Pregnenolone Stimulates The Thyroid

[haidut]

Hi everybody, and @haidut,

I found it very interesting that PCN/"preg" could potentialy stimulate the thyroid. The study you posted pointed to that and said it resulted " from alteration of the peripheral metabolism of thyroxin."
I was interested and have been doing some reading and found this other study, wich makes me frustrated really. According to this study, and if understood it correctly, the stimulation would actually come from PCN/"preg" lowering T4 and subsequent excessive stimulation of the thyroid and production of TSH leading to Neoplasia(Tumor).
Frustrated, Not what I was hoping to find.. Maybe I got something wrong, I would like to hear what you guys think, @haidut ?

Thank you.

link to the full text : Promotion of Thyroid Tumors in Rats by Pregnenolone-16α-Carbonitrile (PCN) and Polychlorinated Biphenyl (PCB) | Toxicological Sciences | Oxford Academic

Promotion of Thyroid Tumors in Rats by Pregnenolone-16α-Carbonitrile (PCN) and Polychlorinated Biphenyl (PCB)
Promotion of Thyroid Tumors in Rats by Pregnenolone-16α-Carbonitrile (PCN) and Polychlorinated Biphenyl (PCB) | Toxicological Sciences | Oxford Academic
Published:

16 June 2004

Abstract
Pregnenolone-16α-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum thyroid hormone levels in rats, but only PCN consistently produces an increase in serum thyrotropin (TSH). PCN-mediated increases in TSH result in increased thyroid follicular cell proliferation and hyperplasia, which may represent early events on a morphological continuum leading to neoplasia. The purpose of this study was to assess whether PCN, a compound that increases serum TSH, and PCB, which does not increase TSH, promote thyroid tumors in a two-stage carcinogenesis model. Male SD rats were administered the thyroid tumor initiator diisopropanolnitrosamine (2.5 g/kg, sc), and after seven days were fed control diet, diet containing 1000 ppm PCN, or diet containing 100 ppm PCB for 19 weeks. Body weights were unaffected by PCN treatment, but were reduced 21% after 19 weeks of PCB treatment compared to control. PCN treatment significantly reduced serum T4 through week 3 before returning to control concentrations, whereas T4levels following PCB treatment fell below detection limits by week 3 and remained drastically reduced through week 19. TSH concentrations in PCN-treated rats increased three-fold at week 2, then declined to near control values at week 19. After one week of PCB treatment, TSH concentrations reached nearly twice that of controls, and were sustained until week 6. The incidence of thyroid follicular cell proliferative lesions, including cystic and follicular hyperplasia, cystic and follicular adenoma, and follicular carcinoma, was significantly increased following PCN treatment, but not following PCB treatment. PCB treatment caused an increase in thyroid carcinomas (4 of 22 rats) not associated with the proliferative-type lesions produced by PCN, despite an increase in TSH serum concentrations. In conclusion, PCN appears to promote thyroid tumors in a manner consistent with known effects of excessive TSH stimulation. However, thyroid carcinomas stemming from PCB treatment indicate that separate mechanisms exist for the production of thyroid cancer in rodents by chemicals classically considered microsomal enzyme inducers.

Peat does not recommend PCN, he says it is toxic. I posted that study only to highlight that pregnenolone is stimulating of the thyroid function. The first study says PCN changes peripheral thyroid metabolism, which means the conversion of T4 into T3. This is probably the same mechanism behind the thyromimetic effect known to occur with 5-AR derived androgens like DHT and androsterone, which have also been shown to increase tissue conversion of T4 into T3.

 

[No_Energy]

Peat does not recommend PCN, he says it is toxic. I posted that study only to highlight that pregnenolone is stimulating of the thyroid function. The first study says PCN changes peripheral thyroid metabolism, which means the conversion of T4 into T3. This is probably the same mechanism behind the thyromimetic effect known to occur with 5-AR derived androgens like DHT and androsterone, which have also been shown to increase tissue conversion of T4 into T3.

Hi @haidut, Thanks for the reply mate.

I think "peripheral thyroid Metabolism" can also mean deactivation/clearing of T4. And I think that is what the study I linked is saying : "PCN treatment significantly reduced serum T4 through week 3 before returning to control concentrations ". From what I read, It reduces T4 , but then TSH is stimulated to bring t4 levels back, and it does, but, this overstimulation of TSH is what induces the hiperplasia and tumors. According to this study., I think that's the rationale.
I still haven't figured the human equivalent dosage used.

 

[haidut]

Hi @haidut, Thanks for the reply mate.

I think "peripheral thyroid Metabolism" can also mean deactivation/clearing of T4. And I think that is what the study I linked is saying : "PCN treatment significantly reduced serum T4 through week 3 before returning to control concentrations ". From what I read, It reduces T4 , but then TSH is stimulated to bring t4 levels back, and it does, but, this overstimulation of TSH is what induces the hiperplasia and tumors. According to this study., I think that's the rationale.
I still haven't figured the human equivalent dosage used.

That missing T4 has to go somewhere. The only two routes it can take are conversion into rT3 or T3. Given that PCN boosted metabolism and led to weight loss in another study, the conversion into T3 is much more likely. So, increase T3 and lower T4 are not bad things IMO.
https://raypeatforum.com/community/threads/pregnenolone-for-obesity-and-insulin-resistance.6902/

 

[No_Energy]

That missing T4 has to go somewhere. The only two routes it can take are conversion into rT3 or T3. Given that PCN boosted metabolism and led to weight loss in another study, the conversion into T3 is much more likely. So, increase T3 and lower T4 are not bad things IMO.
https://raypeatforum.com/community/threads/pregnenolone-for-obesity-and-insulin-resistance.6902/

@haidut, I really wished that was the case, but, not according to this study.
I agree that the T4 has to go somewhere. But it doesn't seem to be the case that t3 and rt3 are the only two routes. There is T4 glucuronidation , where it is being excreted. That is what they say it is happening:
" Certain inducers, namely phenobarbital and pregnenolone-16α-carbonitrile (PCN), increase T4 glucuronidation as well as increase serum TSH and thyroid cell proliferation. "

 

[haidut]

@haidut, I really wished that was the case, but, not according to this study.
I agree that the T4 has to go somewhere. But it doesn't seem to be the case that t3 and rt3 are the only two routes. There is T4 glucuronidation , where it is being excreted. That is what they say it is happening:
" Certain inducers, namely phenobarbital and pregnenolone-16α-carbonitrile (PCN), increase T4 glucuronidation as well as increase serum TSH and thyroid cell proliferation. "

Yeah, I saw that in the study, but something does not add up. They say PCN increase glucuronidation of both T3 and T4, while also increasing TSH but do not cite specific references that found such an effect. A chemical that drops T3 and T4 while increasing TSH by definition induces hypothyroidism. How do you reconcile that with the significant weight (mostly fat) loss in the other study?

 

[No_Energy]

Yeah, I saw that in the study, but something does not add up. They say PCN increase glucuronidation of both T3 and T4, while also increasing TSH but do not cite specific references that found such an effect. A chemical that drops T3 and T4 while increasing TSH by definition induces hypothyroidism. How do you reconcile that with the significant weight (mostly fat) loss in the other study?

Thanks @haidut,

I saw that study (pregnane X. Well, I suppose there we are dealing with a different mechanism, not directly related to the thyroid. (Pregnane X receptor)

Here the references on their paper:

"Alteration of the enzymes involved in thyroid hormone metabolism has been described as a mechanism for reducing the concentrations of available thyroid hormone in the circulation (Curran and DeGroot, 1991). Some chemicals that increase the activity of hepatic microsomal enzymes are believed to alter thyroid homeostasis by increasing the glucuronidation and biliary excretion of thyroid hormones (McClain et al., 1989;Semler et al., 1989). This causes a reduction in serum thyroid hormones, which in turn leads to reduced negative feedback at the pituitary, resulting in elevated TSH secretion. The microsomal enzyme inducer phenobarbital has been shown to increase thyroid gland weight, follicular cell hypertrophy, and hyperplasia (Japundzic, 1969). It has also been found to promote thyroid follicular tumors in a rat two-stage carcinogenesis model (Hiasa et al., 1982a; McClain et al., 1988). "

By that definition of hypo, we could say you would be hypo for a little while but then T4 raises again and TSH lowers, but with the deletarious effect on the thyroid, according to that study.

I think the rationale there is, the substance lowers T3/T4 by glucuronidation , the response is augmentation of TSH , thyroid function, cell proliferation, more production of T4 to compensate for the loss. In time T4 goes back up to previous levels, but, at the cost of hyperplasia, neoplasia.

It frustrates me, but here's their conclusion there : " In conclusion, PCN appears to promote thyroid tumors in a manner consistent with known effects of excessive TSH stimulation. "

 

[Wilfrid]

There is at least one point in all of the studies posted here ( and in the other linked thread on obesity ) that need to be first addressed:

pregnenolone-16α-carbonitrile only weakly activates human PXR but is an efficacious activator of rodent PXR :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508967/pdf/1021016.pdf ( see page 1020 )
Nuclear Receptor PXR, transcriptional circuits and metabolic relevance
From the second study:

« The ligand dependent PXR activation has been shown to be species specific at times. For example, in humans and rabbits the antibiotic RIF is a potent PXR activator. However, the same drug has little effect on the mouse or rat PXR. In contrast, the synthetic anti-glucocorticoid pregnenolone-16a-carbonitrile (PCN) can activate the mouse and rat PXR but has no effect on hPXR. These species-species differences represent a challenge for pharmaceutical companies attempting to select appropriate animal models to evaluate candidate drugs. The same notion has also led to the initial creation and characterization of the hPXR humanized mice »

Since PXR activation can interact with the homeostasis of numerous endobiotics, including glucose, lipids, steroids, bile acids, hormones (for ex, thyroxin), etc.....
I don’t think that those studies can be accurately extrapolate in human.

 

[Wilfrid]

Plus, there isn’t even the slightest doubt that fundamental differences in circadian rhythm of hepatic activity do exist between nocturnal/diurnal species and that those antagonisms do play a fundamental role in hormones metabolism ( synthesis, excretion etc....), which further biased any hypothetical accurate interpretation ( when it comes to extrapolate data from rodents to humans ).

 

[Wilfrid]

@haidut
" Certain inducers, namely phenobarbital and pregnenolone-16α-carbonitrile (PCN), increase T4 glucuronidation as well as increase serum TSH and thyroid cell proliferation. "

Yes because PCN strongly activates PXR in the rat model and PXR activation " or its rodent orthologues have also been shown to be involved in heme, bilirubin and thyroxin clearance, in bone homeostasis and vitamin D metabolism. (Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions)
The rat hypothalamus-pituitary-thyroid system try to compensate this ( the raising level of T4 glucuronidation via PXR stimulation ) by increasing the TSH like you said, but the real cause here is the chemically induced PXR activation by PCN in a very receptive animal model.
Which is very unlikely to be valid for human.

 

[No_Energy]

That study really bugged me..
Do you guys know of people using pregnenolone for many years? have we ever heard of anything that relates to this? If this study was to be correct AND if Pcn had exact same effects as pregnenolone, by now, I suppose we should have a lot of people developing thyroid problems/hyperplasias/tumors by the use o pregnenolone, right? Unless, the connection was never made.. but this seems mental..something is not right..
Going to read it again.

@Wilfrid, great contribution, thank you. I'm going to read carefully the studies you linked later. There is no mention to PXR on the tumor study (the other study haidut posted, the obesity study is the one that looks at pxr, but also at a different mechanism). I think they just considered established that these compounds, like phernobital and PCN, lower Thyroxine by glucuronidation.I will read the studies they referenced:

"Alteration of the enzymes involved in thyroid hormone metabolism has been described as a mechanism for reducing the concentrations of available thyroid hormone in the circulation (Curran and DeGroot, 1991). Some chemicals that increase the activity of hepatic microsomal enzymes are believed to alter thyroid homeostasis by increasing the glucuronidation and biliary excretion of thyroid hormones (McClain et al., 1989;Semler et al., 1989). This causes a reduction in serum thyroid hormones, which in turn leads to reduced negative feedback at the pituitary, resulting in elevated TSH secretion. The microsomal enzyme inducer phenobarbital has been shown to increase thyroid gland weight, follicular cell hypertrophy, and hyperplasia (Japundzic, 1969). It has also been found to promote thyroid follicular tumors in a rat two-stage carcinogenesis model (Hiasa et al., 1982a; McClainet al., 1988). ""

thank you.

 

[vulture]

No problem, I didn't mean you specifically. I just know that some people on the forum have repeatedly stated that pregnenolone raises their cortisol, but so far I have not seen studies backing this up or blood test results.
Yes, stopping adrenal function completely would not be advisable, especially in the absence of well-working thyroid.
Progesterone stimulates the thyroid, but so does DHEA (in smaller doses only). So, I wonder if the pregnenolone effect above is the result of conversion into progesterone and DHEA (which we know is what mostly happens to pregnenolone upon ingestion), or direct effect on thyroid. As Peat said cortisol inactivates T3 and inhibits synthesis of T4. So cortisol is antagonistic to thyroid function (more or less). If pregnenolone is indeed a cortisol antagonist then it is probably acting directly itself on thyroid

Problem is, haidut, there's people here saying something raised their cortisol without a lab test...they might have some symptom that could be accounted to several other things and say it is cortisol or T or DHT or whatever.

 

[Wilfrid]

That study really bugged me..
@Wilfrid, great contribution, thank you. I'm going to read carefully the studies you linked later. There is no mention to PXR on the tumor study (the other study haidut posted, the obesity study is the one that looks at pxr, but also at a different mechanism). I think they just considered established that these compounds, like phernobital and PCN, lower Thyroxine by glucuronidation.I will read the studies they referenced:

"Alteration of the enzymes involved in thyroid hormone metabolism has been described as a mechanism for reducing the concentrations of available thyroid hormone in the circulation (Curran and DeGroot, 1991). Some chemicals that increase the activity of hepatic microsomal enzymes are believed to alter thyroid homeostasis by increasing the glucuronidation and biliary excretion of thyroid hormones (McClain et al., 1989;Semler et al., 1989). This causes a reduction in serum thyroid hormones, which in turn leads to reduced negative feedback at the pituitary, resulting in elevated TSH secretion. The microsomal enzyme inducer phenobarbital has been shown to increase thyroid gland weight, follicular cell hypertrophy, and hyperplasia (Japundzic, 1969). It has also been found to promote thyroid follicular tumors in a rat two-stage carcinogenesis model (Hiasa et al., 1982a; McClainet al., 1988). ""

thank you.

Thank you for your reply. I don't know why there is no mention about PCN and PXR relative causation for increased glucuronidation in the rat study you posted...

NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16 -CARBONITRILE
http://dmd.aspetjournals.org/content/dmd/31/7/908.full.pdf
"

The present study shows for the first


time that treatment of mice with PCN increased hepatic UGT


activities toward T4 and T3 in a PXR-dependent manner, which is


correlated with changes in mRNA levels of mouse Ugt1a1 and


Ugt1a9. These results suggest that thyroid hormones may be


glucuronidated in mice by bilirubin and phenol UGTs, which are


regulated by the ligand-activated transcription factor PXR. It


should be noted that our results cannot exclude the possibility that


thyroid hormones are glucuronidated by some unknown PCNinducible


UGTs. Future studies are needed to determine whether


induction of thyroid hormone glucuronidation by PCN in mice


would be associated with disturbed thyroid homeostasis, as seen in


rats."

*Keep also in mind that the study you posted was made on rat instead of mice ( from the same reference ):
" ......the induction of hepatic UGT activities by the potent PXR ligand PCN in rats is well documented in the literature (Watkins et al., 1982; Watkins and Klaassen, 1982)."

 

[haidut]

Problem is, haidut, there's people here saying something raised their cortisol without a lab test...they might have some symptom that could be accounted to several other things and say it is cortisol or T or DHT or whatever.

Very true. And many of them take quite a few other things they do not mention in the post and only when questioned say things like "oh yeah, I am on high dose T injection, Anavar, tamoxifen, GH, etc but I don't think these could be causing my symptoms. It's definitely the pregnenolone"

 

[haidut]

That study really bugged me..
Do you guys know of people using pregnenolone for many years? have we ever heard of anything that relates to this? If this study was to be correct AND if Pcn had exact same effects as pregnenolone, by now, I suppose we should have a lot of people developing thyroid problems/hyperplasias/tumors by the use o pregnenolone, right? Unless, the connection was never made.. but this seems mental..something is not right..
Going to read it again.

@Wilfrid, great contribution, thank you. I'm going to read carefully the studies you linked later. There is no mention to PXR on the tumor study (the other study haidut posted, the obesity study is the one that looks at pxr, but also at a different mechanism). I think they just considered established that these compounds, like phernobital and PCN, lower Thyroxine by glucuronidation.I will read the studies they referenced:

"Alteration of the enzymes involved in thyroid hormone metabolism has been described as a mechanism for reducing the concentrations of available thyroid hormone in the circulation (Curran and DeGroot, 1991). Some chemicals that increase the activity of hepatic microsomal enzymes are believed to alter thyroid homeostasis by increasing the glucuronidation and biliary excretion of thyroid hormones (McClain et al., 1989;Semler et al., 1989). This causes a reduction in serum thyroid hormones, which in turn leads to reduced negative feedback at the pituitary, resulting in elevated TSH secretion. The microsomal enzyme inducer phenobarbital has been shown to increase thyroid gland weight, follicular cell hypertrophy, and hyperplasia (Japundzic, 1969). It has also been found to promote thyroid follicular tumors in a rat two-stage carcinogenesis model (Hiasa et al., 1982a; McClainet al., 1988). ""

thank you.

I know people with Hashimotos that have been taking high dose pregnenolone (200mg-500mg daily) for years. These people regularly undergo thyroid ultrasound and so far no abnormalities have been found. One of them had their antibodies go back to normal, and the other two had decrease but are still in Hashimoto territory.

 

[No_Energy]

.

 

[Frankdee20]

I had a nice little run with oral Pregnenalone and then started getting bad depersonalization from it. Had to be my favorite supplement back then.

 

[danishispsychic]

Pregnenolone in high doses can lower blood sugar due to conversion into pregnenolone sulfate (PS), which increases insulin production. I am not sure what the optimal dose would be but I agree that with people in compromised health pregnenolone and androsterone could be less risky as they should not lead to increased estrogen like DHEA. I personally feel pregnenolone in doses of 30mg - 50mg daily is probably optimal for most people unless there is a deficiency but if you feel better on a higher dose then do what feels best.

I agree- I have done well at 50 mg

 

[No_Energy]

Thanks again, @haidut.
@Wilfrid , Thanks for feedback, replies, links and info provided. Sorry I didn't reply earlier, I still want to look and read more into this. Well, in rats, that's what these studies seem to be showing, PCN/Pregnenolone 16α-carbonitrile "stimulating" the thyroid, but unfortunately not in a good way, It actually acts to lower thyroid hormones, increase glucuronidation, later on Tsh is being raised in response, thus yes, you get a subsequent stimulation just to compensate for the actual loss of the hormones, but by raising tsh and harmful effects on the thyroid, hyperplasia, neoplasia/tumor..That tumor study didn't touch on Pxr, thanks for the other one you provided above.

Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis.
Ohara A1, Yamada F1, Fukuda T1, Suzuki N1, Sumida K1.
Author information

Abstract
Transcriptomics technologies have been used for risk assessment of chemicals, mainly to predict the modes of action (MOAs) of chemicals or identify biomarkers. Transcriptomics data may also be helpful to understand MOAs of chemicals at the molecular level in more detail. As an example of the known MOAs, there are two MOAs of thyroid toxicity: inhibition of thyroid hormone synthesis ("direct" effect) and hypermetabolism of thyroid hormone by enzyme induction in liver ("indirect" effect). In the present study, global profiles of gene expression were analyzed in rats treated with chemicals acting directly on the thyroid (thyroid peroxidase inhibitors such as propylthiouracil and methimazole) and chemicals acting indirectly on the thyroid (hepatic enzyme inducers such as phenobarbital and pregnenolone-16α-carbonitrile) using microarrays. Using a subtraction method between these two types of chemicals, we identified characteristic gene expression changes on the thyroid hormone synthesis pathway by direct-acting chemicals. Based on the functions of these genes, alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and might be helpful in more accurate evaluation of MOAs for thyroid toxicity.

--

Effects of Microsomal Enzyme Inducers on Thyroid Follicular Cell Proliferation and Thyroid Hormone Metabolism

CURTIS D. KLAASSEN AND ALAN M. HOOD

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7140

ABSTRACT

The effects of microsomal enzyme inducers on thyroid hormone homeostasis and the thyroid gland are of concern. We have investigated the effects of microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism in rats. We have shown that small increases in serum TSH can result in large increases in thyroid follicular cell proliferation. Furthermore, only those microsomal enzyme inducers that increase serum TSH—that is, phenobarbital (PB) and pregnenolone-16 -carbonitrile (PCN)—increase thyroid follicular cell proliferation, whereas those microsomal enzyme inducers that do not increase serum TSH— that is, 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB)—do not increase thyroid follicular cell proliferation. Deiodination does not appear to be the reason why serum T3 concentrations are maintained in microsomal enzyme inducer–treated rats. We have also shown that those microsomal enzyme inducers that increase serum TSH increase T3 UDP-glucuronosyltransferase (UGT) activity, whereas those microsomal enzyme inducers that do not increase serum TSH do not increase T3 UGT activity. This Ž finding suggests that induction of T3 glucuronidation, rather than T4 glucuronidation, mediates increases in serum TSH of microsomal enzyme inducer treated rats.

 

[BGZ]

Taking 2x2 Pansterone drops per day made me feel warm during my coldshowers.
Been taking coldshowers for six months before taking Pansterone.
I’m positive that it has a thermogenic effect.

 

[CLASH]

@haidut
I know this is an old post but if i’m not mistaken the negative effects from PCN on thyroid may be due to the nitrile component. Nitriles are known goitrogens in cruciferous vegetables.

@Frankdee20
In my experience pregnenolone builds up in the system over the course of a few days with consecutive use, especially topically. If you try dosing every other day or every second day you may get a different effect. I got sides from using preg everyday as well.