Aromatase: On Becoming A Woman, Or A Man

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).

________
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.
________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.

Candy Bars Move Underground

From Canada's Winnipeg Free Press today:

Kelvin Students Run 'Black Market' In Sweet Treats

When the school board banned the sale of junk food in cafeterias and vending machines, some students took matters into their own hands:

"I am taking matters into my own hands by selling the stuff out of my locker," said one boy. He also wrote, in response to another boy selling out of his locker: "you better give me a discuont or I will kill you."

Another boy: "I ought to bring a big case of chocolate bars and sell 'em for 75 cents each."

________Hat tip: Food Law Prof Blog

True or False: A Carb is a Carb is a Carb?

Preface:
True or False: A Calorie Is A Calorie Is A Calorie?

True. A calorie is a unit of measure for energy. Specifically, a calorie is the amount of energy needed to raise one gram of water 1 degree Celsius (at atmospheric pressure). What we call a calorie is technically a kilocalorie, the amount of energy needed to raise 1 kilogram of water 1 degree Celsius.

However, "a calorie is a calorie is a calorie" loses its absoluteness when you consider the vehicle used to carry that calorie into the body, and the state of the body accepting the calorie.

"It's not just the calories [contributing to the rise in obesity]. That's the point. It's the effect of the calories on the hormones, and the effect of the hormones on how your body decides to use the calories you're eating -- is it going to burn them as fuel or store them as fat -- and that effect on hunger."
- PBS Frontline, Interview with Gary Taubes, 2004

So ...
True or False: A Carb is a Carb is a Carb?

True. If you saw a carbohydrate strolling down a fashion runway you would be hard-pressed to call it fat. Technically, a carbohydrate is an organic compound, an aldehyde or ketone with lots of -OH groups attached. It is very distinct structurally from a fat or protein.

However, carbohydrates come in many forms, which cause them to elicit different effects upon entering the body.

Sherri passed on this study which appeared in this month's journal Obesity. It describes a case where different forms of carbohydrate (but the same amount of carbohydrate, and the same amount of calories) fed to mice resulted in different effects.

Hepatic Steatosis and Increased Adiposity in Mice Consuming Rapidly vs. Slowly Absorbed Carbohydrate
Here's a summary:
Quick-Burning Carbs May Cause Fatty Liver

Study Basics

• Male mice were fed either high glycemic index (GI) carbohydrates or low GI carbohydrates.
  
• High GI carb was provided by high amylopectin cornstarch. Low GI carb was provided by high amylose cornstarch.
  
• Diets were isocaloric and controlled for macronutrient and micronutrient content. (Diets had the same calories, and the same amounts of carbohydrate, fat, and protein.)
  
• Study lasted 25 weeks

Findings

• No difference between the groups in body weight.
  
• Mice fed high GI diet had higher total body fat.
  
• Mice fed high GI diet had fattier livers (containing almost twice the amount of triglycerides).
  
• Mice fed high GI diet had higher blood levels of insulin (a fat-storing hormone) and triglycerides.

Mechanism
The two carbohydrates in the study differed structurally. This caused a difference in their rate of absorption, and consequently, their impact on postprandial (after-eating) blood glucose, and insulin response.

The high Glycemic Index cornstarch's carbohydrate looked like this:



The low Glycemic Index cornstarch's carbohydrate looked like this:



How the above structures of starch translate into different effects in the body:

• Amylose (bottom figure) is one long, continuous chain of glucose units. Enzymes nip off the end glucose, so you can only free one glucose unit at a time = slower digestion.
  
• Amylopectin has lots of end glucose units, lots of places for enzymes to nip off terminal glucoses simultaneously = faster digestion.
  
• Thus, our bodies experience a faster and higher rise in blood glucose after eating starches with more amylopectin. (The Glycemic Index ranking of a food takes this into account.)
  
• Glycogen, the storage form of starch in our bodies is even more branched than amylopectin, plant's storage form of starch. When we mobilize our glycogen, boy can we dump sugar into our blood!

Comment
The implication of this study is that eating carbohydrates with a high GI may deposit more fat (triglycerides) in our liver, bloodstream, and possibly other organs than eating the same amount of carbohydrates with a lower GI.

Foods with a high GI tend to be highly refined, including any product made from flour, e.g. bread, breakfast cereals, or pasta. White and 100% whole wheat breads have similar GIs because the action of grinding the grain frees the starch for digestion.

See my post on Glycemic Index/Glycemic Load for how to eat a lower GI diet.

If you've had an abnormal liver test, had higher-than-normal levels of liver enzymes, the message this study brings suggests an alternative, drug-free remedy.
________Photos from Mario's Biology Place. Mário Moniz de Sá is an instructor at Langara College, Canada.

Gary Taubes Discusses Epidemiology

Gary Taubes, a science journalist whose 2002 article in the New York Times Magazine, "What If It's All Been A Big Fat Lie" shined a spotlight on low-carbohydrate diets, has written another piece. This one is on epidemiology. It was also published in the New York Times Magazine this past Sunday.

The article is, in essence, a summary of some very basic tenets of the field of epidemiology - the study of the distribution of diseases in populations. I enjoyed it.

If you'd like a taste of what Epidemiology 101 is like, read Mr. Taubes article:

Do We Really Know What Makes Us Healthy?

If you'd rather hear Mr. Taubes tell you what it said, listen to an interview he did with Brian Lehrer of New York Public Radio the day after his article was published:

Weird Science

The site includes some terse listener comments.

Some Background On Epidemiological Studies

Large epidemiological studies (observational as opposed to an intervention), such as the Nurses Health Study (120,000 participants followed since the 1970s), can be used to generate hypotheses, e.g.:

Study 1 (Observational): In the Nurses Health Study, we found that women who took hormone replacement therapy (HRT) also had fewer heart attacks. We hypothesize that HRT can lower the risk for heart attacks.

What we derive from epidemiologic studies are associations and hypotheses. We don't derive cause and effect, so these associations cannot be applied to an individual. For that you need a follow-up clinical trial which tests the hypothesis, e.g.:

Study 2 (Clinical Trial): We gave 1000 women HRT, and another 1000 women a placebo. After 5 years we found that those taking HRT had more heart attacks than those taking placebo.

As you can see, the hypothesis generated from the observational study can be refuted in a clinical trial. Just because it was observed that women who took HRT in Study 1. had fewer heart attacks does not rule out other possible unobserved causes, such as ... are women who take HRT healthier? wealthier with better access to healthcare? These other possible causes, or confounders, may in fact be the true mechanism, not HRT.

To narrow down a mechanism for the observed association you need an intervention, like Study 2. But Study 2 has its own limitations. Note the smaller population size. Clinical trials are also expensive, usually shorter in duration, and come with their own set of confounders (only certain types of people sign up for clinical trials). They're also utterly uselss if you're trying to test a hypothesis that would require exposing one group to a strongly suspected pathogen or other dangerous therapy.

Bad Science?

Mr. Taubes goes into a lot more detail, with many examples. Alas, he takes a dimmer view of epidemiology than I do: "What if it's just bad science?"

Science is a tool. It can be useful, e.g. epidemiological studies first discovered the link between smoking and lung cancer. But it can also be abused, especially when used to advance the agenda of profit-seeking drug companies, reputation-protecting political entities, or fund-seeking academics. So, I can understand Mr. Taubes' cynicism. The media will grab the association from an observational study and run with it, implying that it has ramifications for an individual's health. (Even some study authors will do this.) That is not and never was the case. But you'll see it written up in an Associated Press article that way: "HRT found to protect against heart disease!" Millions of women will start, or continue to take costly hormones with the hope of protecting their heart only to find they've increased their risk for cancer.

Gary Taubes In Quotes

To close, I'll list three quotations from that Gary Taubes' WNYC interview that made me perk up:

Taubes: "Exercise makes you hungry. It does not make you lean."

That was interesting.

Lehrer: "Do you have a hypothesis [as to what causes breast cancer]?"
Taubes: "Yes, I do."
Lehrer: "Which is?"
Taubes: "Which is ... the refined carbohydrates and the sugars in the diet."

Now that's a hypothesis begging to be tested.

Lehrer: "You can't prove your hypothesis either, which is that carbohydrates cause metabolic syndrome."
Taubes: "You cannot prove any hypothesis true. All you can do is refute the hypotheses and see which ones you have left."

This is an elementary fact of science. You cannot prove something is true. You can only disprove, and then refine your hypotheses.

Note: Gary Taubes has a book due out in a few weeks: Good Calories, Bad Calories: Challenging the Conventional Wisdom on Diet, Weight Control and Disease.
________ Photo from WNYC's The Brian Lehrer Show

Breakfast In (Part Of) America

Marion Nestle, on her blog, What To Eat, posted this link today. (Clicking the photos will also take you there.) It's a collection of photographs of people along with their breakfasts by photographer Jon Huck.

I love sneaking a peek at what people eat. I felt like such a voyeur flipping through them. Although it's hard to tell how staged they are.

As slices of America go, this is a very thin one. I believe all of the subjects were Huck's friends living near him in Los Angeles, CA. I noticed a recurrence of certain food items, perhaps owing to their demographics? Have a look and see what you think.

What did you have for breakfast?________

Low-carb Diet Not As Good As Higher-carb In Measure Of Cognitive Function

In my continued exploration of low-carb diets, I ran across the following study from this month's American Journal of Clinical Nutrition. It compared a low-carbohydrate, high-fat (LCHF) diet with a high-carbohydrate, low-fat (HCLF) diet - and their effects on mood and cognitive function:

Low- And High-Carbohydrate Weight-Loss Diets Have Similar Effects On Mood But Not Cognitive Performance

Study Basics

• 93 overweight participants (mean BMI: 33 kg/m²) were randomly assigned to either a LCHF or HCLF diet for 8 weeks
  
• LCHF provided 4% of energy as carb, 61% as fat
  
• HCLF provided 46% of energy as carb, 30% as fat
  
• Mean age of participants: 50.2 years
  
• Diets were isocaloric: no difference in energy intake between the two groups
  
• Women consumed about 6000 kj/day (1428 kcal)
  
• Men consumed about 7000 kj/day (1667 kcal)

Findings

• Both groups significantly reduced body weight:
  LCHF group lost an average of 7.8 kg (17.2 lbs)¹
  HCLF group lost an average of 6.4 kg (14.1 lbs)
  
  
• There was no significant difference between groups in psychological wellbeing. Both groups showed improvements in mood markers (tension, depression, anger, vigor, fatigue, and confusion).
  
  
• There was a significant difference in cognitive function. Cognitive function, as measured by speed of processing, improved less in the low-carb group.

Comment

This study did not support the claim that low-carb diets uniquely result in elevation of mood. Mood improved the same regardless of carbohydrate intake.

I find it troubling that the low-carb diet resulted in less improvement in cognitive function. What's going on inside the bodies and brains of people eating fewer carbohydrates that caused this?

A Note On How Much Carbohydrate Constituted A Low-carb Diet

One medium apple (2 and 3/4 inch diameter), as shown in the photo, provides about 19 grams of carbohydrate. That's about 35% more carbohydrate than the women in the low-carb group in this study ate in an entire day. Most fruits have too much carbohydrate to be compatible with a low-carbohydrate diet.

If you ate just 2/3s of this apple, you could not eat any whole grains, beans, nuts and seeds, milk and other dairy foods, and most vegetables (including lettuce, spinach, and other greens) for the rest of that day, since all those foods contain carbohydrate and you would have already met your allotment.
________ ¹ The additional weight loss in the LCHF group may be explained by fluid loss associated with glycogen loss, since there were higher levels of ketones in the LCHF group.

Photo: Homegrown

Preventing Vision Loss

A story from Reuters last week:

Study Finds Spinach, Eggs Ward Off Cause Of Blindness

Some excerpts:

"Two nutrients found in eggs, spinach and other leafy green vegetables offer some protection against the most common cause of blindness among the elderly, researchers said on Monday."

"Age-related macular degeneration affects 1.2 million Americans, mostly after age 65."

Macular Degeneration Vs. Diabetic Retinopathy

While macular degeneration (MD) is a scourge upon the elderly, I question whether it is the most common cause of blindness in the US. Given the large and growing number of people with diabetes in this country, I would say that diabetic retinopathy (DR) has likely surpassed MD as the most common cause of blindness, at least new cases of blindness.

If we look at how many adults in this country are thought to have diabetes:

"The total prevalence of diabetes among people aged 20 years or older, United States, 2005: 20.6 million; 9.6 percent of all people in this age group have diabetes."
- National Diabetes Statistics

And we apply a prevalence rate for blindness-causing diabetic retinopathy to that number:

"Among an estimated 10.2 million US adults 40 years and older known to have DM [in 1999-2000], the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively."
- National Eye Institute: The Prevalence of Diabetic Retinopathy Among Adults in the United States

We arrive at 9.99 million (40.3% plus 8.2% of 20.6 million adults) or roughly 10 million US adults with some form of diabetic retinopathy in 2005. Even if we apply the more conservative 8.2% prevalence rate for those with advanced vision complications, we still surpass the 1.2 million afflicted with macular degeneration.

Age Group Afflicted

Where age-related macular degeneration usually occurs in an older age group (65+ years), diabetic retinopathy can and does strike a younger population.

The ADA states:

"After 20 years of diabetes, nearly all patients with type 1 diabetes and >60% of patients with type 2 diabetes have some degree of retinopathy."
- American Diabetes Association: Diabetic Retinopathy

Type 1 diabetes is usually diagnosed in people under 30, and often in young teenagers.

Type 2 diabetes can strike at any age. The average age for diagnosis has moved from the 40s and 50s in recent years towards a younger population, with diagnoses occurring in children as young as 2 years old.

Type of Vision Loss

Finally, the two conditions, MD and DR, don't result in similar forms of vision loss. In addition to blurred vision that occurs with both conditions, MD results in central vision loss; DR results in dispersed areas of vision loss.

Here's a normal view:

Here's that same view through the eyes of someone with macular degeneration:

Here's that same view through the eyes of someone with diabetic retinopathy:

You can turn your head and compensate for central vision loss. Compensation for dispersed loss is more challenging.

In sum:

• ~1.2 million Americans have MD
  
• ~10 million Americans have DR

• MD strikes an older population
  
• DR can strike anytime throughout a person's life

• MD results in central vision loss
  
• DR results in widespread vision loss,

So, if diabetic retinopathy strikes more people, at a younger age, with potentially greater repercussions if left untreated, that would say to me it's probably more important to keep blood glucose consistently under 140 mg/dl (diabetes or not), if you're concerned about your sight, than it is to make sure you're getting enough lutein and zeaxanthin.

Not that I'm panning spinach. Actually, I am panning spinach, as much as will fit, along with kale and collards. Greens do a body good!
________Photo of spinach from Mahanandi, a very beautiful and inspirational Indian cooking blog.
Photos of vision loss from NIH National Eye Institute via Wikipedia.

Carbohydrates Are Not The Villain

In my ongoing exploration of low-carb diets ...

I'm not convinced that "carbohydrates" are a problem - not for heart disease, not for diabetes, not for weight disorders.¹ "Carbohydrates" is an all-encompassing word, as are "fat" and "protein". There are many different structures of carbohydrates, as there are fats and proteins, and every single structural difference equates to a difference in function. To tag "carbohydrates" a villain is not to appreciate its fundamental role in our existence.

Having to deal with my own IGT (Impaired Glucose Tolerance) has given me incentive to study further how foods affect metabolism. And I want to say right off ... what goes on in people's bodies when they eat is downright breathtaking.

I'm leaning towards the idea that eating a low-carbohydrate diet is merely treating a symptom of a more systemic metabolic disorder. One symptom of this metabolic disorder is high levels of blood glucose (and its attendant levels of hormones which result in weight disorders, dyslipidemia, etc.). A simplistic solution would be to limit consumption of carbohydrates, since they are a primary source of glucose in our blood, especially after we eat.

One drawback to this simple solution is that we eat fewer carbohydrate-rich foods. These foods offer nutritional benefits. Here are a few:

• They provide nutrients in amounts that fat- and protein-rich foods struggle to provide.
  
• They are foods we evolved to consume.
  
• They are (in addition to fat- and protein-rich foods) pleasurable to eat. Pleasure, with its positive effects on the psyche and immune system, is as important as utility.

I find myself asking, why do we secrete amylase - an enzyme in our saliva that breaks down starches to sugars? (And why, as reported in the journal Nature Genetics this week, do humans have more copies of the gene AMY1 which codes for amylase than other primates? ^{2, 3} )

Why do we have taste buds for sweet foods - foods, such as sugar-laden ripe fruits, that are often carbohydrate-rich?

Why are our intestines lined with microorganisms that convert carbohydrates we eat into chemicals from which we derive benefit?

Low-carb Diets Are Not A Panacea

Another question I've been asking ... Why is glucose getting stuck in the blood? Why isn't it leaving the bloodstream and entering the cells where it can be used? It's natural for glucose to enter the bloodstream after a meal. It's unnatural for it to linger there.

If there was any one group of compounds (and I don't believe there is) that are responsible for weight disorders, heart disease, diabetes, etc., it would not be carbohydrates. It would be the chemical messengers (such as insulin, epinephrine, thyroxin, serotonin, growth hormone, adiponectin, leptin, etc.) that regulate glucose, fat, and protein metabolism.

Those chemical messengers are affected by a host of stimuli. Eating behaviors describe one group of stimuli. But eating behaviors are accompanied by sleeping behaviors, responses to stressful situations, physical activity, rest, environmental pressures, etc.

Regarding eating behaviors, I've incorporated methods to control my blood glucose (and its attendant levels of hormones which can result in weight disorders, dyslipidemia, etc.) that allow me to eat carbohydrate-rich foods without postprandial (after-eating) BG spikes. None of these methods are a secret, and if you've met with a nutritionist or Certified Diabetes Educator, or read this blog, you know them. If I can eek a few more minutes, I'll consolidate them.
________¹ This is not an endorsement of white flour, white sugar, high fructose corn syrup-containing products, and other highly refined foods.
² Diet And The Evolution Of Human Amylase Gene Copy Number Variation
³ BBC summary of above study: Starch "Fuel Of Human Evolution"

Serum Cholesterol Basics

In response to my post linking Dr. Davis' interview about arterial plaque, Melinda asked:

"Are the "small LDL" cholesterol particles the same as VLDL?"

________
Here are some basics:

• VLDL: Very Low Density Lipoprotein
  
• IDL: Intermediate Density Lipoprotein
  
• LDL: Low Density Lipoprotein
  
• HDL: High Density Lipoprotein

VLDL is not the same as the pro-atherosclerotic small, dense LDL. But, by itself, VLDL is also a risk factor for atherosclerosis.

Some Facts About VLDL

• VLDL is generally larger in size than LDL, and less dense (more fatty).
  
• VLDL is triglyceride-rich.
  
• VLDL + LDL + HDL = Total Cholesterol. (Assuming the lab includes IDL in the LDL figure. Lp(a) is also included in the LDL figure.)
  
• VLDL is converted to IDL, and then to LDL, in the bloodstream. (VLDL --> IDL --> LDL)

Why is Small, Dense LDL a Problem?

Small, dense (protein-rich) LDL is more of a problem than larger, less dense (fat-rich) LDL because the small variety:

• Doesn't get cleared as quickly from the bloodstream as larger LDL. (Larger LDL fits the LDL-receptor better.)
  
• Tends to stick more easily to the artery wall.
  
• Is more susceptible to oxidation. The oxidation of LDL is one of the larger contributors to the development of a fatty streak.

Relationship Between VLDL and Small LDL

One relationship between all these types of fats:

• When your triglycerides are low, your VLDLs contain less triglyceride and are smaller. They tend to convert to larger LDL in the bloodstream.
  
  
• When your triglycerides are high, your VLDLs contain more triglyceride and are larger. They tend to convert to smaller LDL in the bloodstream.

Lowering Small LDL

One goal then to lower levels of small, dense LDL is to lower triglycerides. This can be accomplished by:

• Weight loss.
  
• Lowering the glucose load (eating fewer refined carbohydrates and sugars), although this effect may not have as great a long-term effect as weight loss.
  
• Consuming omega-3 fatty acids, especially EPA and DHA (found in fish oil), which have been shown to sharply reduce levels of triglycerides.
  
• Taking niacin (nicotinic acid).
  
• Taking fibrates (a unique mechanism of action that I hope to write about later).
  
• Increasing physical activity.

All of the above, except for fish oil, also tend to increase HDL, which is good.
________

An Interview About Heart Disease That May Change Some Of Your Preconceptions

See these numbers?
Total cholesterol: 248 mg/dl
LDL cholesterol: 171 mg/dl

They may, by themselves, have very little to say about your actual coronary plaque buildup.

Dr. Davis from The Heart Scan Blog was recently interviewed by Jimmy Moore on his Livin' La Vida Low-Carb™ Blog.They discussed:

• Typical Cholesterol Panel vs. Lipoprotein Testing
  
• Saturated Fat Intake
  
• The Atkins Diet
  
• Heart Scans

The entire interview is on Jimmy Moore's blog:
Davis: Wanna Cut Plaque In Your Arteries? Slash Your Carbohydrates!

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Here were a few passages that stood out for me:

From Question 3:

Moore: Why is [LDL cholesterol] such a poor way to gauge heart disease risk?


Dr. Davis: It's no secret: LDL cholesterol has proven a miserable failure as a detector of coronary heart disease.

Abundant clinical trial experience has borne this fact out: LDL cholesterol of the average American: 132 mg/dl; average LDL cholesterol of someone suffering a heart attack: 134 mg/dl - they’re virtually indistinguishable.

Cholesterol is a predictor on a statistical basis, but fails miserably when applied to a specific individual.

From Question 4:

Moore: What’s wrong with the low-fat, low-salt, low-cholesterol (DASH) diet recommendation that Dr. Ornish and virtually every other medical professional prescribes to people who are developing or already have heart disease?

Dr. Davis: The misguided advice offered to most people is that a low-fat diet reduces cholesterol and heart disease. This is simply untrue for the majority of people.

In fact, the opposite is true: a low-fat, high-carbohydrate diet filled with wheat products like whole grain bread, wheat crackers, pretzels, fiber breakfast cereals, and wheat pasta raise cholesterol. Corn starch-containing products, white rice, potatoes, and processed carbohydrates are similarly to blame.

They raise small LDL cholesterol particles, the worst form of cholesterol of all. While large cholesterol particles are rather harmless, the small cholesterol particles are the ones behind heart disease in over 70% of cases. And it's small LDL cholesterol that is hugely magnified by high-fiber, high-carbohydrate diets.

From Question 8:

Moore: Just so we're perfectly clear about what you are saying, am I right in assuming you believe people should stop worrying about their cholesterol numbers because they really don’t have a bearing on heart disease? How about those who are taking cholesterol-lowering statin medications like Lipitor, Zocor, and Crestor, among many others to lower their “high” cholesterol? Is there a reason for them to remain on those drugs in light of what we now know about heart disease?

Dr. Davis: The cholesterol reducing drugs do have role - unfortunately, the majority of people are put on these drugs for the wrong reasons.

Let me explain. Someone will come in because of a reportedly high cholesterol. We do more testing and discover that the majority, say, 90%, of the cholesterol particles are small. This pattern is very likely to contribute to formation of plaque in the arteries. It also responds exceedingly well to a reduced carbohydrate diet. Many, many times, a person with this pattern will follow a diet that slashes carbohydrate content and cholesterol levels drop like a stone. In this instance, statin cholesterol drugs may be entirely unnecessary.

Another exception: A person with a high cholesterol that is not truly high. When you are provided an LDL cholesterol from your doctor’s office, it has not been measured, it has been estimated. The crude estimation is based on a calculation called the "Friedwald equation," an equation derived in the 1960s when new technology for testing was not yet available.

It sounds ridiculously simple, but simply measuring cholesterol can provide insights that can often suggest that a statin cholesterol drug is not necessary. The more sophisticated testing is called "lipoprotein testing."

From Question 9:

Moore: Who or what do you believe is driving this heart disease “business”?

Dr. Davis: Performing heart procedures pays big money. Prevention of heart disease does not.

Physicians and hospitals ... operate businesses that are meant to profit from treatment of disease. ... Put in a stent and reap about $2000 to the cardiologist, $25000 or more to the hospital. Perform a heart bypass operation, and the physician gets at least $5000, the hospital $70-100 thousand.

Prevent a heart attack and you get paid . . . maybe a couple of hundred dollars for several hours work.

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A point Dr. Davis drove home here for me was the rising significance of small, dense LDL cholesterol in the formation of arterial plaque ... and the waning significance of LDL alone.

LDL cholesterol is especially nebulous as a indicator for coronary risk:

1. When that LDL-C amount is estimated, not measured. This is a point Dr. Davis makes often on his blog. The estimate, as I understand it, is provided by the Friedewald equation:
   LDL = TC - HDL - TG/5
   That is, LDL cholesterol = Total cholesterol, minus HDL cholesterol, minus one-fifth of Triglycerides. TG/5 is an estimation for VLDL. All concentrations in mg/dl.
   
   
2. When that LDL amount is not considered together (as a ratio) with other cholesterol fractions and fats in the blood.
   This is a reason why total cholesterol (TC), by itself, also doesn't say much. For example, if your TC is in the desirable range (less than 200 mg/dl), but that portion of it that is HDL is relatively low, that would be a worse atherosclerotic scenario than if HDL's contribution was higher.

The development of atherosclerotic plaque involves many players. One player I've been reading about is lipoprotein(a) or Lp(a) for short. LP(a) is a particle of LDL attached to a carbohydrate-rich particle that contains a specific protein: apolipoprotein(a) or apo(a) for short.

Some things about Lp(a):

1. It responds very weakly if at all to statin drugs.
   
2. The attached protein, apo(a), causes the whole Lp(a) complex to behave in a pro-atherosclerotic way. More on that later.
   
3. The Friedewald-equation-estimate of LDL has buried in it the LDL contained in Lp(a). If your statin therapy is not producing desirable outcomes, it may be that statin-resistant Lp(a) makes up a sizable portion of your LDL.

There's a whole lot more about Lp(a) and other lipoproteins on Dr. Davis' blog.
For some basic information about cholesterol, spurred by Melinda's question, "Are the "small LDL" cholesterol particles the same as VLDL?", see my post, Serum Cholesterol Basics.


A question I have after reading the above interview:
How do insurance companies weigh in? Do they make more money in premiums, deductibles, and copays than they put out in invasive heart procedures? (It would seem they do, as they continue to prioritize pay-outs for these procedures over prevention methods.)

One thing I like about Dr. Davis ... He's an optimist. His eyes are always open. And for him, as I see it, the answer to a reduction in heart disease is not static. It's dynamic, a collaborative journey.
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The Face of Diabetes

The photo I chose to illustrate my previous post on depression and its relationship to diabetes (Depression Ups Risk For Heart Attack) is typical of the Face of Diabetes for me. The photos below, from actual diabetes-related advertisements, are not typical of the Face of Diabetes for me.



Below are a few more photos of what diabetes looks like to me. I'm not saying that I never see diabetes in the slender, the smiling, the socially and economically secure. But the people in the photos below are more familiar to me.




The photos above are from a series of articles the New York Times ran on diabetes in January, 2006.¹ There are more at this link.
________¹ The New York Times four-part series on diabetes. (I think you can get to most of them without signing in.):
Diabetes and Its Awful Toll Quietly Emerge as a Crisis
By the Numbers: One Scourge in 2 Forms
In the Treatment of Diabetes, Success Often Does Not Pay
East Meets West, Adding Pounds and Peril
Living at an Epicenter of Diabetes, Defiance and Despair
I think the photographer, Vincent Laforet, did a great job of capturing the reality of this disease.

Depression Ups the Risk for Heart Attack

Over the years, I've seen a number of studies that support a link between depression and heart disease, depression and stroke, depression and diabetes. Anecdotally, I've witnessed this.

The ability of depression to predict heart disease and heart attack was found to be independent of risk factors you might think would be more predictive. Barefoot et al. controlled for age, sex, systolic blood pressure, total cholesterol, triglycerides, insulin, smoking, pulmonary function, sedentary work, and sedentary leisure and still found that depression independently increased the risk for heart attack and death.¹

So, you may have your cholesterol, blood pressure, and blood sugar under control. You may get enough exercise and not smoke. But if you can identify with items in the lists below, controlling for the factors I just mentioned may not be enough to stave off heart failure.

Medscape has a nice synopsis (registration is free):
Depression and Stress Hit Hard on Heart

In my experience, people are eager to tell you the intricacies of their blood work. Every last mg/dl. But they're less inclined to tell you that they haven't slept through the night in years, or that they'd rather stay in bed than do anything else. They won't tell you they barely overcome a sense of anxiousness or despair to leave the house. They'll say they've just been feeling tired lately, when what might better describe their reluctance to do things is a loss of interest ... in people, in what they used to enjoy, in life.

The National Institute of Mental Health lists the following as symptoms of depression and mania:

Depression

• Persistent sad, anxious, or "empty" mood
  
• Feelings of hopelessness, pessimism
  
• Feelings of guilt, worthlessness, helplessness
  
• Loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex
  
• Decreased energy, fatigue, being "slowed down"
  
• Difficulty concentrating, remembering, making decisions
  
• Insomnia, early-morning awakening, or oversleeping
  
• Appetite and/or weight loss or overeating and weight gain
  
• Thoughts of death or suicide; suicide attempts
  
• Restlessness, irritability
  
• Persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain

Mania

• Abnormal or excessive elation
  
• Unusual irritability
  
• Decreased need for sleep
  
• Grandiose notions
  
• Increased talking
  
• Racing thoughts
  
• Increased sexual desire
  
• Markedly increased energy
  
• Poor judgment
  
• Inappropriate social behavior

Although depression typically conjures a low mood, or in the case of bipolar depression, a low-high mood swing, aggression and anger are emerging as diagnosable traits for depression.²

The Medscape article from above says about anger:

"A long-term study of more than 1000 men found that those who had angry or irritable responses to stressful situations were 3 times more likely to be diagnosed with heart disease and 5 times more likely to suffer a heart attack before the age of 55. ... These results were independent of cholesterol levels, body mass index, or blood pressure. Anger was also found to increase the risk of depression and anxiety."

I'll see people shrug off, or attempt to shrug off, feelings listed above. That shrug is equivalent to ignoring the effects of clogged arteries, elevated blood pressure, sugar-loaded blood vessels, even a previous heart attack. Depression is an underrecognized, undertreated, and potent risk factor for cardiac failure.

If the goal is to fend off heart attack, why aren't physicians as eager to prescribe antidepressants and talk therapy as they are statins and ACE inhibitors? Why aren't insurance companies as eager to cover treatment for depression?

Roland von Kanel, MD, a professor of medicine and head of the psychosomatic division at University Hospital Berne in Switzerland, in response to a depression/heart attack study that appeared in the Journal of the American Collage of Cardiology in December, 2006³, said:

"Given what we now know, I believe that screening for depression should be part of today's clinical practice in a cardiology setting any time a patient is referred to the ICU with a heart attack. ... Depressed patients should be treated with counseling, referral to a psychotherapist and/or antidepressant medication - preferably an SSRI (selective serotonin reuptake inhibitor) - depending upon the severity of their depression."
- Heart Attack-Related Depression Puts Patients At Risk For Further Cardiovascular Emergencies

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Depression And Diabetes

Depression is rampant in the diabetic community. One recent study placed the prevalence at about 25%.⁴ As a comparison, the NIH reports that about 9% of the general adult population suffers mood disorders. A study from June found that having diabetes almost doubles the risk for depression, and that there may be a link to high HbA1c (higher-than-normal blood glucose levels).⁵

As alluded above, those with heart disease also experience depression at a higher rate. One meta-analysis (a study of studies) found that depression can at least double or triple the risk of having a second heart attack, or of dying.⁶

A number of hypotheses have been put forth to explain the associations between depression and diabetes or heart disease, some organic (internal chemistry), some functional (situational, e.g. "Who wouldn't be depressed if they had to prick their finger 3 times a day and watch everything they ate?"). No one argues that the combination of depression and diabetes, or depression and heart disease, exacerbate one another. And as the meta-analysis cited above reveals, when depression and diabetes or heart disease coexist, death can come sooner.

Abstracts presented at The American Psychosomatic Society's annual meeting this year bear this out. The Washington Post summarized one of them here:
Heart Disease, Diabetes, Depression a Deadly Mix

So if the leading cause of death among people with diabetes is heart attack, and if depression hastens heart attack, and if depression is widespread among diabetics, wouldn't it make sense to have mental health screening part of the care package for these chronic diseases? I think it would.⁷

________¹ Symptoms Of Depression, Acute Myocardial Infarction, And Total Mortality In A Community Sample
² Anger Attacks In Bipolar Depression: Predictors And Response To Citalopram Added To Mood Stabilizers
³ Only Incident Depressive Episodes After Myocardial Infarction Are Associated With New Cardiovascular Events
⁴ Depression Treatment And Satisfaction In A Multicultural Sample Of Type 1 And Type 2 Diabetic Patients
⁵ Diabetes Mellitus, Glycemic Control, And Incident Depressive Symptoms Among 70- To 79-Year-Old Persons
⁶ Prognostic Association Of Depression Following Myocardial Infarction With Mortality And Cardiovascular Events: A Meta-Analysis
⁷ If an herb like St. John's wort can be shown to be as effective as pharmaceutical antidepressants ... at a lower cost and with fewer side effects ... why shouldn't we standardize and prescribe it?

Photo: American Diabetes Association

St. John's Wort Vs. Celexa

A once-daily dose of St. John's wort extract finished in a dead heat against the popular pharmaceutical anti-depressant Celexa for cases of moderate depression. Side effects were fewer in those taking St. John's wort compared to Celexa. (Lexapro is the newer version of Celexa.)

That was the result of a study conducted in Germany last year and reported in the journal Pharmacopsychiatry .^{1, 2}

Study Specs

• Clinical trial: Double-blind, randomized, placebo-controlled, multicenter
  
• Participants: 388 outpatients, 6-week treatment
  
• Interventions: St John's wort 900 mg/day, or Celexa (citalopram) 20 mg/day, or Placebo

Findings

Based on changes in mood and number of people responding, "The hypericum [St. John's wort] group was not statistically different from the citalopram [Celexa] group, and significantly superior to the placebo group."

"Significantly more adverse events with "certain", "probable" or "possible" relation to study medication were documented in the citalopram group."

"These results revealed that hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression."

There's a wealth of untapped therapeutic aid to be found in botanicals. It's unfortunate there isn't a good pool of research to assure its safety and efficacy, not in the US at least. I don't expect that will change soon given the disparity in industry profits between herbals and synthetics:

Retail price for 30 day supply:

• St. John's wort extract, 300 mg, 90 caps: $8.99 (Vitamin Shoppe brand)
  
• Celexa (Forest Pharmaceuticals), 20 mg, 30 tabs: $103.62 (Drugstore.com)

No wonder Europe embraces herbal medicine. (The National Institute of Mental Health states that, "Today in Germany, Hypericum [St. John's wort] is used in the treatment of depression more than any other antidepressant.") Their governments are footing their healthcare bills.


Related Post: Depression Ups the Risk for Heart Attack

________¹ Comparative Efficacy and Safety of a Once-Daily Dosage of Hypericum Extract STW3-VI and Citalopram in Patients with Moderate Depression: A Double-Blind, Randomised, Multicentre, Placebo-Controlled Study
² It's a good idea to check with your doctor before self-medicating depression. There's a risk in undertreating more potent, clinical depression. And it's come to light that children and adolescents may experience sudden, undesirable changes in mood while taking an antidepressant. In regards to St. John's wort specifically, this herb affects a particular enzymatic pathway that the body uses to metabolize drugs. As such, it may interfere with the action of other drugs you may be taking. Just get the nod from your doc.