Metabolic Diseases: Methods of Management

From New Approaches in Endocrinology, sponsored by the University of Chicago Pritzker School of Medicine, Chicago, IL

Educational Objectives

The goal of this program is to improve the management of polycystic ovary syndrome (PCOS), vitamin D deficiency, and metabolic syndrome. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the effects of impaired glucose tolerance and b–cell dysfunction in PCOS.

2.   Discuss the association between obstructive sleep apnea and PCOS.

3.   List the consequences of vitamin D deficiency.

4.   Identify and treat vitamin D deficiency.

5.   Review recent data about obesity and hyperaldosteronism in patients with metabolic syndrome.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Drs. Ehrmann, Favus, and Bakris spoke in Chicago, IL, at New Approaches in Endocrinology, presented May 14-15, 2009, by the University of Chicago Pritzker School of Medicine. The Audio-Digest Foundation thanks the speakers and the Uni­versity of Chicago Pritzker School of Medicine for their cooperation in the production of this program.

Polycystic Ovary Syndrome

David A. Ehrmann, MD, Professor of Medicine, University of Chicago Pritzker School of Medicine, Chicago, IL

Polycystic ovary syndrome (PCOS): reproductive disorder characterized by anovulation (manifests as oligomenor­rhea or amenorrhea, infertility, or endometrial carcinoma) and hyperandrogenemia (manifests as hirsutism, acne re­fractory to treatment, and male-pattern hair loss); associated metabolic and cardiovascular derangements  —  obesity; insulin resistance; b-cell dysfunction (results in impaired glucose tolerance [IGT] and increased risk for type 2 diabetes); hyperlipidemia; hypercoagulability; hypertension; endothelial dysfunction; obstructive sleep ap­nea (OSA; can both precipitate and be exacerbated by some metabolic disorders)

Prevalence of IGT in PCOS: 35% of women ³28 yr of age who have PCOS have impaired glucose tolerance (5%-10% frankly diabetic); prevalence of IGT in PCOS nearly identical to prevalence of IGT in Pima Indian women (ie, group with highest risk, prevalence, and incidence of type 2 diabetes); women with PCOS at higher risk of develop­ing diabetes at early age; risk for diabetes significantly lower in white women without PCOS; in United States, es­timated prevalence of PCOS, 5% to 8% (6-9 million women; nearly 1 million diabetic, and slightly over 3 million have IGT)

Obesity and insulin resistance: study of obese and lean women with and without PCOS saw highest insulin resis­tance in obese women with PCOS; obese women in control group significantly less insulin-resistant despite identi­cal body mass index (BMI) and body fat composition; lean women with PCOS more insulin-resistant than women in control group; obese women in control group and lean women with PCOS similarly insulin-resistant; suggests involvement of other factor(s) in development of insulin-resistance in PCOS

b–cell dysfunction: contributes to development of type 2 diabetes; normal obese person can produce sufficient insu­lin to compensate for degree of insulin resistance and maintain normal glucose tolerance; once glucose levels rise above normal, b cells unable to compensate; in order to maintain normal glucose tolerance as insulin resistance worsens, b cells must produce more insulin to maintain normal blood glucose; patients with early gestational diabe­tes tend to have b-cell dysfunction; b-cell dysfunction in patients with PCOS largely determined by presence or ab­sence of first-degree relative with type 2 diabetes; women with negative family history of diabetes tend to have better b-cell function (suggests role of genetic factors in ability to secrete insulin to maintain normal glucose toler­ance); women with PCOS and positive family history of diabetes unable to compensate as glucose levels rise, com­pared to women with PCOS and negative family history

Metabolic syndrome: increased waist circumference (>88 cm) common in women with PCOS; visceral adiposity more significant risk factor for diabetes than peripheral or subcutaneous adiposity; women with PCOS tend to have more android, male-type body fat distribution; high prevalence of low high-density lipoprotein (HDL) and high tri­glyceride levels; fasting blood glucose (FBG) levels elevated in »10%; »10% may be diabetic; hypertension not as common (may be due to younger age of women with PCOS; women followed over time found to develop hyperten­sion); prevalence of hypertension in PCOS questionably elevated

Family history and ethnicity: average waist circumference of patient with PCOS and first-degree relative with type 2 diabetes, 4.8 cm greater than patient with negative family history; whites and Hispanics relatively protected from some metabolic abnormalities; overweight black women with positive family history of type 2 diabetes at highest risk for individual components of metabolic syndrome; stratify risk in women with first-degree relative with type 2 diabetes, and black women

Obstructive sleep apnea: electroencephalography (EEG) slow-wave activity sleep associated with risk for diabetes; sleep loss, sleep fragmentation, and hypoxia contribute to insulin resistance; higher prevalence of OSA in men may be due to testosterone; women tend to have more slow-wave activity (protective against OSA); studies  —  1) looked at small group of women with PCOS, and control group of women matched identically by age and BMI; polysom­nography used to quantify apnea-hypopnea index (AHI; number of apneic or hypopneic events per hour of sleep); mean AHI in women with PCOS, 22 (in control group, 7; <5 normal; 5-15 considered intermediate or moderate; >15 severe; >30 extremely severe); twice as many women with PCOS had OSA compared to control group; severe OSA 8 times higher in women with PCOS; 2) subsequent study showed women with PCOS 30 times more likely to have sleep-disordered breathing or OSA, and 9 times more likely to have daytime sleepiness (after statistically con­trolling for BMI); insulin resistance stronger predictor of sleep-disordered breathing than age, BMI, or testosterone level; effect of reducing slow-wave sleep  —  OSA characterized by frequent microarousals (ie, awakenings deter­mined by EEG changes, but not by conscious awakenings) and reductions in slow-wave sleep; study selectively dis­rupting slow-wave sleep for 3 nights in normal individuals saw significant reduction in glucose tolerance (as defined by intravenous [IV] glucose tolerance testing) and reduction in insulin sensitivity; study of women with PCOS 18 to 40 yr of age  —  >50% of women with PCOS had OSA, compared to 19% in control group (prevalence in general population, 4%-8%); after adjusting for BMI, body fat distribution, family history of diabetes, and eth­nicity, patients with PCOS found »7 times more likely to have OSA than patients without PCOS; as severity of OSA increases, prevalence of glucose intolerance increases

Questions and answers: effect of treatment of OSA on fertility or ovulation  —  indirect studies looking at sex steroid levels in response to stimulation before and after treatment with continuous positive airway pressure (CPAP) under way; screening women with PCOS for OSA  —  after PCOS diagnosed, consider performing oral glucose tolerance testing morning after performing sleep study; overweight women at higher risk for OSA; predictive value of Berlin questionnaire (eg, “do you snore?; do you have morning headaches?”) fairly good; CPAP and insulin resistance  —most published studies in non-PCOS populations show evidence that CPAP results in some improvement in insulin sensitivity in short-term; insulin sensitivity in obese women tends to be so low that changes in insulin sensitivity may not be remarkable (ie, IV glucose tolerance test may be too insensitive to show improvement); some studies show glucose intolerance and insulin resistance improve with long-term use of CPAP

Vitamin D Deficiency and Metabolic Bone Disease

Murray J. Favus, MD, Professor of Medicine, University of Chicago Pritzker School of Medicine, Chicago, IL

Metabolic pathway of vitamin D: vitamin D₃ synthesized in skin in response to UV light, then quantitatively trans­ferred to 25-hydroxyvitamin D in liver; small amount of vitamin D in blood; 25-hydroxyvitamin D hydroxylated to form 1,25-dihydroxyvitamin D (calcitriol; renal conversion regulated by hormonal factors in response to body re­quirements for calcium [eg, during adolescence, pregnancy]); degradative deactivation processes to 24-hydroxylate and 1,25-dihydroxyvitamin D can be inactivated by conversion to 25-hydroxyvitamin D; vitamin D₂  —  ergocalciferol; derived from plants; potent in humans; not biologically active unless 25-hydroxylation and 1-hy­droxylation occur; vitamin D₃  —  cholecalciferol; occurs naturally; biologically inert until hydroxylated

Sources of vitamin D: sun exposure  —  affected by seasons; in midwestern United States, no vitamin D made in skin between late October and late March; in Chicago, vitamin D blood levels drop by »50% between late September and early April; vitamin D production depends on duration of sun exposure and skin pigmentation (less vitamin D made with greater pigmentation); in older age, skin less efficient in converting precursor to cholecalciferol (by age ³70 yr, little or no vitamin D produced); disease or dysfunction of liver disrupts metabolic pathway of conversion; food  — only »100 IU of vitamin D in 8 fl oz of milk; found in fatty fish and fortified cereal, but also in inadequate amounts; supplements  —  most calcium supplements contain vitamin D; multivitamins contain 200 or 400 IU; over-the-counter gel capsules or tablets; prescribed calcitriol

Consequences of vitamin D deficiency: decline in intestinal calcium absorption, leading to decreased serum cal­cium; increase in parathyroid hormone (PTH) secretion (leads to increased bone resorption and decreased bone density; particularly noticeable during winter months); increase in 1,25-dihydroxyvitamin D production reestab­lishes intestinal calcium absorption (if sufficient 25-hydroxyvitamin D present); upward deflection of PTH seen when serum level of 25-hydroxyvitamin D 27 to 39 ng/mL (30 ng/mL important threshold for preventing rise in PTH)

Identifying vitamin D deficiency: measure serum 25-hydroxyvitamin D; to prevent bone loss, be vigilant about identifying  deficiency before patients become symptomatic; prevalence of rickets in children increased in North America; children have low levels long before showing clinical signs of deficiency; measure vitamin D in at-risk children; in Europe, most cases of hip fractures associated with deficiency and changes in bone architecture consis­tent with osteomalacia; 25-hydroxyvitamin D £10 ng/mL classified as deficiency (10-30 ng/mL classified as insuf­ficiency; ³30 ng/mL, normal)

Predisposing factors: black ethnicity (levels £10 ng/mL seen in nearly 30%); older age; »30% of Mexican American men vitamin D insufficient (rate of depletion higher in women); »30% of white women vitamin D insufficient; at­tributed to inadequate supplementation (ie, <400 IU/day; however, 45% of those who take >400 IU/day have low vitamin D levels); national standards clearly inadequate

Correlation between deficiency and incidence of fractures: results in decreased femoral neck bone density (predis­posing factor for hip fracture); low trauma fractures (97% have serum 25-hydroxyvitamin D levels <30 ng/mL, 80% have <20 ng/mL); »50% of people with hip fractures in United States have 25-hydroxyvitamin D level <30 ng/mL; bone biopsy studies found 25% of patients with hip fractures have osteomalacia

Management: sun exposure  —  sun exposure for 1 day can increase vitamin D level to 32 ng/mL (depletes after 1 wk without additional sun exposure); no benefit of sun exposure when sunscreen used (when lowest strength sunscreen used, low level [eg, 8 ng/mL] may be sustained); supplementation  —  400 IU/day recommended for newborns and older children into adolescence; 1000 to 2000 IU/day recommended for adults; single dose of vitamin D₂ peaks in 5 days and returns to baseline in »2 wk; metabolic response to 50,000-IU capsule of vitamin D₂ highly variable; half-life of vitamin D₃ >30 days; patients with vitamin D level 20 to 30 ng/mL  —  give vitamin D₃, 4000 IU/day for 4 days, then decrease to 2000 IU/day; recheck 25-hydroxyvitamin D, PTH, and calcium periodically; patients with vitamin D level <20 ng/mL  —  give 4000 IU/day for 10 days, then decrease to maintenance dose; monitor levels

Vitamin D toxicity: need 40,000 IU/day to cause hypercalcemia and renal impairment; vitamin D intoxication indi­cated by 25-hydroxyvitamin D level >200 ng/mL; 4000 IU/day not associated with hypercalcemia or impairment in renal function; 1000 to 2000 IU/day safe, inexpensive, and effective

Questions and answers: treat patients with low (7-10 ng/mL) levels, even if PTH normal; less frequent dosing for older patients  —  loading patients with vitamin D₃ once weekly may be effective; monitor levels

Metabolic Syndrome

George Bakris, MD, Professor of Medicine, and Director, Hypertensive Disease Unit, University of Chicago Pritzker School of Medicine, Chicago, IL

Metabolic syndrome: compilation of cardiovascular risk factors (eg, abdominal obesity, elevated triglycerides, ele­vated blood pressure [BP], impaired glucose tolerance) that signify dramatically increased risk for cardiovascular disease

Epidemiology: in 2000, 64 million adult Americans had metabolic syndrome; 1 in 4 adults has diabetes or metabolic syndrome; high risk groups include blacks and Hispanics; important to consider many (some estimates as high as 4 million) patients with impaired FBG have undiagnosed diabetes; prevalence of metabolic syndrome increases with age, especially in men; at age 50 yr, prevalence in men and women similar; at age ³70 yr, prevalence in women ex­ceeds that of men

Aldosterone: adipocyte recognized as endocrine organ; recent data demonstrate blocking aldosterone dramatically affects BP in obese individuals; metabolism of obese individuals without primary hyperaldosteronism behaves as intermediate phenotype of hyperaldosteronism; human subcutaneous adipocytes induce extracellular signal-related kinases (ERK1/2; mitogen-activated protein [MAP] kinases), which causes upregulation of steroidogenic acute reg­ulatory proteins and sensitization of angiotensin II in adrenal cortical cells; results in mild increase in aldosterone production; aldosterone increases to high normal level, or 1 SD above upper limit of normal; BP control beneficial in obese patients (most dramatic effect on BP control seen in obese black women)

Metabolic syndrome and early hypertension: propensity for atherosclerosis starts earlier; profound atherosclerotic disease noted in studies of Vietnam War veterans 23 to 27 yr of age

Suggested Reading

Bischoff-Ferrari H: Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Best Pract Res Clin Rheumatol 23:789, 2009; Ehrmann DA et al: Effects of race and family history of type 2 diabetes on meta­bolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:66, 2005; Ehrmann DA et al: PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 91:48, 2006; Fisher A et al: Elevated Serum PTH Is Independently Associated with Poor Outcomes in Older Patients with Hip Fracture and Vitamin D Inadequacy. Calcif Tissue Int 2009 Sep 11. [Epub ahead of print]; Glendenning P et al: Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after sup­plementation with ergocalciferol and cholecalciferol. Bone 45:870, 2009; Hoffman LK et al: Cardiometabolic features of polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 4:215, 2008; Krug AW et al: Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II-sensi­tization in human adrenocortical cells. Int J Obes (Lond) 31:1605, 2007; Mortensen M et al: Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. J Clin Endocrinol Metab 94:1579, 2009; Tasali E et al: Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab 93:3878, 2008; Tasali E et al: Polycystic Ovary Syndrome and Obstructive Sleep Apnea. Sleep Med Clin 3:37, 2008.