Steve Provonsha MD MPH

• Journal of Clinical Endocrinology and Metabolism 2006; 91:4237- 45• Recognized that it is difficult to define a syndrome• Never-the-less, they reviewed a large number of papers

with a large number of patients to determine the most consistent predictors of PCOS.

• Hyperandrogenemia in 60 – 80% (free testosterone) 25% with supranormal levels of DHEAS (not DHEA). In 10% elevated DHEAS may be the sole abnormality.

• Hirsutism in 60% (Especially White, Black, Southern Asians, Maori, Pacific Islanders)

• Acne in 15 – 20% (may be the same prevalence as general population – more studies need to be done)

• Polycystic ovaries in 75% (ovary volume > 10 cubic centimeters OR 12+ follicles measuring 2-9 mm in diameter)

• Eumenorrehic patients can also have the syndrome: Test the progesterone level 20 – 24 days after onset of vaginal bleeding and look for a result below 3 – 5.

• Androgen related disorders affect 6 – 8% of women of reproductive age.

• 70 – 90% of these are women with PCOS• The rest are adrenal hyperplasia, androgen secreting

tumors, and “severe insulin resistance.” ??

• Idiopathic Hirsutism affects 5 – 15% of women• Non-classic adrenal hyperplasia due to 21-

hydroxylase deficiency, affects between 1 – 8% of women with androgen excess and is one of the most common autosomal recessive disorders of man.

• The expert consensus is that this is not known.• In my opinion, this usually means researchers have not

found any “key” biochemical reaction they can create a drug for.

• Androgen Excess Society.• On their website (at least) are not very clear about any

connection between insulin resistance and PCOS. Possibly drawing a line between insulin resistant versions of PCOS and another genetic or epi-genetic cause for the syndrome.

• The American College of Obstetrics and Gynecology (ACOG) appears more committed to a relationship between PCOS and insulin resistance.

• Some textbooks comment on the number of shared symptoms between PCOS and..• Acromegaly• Cushing’s Syndrome

• And indeed they do share a lot of symptoms which is interesting because both are conditions that create insulin resistance.

We have the machinery within us to be insulin resistant – In fact, it’s extensive and fundamental to our physiology:

• There are four reasons we are naturally insulin resistant.

We have the machinery within us to be insulin resistant – In fact, it’s extensive and fundamental to our physiology:

• There are four reasons we are naturally insulin resistant.– Injury (I.R. due to hormones including cortisol. Also

cytokines)

We have the machinery within us to be insulin resistant – In fact, it’s extensive and fundamental to our physiology:

• There are four reasons we are naturally insulin resistant.– Injury (I.R. due to hormones including cortisol. Also

cytokines)– Growth (I.R. is related to Pituitary GH and IGF-1)

We have the machinery within us to be insulin resistant – In fact, it’s extensive and fundamental to our physiology:

• There are four reasons we are naturally insulin resistant.– Injury (I.R. due to hormones including cortisol. Also

cytokines)– Growth (I.R. is related to Pituitary GH and IGF-1)– Lactation (Prolactin causes Insulin Resistance)

We have the machinery within us to be insulin resistant – In fact, it’s extensive and fundamental to our physiology:

• There are four reasons we are naturally insulin resistant.– Injury (I.R. due to hormones including cortisol. Also

cytokines)– Growth (I.R. is related to Pituitary GH and IGF-1)– Lactation (Prolactin causes Insulin Resistance)– Pregnancy (The chemistry of pregnancy can cause GD)

• These four interact on purpose.

The Rule

• The body is set up to be insulin resistant for one thing at a time.

• The conditions are in a hierarchy of importance.

• First & foremost, emergency / injury trumps all:– Injury and chronic illness: will stunt growth.– Injury or extreme stress: will stop lactation.– Injury or extreme stress: will initiate labor or

cause abortion. Of course it also prevents conception.

• Estrogen: The VERY hormone that makes fertility possible makes growth impossible.

• Estrogen closes growth plates• Estrogen feeds back to pituitary GH and inhibits it.

• Estrogen matures sperm, so is also important for fertility in males.

• Thus we grow first, and then the sex steroids add finishing touches. Growth is done. Children should not be having children.

Lactation

• Prolactin stops the menstrual cycle.

• So• Among the 4 natural reasons for insulin resistance –

pregnancy has the lowest priority.• Injury inhibits it – Stress hormones / Cortisol / Cushing’s• Growth inhibits it – IGF-1 / Acromegaly• Lactation inhibits it – Prolactin / Prolactinoma• In addition, starvation also inhibits fertility and is a

passive form of insulin resistance

• All but certainly has something to do with the fact that when insulin resistant, the potentially calorically competitive function known as fertility has to be turned off. So even spontaneous abortion is more likely.

• Growth, or injury or lactation ultimately activates a common cytokine-mediated signaling system that prevents competition for calories.

The Reason for Insulin Resistance• The purpose of insulin resistance is to

redirect calories.

Resistance

Calories Lean Body Mass

The Bloodstream

Resistance

Calories Lean Body Mass

The BloodstreamTraumaGrowth platesNursing newbornFetus

TraumaGrowth platesNursing newbornFetus

Elevated Peripheral Insulin level

• The natural reasons for insulin resistance include something that is a calorie drain. Like a pressure relief valve. Calories are tapped away.• Healing – wounds.• Growing – growth plates / GI tract / muscles• Milk production for a newborn• Fetal growth and development

• When insulin resistant and none of these are present, we have a problem.

• In the discussion of insulin resistance, there is a curious confusion: The same author saying that weight causes it while at the same time inferring that insulin resistance results in weight gain. No one ever challenges this.• Cushings disease – Insulin resistance first – weight next.• Acromegally – Ditto• Prolactinoma – Again Ditto• Gestational Diabetes – When uncontrolled the baby is

heavier. Controlled and the mother gains more weight. Ditto.

Any disease condition that inappropriately activates insulin resistance when it is not needed, always has weight gain as one of its symptoms.

Because of resistance, the calories we can’t assimilate, must be disposed of as body fat. Fat cells are the most sensitive cells to insulin. It has to be this way, our bodies have no choice.

Resistance

Calories Lean Body MassThe Bloodstream

Body Fat

Resistance

Calories Lean Body MassThe Bloodstream

Body Fat

This is abundantly clear in Cushing’s disease where the cortisol effect is strong enough to cause lean body mass changes like osteoporosis and loss of muscle mass (Cushing’s patients are notoriously weak – cannot do protein synthesis).

Yet the cortisol levels are not so much high, as they are elevated to night time (diurnal) levels during the day when the subject eats.

• Regarding Cushing’s Syndrome• “In this disease due to adrenocortical hyperplasia, the

plasma cortisol level may be either normal or elevated, but it remains at approximately the same level throughout the 24 hour period.” Vol. 1 Page 640.

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• It appears that the only thing blunted by insulin resistance is the ability to control blood sugar.

• The resulting abnormal levels of insulin adjust any other insulin dependent function to abnormal.• Reduce IGF-1 BP3 (growth hormone binding protein)• Reduce SHBG (sex hormone binding globulin)• Water retention at the kidney• Activate Calorie uptake in adipose tissue.• Increase hunger• Many others.

• Two most populated nations: China and India• At one time an economic difference:

• Could not afford the diet of the west.• Could not afford cars. Walked, rode bikes.

• America (wealthy nations):• Adopt children from all over the world, China and India

included.• Numerous fertility clinics• Fertility drugs and treatments - Triplets, Quadrouplets,

Pentuplets, Sextuplets, Septuplets, Octamom

• Their traditional diets include a higher percentage of carbohydrate (potatoes, beans, rice, other grains) than ours.

• They are smaller, slimmer, and appeared to be more fertile.• China 1.34 BILLION people – Unfortunately, infertility is on

the rise (In men too) 3% infertility in the 1980’s. Now 10%• India 1.16 BILLION people – Infertility is also on the rise.

• What is also on the rise is…• Their income and therefore their animal protein

consumption. This ALWAYS happens. “Got money” – “where’s the beef”.

• The Nurses Health Study:• Lowest group 77 grams protein per day• Highest group 115 grams protein per day• The women in the highest protein group were 41% more

likely to have reported problems with ovulatory infertility than the lowest protein group.

• Ovulatory infertility was 39% more likely in women with the highest intake of animal protein than those with the lowest.

• When total calories kept constant, adding one serving a day of red meat, chicken or turkey predicted nearly a 33% increase in the risk of ovulatory infertility.

• Found that for every 25 grams of plant protein substituted for animal protein, fertility went up 50%

• Studies show vegetarians are the least insulin resistant. The longer vegetarian, the less insulin resistant.• Kuo, Eur J Clin Nutr, 58, Feb 2004• Valachovicova, Eur J Nutr, 45, Feb 2006• Hung, C. J., P. C. Huang, et al. (2006). "Taiwanese vegetarians

have higher insulin sensitivity than omnivores." Br J Nutr 95(1): 129-135.

• Lyon Heart Study• Mediterranean plant emphasizing diet with fish (anti-

inflammatory fish oils) reduced risk of heart attack• Best predictor of heart attack. White cell count. The immune

system as a predictor of heart attack?• The people of the Mediterranean are abandoning their diet.

Obesity is on the rise.

• The lay public commonly believes that sugar makes you insulin resistant simply because they know insulin has something to do with sugar, AND Dr. Atkins said it.

• However, infusing 30 g essential amino acids has a greater effect on insulin (183 uU/ml) secretion than 30 grams of glucose (52 uU/ml). Floyd JC, Fajans SS, Conn JW, Knopf RF Stimulation of insulin secretion by amino acids. J Clin Invest 1966 Sep, 45(9): 1487-1502

• Arginine alone or essential l-amino acids were the most potent stimulus for insulin secretion. 120 microunits per ml for the essential amino acids and 81 for the arginine. Histidine, an essential amino acid in infants is the least 6 microunits per ml.

• What is different between amino acid infusion and glucose infusion is the production of IGF-1 and glucagon. Both respond to amino acids, but not to glucose.

• However glucose indirectly increases IGF-1’s effect.• IGF-1: Remember, type I diabetics must inject more

insulin during the growth spurt.• Glucagon: - not really Protein’s “insulin”

• Makes the liver give up its glycogen stores and converts protein to sugar. It shifts insulin’s glucose control activity to the peripheral circulation instead of the liver. It also activates clotting factor and platelet production, compliment synthesis, intestinal atony and can decrease digestive enzyme production.

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Date Wt Insulin Glucagon Chol HDL Trig LDL Ratio Diet

July 96 241 11 304 46 338 173 6.6 Mixed

Sept 96 215 8.9 38 165 47 120 94 3.5 Veg.

Oct 96 10 41 172 48 225 79 3.6 High Prot.

Dec 96 11.1 53 192 62 95 111 3.1 High Prot.

May 97 15.9 48 210 58 114 129 3.6 High Prot.

Mar 98 12.6 73 235 58 128 151 4.1 High Prot.

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Richard Gray, Peter Butler, Thomas Beers, Journal of Clinical Endocrinology and Richard Gray, Peter Butler, Thomas Beers, Journal of Clinical Endocrinology and Metabolism 81:1508-1511, 1996Metabolism 81:1508-1511, 1996

• Muscle: Biggest protein depot in the body. If something is going to grow, these are the kind of amino acids we need for a LOT of growing.

• Milk: for making mammals grow.• Egg White: Essential amino acid starter kit.

• Don’t nurse and don’t have the muscle mass of land animals.

• Either carnivorous or often eat a lot of seeds (Higher protein)

• However with respect to growth, the body must adapt to the composition of the diet.

IGF-

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BP

Must use protein as fuel. Less for growth.

Uses carbs as fuel – more protein for getting bigger.

InsulinInsulin

• Carbs don’t make you fat, they make it possible for protein to grow you bigger.

Insulin

InsulinInsulin

EA

A’s EA

A’s

Unrefined Carbs

Refined Carbs

Amino acids still activate insulin

• We’re kidding ourselves when it comes to the morbidly obese.• People don’t gain weight, they grow bigger.

• More skin• More fat cells – Physics - a fat cell can only get so big.• Blood vessels – a mile of capillaries in every pound of body

fat.• Nerves to the skin• Blood cells in the blood vessels (otherwise anemic)

• Think about that, the next time you consider “weight set point.”

• The obese have a higher RMR (metabolism) because there is more living tissue.

• The obese have a higher risk of cancer.

• Where there is growth there is cancer• Estrogen and breast /

endometrial• Testosterone and

metastatic prostate cancer

• Free IGF-1 Do a pub med search in IGF- and cancer and you get…

• Inhibition of apoptosis when the body is being instructed to grow.

• 1930’s McCay• 2003 Zimmerman and Methionine (and

Tryptophan)• Currently

• Taking the same mice and knocking out their growth hormone receptors. They live 2x as long and starving them doesn’t make them live any longer.

• Bonkowski M, Rocha J, Masternak M, Regaley K, Bartke A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. PNAS May 16, 2006 103:20 7901-7905.

• Telemeres – Dolly the Fin Dorset sheep• The Metronome principle

• The Hayflick limit.

• Studied high protein diets in the Nurse’s Health Study

• Found an increased all cause mortality (including cancer) in men and women if the protein was animal protein, and a decreased all cause mortality if the protein was of plant origin. Fung Ann Intern Med 2010

• Increased risk of Type 2 diabetes on a low carb diet.• de Koning 2011 Am J Clin Nutr

• Studies have been done comparing Metformin to lifestyle for delaying the onset of Metabolic Syndrome / diabetes• Incidence of Metabolic syndrome decreased by 41% in the

lifestyle group and by 17% in the Metformin group.

• Metformin – just the liver• Lifestyle – all of it.

• Orchard, T. J., M. Temprosa, et al. (2005). "The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial." Ann Intern Med 142(8): 611-619.

• Knowler, W. C., E. Barrett-Connor, et al. (2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin." N Engl J Med 346(6): 393-403. (3234 people)

• The dangerous side effect of Metformin? – Lactic acidosis• When we are injured, the liver participates in the Cori Cycle.• There is anaerobic metabolism in any tissue that

experiences disruption of blood flow. The lactate goes to the liver and it is converted to sugar. The liver also releases its own stored glucose and is in a state where it will NOT take up glucose.

• This is all to feed the damaged tissue.• Metformin appears to interrupt this mechanism, and

successfully reduces blood sugar.

PainPainStopsStops ExerciseExercise

LiverLiverInflammatory Chemistry

Lactic Acid

Inflammatory Chemistry

Lactic Acid

Provides Fuel ForProvides Fuel For

SugarSugarInjuryInjury

Provides Fuel ForProvides Fuel For

Shuts DownShuts Down

Petersen et al.

• An inverse relationship between vegetarian dietary pattern and metabolic syndrome. Amini M, Esmaillzadeh A, Relationship between major dietary patterns and metabolic syndome among individuals with impaired glucose tolerance. Nutrition. 2010 Oct,26(10): 986-92.

• Almonds and walnuts had some mild benefit for PCOS

• Low glycemic index foods were mildly helpful• Fish oil helps• Ezzat, V. A., E. R. Duncan, et al. (2008). "The role of

IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease." Diabetes Obes Metab 10(3): 198-211.

• Vegetarians have lower serum ferritin levels - IL-6. Donovan J Am Coll Nutr 1995

• Vegetarians have decreased platelet counts. Kjeldsen-Kragh, Scand J Rheumatol 1995

• Vegetarians have decreased leukocyte counts with no increase in rate of infection. Kjeldsen-Kragh, 1995 and Ball, Eur J Clin Nutr 1994

• Vegetarians have reduced compliment levels. Kjeldsen-Kragh, 1995

• A lifestyle improvement and risk reduction program

• Goals:• Restoration of menstrual cycle• Return of fertility• Better health and long term risk reduction

• A program for losing weight.• A program for prescribing Metformin (Glucophage)

• Initial one time group session.• Educational booklet• Table on Glycemic index• Food examples – recipes 90% vegetables and fruit – animal

protein as an ingredient / condiment.• Fish oil 2000 mg daily• Vitamin D assay – 25-oh Vitamin D (Vitamin D is a sterol and

seems to have some anti-inflammatory properties like cortisol, another sterol). If low, supplement 2000 – 3000 international units daily.

• Exercise

• Individual follow-up• Metformin• Appetite suppression if desired.

• Second group session for support.

Methionine

• Our biggest protein depot – muscles, do not contain much methionine or tryptophan RELATIVE to other essential amino acids. And in fact, the body doesn’t contain much methionine period.

• Plants and animals don’t either• Furthermore, plant proteins are abundant enough

in the other essential amino acids – just naturally low in methionine and tryptophan.

• Have little methionine and tryptophan relative to other amino acids.

• It’s just that meat, being so high in protein and because it is muscle, has a lot of both but especially methionine.

• In animal husbandry, they feed extra methionine to chickens and pigs and cows to make them… Bigger.

• This is an interesting choice.

Ala A GCU, GCC, GCA, GCG Leu L UUA, UUG, CUU, CUC, CUA, CUG

Arg R CGU, CGC, CGA, CGG, AGA, AGG Lys K AAA, AAG

Asn N AAU, AAC Met M AUG (start)

Asp D GAU, GAC Phe F UUU, UUC

Cys C UGU, UGC Pro P CCU, CCC, CCA, CCG

Gln Q CAA, CAG Ser S UCU, UCC, UCA, UCG, AGU, AGC

Glu E GAA, GAG Thr T ACU, ACC, ACA, ACG

Gly G GGU, GGC, GGA, GGG Trp W UGG

His H CAU, CAC Tyr Y UAU, UAC

Ile I AUU, AUC, AUA Val V GUU, GUC, GUA, GUG

Start AUG for Methionine Stop UAG, UGA, UAA

A Significant Place / A Pivotal Amino Acid

64 base pair combinations for 21 amino acids - duplication

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Don’t forget Methionine and its relationship to Homocysteine

• It is “body protein” / building material, and promotes growth just as egg white and milk should. The more protein you eat, the bigger you can get.

• But what happens when the growth plates fuse?• Then only soft tissue can grow.• Again people don’t gain weight – they grow bigger

• Methionine precursor to homocysteine. The vitamins didn’t work.

• Methionine shortens the life of rats and makes their abdomens bigger.

• OK, Done.