Cyproheptadine Is An Estrogen Antagonist, May Treat Breast Cancer

haidut

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Ray wrote in some of his articles that estrogen mediates its effects through histamine and the cholinergic system, so anti-histamines and anti-cholinergic drugs can block estrogen's effects. Well, cyproheptadine is both an anti-histamine and an anti-cholinergic so it is not surprising to find that it has a functional anti-estrogen effects. However, this study goes a step further by discovering that cyprohetadine has an effect of downregulating directly the ERa "receptor". So, in effect, cyproheptadine is a direct estrogen antagonist in addition to its functional estrogen antagonism. Furthermore, cyproheptadine accelerated the actual degradation of the estrogen receptor, similar to the effects of progesterone and caffeine I have posted abotu in the past. The estrogen antagonistic effects of cyproheptadine found in this study was independent of its anti-histamine and anti-serotonin properties.
Finally, as is to be expected of any estrogen antagonist, cyproheptadine displayed effectiveness in treating breast cancer. Given the other recent post I did about bromocriptine and breast cancer, I think the combination of the two drugs may be even more effective, due to complenentary mechanisms of both drugs.
The HED for cyproheptadine for treating breast cancer was on the high end (1.5mg/kg daily) but this is very similar to the doses used for bromocriptine and likely still safe. Also, even a single administration of cyproheptadine caused tumor regression, so given its relatively long half-life I suspect that even as little as taking ti 2-3 times weekly will have profound anti-cancer effects, especially in combination with bromocriptine.

Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent T... - PubMed - NCBI

"...Set7/9-mediated methylation of Lys302 of ERα is involved in the stabilization of ERα. 7 We therefore examined the effect of cyproheptadine on the expression of ERα in human breast cancer cells expressing endogenous ERα (MCF7 cells). As shown in Figure 3A−C, cyproheptadine, as well as Set7/9 knockdown, reduced the amount of ERα in a dose- and time-dependent manner. The level of ERα mRNA expression was almost identical between control and cyproheptadine treated MCF7 cells (Figure 3D). In agreement with a previous report,7 these results suggest that the inhibition of Set7/9 by cyproheptadine destabilizes ERα."

"...Next, we determined the half-life of ERα in cyproheptadinetreated MCF7 cells by using cycloheximide (CHX), an inhibitor of protein synthesis. The half-life of ERα in the absence of cyproheptadine was 15.6 ± 1.2 h, whereas it was 10.3 ± 1.0 h in drug-treated cells (Figure 3E), indicating that treatment with cyproheptadine accelerated the degradation of ERα."

"...The reduced ERα expression in the presence of cyproheptadine was restored by treatment with Z-Leu-Leu-Leu-al (MG132), a proteasome inhibitor (Figure 3F). Taken together, we conclude that cyproheptadine induces the destabilization of ERα through enhanced degradation of ERα by the proteasome. Cyproheptadine is an antagonist to both H1 and 5-HT2A. To rule out the possibility that the destabilization of ERα was due to cyproheptadine’s other antagonistic activities, we examined the effect of structurally unrelated antagonists on ERα expression. Treatment with triprolidine, a histamine antagonist (Supporting Information Figure S3A), or ketanserin, a serotonin antagonist (Supporting Information Figure S3B), did not affect the expression of ERα in MCF7 cells (Supporting Information Figure S3C and Figure S3D). Consistent with this, both antagonists did not inhibit Set7/9 (Supporting Information Figure S3E). These results demonstrate that cyproheptadine promotes ERα degradation through a mechanism distinct from its activity against H1 and 5-HT2A."

"...ERα regulates the transcription of specific target genes, such as pS2, by binding to the cognate estrogen responsive element (ERE) in response to estrogen. Because the expression of ERα was decreased in cyproheptadine-treated MCF7 cells (Figure 3), we examined whether cyproheptadine affected estrogen-induced transcriptional activation. Treatment with cyproheptadine for 48 h, as well as tamoxifen, an antagonist of ERα, inhibited ERE-dependent promoter activation and the increase of pS2 mRNA expression normally induced by β-estradiol (Figure 4A and Figure 4B). Moreover, cyproheptadine inhibited estrogen-dependent cell viability in MCF7 cells (Figure 5A), having a dose dependency similar to its inhibition of ERα protein expression and ERα-dependent transcription (Figures 3A and 4A). In conclusion, the ability of cyproheptadine to inhibit in vitro enzymatic activity coincided with its ability to suppress estrogen signaling in cells. Finally, we tested the in vivo antitumor activity of cyproheptadine by mouse xenograft model using fluorescent ubiquitination-based cell cycle indicator (Fucci) introduced human breast cancer MCF7 cells, as Fucci-MCF7 cell lines xenografted in nude mice can grow.19 Both single and continuous intraperitoneal administrations of cyproheptadine significantly inhibited the growth of FucciMCF7 tumors in nude mice (Figure 5B). Although continuous intraperitoneal administration of cyproheptadine slightly but significantly affected the body weights of xenografted mice, this decrease was recovered after continuous treatment with cyproheptadine for 8 days (Figure 5C). In addition, single intraperitoneal administration of cyproheptadine decreased tumor volumes without affecting the body weights of xenografted mice. These observations suggest that the effect of cyproheptadine on inhibition of tumor growth in xenografted mice is distinct from its potential toxicity."
 

Saracatt

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Does cyproheptadine cause drowsiness? I have been getting some good results from Benadryl, but I can only take it at night because it puts me to sleep.
 

Koveras

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Does cyproheptadine cause drowsiness? I have been getting some good results from Benadryl, but I can only take it at night because it puts me to sleep.

Yes, quite strong - probably more so than benadryl when you're unaccustomed to it.

Many with GI issues take cyproheptadine 3x daily though so there is probably some tolerance to the sedating effects that develops.
 

Saracatt

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Thanks. It might not be the thing for me then. At least during the day.

The benadryl really does improve my mood the day after I take it though.
 

superhuman

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Maybe i need to jump on that cypro wagon for a bit since im on thyroid, high caffeine and all that jazz but nothing raises my temp and pulse or reduces my water retention.
 

scarlettsmum

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I'm doing cypro at the moment, 1mg in the evening and so far feel pretty good. But I am more tired during the day around noon till 3pm usually, even though I go to bed at 10 and have a good nights sleep. What I like about it the most is that I don't feel any sudden effect like with ritanserin which would bring along anxiety. The fatigue comes nice and slowly.
 

paper_clips43

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Do you think Cypro could still be effective at treating breast cancer for someone who is on birth control and has been for almost 20 years?
 

haidut

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Do you think Cypro could still be effective at treating breast cancer for someone who is on birth control and has been for almost 20 years?

I can't answer direct questions like that. This is what the study above is for. And you can search the forum for "bromocriptine breast cancer" for more info.
 
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I wonder if this applies to men and prostate cancer. Seems that prostate cancer shares a lot of similarities to breast cancer (which men also get)
 

haidut

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I wonder if this applies to men and prostate cancer. Seems that prostate cancer shares a lot of similarities to breast cancer (which men also get)

Oh, absolutely. Anything anti-estrogenic should help.
 

sugarbabe

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It definitely has an effect on sex hormones!!! I took it the longest I have ever took it almost everyday for a month at about .5mg or less. I just had a long cycle, I had to stop the cypro and use ascorbic acid and parsley tea to get my period to come. (came the day after that).
 

ddjd

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Ray wrote in some of his articles that estrogen mediates its effects through histamine and the cholinergic system, so anti-histamines and anti-cholinergic drugs can block estrogen's effects. Well, cyproheptadine is both an anti-histamine and an anti-cholinergic so it is not surprising to find that it has a functional anti-estrogen effects. However, this study goes a step further by discovering that cyprohetadine has an effect of downregulating directly the ERa "receptor". So, in effect, cyproheptadine is a direct estrogen antagonist in addition to its functional estrogen antagonism. Furthermore, cyproheptadine accelerated the actual degradation of the estrogen receptor, similar to the effects of progesterone and caffeine I have posted abotu in the past. The estrogen antagonistic effects of cyproheptadine found in this study was independent of its anti-histamine and anti-serotonin properties.
Finally, as is to be expected of any estrogen antagonist, cyproheptadine displayed effectiveness in treating breast cancer. Given the other recent post I did about bromocriptine and breast cancer, I think the combination of the two drugs may be even more effective, due to complenentary mechanisms of both drugs.
The HED for cyproheptadine for treating breast cancer was on the high end (1.5mg/kg daily) but this is very similar to the doses used for bromocriptine and likely still safe. Also, even a single administration of cyproheptadine caused tumor regression, so given its relatively long half-life I suspect that even as little as taking ti 2-3 times weekly will have profound anti-cancer effects, especially in combination with bromocriptine.

Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent T... - PubMed - NCBI

"...Set7/9-mediated methylation of Lys302 of ERα is involved in the stabilization of ERα. 7 We therefore examined the effect of cyproheptadine on the expression of ERα in human breast cancer cells expressing endogenous ERα (MCF7 cells). As shown in Figure 3A−C, cyproheptadine, as well as Set7/9 knockdown, reduced the amount of ERα in a dose- and time-dependent manner. The level of ERα mRNA expression was almost identical between control and cyproheptadine treated MCF7 cells (Figure 3D). In agreement with a previous report,7 these results suggest that the inhibition of Set7/9 by cyproheptadine destabilizes ERα."

"...Next, we determined the half-life of ERα in cyproheptadinetreated MCF7 cells by using cycloheximide (CHX), an inhibitor of protein synthesis. The half-life of ERα in the absence of cyproheptadine was 15.6 ± 1.2 h, whereas it was 10.3 ± 1.0 h in drug-treated cells (Figure 3E), indicating that treatment with cyproheptadine accelerated the degradation of ERα."

"...The reduced ERα expression in the presence of cyproheptadine was restored by treatment with Z-Leu-Leu-Leu-al (MG132), a proteasome inhibitor (Figure 3F). Taken together, we conclude that cyproheptadine induces the destabilization of ERα through enhanced degradation of ERα by the proteasome. Cyproheptadine is an antagonist to both H1 and 5-HT2A. To rule out the possibility that the destabilization of ERα was due to cyproheptadine’s other antagonistic activities, we examined the effect of structurally unrelated antagonists on ERα expression. Treatment with triprolidine, a histamine antagonist (Supporting Information Figure S3A), or ketanserin, a serotonin antagonist (Supporting Information Figure S3B), did not affect the expression of ERα in MCF7 cells (Supporting Information Figure S3C and Figure S3D). Consistent with this, both antagonists did not inhibit Set7/9 (Supporting Information Figure S3E). These results demonstrate that cyproheptadine promotes ERα degradation through a mechanism distinct from its activity against H1 and 5-HT2A."

"...ERα regulates the transcription of specific target genes, such as pS2, by binding to the cognate estrogen responsive element (ERE) in response to estrogen. Because the expression of ERα was decreased in cyproheptadine-treated MCF7 cells (Figure 3), we examined whether cyproheptadine affected estrogen-induced transcriptional activation. Treatment with cyproheptadine for 48 h, as well as tamoxifen, an antagonist of ERα, inhibited ERE-dependent promoter activation and the increase of pS2 mRNA expression normally induced by β-estradiol (Figure 4A and Figure 4B). Moreover, cyproheptadine inhibited estrogen-dependent cell viability in MCF7 cells (Figure 5A), having a dose dependency similar to its inhibition of ERα protein expression and ERα-dependent transcription (Figures 3A and 4A). In conclusion, the ability of cyproheptadine to inhibit in vitro enzymatic activity coincided with its ability to suppress estrogen signaling in cells. Finally, we tested the in vivo antitumor activity of cyproheptadine by mouse xenograft model using fluorescent ubiquitination-based cell cycle indicator (Fucci) introduced human breast cancer MCF7 cells, as Fucci-MCF7 cell lines xenografted in nude mice can grow.19 Both single and continuous intraperitoneal administrations of cyproheptadine significantly inhibited the growth of FucciMCF7 tumors in nude mice (Figure 5B). Although continuous intraperitoneal administration of cyproheptadine slightly but significantly affected the body weights of xenografted mice, this decrease was recovered after continuous treatment with cyproheptadine for 8 days (Figure 5C). In addition, single intraperitoneal administration of cyproheptadine decreased tumor volumes without affecting the body weights of xenografted mice. These observations suggest that the effect of cyproheptadine on inhibition of tumor growth in xenografted mice is distinct from its potential toxicity."
Hi haidut. Question about Cortisol/Estrogen.

I notice cyproheptadine gives me a very bloated belly the morning after I've taken it and had an amazing sleep of course. But I know cypro blocks cortisol and Histamine, so I've always thought my bloated/ sticking out belly was related to high Estrogen or cortisol.

But you're saying here cypro reduces estrogen.

I'm intrigued because your gonadin product along with things like b2r5p, which I think work because they reduce estrogen, completely flatten my big belly.

So is the belly thing to do with Estrogen or cortisol. Or is it something else? I'm not sure whether cypro does reduce estrogen really... At least not in the same way gonadin does

One way would be to try an aromatase inhibitor and see what effect that has!
 

Sonybaloney

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Hi haidut. Question about Cortisol/Estrogen.

I notice cyproheptadine gives me a very bloated belly the morning after I've taken it and had an amazing sleep of course. But I know cypro blocks cortisol and Histamine, so I've always thought my bloated/ sticking out belly was related to high Estrogen or cortisol.

But you're saying here cypro reduces estrogen.

I'm intrigued because your gonadin product along with things like b2r5p, which I think work because they reduce estrogen, completely flatten my big belly.

So is the belly thing to do with Estrogen or cortisol. Or is it something else? I'm not sure whether cypro does reduce estrogen really... At least not in the same way gonadin does

One way would be to try an aromatase inhibitor and see what effect that has!

BUMP

I want to know this too. I've read so much on the forum, but I'm still at a loss about the bloating and whether it's cortisol/estrogen. Also, is gonadin ok for women?
 

ddjd

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BUMP

I want to know this too. I've read so much on the forum, but I'm still at a loss about the bloating and whether it's cortisol/estrogen. Also, is gonadin ok for women?
After more experimentation, the bloated/ pregnant look is due to high cortisol. Cortisol raises estrogen but the problem is more directly due to high cortisol. Gonadin is fantastic at reducing cortisol. Whereas Androsterone is more anti Estrogen. Gonadin works every time for me. Not sure about the female issue but can't see why it would be a problem
 

Diokine

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My understanding is that bloating is from reduced sympathetic (adrenergic) drive, which is primarily due to reduced dopaminergic tone or hypothyroidism, or alternatively adrenergic "receptor" fatigue which is sometimes mediated in an "autoimmune" fashion. I think it could be considered similar to "asthma" of the thorax. Mechanical disturbances of the thoracic splanchnic nerves, along with cholinergic hyperactivity, are very common and contribute to the issue. Cyproheptadine antagonizes histamine "receptors," which are critical for proper autonomic feedback, and can reduce sympathetic drive.

Foam rolling of the spine along with deep breaths that stretch the diaphragm are very helpful.

""
 

A. squamosa

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What is the largest amount of cyproheptadine a person can safely take?

I have been taking 1 gram of it at night for almost a week, and while I can tell it has an impact on my stress hormones, I am still waking up at night, waking in the morning puffy-eyed, and having abnormal bowel symptoms.
 

Nebula

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What is the largest amount of cyproheptadine a person can safely take?

I have been taking 1 gram of it at night for almost a week, and while I can tell it has an impact on my stress hormones, I am still waking up at night, waking in the morning puffy-eyed, and having abnormal bowel symptoms.

I'd consider adding other stress hormone lowering and prometabolic things first in addition to a low amount of cypro. I've had much more potent destressing effects from it when I also supplement some progesterone, sodium, B6 and magnesium.

Cypro on its own only seems to block the effects of some stresses but doesn't necessarily make up for a lack of youth and thyroid hormones or a lack of important vitamins and minerals.
 
Last edited:

haidut

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What is the largest amount of cyproheptadine a person can safely take?

I have been taking 1 gram of it at night for almost a week, and while I can tell it has an impact on my stress hormones, I am still waking up at night, waking in the morning puffy-eyed, and having abnormal bowel symptoms.

You are taking 1 gram or 1 milligram? I highly doubt you are taking 1 gram, that would be highly toxic. Humans studies have used up to 32mg daily for severe cases of Cushing syndrome but even that dose is excessive. The regularly sold dose of 4mg per pop is probably more than enough for most people.
 
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