Monday, October 19, 2009

Aromatase's Effect On Testosterone, Estrogen, and Cancer

Below is a post I wrote in 2007 about the enzyme complex called aromatase. I edited it to address briefly the contribution of insulin and insulin resistance. There are one or two other things I'd like to say about aromatase (in an upcoming post) and I thought this would provide context.

I'm writing this post for someone I know who was recently diagnosed with breast cancer. But it's not just a post for women. Male and female hormones are chemically linked, and are being increasingly implicated in a number of chronic diseases, including cancer, heart disease, and osteoporosis.

Read on ... for why you might want to limit your grapefruit juice and alcohol intake. And your fat intake, especially saturated.


There's an enzyme in the bodies of both men and women called aromatase. Its primary action is to produce female sex hormones, or estrogens. It produces them from male sex hormones (androgens) such as testosterone and their precursors.

In the diagram below, the molecule on the left is the male hormone testosterone. The molecule on the right is the female hormone estradiol, an estrogen. The arrow in the middle represents the action of the enzyme complex aromatase.

Aromatase also converts androstenedione (a sex hormone precursor) to the female hormone estrone, another estrogen, although weaker than estradiol.
  • If you increase the activity of aromatase, you can increase levels of female sex hormones (estradiol, estrone).

  • If you decrease the activity of aromatase, you can decrease levels of female sex hormones, while increasing relative levels of male sex hormones, e.g. testosterone.
There are many things to say about aromatase. I'm presenting just a few here.

Men's bodies normally contain some level of estrogens, in addition to testosterone and their kind. Likewise, women's bodies contain some level of male androgens including testosterone. The ratio of male-to-female hormones contributes to our maleness or femaleness. Aromatase is one chemical that can tweak that ratio. It operates the same in both men and women, although an array of compounds can affect its activity.

Who Cares About Aromatase?
  • Bodybuilders have been capitalizing on the action of this enzyme for years. They know that aromatase inhibitors will lead to effects of increased testosterone such as a greater percentage of lean body mass, less body fat, improved bone mineral density, etc.

  • Some women with cancers of the breast (or ovaries, or uterus) benefit from treatment with aromatase inhibitors. Since some breast tumors (and other reproductive tissue tumors) are dependant upon estrogen for their growth, aromatase inhibitors can be employed to reduce estrogen production, improving patient outcome.

  • Women who experience problems associated with excess estrogen and/or low progesterone, such as those listed below, also benefit from decreasing the activity of aromatase:
    • Fibrocystic breast disease
    • Uterine fibroids
    • Ovarian cysts
    • Heavy menstrual bleeding
    • Endometriosis

  • Aromatase inhibitors are used as a fertility treatment for women who are having difficulty getting pregnant. They can stimulate ovulation.

  • The fall in estrogen output from the ovaries of women as they enter menopause can be partially compensated for by aromatase's production of estrogens which occur in liver, fat and muscle cells. (This is one reason why obese menopausal women can have higher levels of estrogens than their thinner counterparts. Unfortunately, although the extra aromatase-containing fat cells may be helpful in reducing menopausal symptoms such as hot flashes, they can increase the risk for estrogen-dependant cancers.)

  • Men as they age experience a steady decline of male sex hormones, including testosterone. They also experience a relatively higher level of female sex hormones. These lower androgen/higher estrogen levels have been implicated in symptoms some men experience in middle age, including:
    • Decreased libido
    • Fatigue
    • Flushing and night sweats
    • Insomnia
    • Impaired memory and difficulty concentrating
    • Depression
    • Decreased muscle mass
    • Increased fat mass
    • Osteoporosis

    This lower testosterone/estrogen ratio also seems to be linked to problems with male fertility and sperm count, enlarged prostate, and prostate cancer.

    Since many of these symptoms resemble those experienced by women during menopause, the term "andropause" is sometimes used to describe this time in a man's life.

Non-pharmacological Actors In Aromatase Activity

If you're a man entering middle age who can identify with any of the above symptoms, or if you're a woman concerned about breast cancer, you may find it helpful to manage the activity of aromatase.

The following are associated with a decrease in the activity of aromatase. This decrease would result in reduced production of female sex hormones (estrogens), and a relative increased concentration of male sex hormones (androgens, e.g. testosterone):
  • Younger age (Please contact me if you've found a way to achieve this.)
  • Smoking1 (I don't know if the risks of lung cancer, heart disease, diabetes, and wrinkles outweigh the benefit in reduced estrogen production. OK, strike the wrinkles.)
  • Weight loss (Aromatase resides in fat cells.)
  • Lower levels of insulin
  • Flavonoids (studies vary):
    • Chrysin, a flavonoid found in the herb Passiflora incarnata. (From my reading, chrysin is one of the more potent natural aromatase inhibitors.)
    • Quercetin, a flavonoid found in some fruits and vegetables (cabbage, onions/garlic, apples)
    • Apigenin, a flavonoid found in parsley, celery, and chamomile.
    • Genistein and diadzein, isoflavones found in soy.
    • Red wine flavonoids (Note that while alcohol may increase aromatase activity, other components of red wine decrease it.

The following are associated with an increase in the activity of aromatase (favoring production of female sex hormones (estrogens):
  • Older age
  • Overweight and obesity (Aromatase resides in fat cells.)
  • Higher levels of insulin (insulin favors weight gain, fat mass increase)
  • Zinc deficiency
  • Alcohol intake

The Special Case of Grapefruit

I haven't read a study where grapefruit affects aromatase specifically. But compounds found in grapefruit and its juice inhibit an enzyme group in the complex within which aromatase resides (Cytochrome P450). The enzymes inhibited by grapefruit are involved in metabolizing sex hormones - breaking them down. If you reduce degradation or breakdown of estrogens, that may lead to increased concentrations.

This mechanism is implicated in the findings of a large epidemiological study published this summer:

Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study
In a cohort of 50,000 postmenopausal women spanning 5 racial/ethnic groups, "grapefruit intake was significantly associated with an increased risk of breast cancer." The increased risk was about the same seen in women taking hormone replacement therapy (HRT).

The Special Case Of Alcohol

I read one study from 1990 that suggested aromatase activity was increased by ethanol consumption.2 However, this course of study has not been pursued as much as the theory that alcohol interferes with the metabolism or breakdown of female sex hormones, resulting in their increased concentrations.

Either of the above mechanisms may be implicated in the findings of the following studies:
  1. The effects of moderate alcohol supplementation on estrone sulfate and DHEAS in postmenopausal women in a controlled feeding study
    In a randomized, controlled trial, 51 postmenopausal women received either 1 drink, 2 drinks, or placebo. After 8 weeks, those drinking alcohol had higher levels of circulating estrogens.
  2. Wine, liquor, beer, and risk of breast cancer (Presented at last week's European Cancer Conference.)
    News Summary:
    3 drinks a day raises breast cancer risk: All types of alcohol linked to increase in disease, researchers find
    In a cohort of 70,000 women, alcohol intake was significantly associated with an increased risk of breast cancer. In this particular study, it made no difference where that alcohol was coming from, wine (red or white), liquor, or beer. They all raised risk about the same amount.

In men, excessive intake of alcohol can lead to breast enlargement and shrinking of the testes. This results from a damaged liver's inability to break down estrogens.
"Gynecomastia due to alcoholic cirrhosis - A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no history of drug ingestion, no other endocrine abnormalities and a normal neurological examination. Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis (Laennec's Cirrhosis)."

The Special Case Of Insulin

This warrants a post unto itself. Briefly, a diet that leads to higher levels of circulating insulin has been shown to result in higher levels of estrogens (and lower levels of male androgens).

Insulin resistance, a condition that affects over 25% of the US population (most don't know they have it), a condition that precedes or accompanies diabetes, a condition that is linked to obesity and lack of exercise, can lead to higher levels of circulating insulin.

When it comes to diet, The more fat you eat, and the more saturated that fat, the greater your risk for insulin resistance:

The Influence Of Dietary Fat On Insulin Resistance, Current Diabetes Reports, Oct, 2002
Dietary fat has been implicated in the development of insulin resistance in both animals and humans. ... Clinical trials demonstrate that high levels of dietary fat can impair insulin sensitivity independent of body weight changes. ... Saturated and certain monounsaturated fats have been implicated in causing insulin resistance, whereas polyunsaturated and omega-3 fatty acids largely do not appear to have adverse effects on insulin action.
Dietary Fat, Insulin Sensitivity And The Metabolic Syndrome, Clinical Nutrition, Aug 2004
Insulin resistance:
"Insulin sensitivity is affected by the quality of dietary fat, independently of its effects on body weight. Epidemiological evidence and intervention studies clearly show that in humans saturated fat significantly worsen insulin-resistance, while monounsaturated and polyunsaturated fatty acids improve it."

Blood pressure:
"Shifting from saturated to monounsaturated fat intake reduces diastolic blood pressure."

"Substitution of unsaturated fat for saturated fat not only reduces LDL cholesterol but contributes also to reduce plasma triglycerides in insulin resistant individuals."
There's more I'd like to say but I've run out of space on this post. Maybe I'll say more in future posts.

Update: See related post: Mushrooms Inhibit Aromatase. That's Good.
1 Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro
2 Effects of chronic ethanol intake on aromatization of androgens and concentration of estrogen and androgen receptors in rat liver
Photo of Marie Green's painting, "overlapping male and female with organic lines" from her site.


Sandy Hutchens said...

Now that General Petraeus is widely known to have prostate cancer, it will bring more needed attention to this form of cancer.

Bix said...

Petraeus has prostate cancer? Ouch. He's so young, in his mid-50s I think. said...

You said: "... you might want to limit ... your fat intake, especially saturated."

I'm overweight, with Type 2 diabetes. After reading Gary Taubes' "Good Calories, Bad Calories," I'm trying a low-carbohydrate diet, including lots of whole eggs fried in canola oil. I guess you disapprove?

Anonymous said...

Jim, I'd fry eggs less. Hard boil or poaching would reduce risk from AGE's. My favorite is deviled eggs. Get creative mixing the soft yolk with your favorite healthy ingredients.

ElDoubleVee said...

Good for you Jim Purdy. Now you are sure to die of heart disease. Why leave things to chance when you can assure what you will die of. Diabetes is an insidious disease that destroys you bit by bit over a longer time. A heart attack can be real quick, unless you have a stroke first and become a drooling, incontinent burden. Of course losing weight would really limit or even cure your diabetes but why do that when you can still overeat bad food and point to a book as the fault. You're blameless.

Bix said...

I've seen people lose weight on a low-carb diet, resulting in improved glucose and blood pressure scores. I've seen people lose weight on a low-fat diet, resulting in improved glucose and BP. Weight loss, regardless of the means, often leads to improvements.

Both low-carb and low-fat diets can cause problems, especially in the long-term. People on low-carb diets tend to consume more oxidized fat (grilling/searing/frying) and environmental pollutants. People on low-fat diets tend to consume more overly-processed packaged foods. These choices promote inflammation, and...

Insulin resistance, diabetes, and atherosclerosis are linked to inflammation.

You have to look at the whole diet, what people are actually eating, all the time. And you have to look at the person, their particular condition... physically/mentally/emotionally/socially. What will they do? What can they do?

If you are eating a diet and you aren't experiencing improvements in inflammatory scores, weight, glucose, BP, lipids, bone density, joint motility, sleep patterns, etc. - within a few months - then I would try another diet. I would not abandon a dietary solution.

John M said...

To be quite short .. you right .. I student at a Pharmacology College and I have to say that you're right in the optional classes we learn about this type of what effects and stimulates this endocrine glands so .. I am glad to see that other people .. regular people have knowledge on this matters :)


Anonymous said...

"I'm overweight, with Type 2 diabetes. After reading Gary Taubes' "Good Calories, Bad Calories," I'm trying a low-carbohydrate diet, including lots of whole eggs fried in canola oil. I guess you disapprove?"

Luis- I'm not one to waste time writing cautionary tales to other people but I feel generous today.

Take it from someone who has first hand experience with 'low carb' 'paleo' 'whatever u wanna call it' no carb type of diets.

They are hell, yes they are the most effective at making you lose weight because they simply will shut YOU down, your body starts eating itself and you watch pounds melt off. Trouble starts if you wtick with it (like I did) for months (hey the rsults are good that's what I said to myself) first thing to go is your sex drive, then be ready for a major depression/fatigue and then the heart murmors etc...

One day I will write about my experience but not in this format... my advise something like the zone diet, mediterranean diet is the best for optimal health I'd say slow acting carbs like garbanzo beans and sweet potatoes lots of fish cut the meat and eat as many vegetables as you can

hope it helps

Bix said...

"garbanzo beans and sweet potatoes"

Now, there's a diet.
Thanks for the input, Manu. I agree, "eat as many vegetables as you can." You really can't go wrong.

Anonymous said...

No Thank you Bix, your website is a voice of reason and common sense amidst the misinformation and hidden agendas that infect all the other nutritional websites.

It does sometime get too technical for me, esp since it's not in spanish but let me tell you that every one of your posts about nutrition is rewarding to read. I'll write about my experience with the 'low carb' 'paleo' diet in the future and would love for you to read it.

Bix said...

It's a food journey, isn't it. For all of us.

Would love to hear about your experience, Manu ... how long were you eating low-carb, what foods you did eat and didn't eat, and why you stopped (you mentioned a few reasons).

Derek said...

with a low-carb or no -carb diet.. i have a feeling ur body is just gonna go into gluconeogenesis and start breaking down your own bodily proteins for energy. this will put ur body into starvation mode and slow metabolic rates. you will have decreased libido, and experience weakness. in the short term, you will shave lbs off fast. but upon eating normal again, you will gain it all back and MORE since you body has become an efficient storing machine from the no/low carb diet.

my suggestion to you, just ration your portions to only eat until you are not hungry anymore. eat 5 small meals a day. limit your meat intake (because with meat, you will always get cholesterol), eat lots of vegy, and a moderate amount of carb. if you have time during your week, alternate your cardio and weight workout sessions 2-3 times a day for starters. it doesn't even need to be that long, just get you heart pumping for at least 10-15 min for starters.

Leonard said...

I love beer! How the hell do I attach a pic to a comment? Well, check out my blog pic, no breasts there. ;) peace.

Anonymous said...

For those who are diabetic. . .Please avoid low/no carb diets. As others have said it will have negative long term affects. My 4yr old son was just diagnosed with type 1 two months ago. I have cut out all cows milk, bleached flour, sugar and salt (because of the harmful byproduct alloxan- which causes diabetes). There ARE alternatives. . .watch the soy though as your body may convert it to estrogen. I have increased his omega 3's, fiber and digestive enzymes. His B/G #'s have been stable ever since. He has been off all insulin for 2 weeks now!! He slowly became more and more sensitive to even the smallest amount until .5 units of humalog would send him spiraling into hypoglycemia. So we stopped giving it to him at all. (We are still ready to administer the insulin if need be, we just have to make that call by carfully monitoring his B/G levels). Stick to fruits and veggies, for your carbs and try to only eat sweets you make yourself with whole organic sugar, whole wheat etc. Diabetes is a horrible disease that you can help control, but PLEASE don't starve your body of healthy carbs!! Hang in there and keep researching until you find the right balance for you!! I wish you the best of luck!! Pick up the book DIabetes without Drugs, when you get a chance. It WILL change your life!!!