belly fat, high androgens and insulin resistance rk law2015 · clinical science. 2002; 102:...
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Belly Fat, High Androgens and Insulin Resistance
Robyn Kutka, NDLead Staff PhysicianLabrix Clinical Services, Inc.
Metabolic Syndrome: a Cluster of the Most Dangerous Heart Attack Risk Factors
• Increased blood pressure• Insulin resistance• Abdominal obesity• High cholesterol
It is estimated that around a quarter of the world’s adult population have metabolic syndrome.
International Diabetes Federation. Metabolic syndrome – driving the CVD epidemic. http://www.idf.org/webdata/docs/Diabetes_meta_syndrome.pdfAccessibility verified 1/21/2015
• People with metabolic syndrome are twice as likely to die from, and three times as likely to have a heart attack or stroke compared with people without the syndrome
• People with metabolic syndrome have a five‐fold greater risk of developing type 2 diabetes
• Up to 80% of the 200 million people with diabetes globally will die of cardiovascular disease
International Diabetes Federation. http://www.idf.org/metabolic syndrome. Accessibility verified 1/21/2015
“Earlier diagnosis is needed to stop this global time bomb. ”
International Diabetes Federation. http://www.idf.org/metabolic syndrome. Accessibility verified 1/21/2015
“The high DHEA and testosterone are suggestive of PCOS or metabolic syndrome (insulin resistance). Serum vitamin D, fasting glucose and insulin testing may be warranted.”
Livingstone C, Collison M. Sex steroids and insulin resistance. Clinical Science. 2002; 102: 151‐166.
Health and Nutrition Examination Survey (NHANES) data over the past 30 years has indicated the prevalence of overweight and obese Americans:• 6‐11 year‐olds the number of obese has almost quadrupled • 12‐19 year‐olds has increased 2.5 fold…• 65‐80% (of US citizens over the age of 25) are either obese or overweight
(10 to 30 pounds over a healthy weight)
Centers for Disease Control and Prevention. Prevalence of overweight, obesity and extreme obesity among adults: United States, Trends 1960‐1962 Through 2009‐2010. Available at: http://www.cdc.gov/nchs/data/hestat/obesity_adult_09_10/obesity_adult_09_10.html. Accessibility verified October 9, 2012. http://www.gallup.com/poll/141734/one‐three‐adults‐obese‐america‐three‐obese‐states.aspx
Obesity is considered primary in etiology of:
• 88–97% of cases of type 2 diabetes• 57–70% of cases of coronary heart disease• 70% of gallstone attacks• 35% of cases of hypertension• 11% of breast cancers• 10% of colon cancers
Encyclopedia of Surgery. Weight Management. Available at: http://www.surgeryencyclopedia.com/St‐Wr/Weight‐Management.html . Accessibility verified January 28, 2013.
How does fat go from merely being vanity pounds to representing an actual health risk?
Haven’t people been overweight for decades… even centuries?
…it’s all in the distribution
Nelson TL, et al. Genetic and environmental influences on waist‐to‐hip ratio and waist circumference in an older Swedish twin population. Int J Obesity. 1999; 23: 449‐55.Evans DJ, et al. Relationship of androgenic activity to body fat topography, fat cell morphology and metabolic aberration in premenopausal women. J Clin Endocrinol Metab. 1983; 57: 304‐10.
Waist to Hip Ratio
Females EstimatedHealth Risk
Estimated Body Shape
0.80 or below Low Pear0.81 to 0.85 Moderate Avocado
0.85+ High Apple
The Skinny on Fat
Harvard Health Publications. Abdominal fat and what to do about it. Available at: http://www.health.harvard.edu/newsweek/Abdominal‐fat‐and‐what‐to‐do‐about‐it.htm . Accessibility verified October 8, 2012.
Visceral Adipose (VAT) is Dysfunctional:
• More insulin resistant • More inflammatory• Acts as a source of hormones and more
Why is fat insulin resistant?
Fat Cells
• Small adipocytes (SCAT) are more insulin‐sensitive and have high avidity for FFAs and TGs uptake, preventing their deposition in non‐adipose tissue.
Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010; 11: 11‐18.Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition. 2003; 19: 457‐66.Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92: 347‐55.
As Adipocytes Grow Larger…
...they become dysfunctional. Large adipocytes (VAT) are: • Insulin resistant• Hyperlipolytic (break down of lipids; hydrolysis of triglycerides into glycerol and free fatty acids)
• Resistant to anti‐lipolytic effect of insulin
Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010; 11: 11‐18.Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition. 2003; 19: 457‐66.Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92: 347‐55.
Why is fat inflammatory?
• Location• Location• Location
Heinrich PC, Castell JV, Andus T. Interlukin‐6 and the acute phase response. Biochem J 1990; 265: 621–636.10. Mårin P, Andersson B, Ottosson M, Olbe L, Chowdhury B, Kvist H, Holm G, Sjöström L, Björntorp P. The morphology andmetabolism of intra‐abdominal adipose tissue in men. Metabolism 1992; 41: 1241–1248.
VAT Location and Inflammation
• Unlike SCAT, VAT venous blood is drained directly to liver via portal vein
• Provides direct hepatic access to free fatty acids (FFAs) and adipokines (pro‐inflammatory molecules) secreted by VAT
• Adipokines activate hepatic immune mechanisms with production of inflammatory mediators such as C‐reactive protein (CRP)
Heinrich PC, et al. Interleukin‐6 and the acute phase response. Biochem J. 1990; 265: 621‐36.Marin P, et al. The morphology and metabolism of intrabdominal adipose tissue in men. Metabolism. 1992; 41: 1242‐48.
Location Impact on Insulin Resistance
• Truncal fat secretes free fatty acids (FFAs)• Excessive FFAs via the portal vein require excessive production of glucose via the liver
• Increased glucose production requires increased insulin production
Insulin resistance
TIME
Kabir M, et al. Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab. 2005; 288: E454‐61.
More than just location?
Macrophages are key mediators of obesity‐induced IR• In lean individuals, macrophages are predominantly M2 and are involved in wound healing and immuneoregulation.
• In adipose tissue, there is a progressive infiltration of macrophages into obese adipose ‐ in the M1 form
• M1 macrophages release pro‐inflammatory cytokines that block adipocyte insulin action – contributing to the development of IR and DMII
Harford KA, Ryenolds CM, McGillicuddy FC, Roche HM. Fats, inflammation and insulin resistance: insights to the role of macrophage and T‐cell accumulation in adipose tissue. Proc Nutr Soc. 2011 Nov;70(4):408‐17
VAT as an Endocrine Organ:A Source of Hormones and More
• Leptin • Adiponectin• Resistin• Angiotensinogen • Plasma activator inhibitors • Pro‐inflammatory cytokines: tumor necrosis factor alpha, CRP and Interleukin‐6
Roubicek T, et al. Increased production of proinflammatory cytokines in adipose tissue of patients with end‐stage renal disease. Nutrition. 2009; 25: 762‐68.Soliman PT, et al. Association between adiponectin, insulin resistance and endometrial cancer. Cancer. 2006; 106: 2376‐81.
VAT as an endocrine organ:A Target for Hormones
Receptor activity:• Glucocorticoid receptors‐higher in VAT• Androgen receptors‐higher in VAT• Estrogen receptors higher in SCAT• Adrenergic receptors higher in VAT
Freedland ES. Role of critical visceral adipose tissue threshold in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutr Metab. 2004; 1: 12.Bjorntorp P. Endocrine abnormalities in obesity. Diabetes Rev. 1997; 5: 52–68.
Excess VAT has been linked to:
• Atherosclerosis, stroke, high blood pressure
• Decreased ability to perform ADLs • Even among normal‐weight people, those with higher waist‐to‐hip ratios had just as much difficulty as those with higher BMIs in carrying out various activities of daily living, such as getting in and out of bed and performing household chores.
Harvard Health Publications Harvard Medical School; December 2006 issue of the Harvard Women’s Health Watch. For more information or to order, please go to http://www.health.harvard.edu/womens August 2006 American Journal of Hypertension. North American Association for the Study of Obesity.
VAT is associated with increased:
• Colorectal cancer risk: a 500,000 women and men study found that, for women, a waist‐to‐hip ratio above 0.85 was associated with a 52% increase incidence
• High blood pressure • Memory loss and less verbal fluency in older people with bigger bellies – even after taking diabetes into account
• Abnormal sleep• Osteoarthritis • Gallbladder diseaseHarvard Health Publications Harvard Medical School;December 2006 issue of the Harvard Women’s Health Watch. For more information or to order, please go to http://www.health.harvard.edu/womensAugust 2006 American Journal of Hypertension. North American Association for the Study of Obesity.
Belly Fat = Insulin Resistance = Belly Fat
• Correlated with overeating and a sedentary lifestyle
• Increased central adiposity (obesity) raises serum resistinlevels (a hormone that increases resistance of cells to insulin), which in turn directly correlate to insulin resistance
Asensio C, et al. Changes in glycemia by leptin administration or high‐fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis. Endocrinology. 2004; 145: 2206–2213.Fujinami A, et al. Enzyme‐linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. ClinChim Acta. 2004; 339: 57–63. McTernan PG, et al. Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab. 2003; 88: 6098–6106. Steppan CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001; 409: 307‐312.
How does all of this relate to hyperandrogenism?
“The high DHEA and testosterone are suggestive of PCOS or metabolic syndrome (insulin resistance). Serum vitamin D, fasting glucose and insulin testing may be warranted.”
Novak ER, Goldberg B, Jones GS. Enzyme histochemistry of the menopausal ovary associated with normal and abnormal endometrium. Am J Obstet . 1965; 93: 669‐682.
Review: Where do androgens in women come from?
• Approximately one half of a woman’s serum testosterone is derived from the peripheral conversion of secreted androstenedione and DHEA
• While the other half is derived from glandular (ovarian and adrenal) secretion
• The ovaries and the adrenal glands contribute equally to testosterone production in women
Textbook of Gynaecology. Rao
In menopause
• Ovarian production of androstenedione declines lending to an overall 50% reduction in serum androstenedione concentration and a decrease in peripheral conversion to testosterone
• DHEA declines with aging• Ovarian production of testosterone remains relatively stable
American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause. Endocr Pract 2006;12(3):315‐337
Hyperinsulinemia Increases Androgens
“Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism.”
• Thus, direct stimulation / insulin stimulation of ovarian androgen production is mediated through its own receptor
Barbieri RL, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin EndocrinolMetab. 1986; 62: 904‐10.
Hyperinsulinemia and AndrogensIndirect Ovarian Stimulation
• Associated with a disordered release of LH, which in turn stimulates more ovarian androgen production
Spero L. Clinical Gynecologic Endocrinology and Infertility. Philadelphia, PA: Lippincott Williams &Wilkins; 2005.Livingstone C, Collison M. Sex steroids and insulin resistance. Clin Sci (Lond). 2002; 102: 151‐66
Hyperinsulinemia and AndrogensSHBG
In addition to direct stimulation of ovarian androgen production, insulin: • Decreases hepatic production or SHBG which increases androgen bioavailability
* Circulating levels of SHBG are inversely proportional to body weight (increased weight = lower SHBG levels = increased free testosterone and estrogen) and decreased SHBG may be an independent risk factor for DM regardless of body weight and fat distribution
González F. Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012; 77: 300‐05. Panidis D, et al. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod. 2012; 27: 541‐9.
SHBG
Decreased by the following: • Androgens• Synthetic progestins (norethindrone, norgestrel, desogestrel, norgestimate)
• Glucocorticoids• Growth hormone• Insulin• Obesity• Acromegaly• Hypothyroidism• Hyperinsulinemia
Medscape Reference. Androgen Excess. Available at: http://emedicine.medscape.com/article/273153‐overview . Accessibility verified October 8, 2012.
SHBG
Increased by the following:• Estrogens and estrogen‐containing preparations• Thyroid hormone• Pregnancy• Pumpkin oil• Beta sitosterols
Medscape Reference. Androgen Excess. Available at: http://emedicine.medscape.com/article/273153‐overview . Accessibility verified October 8, 2012.
Beta Sitosterol• Increases SHBG • Knocks DHT and estradiol off of SHBG (increasing its excretion from the body)
• Inhibits aromatase and 5‐alpha‐reductase... • Alters dietary‐fat and cholesterol metabolism• Reduces LDL cholesterol • Protects against cardiovascular disease• Increases healthy gallbladder function • Promotes healthy functioning of the immune system • Sources of beta sitosterol:
• Plant‐based foods, especially bananas, oranges, legumes, rice, and nuts.
Carson C, Rittmaster R. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology. 2003; 61: 2‐7.Jones PJH, et al. Phytosterols as functional food ingredients: linkages to cardiovascular disease and cancer. CurrOpin Clin Nutr Metab Care. 2009; 12: 147‐51. Calpe‐Berdiel L, et al. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis. 2009; 203; 1: 18‐31.
Hyperinsulinemia and AndrogensAdrenal Stimulation
• Binds receptors in adrenal cortex (zona reticularis) stimulating androgen production
“
Hyperandrogenism (adrenal) and PCOS
• Adrenal enzyme abnormalities are a common finding in women with hyperandrogenism including those with PCOS
• 55% of women with hyperandrogenism have high levels of DHEA and androstenedione from the adrenal glands
• Adrenal and ovarian androgenic abnormalities occurred concurrently in approximately one‐third of hyperandrogenic women
Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005; 352: 1223‐36.Ciottal L, et al. Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia. Hum Reprod. 1999; 14: 2951‐58. Ehrmann DA, et al. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med. 1992; 327; 157‐62.Wang YH, et al. Human cytochrome p450c17: single step purification and phosphorylation of serine 258 by protein kinase a. Endocrinology. 2010; 151: 1677‐84. Bremer AA, Miller WL. Serine phosphorylation, insulin resistance and the regulation of androgen synthesis. In: Diamanti‐Kandarakis E, Nestler JE, Panidis D, Pasquali R, eds. Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation and Treatment. New Jersey: Humana Press; 2007.
No feedback loop• Adrenal androgens increase in response to ACTH stimulation (but not as sensitive as zona fasciculata)
• And androgens do not down‐regulate ACTH secretion
Medscape Reference. Androgen Excess. Available at: http://emedicine.medscape.com/article/273153‐overview . Accessibility verified October 8, 2012.
Hyperinsulinemia and AndrogensIGFBP‐1 (Insulin‐like growth factor‐binding protein 1)
• Inhibits hepatic production of insulin‐like growth factor binding protein, leading to higher circulating levels of IGF‐1. IGF‐1:
• Augments theca cell response to LH• Decreases SHBG
Hyperinsulinemia and Androgens
Additionally, insulin stimulates appetite!
Livingstone C, Collison M. Sex steroids and insulin resistance. Clinical Science. 2002; 102: 151‐166.
FFAs and Androgens
• Increased circulating levels of FFAs (seen in PCOS) increase production of androgens by altering ratio of lyase to hydroxylase activity of human P450c17…. this ratio determines whether steroidogenesis leads to the synthesis of cortisol or sex steroids.
Wang YH, et al. Human cytochrome p450c17: single step purification and phosphorylation of serine 258 by protein kinase a. Endocrinology. 2010; 151: 1677‐84. Bremer AA, Miller WL. Serine phosphorylation, insulin resistance and the regulation of androgen synthesis. In: Diamanti‐Kandarakis E, Nestler JE, Panidis D, Pasquali R, eds. Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation and Treatment. New Jersey: Humana Press; 2007.Baptiste C, Batista M, Trottier A, Baillargeon J. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid BiochmMol Biol. 2010 Oct; 122(0)
Laboratory
Saliva testing
• Free (active) levels of hormone… not total (inactive and active) as found in serum (earlier detection)
• Saliva; 8‐10 hormones• Estrone• Estradiol• Estriol• Progesterone• Testosterone• DHEA• 4 timed cortisols
What elevated androgens tell you
The connection between androgen hormones and blood sugar regulation is one that is often missed, however it can provide a very important early indicator of dysfunction that may lead to more overt disease processes including PCOS, metabolic syndrome or frank diabetes!
Correlating Imbalances
Treat imbalances identified on testing: • Pg/E2: (estrogen dominance)‐most women with these syndromes will not be ovulating regularly and hence will not be producing adequate progesterone…
• EQ: literature suggests that women with PCOS will have a preponderance of estrone (E1), hence monitoring this ratio and treating with estriol (E3) when indicated may be warranted
• Excess androgens • Adrenal dysfunctionStener‐Victorin E, et al. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J Clin Endocrinol Metab. 2010; 95: 810‐9.
Salivary hormone testing provides an early warning signal of blood sugar issuesElevated androgens – testosterone and/or DHEA
Farrah Sample
Polly Sample
Insulin resistance/Hyperinsulinemia Fasting and IGTT• Insulin resistance/Hyperinsulinemia is present when:
• Fasting glucose is elevated (>99)• Fasting insulin is elevated (>20 mcl)• 2 hr. insulin (on IGTT) is elevated (>27)
• Insulin resistance/Hyperinsulinemia is suggested by:• Fasting glucose >90• Fasting insulin >9 mIU/ml• Reduced fasting glucose/insulin ratio <4.5• Insulin level at 2 hrs is 5x or greater than the fasting insulin level
Johnson JL, et al. Identifying pre‐diabetes using fasting insulin levels. Endocr Pract. 2010; 16: 47‐52.American Diabetes Association. How to Tell if You Have Diabetes or Pre‐diabetes. Available at: http://www.diabetes.org/diabetes‐basics/prevention/pre‐diabetes/how‐to‐tell‐if‐you‐have.html. Accessibility verified January 29, 2012.
Metabolic Syndrome
Central obesity AND any two of the following:• Fasting glucose: >100 • Triglyceride: >150 • HDL: <40 male; <50 female• Hypertension: >130 systolic or >85 diastolic
International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf. Accessibility verified January 29, 2013.
Other Laboratory Testing for Metabolic Syndrome
• VAP (Vertical Arterial Profile) • Clotting factors• C‐reactive protein• Homocysteine• Calcium Scores (CT scan)
Al‐Hamodi Z, et al. Association of plasminogen activator inhibitor‐1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects. Cardiovasc Diabetol. 2011; 10: 23.
PCOS Diagnostic Criteria
The presence of polycystic ovaries is not a criterion for the diagnosis of PCOS especially in young adults
Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature.J Clin Endocrinol Metab. 2006 ; 91: 781‐5.
Diagnostic Criteria Summary
Rotterdam, The Netherlands 2004:• Any two of the following:
• Presence of polycystic ovaries on ultrasound examination
• Presence of clinical and/or biochemical hyperandrongenemia
• Oligomenorrhea or anovulation
Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature.J Clin Endocrinol Metab. 2006 ; 91: 781‐5.
Physical Symptoms of Hyperandrogenemia
Hirsutism Acanthosis NigricansThe skin manifests with a brown darkening at the nape of the neck and will spread laterally to the upper thorax and shoulders. This darkened velvety skin can also be noted in the axillary and intertriginous areas.
Dihydrotestosterone
• Testosterone is converted to DHT via the 5‐alpha reductase enzyme.
• Because of its greater affinity for the androgen receptor, DHT is approximately 10 x more potent than testosterone.
• The primary androgen in the hair follicles where it can contribute to …
…..Scalp Hair Loss
• The dermal papilla has a large number of androgen receptors
• Scalp hair follicles sensitive to DHT undergo miniaturization (progressive shrinking). When miniaturization occurs, hair grows for shorter periods, becomes lighter, finer and smaller until it reaches the vellus stage (light‐colored, short, thin, very fine hair)
Inui S, Itami S; Androgen actions on the human hair follicle: perspectives. Exp Dermatol. 2013 Mar;22(3):168‐71.
…..Acne and Hirsutism
• At the facial hair follicle, androgens stimulates IGF‐1 leading to hair growth. (This varies from the scalp follicle where DHT stimulates TGF β1, TGF β2, dickkopf1, and IL‐6)
• Androgens stimulate sebum production, exacerbating acne formation
Inui S, Itami S; Androgen actions on the human hair follicle: perspectives. Exp Dermatol. 2013 Mar;22(3):168‐71.
PCOS and insulin resistance
• PCOS patients have heightened sensitivity to insulin and will readily increase androgen production
• Non PCOS women will also respond to insulin by increased androgen synthesis but only when insulin is in much higher concentrations
PCOS and insulin resistance
• Impaired glucose tolerance and type 2 diabetes is present in 40‐50% of women with PCOS!
• Increases in cardiac risk factors and free androgen levels precede overt glucose intolerance in many patients.
• Insulin resistance is suggested by:• Hyperandrogenism
Karakas SE, Kyoungmi K, Duleba AJ. Determinants of impaired fasting glucose versus glucose intolerance in polycystic ovary syndrome. Diabetes Care. 2010; 33: 887‐93.
Does insulin resistance cause PCOS or vice versa?
• There are multiple theories of etiology:• Hypersecretion of FSH and LH stimulates the ovary to overproduce androgens which leads to insulin resistance?
• Ovary responds abnormally to some other stimulation (environmental) and overproduces androgens?
• Insulin resistance is central and leads to stimulation of LH and direct stimulation of androgen production?
Endotext.org. Evaluation and treatment of polycystic ovary syndrome. Available at: http://www.endotext.org/female/female6/female6.html . Accessibility verified July 24, 2013.
Consequences
• High levels of triglycerides• Increased risk of:
• Breast cancer• Heart disease• Metabolic syndrome• Polycystic ovarian syndrome
• Increased abdominal fat
Not Exclusively in Obesity
Elevated androgens can be seen in all phenotypes! Remember, this is the red flag PRIOR to overt changes in glucose/insulin labs.
“My patient is thin.”
“My patient is athletic; she exercises all the time.”
“My patient has a pretty healthy diet.”
Solutions?
2008 two major clinical trials revealed that:
• Diabetic patients on anti‐diabetic medications gained NO significant protection from heart attack and stroke
• A third study was ended when interim results showed more deaths in volunteers using diabetes drugs for intensive blood sugar control
Skyler JS, et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation. 2009; 119: 351‐57.Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, et al. . Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358: 2545‐59.
Anti‐diabetic drugs vs. lifestyle changes
• 3200 adults with impaired blood sugar control…three groups
• Metformin (drug)• Exercise 150 minutes per week (lifestyle)• Usual care
• After three years… reduction in progression to diabetes:• 58% in lifestyle group• 31% in drug group
KnowlerWC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002; 346: 393‐403.
“What do I give for elevated androgens?”
Treatment
• Dietary/Nutritional intervention• Lifestyle• Bioidentical hormone supplements• Nutritional supplements• Botanical preparations
Exercise
Simkin‐Silverman LR, Wing RR, Boraz MA, Kuller LH.Ann Behav Med. 2003 Dec;26(3):212‐20.
Lifestyle intervention can prevent weight gain during menopause: results from a 5‐year randomized clinical trial.
Hormones, Neurotransmitters and How We Eat
• Estrogens, cortisol, insulin AND… glucagon, testosterone, growth hormone, IGF‐1, thyroid, epinephrine, as well as other neurotransmitters help regulate blood sugar control
Barros RP, Gustafsson JÅ. Estrogen receptors and the metabolic network. Cell Metab. 2011; 14: 289‐99.Shin JY, et al. Serum sex hormone‐binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes. Diabetes Res Clin Pract. 2011; 94: 156‐62.
http://www.whathealth.com/glycemicindex/measurement.html#glucosegraphHyperinsulinemic obesity and carbohydrate addiction: the missing link is the carbohydrate frequency factor. Heller RF, Heller RF. Med Hypotheses. 1994 May;42(5):307‐12.
Glycemic index is critical!
General Supplementation Options
Dunn N. The Natural Diet Solution for PCOS and Infertility. Seattle, WA; Health Solutions Press: 2006.Guerrero‐Romero F, Rodriquez‐Moran M. Complementary therapies for diabetes: the case for Chromium, magnesium and antioxidants. Current Trends Diabetes. 2005; 36: 250‐57. Kaushal N, et al. Chapter 35: Selenium and Inflammation. In: Hatfield DL, Berry MJ, Gladyshev VN, eds. Selenium: Its Molecular Biology and Role in Human Health. 3rd ed. New York: Springer; 2012.Guillot X, et al. Vitamin D and inflammation. Joint Bone Spine. 2010; 77: 552‐57. Natural Medicines Comprehensive Database
Cinnamon ½ tsp qdFish oil 2 – 3gms qdCo‐Q‐10 60 – 100 mg qdChromium 200 – 600 mcgBiotin 5000 mcg qdMagnesium citrate 1000 mg qdAlpha lipoic acid 300 mg qdSelenium 200 mcgIodine 12.5 mg qdVitamin D 5000 – 10000 iu qd
The Clinical Importance of Vitamin D
• Higher vitamin D status has been correlated with 60% improvement in insulin sensitivity. (clinical trial using 1332 IU/day vitamin D for 30 days in 10 women with type II diabetes improved 21%)
• Metformin was shown to give a 13% improvement in insulin sensitivity
Borissova AM, et al. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract. 2003; 57: 258‐61.Moghetti P, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double‐blind, placebo‐controlled 6‐month trial, followed by open, long‐term clinical evaluation. J Clin Endocrinol Metab. 2000; 85: 139‐146. Alternative Therapies Sept/Oct 2004 vol. 10, no 5
Treatment Options‐Herbal
Natural Medicines Comprehensive Database
Fenugreek (85%); Reduces blood sugar and insulin following meals, and lowers cholesterol; LDL, TG and total chol.
750 mg; 2 bid
Guar gum lowers chol., TG, and Blood pressure, and helps regulate appetite
2.5 gm qd
Apple pectin, beet powder and oat fiber
slows the absorption of glucose into the blood stream (which also lowers insulin)
Milk thistle lowers fasting glucose, mean daily glucose and fasting insulin levels
200‐400 mg
Gymnema sylvestre lowers glucose and improves insulin sensitivity, and regenerative to beta cells in pancreas
400 mg bid
Bitter mellon (10:1); suppresses blood glucose spike in response to sweets
250 mg bid
High ViscosityTreatment Options – Supplements
Dunn N. The Natural Diet Solution for PCOS and Infertility. Seattle, WA; Health Solutions Press: 2006.DudaMK, et al. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload‐induced cardiac dysfunction. Cardiovasc Res. 2008; 81: 319‐27.Xing LW, et al. Cosupplementationwith vitamin E and coenzyme Q10 reduces circulating markers of inflammation in baboons. Am J Clin Nutr. 2004; 80: 649‐55.Guerrero‐Romero F, Rodriquez‐Moran M. Complementary therapies for diabetes: the case for chromium, magnesium and antioxidants. Current Trends Diabetes. 2005; 36: 250‐57.
Fish oil 2 – 3 g qdCo‐Q‐10 60 mg qdMagnesium Up to 1000 mg qdBromelain 500 – 1000 mg qdQuercetin 500 mg qdGreen tea DailyGinger/curcumin/oregano Frequent consumptionGarlic/onions Frequent consumption
DyslipidemiaTreatment Options – Supplements
Ground Flax 2‐4 Tbs qdNiacin* 2 grams qd*Nattokinase 2000 – 4000 iu qdLecithin 1 – 2 Tbs qdVitamin E gammatocopherol 800 iu qdPhosphatidyl choline Up to 3 g qd
*must titrate up slowly d/t flushing effects
Cholesterol – Clinical Pearls
Cholesterol component Initial treatment approach
Upper range/elevated LDL 2‐4 Tbl ground flax daily
Low range HDL 3000 mg fish oil daily
Upper range/elevated triglycerides Avoid “the whites”
Regulating Menses in PCOSTreatment Options – Botanical
Alternating tincturesFormula I• Days 1‐14
• (4) Vitex• (4) Angelica• (4) Cimicifuga• (4) Medicago
• Sig; 1 tsp bid
Erin Lommen ND 2007
Formula II• Days 15‐28
• (2) Vitex• (4) Mitchella Repens• (4) Smilax• (2) Pulsatilla• (4) Dioscorea
• Sig; 1 tsp bid
Regulating Menses in PCOSTreatment Options – Bioidentical Hormones
• Progesterone (transdermal cream) 20‐60 mg cyclically (days 15‐28)*
• Vitamin D 5000+ iu qd
Dehghani FirouzabadiR, et al. Therapeutic effects of calcium and vitamin D supplementation in women with PCOS. Comp Ther Clin Pract. 2012; 18: 85‐88.Katsiki N, et al. The role of insulin‐sensitizing agents in the treatment of polycystic ovary syndrome. Drugs. 2009; 69: 1417‐31.
*Depending on the current pattern (or lack thereof) of menstrual cycling
PCOSHyperandrogenism Treatment Options
• Saw Palmetto (85%) 320 mg bid • Nettles (.2‐.4 % sterols) 100 mg bid• Pygeum (10%) 100 mg bid• Fenugreek (85%) 750 mg bid
Basch E, et al. Therapeutic Applications of Fenugreek. Alt Med Review. 2003; 8: 20‐27.Longevity Medical Health Center. Polycystic ovarian syndrome: a natural treatment approach. Available at: http://www.longevitymedical.com/articles/?p=polycystic_ovarian_syndrome . Accessibility verified: October 11, 2012. Levin RM. A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens. Urol Res. 2000; 28: 201‐9.
Acne and PCOS
Not Milk• A recent study has shown that the dihydrotestosterone DHT‐(acne‐causing) in cow’s milk is particularly high in pregnant cows‐and since 75‐90% of the dairy on the market is from these cows…
• Study of 6500 adolescent offspring showed a correlation between milk consumption and acne (independent of fat content)
• CONCLUSION: A positive association was found with acne and the intake of total milk and skim milk. We hypothesize that the association with milk may be because of the presence of hormones and bioactive molecules in milk.
(J Am Acad Dermatol. 2005 Feb;52(2):207‐14. High school dietary dairy intake and teenage acne.Adebamowo CA, Spiegelman D, Danby FW, Frazier AL, Willett WC, Holmes MD.(Perricone, 2003).
Facial Cream for Hyperandrogenism and Acne
Stamatiadis D, Bulteau‐Portois MC, Mowszowicz I. Br J Dermatol. Inhibition of 5 alpha‐reductase activity in human skin by zinc and azelaic acid. 1988 Nov;119(5):627‐32.
Summary
• Saliva testing will detect high range and frankly high androgens earlier than serum studies (due to free fraction hormone measurement), thus you can address the condition, and stop the progression of the conditions IR, metabolic syndrom and PCOS
• Nutritional intervention is your most powerful therapeutic agent
• In addition, hormonal and botanical supplements will be critical and instrumental in helping each individual successfully make advances in better health and ultimately also promote those necessary changes to diet and lifestyle… (even if patient cannot begin here)