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.
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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.
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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.
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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.

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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

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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).

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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)."
- MedStudents.com

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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."

Lipids:
"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.