Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.

8f4

Hello all,

I posted this question in the "Ray Peat X" community on twitter, but it's a bit dead, so I'm going to re-post the question here:

"I'm trying to look into Peat's claim about estrogen, progesterone, and their effects on the heart. His claim (in the attached picture) is referencing a study by Szent-Gyorgyi that I can't find, and I've tried looking around.

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The rest of the article is fine, the estrogen and negative ino- and lusitropic effects on the heart are correct, but the argument that progesterone is positively ino- and lusitropic is something I can't find in contemporary literature, other than some niche cases.

Here are the studies/books I've reviewed, with a summary of each.

(Sitzler et al., 1996 + Filice et al., 2011) Negative ino- and lusitropy of estrogen on the heart (human)

(CSAPO & CORNER, 1952) Estrogen builds the staircase effect in uterus, progesterone doesn't (rabbit)

(Rubin & Salter, 1952) Progesterone exhibits small negative inotropy (cat, guinea pig, frog)

(Cheng et al., 2012) Progesterone accelerates repolarization and protects against drug-induced proarrhythmic effects (rabbit)

(Hajdu & Szent-Gyorgyi, 1952) This was the text I thought Peat was citing, although no examination of sex hormones was done (frog)️

(CHEMICAL PHYSIOLOGY OF CONTRACTION IN BODY AND HEART MUSCLE, Szent-Gyorgyi, 1953) Negative staircase effect of progesterone (frog)

Obviously, progesterone inhibiting the staircase effect in the uterus is expected and desired, but in the heart, it seems to also exhibit at least a small amount of inhibition.

Maybe I'm misunderstanding the statement, but I can't find any papers talking about positive lusi- or inotropic effects of prog. I can't find the study by Szent-Gyorgi on RABBIT heart with progesterone and estrogen, only uterine studies. Plz anyone halp.

Bibliography:

Cheng, J., Zhang, J., Ma, X., & Su, D. (2012). Frequency-dependent acceleration of cardiac repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic effects in female rabbits. European Journal of Pharmacology, 689(1–3), 172–178. https://doi.org/10.1016/j.ejphar.2012.05.052
CSAPO, A. I., & CORNER, G. W. (1952). THE ANTAGONISTIC EFFECTS OF ESTROGEN AND PROGESTERONE ON THE STAIRCASE PHENOMENON IN UTERINE MUSCLE. Endocrinology, 51(5), 378–385. https://doi.org/10.1210/endo-51-5-378
Filice, E., Angelone, T., De Francesco, E. M., Pellegrino, D., Maggiolini, M., & Cerra, M. C. (2011). Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart. Cellular Physiology and Biochemistry, 28(1), 41–52. https://doi.org/10.1159/000331712
Hajdu, S., & Szent-Gyorgyi, A. (1952). Action of DOC and serum on the frog heart. The American Journal of Physiology, 168(1), 159–170. https://doi.org/10.1152/ajplegacy.1951.168.1.159
Rubin, B., & Salter, W. T. (1952). THE EFFECTS OF PROGESTERONE AND SOME RELATED STEROIDS ON THE CONTRACTION OF ISOLATED MYOCARDIUM. The Journal of Pharmacology and Experimental Therapeutics, 105(4), 443–449. https://doi.org/10.1016/S0022-3565(25)05095-5
Sitzler, G., Lenz, O., Kilter, H., La Rosee, K., & Böhm, M. (1996). Investigation of the negative inotropic effects of 17β-oestradiol in human isolated myocardial tissues. British Journal of Pharmacology, 119(1), 43–48. https://doi.org/10.1111/j.1476-5381.1996.tb15675.x"

ThinPicking

Inferred from effect on intracellular ca and somewhat known similarity between smol critters and failing hearts?

https://doi.org/10.1016/j.hlc.2004.08.006

What's that story about the frog that turned in to a prince from a shock, later revised to a loving act. (Sorry I'm like this.)

@8f4 said in Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.:

Maybe I'm misunderstanding the statement

You're not, in my opinion.

I posted this question in the "Ray Peat X" community on twitter, but it's a bit dead

Maybe you could start a fire.

I'm trying to look into Peat's claim about estrogen, progesterone, and their effects on the heart.

Why? And what is 8f4. Are you a microbiologist? (ff to decline.)

Homo_normalis

@8f4 I also couldn't find this study. Is it possible Ray was in correspondence with ASG and this was an unpublished work? I also couldn't find a similar study via a Selye search (under the theory that Ray typoed the wrong Hungarian).

It wouldn't surprise me if Szent-Gyorgyi and Selye hypothesized and/or tested this together as the idea would be a combination of parts of each's philosophy. But again, no evidence. I couldn't fund anything in the Selye's In Vivo book for which ASG wrote a forward.

Homo_normalis

@Homo_normalis Another good candidate could be the book "Chemical Physiology of Contraction in Body and Heart Muscle" 1953. I can't get access to it. Maybe someone else has it and can search?

ThinPicking

@Homo_normalis said in Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.:

under the theory that Ray typoed the wrong Hungarian

Not the only "typo" on that site.

8f4

@Homo_normalis Hello, thanks for the reply. I also had access to this book, and examined it, however this was earlier in ASG's work on muscle contraction, and so he didn't get around to testing this exact hypothesis, of heart muscle contraction under the influence of sex hormones.

I think this will just be one of the few unsolved mysteries of Ray's work, haha

8f4

@Homo_normalis said in Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.:

@8f4 I also couldn't find this study. Is it possible Ray was in correspondence with ASG and this was an unpublished work? I also couldn't find a similar study via a Selye search (under the theory that Ray typoed the wrong Hungarian).

It wouldn't surprise me if Szent-Gyorgyi and Selye hypothesized and/or tested this together as the idea would be a combination of parts of each's philosophy. But again, no evidence. I couldn't fund anything in the Selye's In Vivo book for which ASG wrote a forward.

This is possible, and a good theory. I wish we had access to anything concrete.

Homo_normalis

@8f4 said in Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.:

@Homo_normalis Hello, thanks for the reply. I also had access to this book, and examined it, however this was earlier in ASG's work on muscle contraction, and so he didn't get around to testing this exact hypothesis, of heart muscle contraction under the influence of sex hormones.

I think this will just be one of the few unsolved mysteries of Ray's work, haha

Interesting. I thought that might be the one! The funny thing is, that one quote you cited is not the only time Peat said that. When trying to find the citation in his works I noticed he repeated this claim many times, including in more than one of his books.

Here's a possible lead. It's from Nutrition for Women. "Digitalis and progesterone have very similar effects on the heart (Szent-Gyorgyi, Muscle Contraction)." I can't make sense out of this. That's not 1947 Chemistry of Muscular Contraction, and as you say it's also not 1953 Chemical Physiology of Contraction in Body and Heart Muscle. There are other quotes from Peat saying the impetus for the Szent-Gyorgyi study was in fact Selye's mid-1940s work. So I would have thought it might be in this earlier era.

I'll try to remember to post back here if I ever find an answer.

LucH

@8f4 said in Trying to understand the cardiac staircase effect, and the role of estrogen and progesterone in relation.:

"I'm trying to look into Peat's claim about estrogen, progesterone, and their effects on the heart.

Extract from “Nutrition for Women" I made a search with "heart" and stop when RP was speaking about heart, estrogen and progesterone.

&. Menaupausal flushing (p 41 of the PDF).
I have talked to several women in their 20s who complained of sensations of heat around their heads, night sweats, sudden flushing, and other symptoms that are associated with the menopause, Katharina Dalton has found that premenstrual symptoms, which result from a relative estrogen surplus and a progesterone deficiency, otten continue during the menopause. Silteri and his group have discovered that one of the steroids (androstenedione, usually associated with the male hormones) is converted to a form of estrogen at an increasing rate as a person gets older, at all ages they studied, from 20 to 80, in both men and women. Strickler found that only 10% Of his patients with menopausal symptoms such as flushing, could feel and benefit from estrogen when it was alternated with a placebo.
These studies, and a few dozen others, have convinced me that the symptoms of menopause result mainly from a progesterone deficiency, relative to the estrogens. The 10% who really feel better from estrogen possibly have an estrogen deficiency, but this has not been determined, and several other things could account for the "lift" they feel - for example, a healthy thyroid gland will respond to elevated estrogen with an increased output of thyroxin, which at least would make the person feel different, and might raise blood sugar, increase alertness, etc.
In 1979 menopausal flushing was found to be associated with an elevation of the pituitary hormone, LH. A lack of progesterone is known to cause a rise in LH. Digitalis and progesterone have very similar effects on the heart (Szent-Gyorgyi, Muscle Contraction). Digitalis is able to raise blood pressure and increase urine production, apparently by increasing the tone of the arterioles (Abram,
1910). If progesterone's effect on muscle includes such an effect on arterioles, then the " puzzle" of menopausal – and premenopausal - flushing is no puzzle, but is merely one symptom of a progesterone deficiency relative to estrogen.
Progesterone does have a diuretic effect, but this has been attributed to an antagonism to aldosterone, rather than to an effect on arterioles.
Besides the nutrients needed to regulate the estrogen level (protein and B vitamins) and nutrients needed by the thyroid (e.g., iodine, manganese, and cobalt), special attention should be given to the anti-stress vitamins which are involved in progesterone synthesis (vitamin A, pantothenic acid, vitamin C, vitamin E) and to the nutrients that are known to be "wasted" by excess estrogen: folic acid, zinc, and vitamin B6, particularly. Vitamin B6 is needed to synthesize materials that regulate blood vessel tone and that act as brain modulators, governing sleep, emotions, alertness. etc.
Memory of dreams is said to be promoted by adequate B6 (Pfeiffer, 1975). White marks on the fingernails, especially of the right hand, are suggestive of a zinc deficiency. Brittle fingernails are likely to result from too much estrogen. Or inhibited thyroid function; vitamin A and eggs are useful, but calcium and gelatin are not. Magnesium carbonate is very useful for stabilizing nerves and muscles while raising the energy Jevel: one gram a day of magnesium is a reasonable amount. but many tablets now contain only 15 to 50 mgs.

Dalton, K., The Premenstrual Syndrome, C. Thomas. Springfield, III. , & London, 1964.
Hemsell, et aI. , Plasma precursors of estrogen. II. Correlation of the extent and conversion of plasma androstenedione to estrone with age, J. Clin. Endocrino'. Matab. 38, p. 476, 1974.
Grodin. et al., Source of estrogen production in postmenopausal women, J. Clin. Endocrinol Matab 36. p. 207, 1973.
Strickler. Contemporary Obl Gyn, August, 1976.
Mulleyand Mitchell , Lancet, June 26,1976, p. 1397, " Is estrogen therapy justified in menopausal flushing?"
C.C. Pfeiffer, Mental and Elemental Nutrients. Keats Pub!. Co., 1975.

LucH

Postulate:
The symptoms of menopause result mainly from a progesterone deficiency, relative to the estrogens.
=> Search with: Szent-Gyorgyi actin-myosin and excess +estrogen
Talk with ChatGPT
Estrogen hormones are implicated in influencing skeletal muscle contractile function and specifically, the interactions between myosin and actin that facilitate contraction.
Question
How the unbalance between progesterone and an excess estrogen can contribute to a weakness or a deficiency in heart rate. Make a link with Szent-Gyorgyi.
Target the impact of estrogens on heart health.
Please take time to answer and develop.

See summary at the end to see if it’s accurate / pertinent…

ChatGPT
This is a nuanced and important question that bridges endocrinology, muscle physiology, and cardiology. Let's break it down thoroughly.

Estrogen and Progesterone: Hormonal Balance and Cardiovascular Function
Estrogen and progesterone are steroid hormones primarily known for regulating the female reproductive system, but they also exert significant effects on other tissues, including the cardiovascular system and skeletal/cardiac muscle.
Estrogen has cardioprotective effects when balanced, such as improving endothelial function, increasing nitric oxide availability, and modulating lipid metabolism.
Progesterone has more modulatory roles; it can counterbalance estrogen’s effects, especially on smooth muscle and certain ion channels in cardiac tissues.
An imbalance—specifically excess estrogen relative to progesterone (commonly referred to as estrogen dominance)—can lead to dysfunction in various tissues, including the heart, by disrupting calcium signaling, promoting inflammation, and affecting myocyte contractility.
Estrogen's Impact on Cardiac Muscle and Heart Rate Regulation
Cardiac muscle contraction, like skeletal muscle, depends on myosin-actin cross-bridge cycling, which is tightly regulated by calcium dynamics. Estrogens influence this contractile mechanism at several levels:
Gene expression of contractile proteins: Estrogens modulate the transcription of myosin heavy chains (MHCs) and troponins, which affect the speed and force of contraction.
Calcium homeostasis: Estrogens affect the expression of L-type calcium channels, SERCA pumps, and phospholamban, which are critical in cardiac excitation-contraction coupling.
Electrophysiological effects: Estrogens can prolong the QT interval by affecting potassium channels, potentially slowing repolarization and contributing to arrhythmias or heart rate irregularities.
Too much estrogen, without progesterone's counter-regulation, may impair the timing and strength of cardiac contractions, leading to symptoms such as:
Bradycardia (slowed heart rate)
Palpitations
Exercise intolerance
General fatigue or weakness, especially during exertion
Link to Szent-Györgyi’s Work: Actin-Myosin Interactions
Albert Szent-Györgyi, Nobel laureate, is best known for his work in muscle contraction mechanisms, especially the discovery that myosin and actin interactions require ATP and are regulated by calcium.
He helped establish that contraction strength and velocity are tightly tied to the availability of calcium ions, which modulate the binding between actin and myosin.
Estrogen excess alters intracellular calcium handling, potentially dampening contractile efficiency, not just in skeletal muscle but also in cardiac muscle.
Thus, from a Szent-Györgyi-inspired perspective:
If estrogen disrupts calcium fluxes and the phosphorylation states of key contractile proteins, the cross-bridge cycling between actin and myosin becomes less efficient, potentially resulting in weaker cardiac output and slower or irregular heart rate.
Progesterone's Modulating Role and Its Deficiency
While estrogen tends to enhance excitatory functions (e.g., increase nitric oxide, vasodilation, etc.), progesterone stabilizes membranes, opposes estrogen-induced proliferation, and modulates ion channel activity.
Progesterone deficiency in the presence of high estrogen can:
Increase inflammatory cytokines
Promote fibrosis or structural remodeling in cardiac tissue
Increase arrhythmia susceptibility due to unstable ion channel function
Hence, estrogen dominance may result in weakened myocardial contraction and poor regulation of heart rhythm.
5. Clinical and Experimental Evidence
Women often experience cardiovascular changes across the menstrual cycle and especially during perimenopause and menopause, when estrogen and progesterone levels fluctuate dramatically.
Hormone Replacement Therapy (HRT) studies show that unopposed estrogen may increase cardiovascular risk, while combined estrogen-progesterone therapy appears more protective.
Animal studies have shown that estrogen modulates cardiac myocyte electrophysiology and contractility, with significant sex differences in cardiac response to stress.
Conclusion:
An excess of estrogen relative to progesterone can disrupt the delicate orchestration of cardiac muscle contraction by:
Impairing calcium handling
Modifying actin-myosin interaction efficiency
Altering ion channel function and gene expression
Leading to weaker contractile force and heart rate abnormalities
Drawing from Szent-Györgyi’s foundational insights, we understand that efficient muscle contraction depends on calcium-regulated actin-myosin dynamics. Estrogen excess undermines this efficiency, particularly when progesterone’s stabilizing influence is absent, contributing to cardiac weakness or rate irregularities.
Would you like references or a visual diagram summarizing these pathways?

LucH
Yes.

ChatGPT
Thank you for your thoughtful question. Let's delve deeper into the intricate relationship between hormonal imbalances—specifically excess estrogen relative to progesterone—and their impact on heart rate and muscle function, drawing insights from Albert Szent-Györgyi's pioneering work.
Hormonal Imbalance: Estrogen Dominance and Its Cardiovascular Implications
Estrogen plays a pivotal role in cardiovascular health by:
• Enhancing endothelial function, leading to improved blood vessel dilation.
• Modulating calcium handling in cardiac cells, crucial for muscle contraction and relaxation.
• Influencing ion channels that affect heart rhythm and contractility.
Progesterone, in contrast, serves to:
• Counterbalance estrogen's effects, ensuring a harmonious hormonal environment.
• Stabilize cardiac function, particularly during the luteal phase of the menstrual cycle.
An imbalance, characterized by estrogen dominance, can disrupt these processes, leading to:
• Altered calcium dynamics, affecting muscle function and heart rate.
• Increased risk of arrhythmias due to changes in ion channel activity.
• Elevated blood pressure and potential development of cardiovascular diseases.

Szent-Györgyi's Contribution: Actin-Myosin Interactions and Muscle Contraction
Albert Szent-Györgyi's groundbreaking research laid the foundation for understanding muscle contraction mechanisms. His work, particularly in collaboration with Ilona Banga, led to the discovery of actomyosin, the complex responsible for muscle contraction. They elucidated how ATP hydrolysis drives the interaction between actin and myosin, facilitating muscle shortening.
These insights are crucial when considering how hormonal imbalances affect muscle function. Disruptions in calcium handling, influenced by estrogen levels, can impair the actin-myosin interaction, leading to:
• Reduced contractile strength in cardiac and skeletal muscles.
• Slower heart rate due to diminished myocardial contractility.
• Increased fatigue and exercise intolerance.

Estrogen's Impact on Calcium Handling and Heart Rate
Estrogen influences several key proteins involved in calcium handling within cardiac cells:
• L-type calcium channels: Modulate calcium entry during action potentials.
• Ryanodine receptors: Release calcium from the sarcoplasmic reticulum.
• SERCA pumps: Reuptake calcium into the sarcoplasmic reticulum during relaxation.
• Sodium-calcium exchangers: Extrude calcium from the cell.
An imbalance in estrogen levels can lead to:
• Impaired calcium reuptake, resulting in prolonged contraction and impaired relaxation.
• Altered ion channel activity, increasing susceptibility to arrhythmias.
• Dysregulated heart rate, manifesting as palpitations or bradycardia.

Clinical Observations and Hormonal Fluctuations
Clinical studies have observed that:
• Menopausal women often experience heart palpitations and increased heart rate variability, correlating with fluctuating estrogen levels.
• Estrogen therapy has been shown to improve myocardial relaxation and normalize calcium handling, suggesting a protective role against cardiovascular dysfunction.
• Progesterone deficiency, often accompanying estrogen dominance, exacerbates these effects, highlighting the importance of hormonal balance.

Integrating Szent-Györgyi's Insights
Szent-Györgyi's research underscores the importance of calcium-mediated actin-myosin interactions in muscle function. Estrogen's role in regulating calcium handling aligns with these principles, indicating that hormonal imbalances can disrupt the fundamental processes of muscle contraction and relaxation, leading to:
• Weakened cardiac output.
• Altered heart rate.
• Increased risk of cardiovascular events.

Conclusion
An imbalance between estrogen and progesterone, particularly estrogen dominance, can significantly impact heart rate and muscle function by disrupting calcium handling and actin-myosin interactions. Drawing from Szent-Györgyi's foundational work, we understand that these hormonal disruptions can lead to weakened muscle contractions, slower heart rates, and increased cardiovascular risks.
If you require further information or references on this topic, feel free to ask.