Foods/Supplements-Vitamins: Hormones - Progesterone

This post was prompted by a side-discussion in a thread initiated by Nalakrats:

"Protocols For Cycling T, or T use in Metastatic Post ADT".

Member "2548oo" mentions Dr John Lee, & is currently using progesterone cream.

I must admit to being wary when I see Dr John Lee's name mentioned in a PCa group. As with Nobel prize winner Otto Warburg, the name is used to justify a range of beliefs & activities.

Let's start with a nice quote from Dr Lee [1]:

"It is well known that the estradiol level in 55-year old men, for example, is usually a bit higher than that of a 55-year old woman. The man, however, does not develop breasts because he has a higher testosterone level than women do. As men age, their estradiol levels gradually rise, whereas their progesterone and testosterone levels gradually fall. The hormone balance changes. These gradual changes lead to reduction in testosterone benefits and eventually to estrogen dominance. That is, his estradiol effects emerge since his testosterone level is not sufficient to block or balance them. Estrogen dominance stimulates breast cell growth and endometrial cell proliferation in women. In men, estrogen dominance stimulates breast cell growth and prostate hypertrophy. Estrogen dominance is responsible for the majority of breast cancers and is the only known cause of endometrial cancer in women. Since the male prostate is the embryonic equivalent of the uterus, is should not be surprising that estrogen dominance is also a major cause of prostate cancer."

(I have no problem with that, although some might.)

Cholesterol is the starting point for steroidogenesis. The first hormone shown in the diagram [2] is pregnenolone, which I have seen referred to as the "grandmother" hormone. Progesterone is produced from pregnenolone.

There are several paths in the steroid cascade that convert pregnenolone [Preg] to testosterone [T], one of which (c) involves progesterone [Prog] directly:

a) Preg --> 17α-hydroxyPreg --> DHEA --> androstenediol --> T

b) Preg --> 17α-hydroxyPreg --> DHEA --> androstenedione --> T

c) Preg --> Prog --> 17α-hydroxyProg --> androstenedione --> T

d) Preg --> 17α-hydroxyPreg --> 17α-hydroxyProg --> androstenedione --> T

Both Preg & Prog are available as supplements in the U.S., as is DHEA. Supplementation is generally intended to correct age-related declines. The argument against usage is that high-level hormones are like pachinko balls in the steroid cascade. You never know where they will end up.

A man on ADT should never add to the four pathways shown above (for obvious reasons - all four increase T).

Zytiga (abiraterone acetate) inhibits 17α-hydroxylase, which takes Preg --> 17α-hydroxyPreg, & Prog --> 17α-hydroxyProg. It also inhibits 17,20-lyase, which takes 17α-hydroxyPreg --> DHEA, & 17α-hydroxyProg --> androstenedione. With all four pathways blocked, progesterone should become irrelevant.

However, since Zytiga is designed to prevent the metabolism of Preg & Prog to androgens, using either wouldn't make sense.

...

Progesterone & Prostate Cancer Cells.

[3] (1982 - U.S. - Johns Hopkins - Patrick Walsh, et al)

"The presence of comparable amounts of progesterone and androgen receptors in human prostatic cytosol deserves further investigation."

[4] (1984 - U.S.)

Interesting study. BPH patients were given Tamoxifen " for 10 days prior to prostate resection". Tamoxifen is a prodrug which is converted to an estrogen receptor antagonist in the body. There were "decreases in progesterone and nuclear androgen receptors" compared to controls. Which "suggest that estrogen has a role in the biological regulation of steroid receptors in the human prostate."

[5] (2001 - Germany)

"The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression."

"To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression."

"In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA, whereas the ERalpha protein was undetectable by immunohistochemistry (IHC) in a significant number of cases (58 of 97 cases)."

"The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer."

[6] (2015 - Norway)

"A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy." {535 patients}

"... high tumor cell density ... and high tumor stromal cell density level ... of progesterone receptor were both significantly associated with tumor progression and clinical failure."

"... progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure ..." {Risk factor = 2.5.}"

"High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure."

...

Much of the above suggests that progesterone is not to be messed with when PCa exists.

Normally, we have little control over the amount of progesterone the body produces - or of the biological fate of supplemental progesterone. It should be noted, however, that Zytiga, by interfering with its metabolism, potentially increases progesterone levels.

The role of progesterone in the prostate has been under-explored. Progesterone receptors are found in the stroma (PCa occurs in the epithelium). There is crosstalk between stromal & epithelial cells. As PCa develops, changes occur in stromal cells that make the stroma an active participant in progression. One such change is a reduction in progesterone receptors [PR]. This suggests that stromal PR might have a protective role.

But PR in PCa cells is quite another matter, & I see no way that Dr John Lee's old writings can be used to justify the use of progesterone in PCa, given the above. IMO.

-Patrick

[1] johnleemd.com/testosterone-...

[2] en.wikipedia.org/wiki/Stero...

[3] ncbi.nlm.nih.gov/pubmed/618...

[4] ncbi.nlm.nih.gov/pubmed/608...

[5] ncbi.nlm.nih.gov/pubmed/115...

[6] journals.plos.org/plosone/a...

18 Replies

oldestnewest
  • Patrick,

    My doctor told my daughter, I could have been a doctor.

    I am so tired of researching this disease, but I am not tired of living; so that, I continue to read. When I was first diagnosed, a doctor told me we would have to work on getting me, five years. Next month it will be approximately, eighteen years, and one of my goals is to be a marathon man.

    Your research is excellent as usual.

    PS: Did you ever read anything that apple juice effects the metabolism of Bicalutmide?

    Rich

  • Thanks, Patrick--very informative & even entertaining!

    So should we, or at least those of us on Zytiga, be taking some "anti-PR"?

    Neal

  • hi

    A very interesting article, it seems that you prefer castration treatments with their poor QOL and ever increasing health problems. I cannot say that hormone balancing has kept the pc in check for over 2 years because the radiation plus Lupron may have knocked the pc. I do know if I followed the standard treatment that I would be permanently castrate and follow the downward trend that only the drug companies benefit from. For now I will follow this treatment and report any positive or negative effects.

  • Hi 2548oo,

    Could you clarify a couple of things for me? You wrote:

    "psa 0.32-- t 23.5 ... DHT 1.4-- Estrogen 87"

    I am used to testosterone [T] units of ng/dL, with 350 ng/dL being the common cutoff for hypogonadism. 23.5 ng/dL would be castrate. 23.5 nmol/L would be normal. Which unit are you using?

    I'm not sure what you mean by "Estrogen 87" -is this estradiol? pg/mL?

    Life Extention recommends that estradiol [E2] be in the 20-30 pg/mL range. E2=87 pg/mL would be a very high level. Coupled with the T number it would represent the estrogen dominance that Dr Lee warned against.

    -Patrick

  • Patrick,

    I am using estradiol patches to bring down testosterone to castrate levels. As per the oncologist guiding the process, the estradiol target is somewhere between 180-220 pg/ml. or 10 times the LEF suggested ideal level. Do you see a problem?

    jal

  • jal,

    It's a very interesting question. There doesn't seem to be much to go on in the Estradiol [E2] - PCa literature.

    Orchiectomy aside, ADT in the U.S. over the past 75 years roughly breaks down into 45 years of Diethylstilbestrol [DES] followed by 30 years of Lupron & the like.

    DES is an estrogen, but I don't know how much the DES-PCa literature tells us about E2-PCa. DES is synthetic, but seems to mimic E2 pretty well. I understand that it is always an estrogen receptor [ER] agonist (never an antagonist), but there seems to be a differential effect on the two receptors:

    "It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, respectively. However, EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, have been reported, suggesting, in spite of its binding affinity for the two receptors, several-fold preference for activation of the ERβ over the ERα." [1]

    This might have significance in PCa.

    Certainly, DES does more than induce castrate levels of testosterone [T]. A certain percentage of CRPC cases respond to DES. This might explain a negative experience in the UK, when a supply problem resulted in a switch from DES to E2. [2]

    I have cited a number of studies over the past few years that have reported associations between inflammation markers & mortality. A 2013 paper reported [3]:

    "Association between endogenous sex steroid hormones and inflammatory biomarkers in US men."

    "Higher concentrations of total ... and calculated free ... testosterone were statistically significantly associated with lower concentrations of CRP ..."

    "Total and calculated free estradiol (E2) were positively associated with ... CRP ..."

    "These cross-sectional findings are consistent with the hypothesis that higher androgen and lower oestrogen concentrations may have an anti-inflammatory effect in men."

    I think that it is important to monitor inflammation & take steps to control it.

    The negative effects of castate T in ADT cases is well-documented. I'm not clear how elevated E2 might worsen things.

    Personally, I would want the lowest E2 level that would induce castrate T. The UK PATCH study had a paper in 2008 [4]:

    "Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer"

    E2 (oestradiol) levels at 12 weeks are shown in Table 1 as pmol/L units.

    "The median oestradiol level achieved while on the patches was 442 pmol/L; this was lower than expected. The aim of the study was to produce serum oestradiol levels of 1000–1500 pmol/L, a target based on data from Scandinavian studies"

    To get that in perspective, 442 pmol/L = 120 pg/mL, & 1,000 pmol/L = 272 pg/mL. Your "180-220 pg/ml" range doesn't look unreasonably high.

    The ultimate PATCH results may answer questions regarding long-term exposure to high E2 levels.

    I would be very interested in two blood test numbers: (i) Albumin & (ii) C-Reactive Protein [CRP].

    -Patrick

    [1] en.wikipedia.org/wiki/Dieth...

    [2] onlinelibrary.wiley.com/doi...

    [3] ncbi.nlm.nih.gov/pmc/articl...

    [4] ncbi.nlm.nih.gov/pmc/articl...

  • I love you man!! Thank for this and all your supplement examinations and comparisons. I feel more and more like a research biologist the more I read your reviews!! Please know that your hard work is very much appreciated. Keep it up (if you can haha)

  • Is the point of the comment, this: "one should not use progesterone supplements if you have prostate cancer, and Dr John Lee's writings cannot be used to justify this as a practice"?

    If it is, then I don't need to work through the details as its not something that I am interested in, at least so far, and I can wait till later, possibly.

    Lot of stuff in there.

  • hi Patrick

    I will enter the results of saliva tests done in 2016 oestradiol [e2] 5 pmol/L [<8]

    testosterone 131 pmol/L [127-371]

    progesterone 320 pmol/L [41-183]

    p should be less than 300 still working on that. The claim is that saliva tests are more accurate than blood tests. It is good to see that you challenge this treatment as this is how advances in pc treatments progress.

    cheers neil

  • Hi Neil,

    About 8 years ago, having no opinion on saliva tests, I used them for convenience. However, the experience of one man made me doubt them.

    Duane was treated by Dr 'Bob' Liebowitz & was in the T stage of his treatment. He decided to stop treatment sometime in 2008. For the next 4 years or so, he measured (& reported) serum & saliva T. Later blood tests showed him to be near-castrate, whereas the saliva tests always put him well above normal range.

    I'm not sure how fast the T from Dr. Bob would have cleared, but even 3 years later, Duane was blaming it for his saliva results.

    On 12/12/2011 his serum T was 85 ng/dL (348-1197).

    On 1/12/2012 & 3/12/2012 his saliva T was 70 & 71 (15-45). The lab was evidently using different units or methods than yours.

    Now, this clearly isn't just a case of one test being "more accurate" than another.

    Incidentally, Duane was using 40 mg pregnenolone & was a fan of Dr Lee.

    There is an interesting old study where healthy men watched a video 15 minutes before giving a saliva sample. One group watched an erotic video, while a second watched a gruesome dental procedure. A third group watched a 'neutral' video, while a fourth watched an "aggressive" video. Saliva tests were high in the erotic group & low in the dental, compared to the neutral. There was no difference between the aggressive group & the neutral group.

    Meanwhile, one would not expect circulating T to behave in this way.

    -Patrick

  • hi Patrick

    I will pose a question, why is it that middle to older age men develop pc and the numbers per 1000 are increasing, and I don't believe that it only due to more detection rates.

    neil

  • But Neil,

    the SEER data does not support that:

    seer.cancer.gov/statfacts/h...

    These are age-adjusted rates per 100,000 males.

    The drop in rates, I believe, is due to declines in screening (first in men over 70, then in general).

    There are more younger U.S. men with PCa than ten years ago, but that may be explained by screening.

    {An interesting statistic is that there are almost 3 million men living in the U.S. who have had a PCa diagnosis. It's a number I use when someone gets excited about a popular cancer cure, such as the Budwig protocol. If it worked, why hasn't word leaked out?

    (In contrast, there are only 50,000 living pancreatic cancer cases.)}

    -Patrick

  • hi patrick

    In Australia they use nmol/L units and ug/L units for psa. Comparing blood tests and saliva tests mine are about the same. People taking T supplements eg body builders can have reduced testicle size that can lead to sterility, so anything may effect the tests and hormone levels. I found it interesting in dr johns talk about the estrogen effects on male and female sex organs.

    Neil

  • Patrick--I was at my Uro. today. We were talking about a lot of subjects--he said, "he has a patient, by the name of Oshea, who talks a lot like me"--I said, "you mean Patrick". He said, "yeah--how did I know"--I said, "it was a guess". Anyway it appears we live near each other, and have the same Uro.

    I am in Hendersonville.

    Nalakrats

  • Nalakrats,

    I am a little north of Asheville.

    When I moved here 11 years ago, his old office was the only one that would accept my insurance. That changed a long time ago, but I value Dr Donaldson's openness & willingness to support me & I can get there within the hour.

    -Patrick

  • We ought to get together and share a lunch and experiences.

    Nalakrats

  • I'm overdue a visit to Donaldson I'll let you know. -Patrick

  • Sounds good Patrick--I will be leaving for Florida to Fish for 2 months in mid December. Can catch you after your visit, Wednesdays, I am involved in Bridge Tournaments,---how about lunch---I do not do vegan. Suggestions? Or I can choose.

    Nalakrats

You may also like...