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Prostate cancer: the role of estrogen

Introduction.

Despite the general belief that higher serum testosterone increases the risk of developing new and rapid growth of latent prostate cancer (PC), recently some scientists attribute testosterone only a secondary role. And the emphasis is being shifted onto its direct derivative-estradiol.

In a man’s body, enzyme aromatase converts about 0.3-0.4 % of testosterone (T) into estradiol (E2). Probably, the labeling of these compounds as the male’s and the female’s hormones allowed E2 to stay in the shade while the high T content and its well-known anabolic properties attracted much more attention regarding malignant cell growth. Moreover, for the last eight decades, there has been accumulating evidence directly pointing to T in fuelling prostate cancer.

This belief has resulted in a fear of T therapy for both cancer patients and all kinds of men suffering from low T. Evidence-based education of the general public about the true relationship between T, E2, and PC may help to change public consciousness and facilitate future progress in this demanding area. Let’s try to analyze the available data and understand how these two hormones affect the development of prostate cancer.

The evidence backing the role of testosterone in prostate cancer.

In 1941, Huggins and Hodges for the first time showed that PC needs T to survive. They reported that removing T by surgical or chemical castration has been killing most of the PCs in their patients. So, here, removing T affects the PC the same way as starvation on the growing body. The body of cancer starts shrinking and reducing in size.

Can T provoke the development of PC? Yes, it can. In 1977, Robert Noble showed that T can cause PC. He could induce 20% of PC in the strain of rats by exposing them to high doses of T. Here we have a clear causal relationship between cancer and testosterone. 

How does T affect the growing tumor? In 1981, Fowler and Whitmore showed T promoting the growth of the PC. Administration of a high dose of T to advanced PC patients resulted in the worsening of their symptoms, within 30 days.  

If T treatment is preceded by prostate-targeted chemical carcinogen administration, high PC incidences can be induced in rats. Tumor promoting effect of Tis apparent even at the physiological T concentrations and may be an important element in the carcinogenic activity of T by itself.

Besides, in 2005 Bai et al. suggested that testosterone binding to the intracellular androgen receptor (iAR) is essential for PC growth. They showed that blocking the iAR in the PC cell line resulted in halting cell divisions. 

It has also been reported that treatment of rats with T plus an AR-blocking agent eliminates the induction of prostate cancer by the androgen (Bosland M.C. 2005). These studies almost certainly show T involvement in androgen-induced prostate cancer. 

All these experimental and clinical data show that T unfavorably affects the prostate gland. Lowering of the endogenous T leads to shrinking of the prostate and vise versa, adding an exogenous T can result in the initiation of PC or stimulation of PC growth.      

The role of estradiol in prostate cancer.

Estrogens (estrone, estradiol, and estriol) are considered substances with mild mutagenicity. They easily cross the cell membrane and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus. In the nucleus, they bind to specific sites of the DNA molecule and trigger mutations that can initiate cancer. Besides, much higher ratios of these estrogen-DNA complexes have been found in men with prostate cancer as compared to healthy men. Estrogens may influence prostate cancer development and its progression by stimulation of cell divisions, directly causing genetic mutations or compromising the DNA repair system. 

The normal ranges of testosterone and estradiol levels in men may vary largely but, what makes a difference, is the T to E2 ratio. Testosterone levels of 10-35 nmol/L or 300-1000 ng/dL and estradiol levels of 50-200 pmol/L or 14-55 pg/mL (The data of Mayo Clinic) are considered normal. The normal T/E2 ratio is 1.7 ± 0.12. The value taken for T is free testosterone. The company “Life Extension” recommends for men striving the levels of estradiol between 21.80 and 30.11 pg/mL. This is virtually the ideal range and the safest zone for men.  

A study by Jankowska et al (2009), published in the Journal of the American Medical Association measured blood estradiol in 501 men with chronic heart failure. They through the patients into three groups: high E2 levels ( 37.40 pg/mL or above), balanced E2 (between 21.80 and 30.11 pg/mL), and low E2 (under 12.90 pg/mL) and followed them during 3 years. The research found a dramatic increase in mortality in men with unbalanced estrogen. In the groups with high and low E2, the expected mortality rates compared to the balanced group were 133% and 217% respectively. Pay attention, that the high E2 levels in this experiment get into a reference range of 14-55 pg/mL accepted by conventional medicine.

Estrogen application alone results in shutdown of LH and plummet of T production, resulting in a reduction of prostate size. Low doses chronic treatment of rats of five different strains with T alone, has been shown to result in PC incidences ranging from 7 to 37%. (Bosland M.C. 2014). Adding estradiol to testosterone (E2 plus T) resulted in 100% PC development in rodents or malignant degeneration of the prostate tissue cultures. So, E2 enhances the carcinogenic effect of T.

But how is this consistent with the widespread practice of E2 application to treat PC? The explanation looks a bit complicated, but let’s try to understand as science envisions it.  

Any hormone, including estrogen, needs binding to specific molecules on the cell membrane or inside of the cell, called receptors to exert its effect. There are two types of estrogen receptors in the cells: ER-α and ER-β. Most of the receptors of the prostate cells are of the second type. The binding of estrogen to each of the receptors affects cell divisions of the prostate differently. The first complex, estrogen-ER-α, stimulates cell divisions whereas the second complex, estrogen-ER-β, triggers programmed cell death in the prostate.  

Since normal prostate cells have almost no ER-α, the primary effect of the E2 application would be stimulating apoptosis and shrinking of the prostate. That’s what is observed when the level of estrogen is increased at the first stage of prostate cancer treatment. Simultaneously, high levels of the hormone cause some mutations in the prostate cells, which promote to selective growth of the cells with ER-α; 94% of castrate-resistant prostate cancer (CRPC) cells have significant ER-α activity (Bonkhoff H et al. 1999 ).  

Furthermore, treating the mice, which have been switched off the ER-α gene, with E2 plus T resulted in no cases of PC as opposed to the 100% PC rate in regular mice (Ricke WE, et al. 2008). “This proves that ER-α is essential for PCa carcinogenesis. Since T does not bind to ER-α, but E2 does, this proves that E2 is a primary cause of PCa and T is only the secondary cause.” By the way, similar results were obtained upon blocking of androgen receptors plus T treatment (Bosland M.C. 2005). 

Testosterone or Estradiol?

Estimating the role of testosterone and estradiol in all the above studies, E. Friedman from the University of Chicago inclines the idea that blocking the aromatase activity would have resulted in the change of the main conclusions of the experiments. Unfortunately, nobody has tried to use aromatase inhibitors (AI) in their experiments so far (A. E. Friedman, 2016). 

The similarity of the effects of exogenous testosterone and estradiol on male health is obvious.

High estrogen levels in men are associated with various health issues such as gynecomastia (large male breasts), blood clots, stroke, and prostate cancer. 

The seemingly apparent harmful impact of T on the prostate gland and cardiovascular conditions may have been the indirect result of T’s adverse effect on E2 and hematocrit. Exogenous T is known to increase hematocrit and E2 levels. The higher hematocrit means that your blood gets thicker than usual which in turn can lead to clots, heart attacks, and strokes. High local levels of E2 are known to correlate with the incidence of breast cancer in women and PC in men. 

Gynecomastia in men is a side effect of T treatment. However, T is known as a natural burner of fat. An increase of T leads to its increased conversion to E2 which in turn makes a man’s body shape feminine. Administration of an inhibitor of aromatase that is in charge of the conversion prevents gynecomastia. Therefore, it is necessary to check and control E2 levels when administering exogenous T. 

Can we argue that T is harmless to prostate health and that E2 alone is responsible for prostate cancer? Despite the abundant evidence not in favor of estradiol, such a statement would be too premature. Along with structural, there are too many functional similarities between these steroid hormones to expect vast differences in their effects on the prostate. More information about the possible mechanism of the T effect on prostate health you can find here: “Testosterone and prostate health.” 

Traditionally, estrogen and testosterone are considered female and male sex hormones. However, along with multiple other functions estrogen also plays a crucial role in male sexual function. Estrogen receptors, as well as aromatase, are abundant in the brain, penis, and testis playing an essential role in modulating libidoerectile function, and spermatogenesis. Not everyone knows that in men with diminished testosterone, the administration of exogenous estradiol has been shown to increase libido. 

On the other hand, at the level of the brain, estrogen can inhibit the hypothalamus-pituitary axis the same way as the feedback mechanism of T regulation works. As a result, the pituitary stops producing follicle-stimulating and luteinizing hormones, thus dropping the level of blood T and causing erectile dysfunction. 

Lack of adequate knowledge in all the variety of interactions between testosterone, estradiol, and their receptors does not allow unambiguously judging the role of each of them in the development of prostate cancer. Each of them, under certain conditions, can negatively affect the health of the prostate, especially when they are administered together. Structural and functional similarities of these hormones suggest they affect the development of prostate cancer alike, albeit to different degrees.

If we abstract from the separation of sex hormones into diverse entities and focus on androgens as the basis for the synthesis of other hormones, and analyzing the available data, one can conclude: for T to cause PC, it must be aromatized to estrogens and act in concert with these metabolites and their receptors. The genotoxicity of estrogen may play a critical role as well. Only when all these mechanisms are active, prostate carcinogenesis may be the result.

Aromatase maintains a high level of estrogen in the prostate.

Aromatase is an enzyme catalyzing the biosynthesis of estrogens (estrone and estradiol) from androgens (androstenedione and testosterone).

It is obvious that physiological serum levels of E2 cannot be carcinogenic. When parallels are drawn between breast cancer in women and prostate cancer in men, there are clear similarities in their response to estrogen.

The concentration of estrogens in breast cancer tissues is as much as twenty-fold higher than in the neighboring area. Only high local levels of estrogen, in our case, high levels of E2 in the prostate, may have a carcinogenic effect. And an increased level of E2 is maintained through the conversion of testosterone by aromatase. This is where the important role of the aromatase enzyme in the pathogenesis of prostate cancer comes to light. Inhibition of the aromatase enzyme in men as well as in women diminishes estrogen production and has a meaningful effect on the progression of hormone-responsive cancers. It has to note that normal prostate cells don’t possess aromatase activity, whereas malignant epithelial cells and PC cell lines do.

So, aromatase indirectly plays an essential role in the development of prostate malignancy. And indeed, in mice lacking aromatase activity (-A), the effectiveness of T plus E2 to cause PC was significantly less than in wild-type mice (Ricke WE., 2008). In this case, no conversion of T into E2 takes place and as a result, the mice in the -A group have a higher T to E2 ratio compared to the normal mice. Lower E2 decreased the chance of developing PC. 

On the other hand, in the mice with high levels of E2 and reduced T levels which are achieved by overexpression of aromatase gene, no malignant tissues develop. (Morgentaler A. 2011). These findings are consistent with the opinion that both hormones are needed for prostate carcinogenesis.

Summing up the effect of aromatase activity in the prostate, we can conclude:

1. In a normal, healthy prostate, the aromatase gene is considered to be inactive. Consequently, there is no local increase in estrogen production and the likelihood of malignant transformation of the prostate due to T or hormonal imbalance is low;

2. With age, changes occur in the prostate, possibly due to lifestyle, genetics, dietary, endogenous, or environmental toxins, which stimulate the aromatase activity. Besides that, aging men tend to reduce muscle mass and gain abdominal fat. The adipose cells of fat are characterized by high aromatase activity, which eventually lowers the level of T and increases the level of E2. These age-related changes can be prevented by maintaining good physical shape through regular exercise.

3. The prostate gland has its own mechanism of hormone regulation and serum hormone levels provide no information about hormone concentrations in prostate tissue. Due to the autonomous expression of aromatase in the prostate, the local increase of estrogen levels may occur. The level of aromatase activity and accordingly the balance of estradiol you can control by purposefully changing your diet in middle and old age. The foods to include in your diet are listed below.

4. High local levels of estrogen together with testosterone have been shown to have a synergistic effect on prostate malignant transformation.   

Thus, the turning point in the chain of successive events leading to prostate cancer is the activation of the aromatase gene and the increase of estrogen production in the prostate.

How to control estrogen levels in men?

An age-related decrease in T levels, and an increase in aromatase activity, are accompanied by an increase in estrogen levels in the prostate. All this leads to an imbalance in the normal T to E2 ratio which creates a favorable milieu for PC development. It is easy to guess that aromatase activity should be targeted if we want to address the level of estrogen.  

Depending on your health condition, doctors’ advice, and personal preferences, you can use the following ways to keep under control estrogen levels:

  1. Use of synthetic aromatase inhibitors-you get the fastest result but they have a bunch of severe side effects that should be taken into account before the final decision has been made.
  2. Use of natural supplements – aromatase inhibitors. They have much fewer adverse side effects. You can use them on your own, with some precaution, all of them are concentrated bioactive substances.  
  3. Include foods with anti-aromatase activity into your daily diet. You can use them almost without any restrictions not worrying about side effects. Follow this recommendation and you will save yourself health problems, endless visits to doctors, and save a lot of money.    

Synthetic aromatase inhibitors.

Highly selective aromatase inhibitors anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) have shown nearly complete estrogen suppression. However, despite their anti-aromatase potential these agents are not usually recommended for lowering estrogen levels unless they are clinically indicated.

The adverse side effects of the synthetic AIs may include: 

  • decreased bone mineral density 
  • osteoporosis 
  • increased musculoskeletal disorders 
  • increased cardiovascular events
  • diarrhea 
  • diminished libido
  • memory loss with aging. 

Natural supplements as aromatase inhibitors.

Some natural aromatase inhibitors available as food supplements on the market include Chrysin, Nettle root, Maca, Ashwagandha, Zinc, and Grapeseed extract. Reduced side effects of these supplements may be the result of their phytoestrogen activity that alleviates some of the side effects of estrogen deprivation. Remember, all these food additives are biologically active substances and their use for a prolonged time may have undesirable side effects. Discuss these natural options with your doctor first.

Foods as aromatase inhibitors.

Some foods that may help to keep your estrogen levels at bay, include: 

  • Cruciferous vegetables: cabbage, cauliflower, Brussels sprouts, and broccoli contain phytochemicals such as dietary Indole and Diindolylmethane with anti-estrogen activity.
  • Green tea (C. sinensis), coffee (Coffea L. sp.), cocoa (Theobroma cacao L.), collards (Brassica oleracea L.), and tomato leaves (Lycopersicon esculentum Mill.) have been reported to strongly inhibit aromatase (Osawa Y et al, 1990). 
  • Pomegranates are high in estrogen-blocking phytochemicals.
  • Some red wine varieties such as Cabernet Sauvignon and Pinot Noir show strong anti-aromatase activity.
  • Shiitake and White button mushrooms naturally cut aromatase.
  • Red grapes contain natural estrogen blockers Resveratrol and Proanthocyanidin.
Mushrooms to Treat Prostate Cancer? | City of Hope

Exercise and estrogen level. 

Though you can read a lot about how exercise may help lower your estrogen levels, at least these claims are not grounded, not to say, misleading. This is exactly the case when we readily wishful thinking and no one has doubts. 

There are conflicting results about the effect of physical activity on the estrogen levels of males and females. Most of the studies in females show an increase in blood steroids including estrogen, as a reaction to physical exercise. Endurance exercises increased the levels of T, DHT, estradiol, cortisol, and growth hormone in a study by Copeland JL et al (2002). The same results, as to the levels of estrogen, were reported in the studies by Ketabipoor and Jahromi (2015) and Zainab A R et al. (2019). On the other hand, a study by Kenney et al., 2015, found that fitness training to burn fat resulted in reducing the fat mass ultimately leading to a decrease in the estrogen level.  

There is not so much research on the effect of workouts on estradiol levels in men. The results of a randomized controlled trial published by Hawkins. VN et al. in 2008 showed no statistically significant differences in testosterone, free testosterone, estradiol, or free estradiol in exercisers versus controls. Though, the training increased the levels of dihydrotestosterone and sex hormone-binding globulin. The study has lasted for 12 months and involved 102 men of 40-75 yr.

Of course, the mentioned data does not mean we have to ignore physical exercises. Although they do not affect a man’s blood estrogen levels, exercise is important for maintaining a healthy hormonal balance. 

 

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Literature.

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  • Bosland M.C. A PERSPECTIVE ON THE ROLE OF ESTROGEN IN HORMONE-INDUCED PROSTATE CARCINOGENESIS. PMC3921257
  • Osawa Y et al. Aromatase inhibitors in cigarette smoke, tobacco leaves and other plants. J Enzyme Inhib. 1990; 4(2):187-200.
  • Copeland JL, Consitt LA, Tremblay MS Hormonal responses to endurance and resistance exercise in females aged 19-69 years. J Gerontol A Biol Sci Med Sci. 2002 Apr; 57(4):B158-65.
  • Ketabipoor SM, Jahromi MK. Effect of aerobic exercise in water on serum estrogen and C-reactive protien and body mass index level in obese and normal weight postmenopausal women. Womens Health Bull. 2015;2:e25048. 
  • Zainab A R et al. Effect of aerobic and anaerobic exercise on estrogen level, fat mass, and muscle mass among postmenopausal osteoporotic females. Int J Health Sci (Qassim). 2019 Jul-Aug; 13(4): 10–16.
  • Hawkins. VN et al. Effect of Exercise on Serum Sex Hormones in Men. A 12-Month Randomized Clinical Trial. Medicine & Science in Sports & Exercise: February 2008 – Volume 40 – Issue 2 – p 223-233
  • Jankowska EA, Rozentryt P, Ponikowska B. Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA. 2009 May 13;301(18):1892-901.
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READ  What does cause the development of prostate cancer in men?

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