. It is concluded that the ingestion of NaHCO3 by trained middle-distance runners prior to an 800-m race has an ergogenic benefit.

J Sports Sci. 1992 Oct;10(5):425-35.
Sodium bicarbonate ingestion and its effects on anaerobic exercise of various durations.
McNaughton LR.
Four groups of male subjects participated in anaerobic testing on a Repco EX10 cycle ergometer to determine the effectiveness of sodium bicarbonate (0.3 g kg-1 body mass) as an ergogenic aid during exercise of 10, 30, 120 and 240 s duration. Blood was collected 90 min prior to ingestion of sodium bicarbonate (NaHCO3), after ingestion of NaHCO3 and immediately post-exercise from a heated (43-46 degrees C) fingertip and analysed immediately post-collection for pH, base excess, bicarbonate and lactate. The total work undertaken (kJ) and peak power achieved during the tests were also obtained via a Repco Work Monitor Unit. Blood bicarbonate levels were again increased above the control and placebo conditions (P < 0.001) and blood lactate levels were also increased following the bicarbonate trials. The pH levels fell significantly (P < 0.05) below the control and placebo conditions in all trials. The results indicate that NaHCO3 at this dosage has no ergogenic benefit for work of either 10 or 30 s duration, even though blood bicarbonate levels were significantly increased (P < 0.05) following ingestion of NaHCO3. For work periods of 120 and 240 s, performance was significantly increased (P < 0.05) above the control and placebo conditions following NaHCO3 ingestion.

Br J Sports Med. 1989 March; 23(1): 41–45.
Effect of sodium bicarbonate ingestion upon repeated sprints.
G Lavender and S R Bird
The purpose of the study was to assess the effect of sodium bicarbonate ingestion upon repeated bouts of intensive short duration exercise. Twenty-three subjects participated in the investigation (8 females and 15 males, age 21.4 +/- 2.3, mean +/- sd). Subjects completed six trials; three following the ingestion of sodium bicarbonate (300 mg/kg body weight) and three following the ingestion of a placebo (8 g sodium chloride). Each trial consisted of ten ten-second sprints on a cycle ergometer with 50 seconds recovery between each sprint. ‘Peak power’ and ‘average power output’ during each ten second sprint was measured from the flywheel of the ergometer using a light-sensitive monitor (Cranlea) linked to a BBC microcomputer. The power outputs recorded during each ten-second sprint of the bicarbonate trials were then compared with those recorded during the corresponding sprint of the placebo trials. The bicarbonate trials produced higher mean ‘average power’ outputs in all ten of the ten-second sprints, with the difference in ‘average power’ output being statistically significant in eight of these (p less than 0.05). The results also revealed that the difference in the ‘average power’ outputs attained during the bicarbonate and placebo trials increased as the number of sprint repetitions increased (p less than 0.01). ‘Peak power’ output was also greater in the bicarbonate trials with it being significantly higher (p less than 0.001) during the final ten-second sprint. It was concluded that during exercise consisting of repeated, short-duration sprints, power output was enhanced following the ingestion of sodium bicarbonate, (300 mg/kg body weight).

Boll Soc Ital Biol Sper. 1984 Mar 30;60(3):617-23.
[Acid-base equilibrium, blood lactic acid and pyruvic acid in albino rats after muscular exertion under conditions of normal oxygen, hypoxia and hypoxia-hypercapnia].
[Article in Italian]
Quatrini U, Licciardi A.
Albino rats of the Wistar family were subjected at three subsequent equal trials of muscular work: the first in normoxyc conditions; the second in hypoxic normobaric conditions; the third in hypoxic-hypercapnic normobaric conditions. The modifications of the lactacidemia, pyruvicemia and acid-base balance were greatest at the end of hypoxic trial. Added CO2 (2%) sensitively reduced the acidificant effects of the muscular work on the acid-base balance.

Rev Pneumol Clin. 1986;42(5):238-41.
Acid-base balance and blood lactate and pyruvate levels in albino rats bred under normobaric hypoxia or normoxia, after muscular work in a hypoxic or hypoxic-hypercapnic environment.
Quatrini U, Licciardi A.
Albino rats, Wistar family, have been raised since birth in normobaric hypoxic environment (10-12% O2). This hypoxic animal group and a normoxic animal group were subjected to muscular fatigue by forced march within revolving room. Normoxic animals were subjected to 3 spaced trials: in normoxic environment; in hypoxic normobaric environment; in the same hypoxic normobaric environment with about 2% CO2 added. Hypoxic animals were subjected to 2 spaced trials: in hypoxic normobaric environment; in the same hypoxic environment with about 2% CO2 added. At the end of every single trial, lactatemia, blood pyruvate, acid-base balance and the erythrocytic number were examined. Albino rats raised in hypoxic environment since birth, subjected to muscular work in hypoxic environment showed a smaller increase of lactatemia and a moderate variation of the acid-base balance, compared to normoxic animals in the same conditions. CO2 added to the respired hypoxic mixture during muscular work, attenuated in both animal groups, the observed modifications. Finally we found that the erythrocytes per mm3 of blood increased from the second drawing of blood.

Cor Vasa. 1981;23(5):359-65.
Heart rhythm disturbances in the inhabitants of mountainous regions.
Mirrakhimov MM, Meimanaliev TS.
The authors studied 513 males, permanently living in the high-mountain regions of Tian Shan and the Pamirs (2800 – 4000 m above sea level). A control group consisted of 404 males permanently living at low altitudes (780-900 m above sea level) in the Kemin District, Kirghiz SSR. The probands’ ages were 30-59 years. In all of them the resting electrocardiograms were recorded; 110 exercise tests were made in the high mountains, and 35 tests, at the low altitudes. The prevalence of heart rhythm disturbances was statistically significantly higher in the inhabitants of the high-mountain regions (12.1%) than in the low-altitude inhabitants (2.9%; p less than 0.0001). The most frequent disturbance was the 1st-degree a-v block (6 per cent). In the high mountains cardiac arrhythmias are usually associated with right ventricular hypertrophy, caused by high-altitude hypoxia. During exercise heart arrhythmias appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants.

N Engl J Med. 1977 Mar 17;296(11):581-5.
Reduction in mortality from coronary heart disease in men residing at high altitude.
Mortimer EA Jr, Monson RR, MacMahon B.
In New Mexico, where inhabited areas vary from 914 to over 2135 m above sea level, we compared age-adjusted mortality rates for arteriosclerotic heart disease for white men and women for the years 1957-1970 in five sets of counties, grouped by altitude in 305-m (1000-foot) increments. The results show a serial decline in mortality from the lowest to the highest altitude for males but not for females. Mortality rates for males residing in the county groups higher than 1220 m in order of ascending altitude were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less than 0.0001). The results do not appear to be explained by artifacts in ascertainment, variations in ethnicity or urbanization. A possible explanation of the trend is that adjustment to residence at high altitude is incomplete and daily activities therefore represent greater exercise than when undertaken at lower altitudes.

J. Appl Physiol 1991 Apr;70(4):1720-30.
Metabolic and work efficiencies during exercise in Andean natives.
Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS
Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.

J Appl Physiol. 1991 May;70(5):1963-76.
Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.
Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW.
Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

Eur J Appl Physiol Occup Physiol. 1999 Jun;80(1):64-9.
Sodium bicarbonate can be used as an ergogenic aid in high-intensity, competitive cycle ergometry of 1 h duration.
McNaughton L, Dalton B, Palmer G.
The aim of this study was to determine whether a dose of 300-mg x kg(-1) body mass of sodium bicarbonate would effect a high-intensity, 1-h maximal cycle ergometer effort. Ten male, well-trained [maximum oxygen consumption 67.3 (3.3) ml x kg(-1) x min(-1), mean (SD)] volunteer cyclists acted as subjects. Each undertook either a control (C), placebo (P), or experimental (E) ride in a random, double-blind fashion on a modified, air-braked cycle ergometer, attached to a personal computer to which the work and power data was downloaded at 10 Hz. Fingertip blood was sampled at 10-min intervals throughout the exercise. Blood was also sampled at 1, 3, 5, and 10 min post-exercise. Blood was analysed for lactate, partial pressure of Carbon dioxide and oxygen, pH and plasma bicarbonate (HCO-) concentration. Randomly chosen pairs of subjects were asked to complete as much work as possible during the 60-min exercise periods in an openly competitive situation. The sodium bicarbonate had the desired effect of increasing blood HCO3- prior to the start of the test. The subjects in E completed 950.9 (81.1) kJ of work, which was significantly more (F(2,27) = 5.28, P < 0.01) than during either the C [835.5 (100.2) kJ] or P [839.0 (88.6) kJ] trials. No differences were seen in peak power or in the power:mass ratio between these three groups. The results of this study suggest that sodium bicarbonate may be used to offset the fatigue process during high-intensity, aerobic cycling lasting 60 min.

Med Sci Sports Exerc. 2003 Aug;35(8):1303-8.
Effects of sodium bicarbonate ingestion on prolonged intermittent exercise.
Price M, Moss P, Rance S.
PURPOSE:
The aim of this study was to determine the effects of sodium bicarbonate ingestion on prolonged intermittent exercise and performance.
METHODS:
Eight healthy male subjects (mean +/- SD: age 25.4 +/- 6.4 yr, mass 70.9 +/- 5.1 kg, height 179 +/- 7 cm, VO(2max) 4.21 +/- 0.51 L.min-1) volunteered for the study, which had received ethical approval. Subjects undertook two 30-min intermittent cycling trials (repeated 3-min blocks; 90 s at 40% VO(2max), 60 s at 60% VO(2max), 14-s maximal sprint, 16-s rest) after ingestion of either sodium bicarbonate (NaHCO(3); 0.3 g.kg-1) or sodium chloride (NaCl; 0.045 g x kg(-1). Expired air, blood lactate (BLa), bicarbonate (HCO(3)-), and pH were measured at rest, 30 and 60 min postingestion, and during the 40% VO(2max) component of exercise (4, 10, 16, and 29 min).
RESULTS:
After ingestion, pH increased from rest to 7.46 +/- 0.03 and 7.40 +/- 0.01 for NaHCO(3) and NaCl, respectively (main effect for time and trial; P < 0.05). Values decreased at 15 min of exercise to 7.30 +/- 0.07 and 7.21 +/- 0.06, respectively, remaining at similar levels until the end of exercise. BLa peaked at 15 min (12.03 +/- 4.31 and 10.00 +/- 2.58 mmol.L-1, for NaHCO(3) and NaCl, respectively; P > 0.05) remaining elevated until the end of exercise (P < 0.05). Peak power expressed relative to sprint 1 demonstrated a significant main effect between trials (P < 0.05). Sprint 2 increased by 11.5 +/- 5% and 1.8 +/- 9.5% for NaHCO(3) and NaCl, respectively. During NaHCO(3), sprint 8 remained similar to sprint 1 (0.2 +/- 17%), whereas a decrease was observed during NaCl (-10.0 +/- 16.0%).
CONCLUSION:
The results of this study suggest that ingestion of NaHCO(3) improves sprint performance during prolonged intermittent cycling.

Med Sci Sports Exerc. 2004 Jul;36(7):1239-43.
Effects of ingestion of bicarbonate, citrate, lactate, and chloride on sprint running.
Van Montfoort MC, Van Dieren L, Hopkins WG, Shearman JP.
PURPOSE:
Ingestion of sodium bicarbonate is known to enhance sprint performance, probably via increased buffering of intracellular acidity. The goal was to compare the effect of ingestion of sodium bicarbonate with that of other potential buffering agents (sodium citrate and sodium lactate) and of a placebo (sodium chloride) on sprinting.
METHODS:
In a double-blind randomized crossover trial, 15 competitive male endurance runners performed a run to exhaustion 90 min after ingestion of each of the agents in the same osmolar dose relative to body mass (3.6 mosmol x kg) on separate days. The agents were packed in gelatin capsules and ingested with 750 mL of water over 90 min. During each treatment we assayed serial finger-prick blood samples for lactate and bicarbonate. A familiarization trial was used to set a treadmill speed for each runner’s set of runs. We converted changes in run time between treatments into changes in a time trial of similar duration using the critical-power model, and we estimated likelihood of practical benefit using 0.5% as the smallest worthwhile change in time-trial performance.
RESULTS:
The mean run times to exhaustion for each treatment were: bicarbonate 82.3 s, lactate 80.2 s, citrate 78.2 s, and chloride 77.4 s. Relative to bicarbonate, the effects on equivalent time-trial time were lactate 1.0%, citrate 2.2%, and chloride 2.7% (90% likely limits +/- 2.1%). Ingested lactate and citrate both appeared to be converted to bicarbonate before the run. There were no substantial differences in gut discomfort between the buffer treatments.
CONCLUSION:
Bicarbonate is possibly more beneficial to sprint performance than lactate and probably more beneficial than citrate or chloride. We recommend ingestion of sodium bicarbonate to enhance sprint performance.

J Appl Physiol. 2006 Sep;101(3):918-25. Epub 2006 Apr 20.
Effects of chronic NaHCO3 ingestion during interval training on changes to muscle buffer capacity, metabolism, and short-term endurance performance.
Edge J, Bishop D, Goodman C.
This study determined the effects of altering the H(+) concentration during interval training, by ingesting NaHCO(3) (Alk-T) or a placebo (Pla-T), on changes in muscle buffer capacity (beta m), endurance performance, and muscle metabolites. Pre- and posttraining peak O(2) uptake (V(O2 peak)), lactate threshold (LT), and time to fatigue at 100% pretraining V(O2 peak) intensity were assessed in 16 recreationally active women. Subjects were matched on the LT, were randomly placed into the Alk-T (n = eight) or Pla-T (n = eight) groups, and performed 8 wk (3 days/wk) of six to twelve 2-min cycle intervals at 140-170% of their LT, ingesting NaHCO(3) or a placebo before each training session (work matched between groups). Both groups had improvements in beta m (19 vs. 9%; P < 0.05) and V(O2 peak) (22 vs. 17%; P < 0.05) after the training period, with no differences between groups. There was a significant correlation between pretraining beta m and percent change in beta m (r = -0.70, P < 0.05). There were greater improvements in both the LT (26 vs. 15%; P = 0.05) and time to fatigue (164 vs. 123%; P = 0.05) after Alk-T, compared with Pla-T. There were no changes to pre- or postexercise ATP, phosphocreatine, creatine, and intracellular lactate concentrations, or pH(i) after training. Our findings suggest that training intensity, rather than the accumulation of H(+) during training, may be more important to improvements in beta m. The group ingesting NaHCO(3) before each training session had larger improvements in the LT and endurance performance, possibly because of a reduced metabolic acidosis during training and a greater improvement in muscle oxidative capacity.

J Strength Cond Res. 2004 May;18(2):306-10.
Combined creatine and sodium bicarbonate supplementation enhances interval swimming.
Mero AA, Keskinen KL, Malvela MT, Sallinen JM.
This study examined the effect of simultaneous supplementation of creatine and sodium bicarbonate on consecutive maximal swims. Sixteen competitive male and female swimmers completed, in a randomized order, 2 different treatments (placebo and a combination of creatine and sodium bicarbonate) with 30 days of washout period between treatments in a double-blind crossover procedure. Both treatments consisted of placebo or creatine supplementation (20 g per day) in 6 days. In the morning of the seventh day, there was placebo or sodium bicarbonate supplementation (0.3 g per kg body weight) during 2 hours before a warm-up for 2 maximal 100-m freestyle swims that were performed with a passive recovery of 10 minutes in between. The first swims were similar, but the increase in time of the second versus the first 100-m swimming time was 0.9 seconds less (p < 0.05) in the combination group than in placebo. Mean blood pH was higher (p < 0.01-0.001) in the combination group than in placebo after supplementation on the test day. Mean blood pH decreased (p < 0.05) similarly during the swims in both groups. Mean blood lactate increased (p < 0.001) during the swims, but there were no differences in peak blood lactate between the combination group (14.9 +/- 0.9 mmol.L(-1)) and placebo (13.4 +/- 1.0 mmol.L(-1)). The data indicate that simultaneous supplementation of creatine and sodium bicarbonate enhances performance in consecutive maximal swims.

Int J Sport Nutr Exerc Metab. 2008 Apr;18(2):116-30.
Effects of sodium bicarbonate, caffeine, and their combination on repeated 200-m freestyle performance.
Pruscino CL, Ross ML, Gregory JR, Savage B, Flanagan TR.
The purpose of this study was to investigate the effects of sodium bicarbonate (NaHCO(3)), caffeine, and their combination on repeated 200-m freestyle performance. Six elite male freestyle swimmers ingested NaHCO(3) (0.3 g/kg; B), caffeine (6.2 +/- 0.3 mg/kg; C), a combination of both (B+C), and placebo (P) on 4 separate occasions before completing 2 maximal 200-m freestyle time trials (TT1 and TT2) separated by 30 min. No significant differences (p = .06) were observed for performance in TT1 (B 2:03.01 +/- 0:03.68 min, C 2:02.42 +/- 0:03.17 min, B+C 2:01.69 +/- 0:03.19 min, P 2:03.77 +/- 0:03.21 min) or TT2 (B 2:02.62 +/- 0:04.16 min, C 2:03.90 +/- 0:03.58 min, B+C 2:01.70 +/- 0:02.84 min, P 2:04.22 +/- 0:03.75 min). The drop-off in performance time from TT1 to TT2, however, was significantly greater when C was ingested than with B (-1.5%, p = .002) or B+C (-1.2%, p = .024). This is likely because of the lower blood pH and slower recovery of blood HCO(3) post-TT1 after C ingestion. These findings suggest that the ergogenic benefit of taking C alone for repeated 200-m swimming performance appears limited. When combined with NaHCO(3), however, its negative impact on repeated maximal exercise performance is reversed.

J Appl Physiol. 1977 Dec;43(6):959-64.
Effect of pH on cardiorespiratory and metabolic responses to exercise.
Jones NL, Sutton JR, Taylor R, Toews CJ.
Five male subjects performed exercise at 33, 66, and 95% of their maximum power output on three occasions in random order. Each study was preceded by a 3-h period in which capsules were taken by mouth, containing either CaCO3 (control, NH4Cl (acidosis), or NaHCO3 (alkalosis) in a dose of 0.3 g/kg body wt; preexercise blood pH was 7.38 +/- 0.015, 7.21 +/- 0.033, and 7.43 +/- 0.029, respectively. Exercise was continuous and maintained for 20 min at the two lower power outputs and for as long as possible at the highest. Compared with control (270 +/- 13 s), endurance time at the highest power output was reduced in acidosis (160 +/- 22 s) and increased in alkalosis (438 +/- 120 s). No differences were observed for central cardiovascular changes in exercise (cardiac output, frequency, or stroke volume). The respiratory changes expected from changes in blood pH were observed, with a higher alveolar ventilation in acidosis. At all power outputs arterialized venous lactate was lowest in acidosis and highest in alkalosis. Plasma glycerol and free fatty acids were lowest in acidosis. Changes in blood [HCO3-] and pH were shown to have major effects on metabolism in exercise which presumably were responsible for impaired endurance.

Int J Sport Nutr Exerc Metab. 2011 Jun;21(3):189-94.
Effect of sodium bicarbonate on [HCO3-], pH, and gastrointestinal symptoms.
Carr AJ, Slater GJ, Gore CJ, Dawson B, Burke LM.
CONTEXT:
Sodium bicarbonate (NaHCO₃) is often ingested at a dose of 0.3 g/kg body mass (BM), but ingestion protocols are inconsistent in terms of using solution or capsules, ingestion period, combining NaHCO₃ with sodium citrate (Na₃C₆H₅O₇), and coingested food and fluid.
PURPOSE:
To quantify the effect of ingesting 0.3 g/kg NaHCO₃ on blood pH, [HCO₃-], and gastrointestinal (GI) symptoms over the subsequent 3 hr using a range of ingestion protocols and, thus, to determine an optimal protocol.
METHODS:
In a crossover design, 13 physically active subjects undertook 8 NaHCO₃ experimental ingestion protocols and 1 placebo protocol. Capillary blood was taken every 30 min and analyzed for pH and [HCO₃-]. GI symptoms were quantified every 30 min via questionnaire. Statistics used were pairwise comparisons between protocols; differences were interpreted in relation to smallest worthwhile changes for each variable. A likelihood of >75% was a substantial change.
RESULTS:
[HCO₃-] and pH were substantially greater than in placebo for all other ingestion protocols at almost all time points. When NaHCO3 was coingested with food, the greatest [HCO₃-] (30.9 mmol/kg) and pH (7.49) and lowest incidence of GI symptoms were observed. The greatest incidence of GI side effects was observed 90 min after ingestion of 0.3 g/kg NaHCO₃ solution.
CONCLUSIONS:
The changes in pH and [HCO₃-] for the 8 NaHCO₃-ingestion protocols were similar, so an optimal protocol cannot be recommended. However, the results suggest that NaHCO₃ coingested with a high-carbohydrate meal should be taken 120-150 min before exercise to induce substantial blood alkalosis and reduce GI symptoms.

Strength & Conditioning Journal: August 2012 – Volume 34 – Issue 4 – p 21
Sodium Bicarbonate Supplementation: It’s Worth Another Chance
Koziris, Lymperis (Perry)
SUMMARY: THE BENEFIT TO RISK RATIO OF SODIUM BICARBONATE BUFFER PROTOCOLS MAY BE OPTIMIZED BY REDUCING THE RISK OF GASTROINTESTINAL SIDE EFFECTS. THIS CAN BE ACHIEVED BY COINGESTING A SMALL CARBOHYDRATE MEAL AND ALLOWING ENOUGH TIME FOR INITIAL SIDE EFFECTS TO DECLINE FROM THEIR PEAK.

J Strength Cond Res. 2012 Jul;26(7):1953-8. doi: 10.1519/JSC.0b013e3182392960.
Sodium bicarbonate supplementation and ingestion timing: does it matter?
Siegler JC, Marshall PW, Bray J, Towlson C.
Although a considerable amount of literature exists on the ergogenic potential of ingesting sodium bicarbonate (NaHCO3) before short-term, high-intensity exercise, very little exists on optimal loading times before exercise. The purpose of this study was to determine the influence of NaHCO3 supplementation timing on repeated sprint ability (RSA). Eight men completed 3 (randomized and counterbalanced) trials of ten 10-second sprints separated by 50 seconds of active recovery (1:5 work-to-rest) on a nonmotorized treadmill. Before each trial, the subjects ingested 0.3 g·kg(-1) body weight of NaHCO3 at 60 (H1), 120 (H2), or 180 (H3) minutes before exercise. Additionally, the subjects were assessed for any side effects (gastrointestinal [GI] discomfort) from the NaHCO3 ingestion via a visual analog scale (VAS). Blood buffering was assessed using a 2-way analysis of variance (ANOVA) with repeated measures, whereas repeated sprint performance and GI discomfort were assessed via a 1-way ANOVA with repeated measures. Blood-buffering capacity was not different at preexercise times (HCO3(-) [millimoles per liter] H1: 30.2 ± 0.4, H2: 30.9 ± 0.6, H3: 31.2 ± 0.6; p > 0.74). Average speed, average power, and total distance covered progressively declined over the 10 sprints; however, there was no difference between conditions (p > 0.22). The incidence of GI discomfort was significantly higher (p < 0.05) from preingestion at all time points with the exception of 180 minutes, whereas severity was only different between 90 and 180 minutes. Ingestion times (between 60 and 180 minutes) did not influence the blood buffering or the ergogenic potential of NaHCO3 as assessed by RSA. However, VAS scores indicated that at 180 minutes postingestion, an individual is less prone to experiencing significant GI discomfort.

Eur J Appl Physiol. 2013 Jan;113(1):127-34. doi: 10.1007/s00421-012-2419-4. Epub 2012 May 19.
The physiological stress response to high-intensity sprint exercise following the ingestion of sodium bicarbonate.
Peart DJ, Kirk RJ, Hillman AR, Madden LA, Siegler JC, Vince RV.
The purpose of this study was to investigate the effects of pre-exercise alkalosis on the physiological stress response to high-intensity exercise. Seven physically active males (age 22 ± 3 years, height 1.82 ± 0.06 m, mass 81.3 ± 8.4 kg and peak power output 300 ± 22 W) performed a repeated sprint cycle exercise following a dose of 0.3 g kg(-1) body mass of sodium bicarbonate (NaHCO(3)) (BICARB), or a placebo of 0.045 g kg(-1) body mass of sodium chloride (PLAC). Monocyte-expressed heat shock protein 72 (HSP72) and plasma thiobarbituric acid reactive substances (TBARS) were significantly attenuated in BICARB compared to PLAC (p = 0.04 and p = 0.039, respectively), however total anti-oxidant capacity, the ratio of oxidised to total glutathione, cortisol, interleukin 6 and interleukin 8 were not significantly induced by the exercise. In conclusion, monocyte-expressed HSP72 is significantly increased following high-intensity anaerobic exercise, and its attenuation following such exercise with the ingestion of NaHCO(3) is unlikely to be due to a decreased oxidative stress.

Sodium bicarbonate taken before strenuous exercise reduces the expression of heme oxygenase (Kirk, et al, 2012) and improves endurance. -Ray Peat, PhD

Amino Acids. 2013 Mar;44(3):903-10. doi: 10.1007/s00726-012-1419-3. Epub 2012 Oct 23.
The influence of exogenous carbohydrate provision and pre-exercise alkalosis on the heat shock protein response to prolonged interval cycling.
Peart DJ, Kirk RJ, Madden LA, Siegler JC, Vince RV.
The aim of this study was to observe the intracellular heat shock protein 72 (HSP72) and heme oxygenase-1 (HSP32) response to prolonged interval cycling following the ingestion of carbohydrates (CHO) and sodium bicarbonate (NaHCO(3)). Six recreationally active males (mean ± SD; age 23.2 ± 2.9 years, height 179.5 ± 5.5 cm, body mass 76.5 ± 6.8 kg, and peak power output 315 ± 36 W) volunteered to complete a 90 min interval cycling exercise on four occasions. The trials were completed in a random and blinded manner following ingestion of either: placebo and an artificial sweetener (P-P), NaHCO(3) and sweetener (B-P), placebo and CHO (P-CHO), and NaHCO(3) and CHO (B-CHO). Both HSP72 and HSP32 were significantly increased in monocytes and lymphocytes from 45 min post-exercise (p ≤ 0.039), with strong relationships between both cell types (HSP72, r = 0.83; HSP32, r = 0.89). Exogenous CHO had no influence on either HSP72 or HSP32, but the ingestion of NaHCO(3) significantly attenuated HSP32 in monocytes and lymphocytes (p ≤ 0.042). In conclusion, the intracellular stress protein response to 90 min interval exercise is closely related in monocytes and lymphocytes, and HSP32 appears to be attenuated with a pre-exercise alkalosis.

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By Team FPS – April 3, 2012

Fats and AGEs: PUFAs Are Even Worse than Fructose

Source

Olive oil is mostly monounsaturated fat.
Olive oil is mostly monounsaturated fat. (Photo by Splat Worldwide)
While the exact role AGEs play in aging is still unclear, it seems that reducing their accumulation in the body is a useful goal. And if for no other reason, how about being superficial: liver spots, for example, are a visible sign of AGEs in the skin. If you want to look youthful, glycation is not the way to go. 

The question of how to avoid AGEs has proven to be more difficult than one might think, however. If it was merely a matter of reducing the formation of advanced glycation end-products during cooking, we could just cook our foods at lower heat and use water instead of frying at high temperatures. But as we’ve seen, the AGEs we get directly from food may not be as important as the AGEs that form inside our body as a result of internal glycation.

The term ‘advanced glycation end-product’ is somewhat misleading in the sense that they are not formed only by glycation, which refers to glucose molecules binding to protein or lipid molecules, but also by fructation, which is essentially the same thing but this time with fructose. In fact, fructose is much more prone to form these products than glucose. Since there’s no such term as ‘advanced fructation end-product’, they’re also referred to as AGEs (other sugars like galactose go through a similar process too; more on that in another post).

To complicate this further, similar products are also formed during cooking when fats alone are exposed to high heat and air. This process is known as lipid peroxidation. The end results of lipid peroxidation are referred to as either AGEs or ALEs, short for advanced lipoxidation end-products. For the sake of simplicity, I will refer to all of them as AGEs, unless the difference is important.

So we now have several different ways to accumulate AGEs: eating cooked foods that contain sugars heated with protein or fats, eating uncooked foods that contain sugars, or eating oxidized fats. And, like glycation, lipid peroxidation can also happen endogenously. That is, even if the fats you eat do not contain any AGEs, they can still form AGEs inside the body if they are unstable and prone to oxidation.

The bad news is that not only does lipid peroxidation lead to AGEs, it appears to do so more rapidly than glycation does. CML, a product of the oxidative degradation of glycated protein anda common measure of AGE levels, is actually formed through the oxidation of arachidonic acid in much higher quantities than from glycation (link). CML is a handy way to compare things, because it can be formed through glycation, fructation or lipid peroxidation.

The reason you should keep your fish oil and flax seed oil in the fridge is precisely because they, like other highly unsaturated fats, are easily oxidized (link). Cooking with these oils is a really bad idea. Through lipid peroxidation, polyunsaturated fats or PUFAs are more prone to form AGEs. Below is a comparison of CML formation from three different fatty acids and glucose (link):

AGE formation from glucose and lipids
The left graph shows that arachidonic acid forms CML at about twice the rate as linoleic acid. The formation of CML from oleic acid is close to zero. Compared to glucose in the right graph, the two PUFAs here are at least 10 times as prone to AGE formation – very much like fructose, except that if you look at the fructose graphs, the 10-fold increase is not seen as early as it is in these graphs.

The explanation for the differences is that lipid peroxidation increases exponentially as a function of the number of double bonds (link), i.e. the degree of unsaturation. Arachidonic acid is a 20-carbon chain PUFA with four double bonds and linoleic acid is an 18-carbon chain PUFA with two double bonds. Oleic acid, like all MUFAs, has one double bond. Note that this equation makes the omega-3 fatty acids DHA and EPA (with their 6 and 5 double bonds, respectively) the worst offenders.

So oils high in PUFAs seem to have the ability to raise the AGE burden much more than glucose, or even fructose. This could potentially explain some of the differences in AGE levels between omnivores and vegetarians – maybe vegetarians eat more vegetable oils than omnivores, since glucose and fructose intakes alone are insufficient to explain the results. The authors of the paper state:

Oxidation of fatty acid is clearly a more efficient source of CML, despite the fact that the glucose is in solution throughout the course of the experiment, while the PUFA are only progressively solubilized. Further, after 6 days of incubation, a large fraction of the arachidonate was oxidized based on its solubilization in the aqueous phase, while less than 2% of the glucose is oxidized during this same time period.

In the same study, arachidonic acid produced more than 10 times the amount glyoxal than it did CML. Glyoxal is another inflammatory compound, which in food is created by heating unstable (i.e. polyunsaturated) oils to high temperatures but which, again, can also be formed inside the body. Some of this glyoxal goes on to form AGEs, but the rest that doesn’t isn’t exactly life elixir either.

Unfortunately, the problems don’t end with CML. Polyunsaturated fats also quite easily form other AGEs, such as malondialdehydelysine (MDA-lys) and carboxyethyllysine (CEL). Indeed, rats fed a diet high in PUFAs have over twice the level of MDA-lys in their brains compared to rats fed a diet high insaturated fat diet (link). Their levels of CEL and CML in the brain and MDA-lys in the liver are also significantly higher (although CEL and CML are lower in the liver). Unsurprisingly, MDA and CML deposits in the brain are implicated in Alzheimer’s disease (link).

As I mentioned before, simply avoiding cooking with oils rich in PUFAs is probably not enough, because exposing them to high heat and air in the frying pan isn’t the only thing that causes them to form AGEs. Reactive species such as radicals, transition metals, other electrophiles, and enzymes can also cause their oxidation inside the body (link).

In fact, it’s not certain based on the studies mentioned here just how bad food-derived ALEs are. Perhaps ALEs from food are less important than ALEs formed endogenously. Endogenous AGEs certainly appear to play a bigger role than exogenous AGEs, although consuming excess amounts of AGEs is probably not a good idea either.

Personally, I’m trying to limit both endogenous and exogenous AGEs and ALEs by avoiding cooking at high temperatures and using saturated fats for frying. Stay tuned for more posts on the issue. Meanwhile, see these posts on glycation and fats:

AGE Content of Foods
The 7 Types of Aging Damage That End up Killing You
Green Tea Reduces the Formation of AGEs
Should Saturated Fat Be Avoided in Low-Carb Diets?

 

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By Team FPS – April 3, 2012

“Curing” a High Metabolic Rate with Unsaturated Fats

Also see:
Fat Deficient Animals – Activity of Cytochrome Oxidase
Errors in Nutrition: Essential Fatty Acids
Thumbs Up: Fructose
Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
Medium Chain Fats from Saturated Fat – Weight Management Friendly
Toxicity of Stored PUFA
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
PUFA Accumulation & Aging
Unsaturated Fats and Longevity
Arachidonic Acid’s Role in Stress and Shock
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)

Some of the discoveries listed in the studies below were made by the same researcher (George Burr) who discovered the “essential fatty acids.” With a different perspective, we can conclude that the “EFA” lower the metabolic rate of animals that are “deficient” in these fats.

The implications of this change in perspective is noteworthy. It points out the longevity depressing characteristics of “EFA” and also suggests their non essentiality since the “EFA” cured the skin disease of fat deficient rats only by lowering their metabolic rate and thus their exceedingly high nutritional requirements.

Through misinterpretation, we are poisoning ourselves with fats meant for lower temperatured organisms. Organisms with a high body temperature can consume saturated fats with no harmful side effects. The accumulation of unsaturated fats in the tissues of warm-blooded animals progressively lowers the metabolic rate, increases damage from the toxic form of oxidation (lipid peroxidation), damages the heart, lungs, and liver, promotes diabetes, cancer and immunosuppression, lowers our resistance to stress and shock, and harms development.

Also see this blog in relation to the “EFA’s” effect on cytochrome oxidase, a crucial respiratory enzyme.

Quotes by Ray Peat, PhD:
“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome oxidase.”

“Burr didn’t understand that it was his rats’ high sugar diet, freed of the anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time many experiments have made it clear that it is specifically the fructose component of sucrose that is protective against the antimetabolic fats.

Although Brown, et al., weren’t focusing on the biological effects of sugar, their results are important in the history of sugar research because their work was done before the culture had been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is responsible for increasing the blood lipids.”

“By l950, then, it was established that unsaturated fats suppress the metabolic rate, apparently creating hypothyroidism. Over the next few decades, the exact mechanisms of that metabolic damage were studied. Unsaturated fats damage the mitochondria, partly by suppressing the repiratory enzyme, and partly by causing generalized oxidative damage. The more unsaturated the oils are, the more specifically they suppress tissue response to thyroid hormone, and transport of the hormone on the thyroid transport protein.”

“The choice of foods which have less unsaturated fat tends to reinforce the achievements of evolution.”

“The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the “bliss receptor,” or the cannibinoid receptor.

At birth, the baby’s mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to support the activity of the crucial respiratory enzyme, cytochrome oxidase.”

“The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and this change corresponds to the life-long decline of the person’s metabolic rate.”

Exp Biol Med May 1934 vol. 31 no. 8 911-912
METABOLISM STUDIES WITH EATS SUFFERING FROM FAT DEFICIENCY
GEORGE O. BURR AND A J. BEBER
…The results show clearly that fat-deficient rats are very different from stock animals and that fat-deficient rats which have been cured with small doses of fats return to a much more nearly normal gas exchange. The most marked differences shown by the fat-deficient rats are higher basal rate, higher specific dynamic action of food, and higher respiratory quotients. These results are of especial interest since the runs were made over long periods of time under normal conditions. The respiratory quotients of the fat-deficient rats remain above unity for as long as 12 hours out of 24. They, therefore, synthesize every day large amounts of fat, but this synthetic fat does not prevent the fat deficiency.

Summary
Fat-deficient rats may synthesize much fat each day as indicated by high respiratory quotients. The fat synthesized from carbohydrate does not contain appreciable quantities of the essential fatty acids since these must be added to the diet to prevent decline and death. Although much smaller, the rats have a higher metabolic rate than their controls. Consequently, they have a much higher rate calculated as calories per square meter of surface. A normal diurnal activity is shown for all groups, which is independent of light and food.

J. Biol. Chem., vol. 91, pp. 525-539.
The metabolic rate and respiratory quotients of rats on a fat-deficient diet.
WESSON, L. G., AND G. O. BURR 1931
1. The metabolic rate and respiratory quotients following a
carbohydrate test meal have been determined in the case of rats
maintained for some time on a fat-deficient diet, and are compared
with those obtained on normal rats and under approximately the
same conditions.
2. The respiratory quotients in the 1st hours following the
carbohydrate feeding are in many cases well above unity, definitely
indicating the formation of fat from carbohydrate by these rats in
various stages of the fat-deficiency disease.
3. The fact that no relief is obtained from the symptoms of the
fat-deficiency disease by the fat thus formed from carbohydrate
indicates that the curative linolic and linolenic acids are not
formed by the rat from the carbohydrate or from the fat.
4. The basal and assimilatory metabolic rate in the case of rats
showing the early symptoms of the fat-deficiency disease was well
above the normal value, while the metabolic rate in the later
stages of the disease was normal or subnormal.
5. The possible relationship of thyroid activity to several phases
of the fat-deficiency disease is discussed.

Additional sources portraying the high metabolic rate of animals of “EFA” deficient animals:
Arch Int Physiol Biochim. 1990 Aug;98(4):193-9.
Non-shivering thermogenesis and brown adipose tissue activity in essential fatty acid deficient rats.
Goubern M, Yazbeck J, Senault C, Portet R.
The effects of essential fatty acid (EFA) deficiency on energetic metabolism and interscapular brown adipose tissue (BAT) activity were examined in the cold acclimated rat. Weanling male Long-Evans rats were fed on a low fat semipurified diet (control diet, 2% sunflower oil; EFA deficient diet, 2% hydrogenated coconut oil) for 9 weeks. They were exposed at 5 degrees C for the last 5 weeks. In EFA deficient rats, compared to controls, growth retardation reached 22% at sacrifice. Caloric intake being the same in the two groups, it follows that food efficiency was decreased by 40%. Resting metabolism in relation to body surface area was 25% increased. Calorigenic effect of norepinephrine (NE) in vivo (test of non-shivering thermogenesis) underwent a marked decrease of 34%. BAT weight was 21% decreased but total and mitochondrial protein content showed no variation. A 26% increase in purine nucleotide binding per BAT (taken as an index of thermogenic activity) was observed, suggesting that the enhancement in resting metabolism observed was mainly due to increased BAT thermogenesis. However, BAT mitochondria respiratory studies which are more direct functional tests showed a marked impairment of maximal O2 consumption of about 30% with palmitoyl-carnitine or acetyl-carnitine (both in presence of malate) or with alpha-glycerophosphate as substrate. It is likely that this impaired maximal BAT oxidative capacity may explain the impaired NE calorigenic effect in vivo. A possible increase in mitochondrial basal permeability is also discussed.

J Nutr. 1988 May;118(5):627-32.
Effect of dietary linoleic acid and essential fatty acid deficiency on resting metabolism, nonshivering thermogenesis and brown adipose tissue in the rat.
Rafael J, Patzelt J, Elmadfa I.
Rats were fed a diet either deficient (0.05%) in essential fatty acids (EFA), or providing 4% (control) and 10% (surplus) of the total energy intake in the form of linoleic acid. All diets were isoenergetic and provided 13.9% of the energy as fat. The rats were kept at 29 or 5 degrees C. Growth and food intake of rats fed linoleic acid surplus at either temperature for 10 wk were not different from that of controls; basal metabolism, norepinephrine-induced nonshivering thermogenesis (NST) and thermogenic variables in the brown adipose tissue (amount of mitochondria and mitochondrial uncoupling protein) also were not different. The effects of EFA deficiency were drastically enhanced in the cold: After 10 wk of consuming a diet low in EFA at 5 degrees C, the body weight of rats was 75% of that of controls (87% at 29 degrees C); the food intake was 135% of controls at 5 degrees C (120% at 29 degrees C). The resting respiration in deficient rats was 125% of controls at 5 degrees C (110% at 29 degrees C); body temperatures as low as 35.1 degrees C were measured in deficient rats after 3 wk at 5 degrees C; the cold tolerance of the rats was significantly diminished (30% died within 3 wk at 5 degrees C), thus emphasizing the essential role of dietary EFA during cold stress. Norepinephrine-induced NST and the thermogenic parameters in brown fat were not influenced by EFA deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Comp Biochem Physiol A Comp Physiol. 1989;94(2):273-6.
The effects of essential fatty acid deficiency on brown adipose tissue activity in rats maintained at thermal neutrality.
Yazbeck J, Goubern M, Senault C, Chapey MF, Portet R.
1. The consequences of essential fatty acid (EFA) deficiency on the resting metabolism, food efficiency and brown adipose tissue (BAT) thermogenic activity were examined in rats maintained at thermal neutrality (28 C). 2. Weanling male Long-Evans rats were fed a hypolipidic semi-purified diet (control diet: 2% sunflower oil; EFA-deficient diet: 2% hydrogenated coconut oil) for 9 weeks. 3. They were kept at 28 C for the last 5 weeks. Compared to controls, in EFA-deficient rats the growth shortfall reached 21% at killing. 4. As food intake was the same in EFA-deficient and control rats, food efficiency was thus decreased by 40%. 5. Resting metabolism expressed per surface unit was 15% increased. 6. Non-renal water loss was increased by 88%. 7. BAT weight was 28% decreased but total and mitochondrial proteins were not modified. 8. Heat production capacity, tested by GDP binding per BAT was 69% increased in BAT of deficient rats. 9. The stimulation of BAT was established by two other tests: GDP inhibition of mitochondrial O2 consumption and swelling of mitochondria. 10. It is suggested that the observed enhancement of resting metabolism in EFA-deficient rats is, in part, due to an activation of heat production in BAT.

J Nutr. 1984 Feb;114(2):255-62.
The effect of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats.
Rafael J, Patzelt J, Schäfer H, Elmadfa I.
Rats were fed a diet poor (0.05%) in essential fatty acids (EFA) with hydrogenated coconut oil as fat component, or a control diet containing 4% of the total energy intake in the form of linoleic acid. Effects of dietary EFA deficiency were investigated during a period of 2-30 weeks. Growth retardation becomes significant after 4 weeks of deficiency and attains about 25% when the deficiency is maintained for longer than 12 weeks. Respiration, body weight and age of EFA-deficient rats and controls are in a nonlinear relationship. Basal respiration in relation to the body weight is significantly increased by EFA deficiency; it is unchanged when related to total animals under the employed experimental conditions. Oxidative phosphorylation in isolated liver mitochondria is unaffected by EFA deficiency, i.e., the increased metabolic rate of EFA-deficient rats, related to the body weight, cannot be explained from impaired functional integrity of the inner mitochondrial membrane. Respiratory chain enzyme activities in mitochondria from heart and skeletal muscle and specific amounts of mitochondria in these tissues are unchanged by EFA deficiency.

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By Team FPS – April 3, 2012

Fat Deficient Animals – Activity of Cytochrome Oxidase

Also see:
“Curing” a High Metabolic Rate with Unsaturated Fats
Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
Errors in Nutrition: Essential Fatty Acids
Thumbs Up: Fructose
PUFA Accumulation & Aging
Toxicity of Stored PUFA
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
PUFA Accumulation & Aging
Unsaturated Fats and Longevity
Arachidonic Acid’s Role in Stress and Shock
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
Copper: The Forgotten Essential Nutrient

Quotes by Ray Peat, PhD:
“A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy…Kunkel and Willians (J. Biol. Chem., 1951) found that the very high respiratory rate of animals fed a diet lacking polyunsaturated fats was caused primarily by a great increase in the activity of cytochrome oxidase, and that adding an “essential fatty acid” strongly inhibited this enzyme’s activity.”

“Burr didn’t understand that it was his rats’ high sugar diet, freed of the anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time many experiments have made it clear that it is specifically the fructose component of sucrose that is protective against the antimetabolic fats.

Although Brown, et al., weren’t focusing on the biological effects of sugar, their results are important in the history of sugar research because their work was done before the culture had been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is responsible for increasing the blood lipids.”

“As early as 1951, it was known (Kunkel and Williams, J. BioI. Chern.) that the polyunsaturated fatty acids strongly inhibit the crucial respiratory enzyme, cytochrome oxidase, and that inhibition of this enzyme has a very important effect on the whole animal suppressing its metabolic rate, reducing the number of calories it can burn. It is now known that polyunsaturated fats interfere with thyroid hormone in just about every conceivable way.”

“Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone.”

“A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy.”

“The suppressive effects of unsaturated fats on mitochondrial energy production have been widely investigated, since it is that effect that makes animal fattening with PUFA so economical. Rather than interpreting that as a toxic effect, using the innate structure and function of the mitochondrion as a point of reference from which to evaluate dietary components, the consumption of “good” oils is being used as the reference point from which to evaluate the meaning of metabolism (“efficiency is good,” “low oxygen consumption is good”). Building on the idea that the oils are health-promoters which increase metabolic efficiency, the never-viable “rate of aging” theory was resuscitated: The anti-respiratory effect of PUFA is used (illogically) to return to the idea that aging occurs in proportion to the amount of oxygen consumed, because animals which lack the supposedly essential nutrients (“defective animals”) consume oxygen rapidly–burning calories rapidly, they are supposed to be like a candle that won’t last as long if it burns intensely. The old theory is simply resuscitated to explain why the anti-respiratory action of PUFA might be beneficial, justifying further promotion of their use as food and drugs.”

“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzymes in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome c oxidase.

The enzyme is dependent on the thyroid hormone is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin. Red light, which passes easily through the tissues, reactivates the enzyme, which slowly loses its function during darkness.”

“When mitochondria are functioning fully, either glucose or saturated fats can safely
provide energy. Some glucose or saturated fat can be converted to polyunsaturated fats, that can be used as regulators or signals, for example to activate the formation of stem cells. But those PUFA don’t create disruptive cascades of increasing excitation or inflammation or excessive growth, and, from the evidence of animals that are fed fat free diets, or diets lacking omega -3 and omega -6 fatty acids, they aren’t toxic to mitochondria.”

“Increased estrogen exposure, decreased thyroid hormone, an increased ratio of iron to copper, and lack of light, are other factors that impair the cytochrome oxidase enzyme.”


Source: Danny Roddy

J Biol Chem. 1951 Apr;189(2):755-61.
The effects of fat deficiency upon enzyme activity in the rat.
KUNKEL HO, WILLIAMS JN Jr.
The activity of the cytochrome oxidase, however, is markedly increased in fat deficiency…In each case the activity of livers from rats fed the basal diet was 38 per cent greater than from the linoleate-supplemented animals or from the animals receiving corn oil. This is particularly interesting in view of the observation of Burr and Beeber (8) and Wesson and Burr (9) that fat-deficient rats had a markedly increased metabolic rate. The latter authors reported that the basal and assimilatory metabolic rates of fat-deficient animals were 25 per cent greater than the rates of the control animals. Thus the liver cytochrome oxidase activity appears to parallel the metabolic rate in fat deficiency. This increased cytochrome oxidase activity in liver and perhaps other tissues may account in a large part for the increased metabolic rate.

Summary
A fat deficiency in the rat causes a marked increase in liver cytochrome oxidase activity, a slight increase in choline oxidase activity, and a marked decrease in endogenous respiration. The activity of the succinic oxidase system is not altered by this deficiency condition. Supplementation with 100 mg. of methyl linoleate per rat per day reduced the cytochrome oxidase to the level of that produced by a 5 percent corn oil diet.

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By Team FPS – April 3, 2012

Alcohol Consumption – Estrogen and Progesterone In Women

Also see:
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
How does estrogen enhance endotoxin toxicity? Let me count the ways.
PUFA and Liver Toxicity; Protection by Saturated Fats
Endotoxin: Poisoning from the Inside Out
Fish Oils Increase Intestinal Permeability
Estrogen and Liver Toxicity
Single Bout of Binge Drinking Linked to Immune System Effects

Alcohol and Alcoholism (2000) 35 (5): 417-423.
THE EFFECTS OF MODERATE ALCOHOL CONSUMPTION ON FEMALE HORMONE LEVELS AND REPRODUCTIVE FUNCTION
Studies that have investigated the effect of moderate alcohol consumption on the level of oestrogens and progesterone in both pre- and post-menopausal women are reviewed. It is concluded that several lines of evidence point to an alcohol-induced rise in natural or synthetic oestrogen levels in women. Proposed mechanisms include an increased rate of aromatization of testosterone or a decreased rate of oxidation of oestradiol to oestrone. Moderate alcohol consumption has also been linked to decreased progesterone levels in pre-menopausal women. The relevance of these findings to female health, fertility and the timing of the menopause is considered.

Cancer Epidemiol Biomarkers Prev. 1998 Mar;7(3):189-93.
Alcohol consumption and total estradiol in premenopausal women.
P Muti, M Trevisan, A Micheli, V Krogh, G Bolelli, R Sciajno, H J Schünemann and F Berrino
The present paper analyzes the relation between alcohol intake and serum total estradiol in premenopausal women while attempting to control or reduce several sources of variability of serum estradiol. Sixty premenopausal women were recruited, and alcohol intake was estimated by a semiquantitative questionnaire. Interviews, anthropometric measurements, and blood drawings (after overnight fasting) were conducted twice, 1 year apart. Both blood samples were obtained on the same day of the luteal phase of the cycle, in the same month and in the same hour and minute of the day. Samples from the first drawing were stored at -80 degrees C. Serum from both drawings was assayed simultaneously and in blind fashion. A significant association between alcohol intake and estradiol was found when estradiol was averaged across the two visits (Spearman’s r = 0.29; P < 0.05). To control for intraindividual variability of estradiol over time, participants were then divided into tertiles of hormone distribution for each of the two sets of measurements and classified based on their consistency in estradiol across the two visits. Women showing consistently high estradiol levels at both visits were characterized by a significantly higher alcohol intake (92.8 g/week) in comparison with those showing consistently low estradiol at both visits (31.6 g/week). Furthermore, the prevalence of drinkers in the group with consistently high estradiol was significantly higher than in the group with consistently low estradiol. The present report indicates that drinkers seem to be characterized by consistently higher estradiol than nondrinkers, and that when the variability of estradiol in premenopause is considered, it is possible to identify a relationship between alcohol intake and estradiol.

Psychopharmacology (Berl). 1988;94(4):464-7.
Acute alcohol effects on plasma estradiol levels in women.
Mendelson JH, Lukas SE, Mello NK, Amass L, Ellingboe J, Skupny A.
Acute administration of alcohol (0.695 g/kg) to healthy adult women resulted in peak blood alcohol levels between 70 and 75 mg/dl within 50-60 min after initiation of drinking. Alcohol induced a significant increase (means = 18 pg/ml) in plasma estradiol levels (P less than 0.01). In contrast, after placebo ingestion, plasma estradiol levels did not change significantly. After alcohol intake, plasma estradiol levels reached peak values at 25 min following initiation of drinking when blood alcohol levels averaged 34 mg/ml. It is postulated that the alcohol-induced increase in plasma estradiol is due to changes in hepatic redox states associated with the catabolism of ethanol.

Oncology. 1991;48(6):490-4.
Diet and urine estrogens among postmenopausal women.
Katsouyanni K, Boyle P, Trichopoulos D.
Creatinine-adjusted levels of estrone, estradiol and estriol were determined in overnight urine specimens from 88 postmenopausal women from Athens, Greece, and were correlated with daily nutrient intakes estimated through a semiquantitative food frequency questionnaire. Although obesity was positively and significantly related to all three urinary estrogens and their total, none of the investigated macro- or micronutrients was significantly or suggestively associated to any of these urinary estrogens, after controlling for energy intake, reproductive and biosocial variables. These results suggest that quantitative rather than qualitative aspects of nutrition affect the levels of postmenopausal estrogens, although endogenous factors could also be responsible for the association of these estrogens with obesity. Alcohol intake was also positively associated with urinary estrogens (mainly estrone and estradiol), after controlling for energy intake, obesity and the other indicated variables.

Alcohol. 1992 Sep-Oct;9(5):395-401.
Ethanol decreases progesterone synthesis in human placental cells: mechanism of ethanol effect.
Ahluwalia B, Smith D, Adeyiga O, Akbasak B, Rajguru S.
Fetal alcohol syndrome (FAS) is a set of signs and symptoms in offsprings born to mothers who abuse alcohol during pregnancy. We postulated that impairment in the placental endocrine function contribute to FAS. In this study, we examined in vitro effects of ethanol on the placental cells’ (cytotrophoblast cells) capacity to synthesize progesterone. Cytotrophoblast cells were isolated from normal term placenta and were incubated (2 x 10(6)) with 20-, 30-, and 40-mM doses of ethanol for 6 h. Progesterone was measured in the incubate by RIA. The results showed that, at the 20-mM dose of ethanol, progesterone synthesis was significantly decreased (p less than 0.01), at the 30-mM dose level there was a further decrease of 20%. The differences between 30- and 40-mM ethanol dose levels were not significant. To determine the mechanism of ethanol effects on progesterone synthesis, cytotrophoblast cells were preincubated with 30 mM ethanol followed by 10 microliters of LDL (10 microliters LDL = 80 micrograms cholesterol) and vice versa. The results showed that ethanol effects on progesterone synthesis was dependent on whether ethanol was added prior to or following the addition of LDL in the medium. If ethanol was added in the medium prior to LDL, progesterone synthesis was decreased significantly (p greater than 0.01); however, when ethanol was added after the LDL, ethanol had no effect on progesterone synthesis. In the experiment where ethanol and LDL were added simultaneously in the medium, ethanol blunted the stimulatory effect of LDL on progesterone synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Clin Exp Res. 1996 Oct;20(7):1192-5.
Estrogen-related acetaldehyde elevation in women during alcohol intoxication.
Eriksson CJ, Fukunaga T, Sarkola T, Lindholm H, Ahola L.
Alcohol is more often unpleasant and causes tissue damage more rapidly in women than men. The present study was designed to find out whether acetaldehyde, the primary metabolite of alcohol, could play a crucial role in these actions. Special emphasis was focused on the appropriate determination of blood acetaldehyde and hormonal factors. Occurrence of elevated blood acetaldehyde levels during alcohol oxidation was established in both normally cycling women and ones taking oral contraceptives, but not in men. An association between elevated acetaldehyde levels and high estrogen phases was observed in both groups of women. Estrogen-related acetaldehyde elevation is suggested to be the key factor explaining the gender differences of the adverse effects of alcohol.

Alcohol Clin Exp Res. 1992 Feb;16(1):87-92.
The association between moderate alcoholic beverage consumption and serum estradiol and testosterone levels in normal postmenopausal women: relationship to the literature.
Gavaler JS, Van Thiel DH.
The major source of endogenous estrogens in postmenopausal women is the aromatization of androgens to estrogens; because alcohol is known to increase aromatization, the relationship between moderate alcoholic beverage consumption and serum estradiol levels was evaluated in 128 normal postmenopausal women. Alcohol intake was based on a composite of self-report and food record information. Among the 78.8% of women reporting alcohol use, weekly intake was 4.8 +/- 0.6 drinks. Among abstainers, estradiol levels were 100.8 +/- 12.1 pmol/liter, significantly lower than in alcohol users, 162.6 +/- 11.9 pmol/liter. Significant bivariate correlations were found between the logarithm of estradiol and total weekly drinks. In multiple linear regression analyses inclusion of alcohol as a variable increased the amount of explained variation in estradiol. Similar findings were demonstrable when the crude estimator of aromatization, the estradiol:testosterone ratio logarithm was the dependent variable. Together, these findings suggest that moderate alcohol use is an important factor for postmenopausal estrogen status and may offer a partial explanation for the reported protective effect of moderate alcohol consumption with respect to postmenopausal cardiovascular disease risk.

Alcohol Clin Exp Res. 1999 Jun;23(6):976-82.
Acute effect of alcohol on estradiol, estrone, progesterone, prolactin, cortisol, and luteinizing hormone in premenopausal women.
Sarkola T, Mäkisalo H, Fukunaga T, Eriksson CJ.
BACKGROUND:
Heavy alcohol consumption is associated with menstrual irregularities, including anovulation, luteal-phase dysfunction, recurrent amenorrhea, and early menopause. In addition, moderate to heavy alcohol intake has been found to increase the risk of spontaneous abortions and breast cancer. These adverse effects could at least in part originate from alcohol-mediated changes in hormone levels.
METHODS:
The acute effect of alcohol on the hormone balance in women using oral contraceptives (OC+) and also in nonusers (OC-), was evaluated in 30 OC- and 31 OC+ subjects, representing the whole period of the menstrual cycle. It was also evaluated in 40 OC- and 47 OC+ subjects during the midcycle phase and in 10 OC+ subjects with unknown cycle phase.
RESULTS:
We found that among subjects who used oral contraceptives, estradiol levels increased and progesterone levels decreased after intake of alcohol (0.5 g/kg). No dose effect (0.34-1.02 g/kg) on progesterone was observed in a substudy on 10 OC+ subjects. With regard to estrone levels, no effect was observed, although a significant increase was found in the estradiol-to-estrone ratio. Among subjects not using oral contraceptives, progesterone levels decreased after intake of alcohol (0.5 g/kg). No effect was found in estradiol, estrone, or the estradiol-to-estrone ratio during midcycle in this study group. A transient elevating effect of alcohol (0.5 g/kg) on prolactin levels was observed in both study groups. We found that alcohol (0.5 g/kg) had no significant effect on luteinizing hormone (LH) levels among subjects not using oral contraceptives, and observed a decline among subjects using oral contraceptives at midcycle.
CONCLUSIONS:
We suggest that the estradiol and progesterone effects are related to decreased steroid catabolism, resulting from the alcohol-mediated increase in the hepatic NADH-to-NAD ratio. The transient effect on prolactin levels may reflect acute changes in opioid and dopamine levels in the hypothalamus. The present findings regarding female sex steroids may be of relevance in the association between moderate to heavy alcohol consumption and the development of breast cancer.

Alcohol Clin Exp Res. 1993 Aug;17(4):786-90.
Alcohol and estrogen levels in postmenopausal women: the spectrum of effect.
Gavaler JS, Deal SR, Van Thiel DH, Arria A, Allan MJ.
Compared with alcohol-abstaining normal postmenopausal women, estradiol levels are known to be statistically increased in normal postmenopausal women who consume alcoholic beverages moderately, and to be even further increased in alcoholic postmenopausal women with cirrhosis. This study was undertaken to evaluate whether or not there is a spectrum of changes in levels of sex steroids and pituitary hormones associated with alcohol abstinence, alcohol use, and alcohol-induced cirrhosis in the absence of current alcohol abuse. For levels of estradiol and testosterone, as well as for the estradiol to testosterone ratio, all three groups differed significantly from each other; for the pituitary hormones, levels in the abstainers and alcohol users were similar and statistically different from levels in the alcoholic cirrhotic women. Compared with the alcohol-abstaining women, the relationships of age and estradiol with levels of the other hormones were disturbed for 4 of 11 correlations examined among the alcohol users, and for 9 of 11 correlations evaluated among the alcoholic cirrhotic women. These findings suggest that not only are hormonal relationships markedly disrupted among alcoholic cirrhotics, but also that alcoholic beverage consumption in the range of 0.1-28 total weekly drinks results in detectable perturbations of the normal hormonal relationships expected in postmenopausal women.

Hepatology. 1992 Aug;16(2):312-9.
Hormonal status of postmenopausal women with alcohol-induced cirrhosis: further findings and a review of the literature.
Gavaler JS, Van Thiel DH.
The derangements of levels of sex hormones and gonadotropins in alcoholic cirrhotic men are well delineated. The countersituation in alcoholic cirrhotic women has not yet been fully described. This study was performed in postmenopausal women among whom menstrual cycle variations in hormones no longer occur; with such a study population, it is possible to control for confounding factors and thus optimize detection of differences in levels of hormones and hormone interrelationships. Both estradiol levels and a rough estimate of aromatization of testosterone to estradiol, the estradiol to testosterone ratio, were significantly elevated in the 20 alcoholic subjects with alcohol-induced cirrhosis, as compared with the 27 normal controls; similarly, testosterone, luteinizing hormone and follicle-stimulating hormone were all significantly reduced in the alcoholic cirrhotic women. In addition, the normal relationships of estradiol with luteinizing hormone, follicle-stimulating hormone, body mass and the estradiol/testosterone ratio were detected in the control group but not in the group of cirrhotic women. Further, among the alcoholic cirrhotic postmenopausal women, testosterone, luteinizing hormone, follicle-stimulating hormone and the estradiol/testosterone ratio were all significantly correlated with the Child’s liver disease severity score. That the hormone levels and their interrelationships differ markedly between normal and alcoholic cirrhotic women extends previous findings in both men and postmenopausal women; the correlations of hormone levels and markers of liver disease will require further investigation.

J Pharmacol Exp Ther. 1990 Aug;254(2):407-11.
Alcohol effects on hCG-stimulated gonadal hormones in women.
S K Teoh, J H Mendelson, N K Mello, A Skupny and J Ellingboe
Chronic alcohol abuse is associated with derangements of reproductive function in women. The mechanism of increased risk for alcohol-related abortions and fetal alcohol syndrome is unknown. The goal of this study was to determine if acute alcohol administration affected gonadal steroid hormone levels after administration of human chorionic gonadotropin (hCG) to normal healthy women. hCG was used to simulate the hormonal milieu during the first trimester of pregnancy. Ten women were studied during the mid-luteal phase (between days 17 and 23) of their menstrual cycle. Plasma estradiol, progesterone and prolactin were measured before and after simultaneous administration of 5000 I.U. of hCG (Profasi) and alcohol or placebo solution under double-blind conditions. There was a significant increase in plasma estradiol (P less than .001) and prolactin levels (P less than .01) after hCG and alcohol administration but not after hCG and placebo administration. Plasma progesterone increased significantly (P less than .001) above base line after hCG and placebo administration but this was not observed after hCG and alcohol administration. Since progesterone is essential for the maintenance of pregnancy, alcohol’s attenuation of the expected progesterone response to hCG stimulation could increase the risk of spontaneous abortion. An alcohol-induced increase in estradiol after hCG administration could contribute to risk for fetal dysmorphology during the first trimester of pregnancy.

Maturitas. 1994 Aug;19(2):83-92.
Factors associated with onset of menopause in women aged 45-49.
Torgerson DJ, Avenell A, Russell IT, Reid DM.
This paper uses a cross-sectional sample of women aged 45-49 to investigate factors that might be associated with an early menopause. Using logistic regression analysis we found that age, smoking, age of maternal menopause, parity, social class, meat and alcohol consumption were all independently associated with an early natural menopause. Meat, alcohol consumption and maternal menopausal age do not seem to have been previously noted as associated with the timing of the menopause. These associations would merit further study, preferably using prospective data. However, this study in line with much previous work shows that smoking is associated with a reduction in menopausal age.

The Journal of Clinical Endocrinology & Metabolism June 1, 1988 vol. 66 no. 6 1181-1186
Alcohol Effects on Naltrexone-Induced Stimulation of Pituitary, Adrenal, and Gonadal Hormones During the Early Follicular Phase of the Menstrual Cycle*
SIEW KOON TEOH, JACK H. MENDELSON, NANCY K. MELLO and ALICJA SKUPNY
Chronic alcohol abuse in women is associated with severe derangements of menstrual cycle regularity. However, acute alcohol ingestion has no effect on pituitary-gonadal secretory function. The purpose of this study was to determine whether acute alcohol ingestion altered the effects of naltrexone, a long-acting opioid antagonist, on pituitary, adrenal, and gonadal hormones in normal women. Fourteen women were studied during the early follicular phase (between days 2 and 4) of their menstrual cycle. Plasma LH, PRL, estradiol, progesterone, and cortisol concentrations were measured before and after administration of 50 mg naltrexone, orally, and alcohol or placebo solution given 1 h after naltrexone, under double blind conditions. Naltrexone significantly increased mean plasma LH (P = 0.02), PRL (P = 0.003), E2 (P < 0.03), and cortisol (P < 0.001) levels. Alcohol significantly augmented the naltrexone-stimulated increases in plasma LH (P = 0.006), estradiol (P < 0.004), and cortisol (P < 0.001) levels and significantly decreased plasma progesterone levels (P = 0.001). Plasma PRL increased (P = 0.001) to the same extent after naltrexone and alcohol ingestion or naltrexone and placebo. We conclude that alcohol enhances naltrexone-induced increases in plasma gonadotropins and adrenal and gonadal steroid hormones in women during the early follicular phase of the menstrual cycle.

JNCI J Natl Cancer Inst (1993) 85 (9): 722-727.
Effects of Alcohol Consumption on Plasma and Urinary Hormone Concentrations in Premenopausal Women
Marsha E. Reichman, Joseph T. Judd, Christopher Longcope, Arthur Schatzkin, Beverly A. Clevidence, Padmanabhan P. Nair, William S. Campbell and Philip R. Taylor
Background: Most epidemiologic studies of the relationship between alcohol consumption and breast cancer risk over the past decade have shown that persons who consume a moderate amount of alcohol are at 40%-100% greater risk of breast cancer than those who do not consume alcohol. Dose-response effects have been observed, but no causal relationship has been established. Purpose: This study examines the hypothesis that alcohol consumption affects levels of reproductive hormones. Methods: A controlled-diet study lasting for six consecutive menstrual cycles was conducted. Participants were randomly assigned to two groups, and a crossover design was used. During the last three menstrual cycles, alcohol consumption of the two groups was reversed. Thirty-four premenopausal women, aged 21–40 years, with a history of regular menstrual cycles, consumed 30 g of ethanol (equivalent to approximately two average drinks) per day for three menstrual cycles and no alcohol for the other three. All food and alcohol consumed were provided by the study. Caloric intake was monitored to ensure that each woman would maintain body weight at approximately the baseline level. Hormone assays were performed on pooled plasma or 24-hour urine specimens collected during the follicular (days 5–7), peri-ovulatory (days 12–15), and mid-luteal (days 21–23) phases of the third menstrual cycle for subjects on each diet. Results: Alcohol consumption was associated with statistically significant increases in levels of several hormones. Plasma dehydroepiandrosterone sulfate levels were 7.0% higher in the follicular phase (P =.05). In the peri-ovulatory phase, there were increases of 21.2% (P =.01) in plasma estrone levels, 27.5% (P =.01) in plasma estradiol levels, and 31.9% (P =.009) in urinary estradiol levels. In the luteal phase, urinary estrone levels rose 15.2% (P =.05), estradiol levels increased 21.6% (P =.02), and estriol levels rose 29.1% (P =.03). No changes were found in the percent of bioavailable estradiol, defined by the sum of percent free estradiol and percent albumin-bound estradiol. However, increased total estradiol levels in the peri-ovulatory phase suggest elevated absolute amounts of bioavailable estradiol. Conclusion: This study has shown increases in total estrogen levels and amount of bioavailable estrogens in association with alcohol consumption in pre-menopausal women. Implication: This possible explanatory mechanism for a positive association between alcohol consumption and breast cancer risk merits further investigation.

Alcohol Clin Exp Res. 1998 Aug;22(5):994-7.
Moderate alcohol consumption and estrogen levels in postmenopausal women: a review.
Purohit V.
This report reviews the literature to evaluate association between moderate alcohol consumption and estrogen levels in healthy postmenopausal women. Of the eight studies available in literature on postmenopausal women who were not on estrogen therapy, two analyzed urine samples and six analyzed blood samples for estrogen levels. Of the two urine sample studies, only one reported positive association (p < 0.05) between alcohol consumption and estrogen (estrone and estradiol) levels that increased by 16 to 20%. Of the six blood sample studies, only two–one in American women and one in European women–reported significant increases (p < 0.05) in estradiol levels in response to alcohol consumption. In the American women study, estradiol levels increased only with wine and not with beer or whiskey. In the European women study, estradiol levels increased in Danish and Portuguese women, but not in Spanish women. Thus, further studies are required to establish correlation between moderate alcohol consumption and estrogen levels in postmenopausal women. Of the two studies on postmenopausal women who were on estrogen replacement therapy, one administered estradiol through transdermal patch (0.15 mg) and one orally (1 mg/day). In both studies, blood estradiol levels were measured after administering a single dose of ethanol orally (0.7-0.75 g/kg of body weight). Estradiol levels were increased by 22 and 300% in the transdermal patch and oral studies, respectively. These results suggest that alcohol consumption may increase blood estradiol levels in postmenopausal women who are on estrogen replacement therapy, and this may increase the risk of breast cancer.

Breast Cancer Res Treat. 1997 Jul;44(3):235-41.
Associations of alcohol, height, and reproductive factors with serum hormone concentrations in postmenopausal Japanese women. Steroid hormones in Japanese postmenopausal women.
Nagata C, Kabuto M, Takatsuka N, Shimizu H.
We measured serum levels of estradiol (E2), sex hormone-binding globulin SHBG), progesterone, and dehydroepiandrosterone sulfate (DHEAS) in 61 postmenopausal women drawn from female residents in a community in Japan to evaluate the relationships between these hormone levels and potential breast cancer risk factors. The information on reproductive history, body size, alcohol use, and physical activity was obtained by means of a self-administered questionnaire. There was a significant trend in increasing E2 level with increasing height after taking account of age and body mass index (BMI) (p for trend = 0.04). BMI was inversely associated with SHBG level after controlling age (p for trend = 0.01). Decreasing progesterone with increasing BMI was observed after controlling age and history of hysterectomy (P = 0.05). Alcohol consumption was positively associated with E2 level and there was a strong linear trend after controlling for age, height, and BMI (p for trend = 0.001). Trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy (p for trend = 0.01). Reproductive factors as well as physical activity were not related to any of the hormone levels.

JAMA. 1996 Dec 4;276(21):1747-51.
Effects of Alcohol Ingestion on Estrogens in Postmenopausal Women
Elizabeth S. Ginsburg, MD; Nancy K. Mello, PhD; Jack H. Mendelson, MD; Robert L. Barbieri, MD; Siew Koon Teoh, MD; Micol Rothman; Xiaoying Gao, MD; J. Wallis Sholar
Objective. —To determine if moderate alcohol drinking increases circulating estradiol levels in postmenopausal women who are taking estrogen replacement.
Design. —Randomized, double-blind, placebo-controlled crossover study of the effects of alcohol ingestion on plasma estradiol and estrone.
Setting. —Inpatient Clinical Research Center.
Participants. —Twelve healthy postmenopausal women receiving oral estrogen (estradiol, 1 mg/day) and progestin (medroxyprogesterone acetate) replacement therapy were compared with 12 postmenopausal women who were not using estrogen replacement therapy (ERT).
Intervention. —Each group drank alcohol (0.7 g/kg) and an isoenergetic (isocaloric) placebo (randomized sequence) on consecutive days. Women who were taking ERT were studied during the estrogen-only portion of their replacement cycle, and estrogen was administered each evening at 2100 hours.
Main Outcome Measure. —The impact of alcohol ingestion on plasma estradiol and estrone levels.
Results. — Alcohol ingestion lead to a 3-fold increase in circulating estradiol in women on ERT; however, alcohol did not change estradiol significantly in control women who were not on ERT. In women using ERT, estradiol levels increased from 297 to 973 pmol/L (81 to 265 pg/mL) within 50 minutes (P<.001) during the ascending limb of the blood alcohol curve and remained significantly above baseline for 5 hours (P<.001). No significant increase in circulating estrone was detected in either group. However, estrone levels decreased after alcohol and placebo in women on ERT (P<.05). Blood alcohol levels did not differ significantly in women who used ERT and those who did not. Peak blood alcohol levels of 21 mmol/L were attained in each of the 2 groups within 50 to 60 minutes after drinking began. Changes in estradiol were significantly correlated with changes in blood alcohol levels on both the ascending (P<.001) and descending (P<.001) limb of the blood alcohol curve.
Conclusions. —Acute alcohol ingestion may lead to significant and sustained elevations in circulating estradiol to levels 300% higher than those targeted in clinical use of ERT. Potential health risks and benefits of the interactions between acute alcohol ingestion and ERT should be further evaluated.

BMJ 1998;317:505
Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy
Tina Kold Jensen, postdoctoral fellowa (tk.jensen@winsloew.ou.dk), Niels Henrik I Hjollund, physicianb, Tine Brink Henriksen, physicianc, Thomas Scheike, associate professor of biostatisticsd, Henrik Kolstad, physicianb, Aleksander Giwercman, physiciana, Erik Ernst, physicianc, Jens Peter Bonde, chief doctorb, Niels E Skakkebæk, professora, J⊘rn Olsen, professore
Objective : To examine the effect of alcohol consumption on the probability of conception.
Design : A follow up study over six menstrual cycles or until a clinically recognised pregnancy occurred after discontinuation of contraception.
Subjects : 430 Danish couples aged 20-35 years trying to conceive for the first time.
Main outcome measures : Clinically recognised pregnancy. Fecundability odds ratio: odds of conception among exposed couples divided by odds among those not exposed.
Results : In the six cycles of follow up 64% (179) of women with a weekly alcohol intake of less than five drinks and 55% (75) of women with a higher intake conceived. After adjustment for cycle number, smoking in either partner or smoking exposure in utero, centre of enrolment, diseases in female reproductive organs, woman’s body mass index, sperm concentration, and duration of menstrual cycle, the odds ratio decreased with increasing alcohol intake from 0.61 (95% confidence interval 0.40 to 0.93) among women consuming 1-5 drinks a week to 0.34 (0.22 to 0.52) among women consuming more than 10 drinks a week (P=0.03 for trend) compared with women with no alcohol intake. Among men no dose-response association was found after control for confounders including women’s alcohol intake.
Conclusion : A woman’s alcohol intake is associated with decreased fecundability even among women with a weekly alcohol intake corresponding to five or fewer drinks. This finding needs further corroboration, but it seems reasonable to encourage women to avoid intake of alcohol when they are trying to become pregnant.
Key messages
As alcohol consumption is widespread and increasing in many countries, even a minor effect on fertility is of public health interest
Some studies have found that women with high alcohol intake take longer to become pregnant, but none have found that moderate intake has an effect
The probability of conception in a menstrual cycle decreased with increasing alcohol intake in women, even among those drinking five or fewer drinks a week
Women who are trying to conceive should be encouraged to avoid intake of alcohol

Am J Public Health. 1994 Sep;84(9):1429-32.
Infertility in women and moderate alcohol use.
Grodstein F, Goldman MB, Cramer DW.
OBJECTIVE:
The purpose of this study was to investigate the relationship between moderate alcohol intake and fertility.
METHODS:
Interviews were conducted with 3833 women who recently gave birth and 1050 women from seven infertility clinics. The case subjects were categorized based on the infertility specialist’s assignment of the most likely cause of infertility: ovulatory factor, tubal disease, cervical factor, endometriosis, or idiopathy. Separate logistic regression models were used to assess the relationship between alcohol use and each type of infertility, adjusted for age, infertility center, cigarette smoking, caffeine use, number of sexual partners, use of an intrauterine device (for tubal disease), and body mass index and exercise (for ovulatory factor).
RESULTS:
We found an increase in infertility, due to ovulatory factor or endometriosis, with alcohol use. The odds ratio for ovulatory factor was 1.3 (95% confidence interval [CI] = 1.0, 1.7) for moderate drinkers and 1.6 (95% CI = 1.1, 2.3) for heavier drinkers, compared with nondrinkers. The risk of endometriosis was roughly 50% higher in case subjects with any alcohol intake than in control subjects (OR = 1.6, 95% CI = 1.1, 2.3, at moderate levels; OR = 1.5, 95% CI = 0.8, 2.7, at heavier levels).
CONCLUSIONS:
Moderate alcohol use may contribute to the risk of specific types of infertility.

JNCI J Natl Cancer Inst (1995) 87 (17): 1297-1302.
Alcohol, Height, and Adiposity in Relation to Estrogen and Prolactin Levels in Postmenopausal Women
Susan E. Hankinson*, Walter C. Willett, JoAnn E. Manson, David J. Hunter, Graham A. Colditz, Meir J. Stampfer, Christopher Longcope and Frank E. Speizer
Background: Alcohol use, height, and postmenopausal adiposity have each been positively associated with postmenopausal breast cancer risk in most epidemiologic studies. The mechanism underlying these associations is unclear, although an effect of these factors on hormone levels has been hypothesized. Few previous studies have evaluated the relationship of either alcohol consumption or height with plasma hormone levels. A positive association between adiposity and plasma estrogen levels in postmenopausal women has been reported consistently. Purpose: Using archived frozen plasma samples and corresponding data from participants in the Nurses’ Health Study, we determined plasma hormone levels and assessed these levels in relation to alcohol consumption, height, and adiposity among postmenopausal women. Methods: Blood samples were collected from a subset of participants in the Nurses’ Health Study in 1989 and 1990, then stored in liquid nitrogen. Hormone concentrations in 217 archived plasma samples (from healthy postmenopausal women) were analyzed in 1993. Spearman correlation coefficients were calculated to assess the linear association between alcohol consumption during the previous year (mean daily intake in grams per day ascertained from semiquantitative food-frequency questionnaires completed in 1990 or 1991), height, and adiposity (as measured by body mass index [BMI] in kg/m2, with weight reported at time of blood collection), and plasma hormone levels. Two-sided P values were also calculated. Results: After controlling for age, height, smoking status, and BMI, alcohol consumption was positively associated with estrone sulfate concentrations (r =.17; P =.02); no statistically significant association was noted for the other plasma hormones measured. Mean plasma estrone sulfate levels were 159 pg/mL in women who reported no alcohol use versus 211 pg/mL in women consuming 30 g or more of alcohol per day. After adjusting for the other covariates, we observed a strong positive correlation between BMI and plasma estrogens (r ranging from.37 for estrone and estrone sulfate to.63 for bioavailable estradiol, with all P values <.01; prolactin was the only hormone unassociated with BMI, r =.01). Height was unrelated to either plasma estrogens or prolactin. Conclusions: BMI and alcohol use were positively associated with postmenopausal plasma estrogen and estrone sulfate levels, respectively. Implications: The association of alcohol consumption and postmenopausal obesity with subsequent breast cancer risk might be mediated, at least in part, through an influence on postmenopausal plasa estrogen levels. Additional studies are needed to further quantify the relationship between alcohol consumption and plasma hormone levels and to elucidate the physiologic basis for this association.

Fertil Steril. 1998 Oct;70(4):632-7.
Alcohol and caffeine consumption and decreased fertility.
Hakim RB, Gray RH, Zacur H.
OBJECTIVE:
To examine the effects of alcohol and caffeine on conception.
DESIGN:
Prospective observational study.
SETTING:
Healthy volunteers in two manufacturing facilities.
PATIENT(S):
One hundred twenty-four women who provided daily urine samples for measurement of steroid hormones and hCG, and prospective information about alcohol and caffeine consumption.
MAIN OUTCOME MEASURE(S):
Probability of conception per 100 menstrual cycles.
RESULT(S):
There was >50% reduction in the probability of conception during a menstrual cycle during which participants consumed alcohol. Caffeine consumption did not independently affect the probability of conception but may enhance alcohol’s negative effect. Women who abstained from alcohol and consumed less than one cup of coffee or its equivalent per day conceived 26.9 pregnancies per 100 menstrual cycles compared with 10.5 per 100 menstrual cycles among those who consumed any alcohol and more than one cup of coffee per day.
CONCLUSIONS:
This study revealed an independent dose-related negative effect of alcohol consumption on the ability to conceive. Our results suggest that women who are attempting to conceive should abstain from consuming alcohol.

Am J Physiol Gastrointest Liver Physiol. 2001 Dec;281(6):G1348-56.
Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.
Nanji AA, Jokelainen K, Fotouhinia M, Rahemtulla A, Thomas P, Tipoe GL, Su GL, Dannenberg AJ.
Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-kappa B (NF-kappa B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-kappa B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-alpha and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-kappa B activation and chemokine production, enhancing liver injury. TNF-alpha and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

========================
Feminization of men:

Proc Soc Exp Biol Med. 1995 Jan;208(1):98-102.
The phytoestrogen congeners of alcoholic beverages: current status.
Gavaler JS, Rosenblum ER, Deal SR, Bowie BT.
The idea that alcoholic beverages might contain biologically active phytoestrogenic congeners stemmed from findings of overt feminization observed in alcoholic men with alcohol-induced cirrhosis. Specifically, in addition to being hypogonadal, these chronically alcohol-abusing men with cirrhosis frequently manifest gynecomastia, palmar erythema, spider angiomata, and a female escutcheon. These physical signs of exposure to active estrogen occur in the presence of normal or only minimally elevated levels of endogenous steroid estrogens. Because levels of circulating steroid hormones failed to provide a satisfactory explanation for the feminization observed, alternate explanations were considered. If the estrogenization observed was not entirely a function of tissue expose to steroid estrogens produced endogenously, then perhaps tissues were being exposed to exogenous estrogenic substances from dietary sources. Given the degree of alcohol abuse in the population in which hypotheses for feminization were being formed, alcoholic beverages became a prime candidate as a dietary source of exogenous estrogenic substances.

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By Team FPS – March 31, 2012

Blood Sugar – Resistance to Allergy and Shock

Also see:
Low Blood Sugar Basics
Ray Peat, PhD on Low Blood Sugar & Stress Reaction
PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
Protect the Mitochondria
Saturated and Monousaturated Fatty Acids Selectively Retained by Fat Cells
PUFA Decrease Cellular Energy Production
The Randle Cycle
Low Carb Diet – Death to Metabolism
Free Fatty Acid Suppress Cellular Respiration
Sugar (Sucrose) Restrains the Stress Response
Protection from Endotoxin
Possible Indicators of High Cortisol and Adrenaline
Thyroid peroxidase activity is inhibited by amino acids
Toxicity of Stored PUFA
Belly Fat, Cortisol, and Stress
Sugar (Sucrose) Restrains the Stress Response
PUFA, Development, and Allergy Incidence

Quotes by Ray Peat, PhD:
“Hypoglycemia (which can result from any respiratory defect) can produce malfunction of any tissue, but brain dysfunction and immune dysfunction are very common effects. Adamkiewicz has shown that allergic reactions to a given substance will decrease from 100 percent to zero, when the blood glucose increases from, for example, 50 mg. to 150 mg. or more.”

“Thyroid, progesterone and pregnenolone help to normalize the blood sugar by improving respiration, and should be the basic treatment for allergies.”

‎”…Blood sugar is usually the thing to pay most attention to, everything becomes an allergen if the glucose is chronically low. Thyroid is the main thing that stabilizes the blood sugar. Aspirin usually helps with allergies…”

“While Warburg was investigating the roles of glycolysis and respiration in cancer, a physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen made the difference between health and sickness, and that the cancer metabolism could be corrected by restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as cancer.”

AJP – Legacy Content January 1960 vol. 198 no. 1 51-53
Glucose and the dextran ‘anaphylactoid’ inflammation
V. W. Adamkiewicz and Lidia M. Adamkiewicz
Male Sprague-Dawley rats, 120–150 gm in body weight, injected simultaneously with the glucan dextran (1 ml 6% w/v, i.p.) and with an overdose of glucose (3 x 5 ml, 25% w/v, s.c.) which cannot be markedly reduced by excretion in about 24 hours, do not undergo dextran ‘anaphylactoid’ inflammation. If the amount of glucose is smaller (2 x 5 ml, 25% w/v, s.c.) and can be reduced by excretion within about 10 hours, the inflammation occurs, but is greatly delayed in time and diminished in intensity. The specific inhibitory action glucose exerts on the biological activity of the glucan dextran is discussed.

The Journal of Immunology January 1, 1964 vol. 92 no. 1 3-7
Glycemic States and the Horse-Serum and Egg-White Anaphylactic Shock in Rats1
V. W. Adamkiewicz, P. J. Sacra and J. Ventura
The hypoglycemic state produced in rats by 48 hr fasting or by administration of 4 units of insulin aggravated anaphylactic shock when produced by horse serum or egg white, and as measured by per cent mortality, occurrence of lesions in the ileum and hypothermia. Neutralization of the hypoglycemic state by injection of glucose restored the resistance of rats to anaphylactic shock. The degree of hypothermia in anaphylactic shock did not parallel the intensity of the lesions or the per cent mortality.

Br. J. Pharmac. Chemother. (1967), 31, 351-355.
THE RELATIONSHIP OF THE BLOOD SUGAR LEVEL TO THE SEVERITY OF ANAPHYLACTIC SHOCK
H. L. DHAR, R. K. SANYAL AND G. B. WEST*
In rats and mice, the severity of anaphylactic shock is altered by changes in the
concentration of glucose in the blood. When hypoglycaemia is induced by Bordetella
pertussis vaccine or insulin, shock is potentiated whereas in hyperglycaemia induced by injections of alloxan or glucose shock is delayed and severity is decreased.

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By Team FPS – March 31, 2012

Progesterone: Essential to Your Well-Being

By Raymond F. Peat, Ph. D.

Editor’s Note: In her “Of Many Things” column this January, Betty Franklin introduced Dr. Raymond Peat’s work with natural progesterone, applied externally. Response from readers has been tremendous, so we invited Dr. Peat to write a follow-up, more comprehensive report on the subject. His doctorate, from the University of Oregon, is in biology and he has taught courses in immunology, endocrinology, biochemistry, brain physiology}~ nutrition and humanities at several universities and colleges.

The hormone progesterone participates in practically every physiological process, in both men and women. Its tremendous increase during pregnancy serves to stabilize the organisms, both mother and child, during that crucial time. At levels reached just before delivery, progesterone produces anesthesia and contributes to tissue elasticity. The fetus requires large amounts of glucose, and progesterone makes it possible to be provided in abundance for ideal brain growth, by promoting the mother’s ability to use fat for her own energy. It is this efficient use of fat which gives women greater long-range endurance than men. When progesterone is deficient, there tends to be hypoglycemia, often combined with obesity.

The stabilizing action of progesterone is especially visible in muscle tissue, such as the uterus, blood vessel walls, the heart, the intestines and the bladder. Less visibly, progesterone stabilizes and normalizes nervous, secretory and growth processes. Biochemically, it provides the material out of which all the other steroid hormones (such as cortisone, testosterone, estrogen and salt-regulating aldosterone) can be made as needed. Progesterone’s simple molecular structure allows it to balance either an excess or deficiency of those other hormones, even when there is a defect in their synthesis.

Many factors, including poor nutrition, climate, emotional or physical stress (even excessive running) and toxins, can cause a progesterone deficiency. Use of estrogens, birth control pills and even IUDs can also bring about a deficiency. Animal studies and clinical experience suggests that the prenatal hormonal environment (a mother’s excess of estrogen during pregnancy) can incline a person toward a deficiency of progesterone relative to estrogen.

Recent studies show that progesterone prevents stress-induced coronary blood vessel spasms in aged hearts-probably explaining women’s relative freedom from heart attacks, so long as they retain functioning ovaries. Other studies suggest that progesterone has a role in regeneration of damaged brain cells and prolonged growth of the brain. Delayed aging and longer life span have been very clearly related to extra progesterone. Many types of tumors have been prevented and helped with progesterone. Excessive blood clotting caused by excess estrogen is alleviated by progesterone. Pregnancy toxemia and tendency to miscarry or to deliver prematurely are often corrected by progesterone. When epilepsy occurs premenstrually, or first appears around puberty, it is often stopped by progesterone therapy. The hormone has been used successfully in suicidal depression, Reynaud phenomenon, Meniere’s disease, agoraphobia (especially when associated with porphyria, an abnormality of liver metabolism), Bright’s disease (a kidney disorder) and, used as a lotion, in a variety of genital skin problems in children, adults and postmenopausal women. Hot flashes and other menopause problems respond to progesterone therapy.

Since progesterone normalizes the immune system (it causes thymus regeneration, for example) it is very effective in autoimmune diseases (which result from adverse reactions to one’s own tissues) and in those degenerative disease which have an autoimmune component.

In several ways both progesterone and thyroid hormone can be considered primary regulatory hormones. Both of them regulate metabolism directly at the energetic and synthetic levels: both have a normalizing, anti-stress action on the pituitary gland; and each has a promoting action on the other. Both are blocked (and consumed) by stress and promoted by light and good nutrition. Both are nutrients in cultures that eat the whole animal, including ovaries and thyroid, butter, cream and milk contain small amounts of progesterone and shellfish seems to be a good source.

Disregarding most of the information promoted by pharmaceutical companies and the medical texts and journals which for 30 years have reflected the opinion of those companies (especially regarding the patented synthetic estrogens and glucocorticoids), we can trace a line of research and ideas on the sex hormones, from pioneers such as Loeb, Korenchevsky, and Selye, through a generation that continued to demonstrate the toxicity of estrogen, and the value of progesterone including people like Lipschutz, Dalton and Soderwall.

In my dissertation research under Soderwall, I had the opportunity to collect and assimilate data indicating an increased estrogen effect in aging animals and recently, with newer techniques, I have seen similar changes in many menopause women. My research showed that the probable mechanism by which estrogen excess causes infertility is through limiting the availability of oxygen. I showed that anti-estrogenic substances, such as progesterone or vitamin B, increased the oxygen content of the uterus. This anti-oxygen effect of estrogen suggests a convergence of reproductive aging research with Warburg’s theory that damaged respiration is the primary defect in cancer and also with Selye’s observation that estrogen’s effect resembles the first shock phase of stress reaction.

Early research had also shown that estrogen diminishes liver glycogen storage while progesterone increases both blood sugar and liver glycogen. It is well known that hypoxia (oxygen deficiency) damages the fetal brain, but probably less well known that hypoglycemia -either chronic or acute- can cause brain damage and retardation. Oxygen deficiency, by lower metabolic efficiency, will cause hypoglycemia. Estrogen causes hypoxia at every imaginable site, from lung, through vascular fibrin (clot material lining blood vessels and red cells) and extracellular collagen (a glue-like part of connective tissue) and edema, to intracellular metabolism. Estrogen is also a promoter of insulin release and action, lowering blood sugar and promoting fat synthesis. Estrogen and another common anti-oxygen material, excessive unsaturated fats (vegetable or fish oils) have both been demonstrated to cause the birth of small-brained, retarded animals. Recent studies imply that about half the children identified as hyperactive have experienced prenatal stress. The most urgent need for progesterone therapy, I think, is preventing a continuing epidemic of brain damage. Beyond that, many studies have found that the use of natural progesterone increases a child’s IQ, typically by around 35 points and produces personalities that are more “independent, individualistic, self-assured, self-sufficient and sensitive” (J.M. Reinish, The Female Patient, April, 1978, p.87).

PROGESTERONE VS. HYPOGLYCEMIA

Protection against hypoglycemia is probably the main mechanism. Diabetic mothers often have precocious children, if they aren’t damaged by drugs and irrational diets. Ten to 15 grams per pregnancy, at increasing dosage, seems to be the optimal amount, when there is some sign of excessive estrogen or unexpected toxemia. The American Medical Association Department of Drugs, which warns against certain sex hormones being used during pregnancy, has specifically excluded progesterone from those others which are “now contraindicated in early pregnancy” (Journal of the American Medical Association, 239 (3), p.236).

Hypoglycemia (which can result from any respiratory defect) can produce malfunction of any tissue, but brain dysfunction and immune dysfunction are very common effects. Adamkiewicz has shown that allergic reactions to a given substance will decrease from 100 percent to zero, when the blood glucose increases from, for example, 50 mg. to 150 mg. or more. Soviet research shows a similar involvement of blood sugar level in various “psychosomatic” ailments. Progesterone (and thyroid) will help in most allergic diseases, including the autoimmune and “collagen diseases,” because it helps to maintain blood sugar (promoting respiration and improving use of fat-sparing glucose) and also because it stabilizes lysosomes (enzyme packets in cells, which are involved in inflammation processes).

The group of enzymes known as superoxide dismutase (SOD) are probably involved in the protective effects of progesterone, since one of my assays to determine the action of estrogen turns out to be an inverse indicator of SOD-that is, progesterone would seem to turn on this protective enzyme.

Although progesterone and cortisone both raise blood sugar and stabilize lysosomes, their effect on the brain is very different. In large doses, progesterone is sedative and anesthetic, while cortisone is stimulating and causes changes in the brain, which resemble aging. An excess of cortisone also tends to elevate estrogen, which was found (in animal experiments) to interfere with memory. High estrogen traits can be acquired by environmental stress and can be passed on to offspring, as discovered by L.C. Strong in his mice, and as confirmed recently in rats that were stressed during pregnancy.

It has been observed that the ratio of brain weight to body weight corresponds directly to longevity. The brain has a nourishing, trophic influence on other tissues. A stable, efficient brain is an anti-stress agent. The hormones of stress age various tissues, including connective tissue. Good nutrition, including the anti-stress substances found in certain foods, will simultaneously optimize intelligence and increase the healthy life span. Congenital defects are increased by stress and poor nutrition during pregnancy and, conversely, reduced by good nutrition hormone supplementation and stress reduction.

An excessive estrogen/progesterone ratio is more generally involved than either a simple excess of estrogen or a deficiency of progesterone, but even this ratio is conditioned by other factors, including age, diet, other steroids, thyroid and other hormones. The relative estrogen excess seems to act by producing tissue hypoxia. Symptoms in cycling women are most common around ovulation and in the premenstrual week, when the estrogen/progesterone ratio is normally highest. The early 20’s, late 30’s and menopause are the periods when the ratio is most often disturbed. These are also the ages when thyroid disorders are commonest in women.

I have observed the use of progesterone transdermally (applied to the skin in about 400 women suffering from the full range of peri-menstrual symptoms, including migraine, acne, depression, mastalgia (breast pain), edema (water retention and swelling), and lethargy. I found that nearly all the women who apply the lotion themselves, are able to find the appropriate dosage for controlling their symptoms. Occasionally, thyroid therapy, weight reduction: or change in some aspect of lifestyle is necessary for complete relief from symptoms. When some women said the progesterone had no effect, it turned out that they were applying it as sparingly as they would a rare perfume-just touching it to their wrists.

Anesthesia (or drunkenness) from a very large overdose is the only negative side effective reported in the literature. Experimenting with very large doses of natural progesterone on myself, for migraine, I found that there is a temporary antagonism to testosterone, causing small symptoms, including a slight sense of gregariousness, an urge to socialize. However, synthetic progestins do have harmful side effects including breast tumors. Unfortunately, most physicians do not yet know the difference between natural progesterone and synthetic progestins.

At our health resort/clinic, we’re finding that most women respond dramatically to progesterone support, but don’t remain chronically dependent on it. During their stay, clients are provided specialized, indulgent care, along with progesterone and other therapies. We consider it essential, as well, to teach them the principles of maintaining optimum health through good nutrition. Results are impressive and usually permanent.

SOURCE

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By Team FPS – March 31, 2012

Dr. Raymond Peat – Thyroid Information

By Mary Shomon

Raymond Peat, Ph.D. is editor and researcher of a popular and well-known monthly newsletter on nutrition and health, as well as author of a number of cutting-edge publications that look at aging, nutrition, and hormones from a biochemical perspective. Some of the key points Dr. Peat makes are:

  • Estrogen blocks the release of hormone from the thyroid gland, and progesterone facilitates the release. Estrogen excess or progesterone deficiency tends to cause enlargement of the thyroid gland, in association with a hypothyroid state.
  • Instead of taking dietary supplements, it is far safer in general to use real foods, and to exclude foods which are poor in nutrients. For example, magnesium is typically deficient in hypothyroidism, and the safest way to get it is by using orange juice and meats, and by using epsom salts baths.
  • Men should be aware that leg cramps, insomnia and depression are often the result of hypothyroidism. Heart failure, gynecomastia, liver disease, baldness and dozens of other problems can result from hypothyroidism.
  • He considers even the lowest TSH within the “normal range” to be consistent with hypothyroidism; in good health, very little TSH is needed.
  • When too little protein, or the wrong kind of protein, is eaten, there is a stress reaction, with thyroid suppression. Many of the people who don’t respond to a thyroid supplement are simply not eating enough good protein.
  • When a person is using a thyroid supplement, it’s common to need four times as much in December as in July.

Source

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By Team FPS – March 29, 2012

Low CO2 in Hypothyroidism

Also see:
Carbon Dioxide Basics
Comparison: Oxidative Metabolism v. Glycolytic Metabolic
Promoters of Efficient v. Inefficient Metabolism
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Low CO2 in Hypothyroidism
Protective Altitude
Lactate Paradox: High Altitude and Exercise
Altitude Improves T3 Levels
Protective Carbon Dioxide, Exercise, and Performance
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Mitochondria & Mortality
Altitude and Mortality

“Low thyroid leads to low production of carbon dioxide and wastage of glucose.” -Ray Peat, PhD

“When carbon dioxide production is low, because of hypothyroidism, there will usually be some lactate entering the blood even at rest, because adrenalin and noradrenalin are produced in large amounts to compensate for hypothyroidism, and the adrenergic stimulation, besides mobilizing glucose from the glycogen stores, stimulates the production of lactate. The excess production of lactate displaces carbon dioxide from the blood, partly as a compensation for acidity. The increased impulse to breath (“ventilatory drive”) produced by adrenalin makes the problem worse, and lactate can promote the adrenergic response, in a vicious circle.” -Ray Peat, PhD

“The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes supplementation of salt and baking soda, can increase the tissue content of CO2.” -Ray Peat, PhD

“Calcitonin, vitamin D-active metabolite, and estrogen-”HRT” treaments can cause respiratory alkalosis (relative hyperventilation), and hypothyroidism produces a predisposition to hyperventilation. Hyperventilation tends to cause calcium loss. In respiratory alkalolis, CO2 (and sometimes bicarbonate) are decreased, impairing calcium retention, and in “metabolic alkalosis,” with increased bicarbonate, calcium is retained more efficiently and bone formation is stimulated, and its dissolution is suppressed.” -Ray Peat, PhD

Can J Anaesth. 1999 Feb;46(2):185-9.
Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism.
Lee HT, Levine M.
PURPOSE:
Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence of perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other physiological derangements. The previously described physiological basis for the increased incidence of postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral ventilatory responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and resultant alveolar hypoventilation. These ventilatory failures are associated most frequently with severe hypoxia and carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting and unique anesthetic presentation of a patient with severe hypothyroidism.
CLINICAL FEATURES:
We describe an unique presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had exceedingly low perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time developed primary acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 mmHg).
CONCLUSION:
Our patient’s ventilatory failure was based on unacceptably low minute ventilation and respiratory rate that was unable to sustain adequate oxygenation. His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation.

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By Team FPS – March 27, 2012