23 Year Old Female with polycystic ovarian syndrome and hypoglycemia

1. 23 Year Old Female with polycystic ovarian syndrome and hypoglycemia Case category: PCOS History of present illness: 23 year old female with chronic fatigue and history of symptomatic low glucose (sweating, carb cravings, headaches and fatigue postprandially). She has had irregular menses and hyperandrogenism, but no formal PCOS diagnosis. No history of high cholesterol. She is recovering from recent sinusitis.

2. Patient Information

3. Patient History

4. Current Medications

5. Labs Worth Noting on No Medications

6. Questions to Consider • Question 1: In young woman, always need to assess plans for childbearing. Irregular menses causing quality of life issues. (She is using barrier contraception.) • Question 2: No attention to diet as she has never been overweight. She reports eating healthy (fruits, vegetables) and exercising 3- 5 times/week. • Question 3: Ascertain hypoglycemic episodes. (She reports her “hypoglycemia” is more likely post high carb meal and she finds she needs to eat every 2 hours to feel less symptomatic.) • Question 4: High CRP and high MPO. Is there any other disease process causing these abnormal inflammatory markers? Consider recheck and work up if persistently elevated. In young woman with high MPO consider dysfunctional HDL as cause. (Sinusitis of recent may be contributing.)

7. Other Labs on No Medications Always rule out thyroid disease as cause of abnormal lipids and also symptoms. Normal TSH.

8. Labs on No Medications (1 of 5) Cholesterol is normal for young woman without other risk factors. With PCOS diagnosis may see “metabolic syndrome criteria” but she has none. Normal blood pressure, no increase in waist circumference, normal HDL-C and triglycerides, normal (low) glucose. Having normal parameters here does not mean insulin resistance is not present. In fact, root cause of PCOS is typically insulin resistance.

9. Labs on No Medications (2 of 5) Lipoprotein analysis is a much more accurate picture of her disease risk. She has discordant LDL, normal LDL–C (117) but high LDL–P (1470). Also insulin resistance noted on full NMR report ( see scanned report), IR score 48 (above 45). Multiple measures of inflammation noted.

10. NMR LipoProfile • Insert NMR Lipoprofile 07122011 DW88 Insert

11. Labs on No Medications (3 of 5)

12. Comments regarding genetic testing • She had additional genetic testing done to better define her cardiovascular risk as there were some unknown early deaths in her family history. She reassuringly has normal apo E genotype E3E3 but also normal Factor V and prothrombin. This is important to know in a young woman that may be prescribed oral contraceptive hormone therapy. I would not prescribe oral estrogen if high risk mutations in either of these present. This would increase her DVT risk. PCOS often is treated with OCPs when irregular menses present.

13. Hypoglycemia • She has self-reported “hypoglycemia”, which is confirmed with high insulin and low glucose on this report. She also has low normal HbA1C at 5.1. This is very common in the setting of insulin resistance. She has insulin resistance which causes the pancreas to work harder when glucose load post-meal, this leads to hyperinsulinemia which in turn drops her glucose low.

14. Labs on No Medications (4 of 5)

15. Labs on No Medications (5 of 5)

16. Initial Treatment & Management • Start metformin ER 500 mg 2-3 tablets daily with slow titration as tolerated for insulin resistance syndrome which is standard of care for PCOS. This will also help regulate her menses and may improve high LDL-P and inflammatory markers. Metformin does not cause hypoglycemia so no concerns even in setting of hypoglycemic reactions. We have many patients with “hypoglycemia” history that feel much better on metformin therapy. • Start Lovaza 4 g/day for elevated CRP, fatigue, low omega 3 index and joint pain. Lovaza can improve joint symptoms even though not indicated for this purpose. • Plan to repeat inflammatory markers especially with joint pain present. She may need autoimmune work up. • Start vitamin D3 4000 IU/day for vitamin D deficiency.

17. Discussion (1 of 4)

18. Discussion (2 of 4)

19. Discussion (3 of 4)

20. Discussion (4 of 4)

21. Follow Up on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (1 of 2) • Insulin Resistance Syndrome – Improved. • Currently on metformin 1500 and Lovaza 4. • Insulin resistance dramatically improved on NMR. IR-Score decreased from 48 to 21. Optimal is <45/100. • HbA1c remained normal at 5.0%. • Patient reports no hypoglycemic events since initiation of metformin. • Continue therapy. Her diet was unchanged from previous visit but advised continuing lower carb diet. • Dyslipidemia – Improved. • LDL-P dropped significantly on metformin 1500 from 1470 to 894. Small dense LDL decreased from 653 to <90. • Total cholesterol decreased to 179 from 184. LDL-C lowered to 100 from 117. Triglycerides reduced to 51 from 86. HDL increased from 51 to 58. • Continue therapy. • Elevated CRP – Improved. • Currently on Lovaza 4. Excellent response. • CRP lowered from 14.96 to 0.2. • MPO reduced to 332 from 560. • Continue therapy.

22. Follow Up on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (2 of 2) • Vitamin D Deficiency – Improved. • Currently taking vitamin D3 4000. • Levels increased from 36 to 50. • Continue therapy. • PCOS – Improved. • Currently taking metformin 1500. • Menses occurring regularly every 4 weeks. • Insulin improved. IR score is down from 48 to 21. • Continue with barrier contraception. • Low Omega 3 Index – Improved. • Currently taking Lovaza 4 (prescription omega 3 ethyl esters) • Omega 3 index increased from 4.5% to 6.6%. Index is still low. Optimal is >8-10%. • Consume more omega 3. Highest sources of Omega 3 come from Atlantic salmon, herring, mackerel, or Bluefin tuna. • Continue therapy. • Joint Pain – Unchanged. • Lovaza 4 did not appear to make a difference. • Recommend follow-up with rheumatologist. She may have autoimmune disease. • Reassuring CRP and MPO did improve.

23. Labs on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (1 of 5)

24. Labs on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (2 of 5)

25. Labs on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (3 of 5)

26. Labs on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (4 of 5)

27. Labs on Metformin 1500, Lovaza 4 and Vitamin D3 4000 (5 of 5)

28. NMR LipoProfile • Insert NMR Lipoprofile 10192011 DW88 Insert

29. Case Summary

30. Clinical Pearls • Metformin helps improve the root cause of PCOS (insulin resistance) but at the same time also improves dyslipidemia. Pioglitazone would also have been a very good choice for her especially as she is normal body weight and possible weight gain from pioglitazone would not likely be issue for her. Also, TZDs are better agents for preservation of beta cell function and pioglitazone also will lower LDL-P and can improve ovulation.

31. Role of Insulin Resistance in PCOS

32. Role of Insulin Resistance in PCOS

33. Management Strategies in PCOS

34. References (1 of 3) Insulin Resistance Syndrome • ADA Standards of Medical Care in Diabetes - 2012. Diabetes Care. Jan 2012 35(1)11-63. • Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005 Apr 19;142(8):611-9. • Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403. • Nathan DM, Davidson M, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. A consensus statement from the American Diabetes Association. Diabetes Care. 2007;30:753-759. Dyslipidemia • El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am CollCardiol. 2007 Feb 6;49(5):547-53. • Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007 May;192(1):211-7. • FestaA, Williams K, Hanley AJ, et al. Nuclear magnetic resonance lipoprotein abnormalities in prediabetic subjects in the Insulin Resistance Atherosclerosis Study. Circulation. 2005 Jun 28;111(25):3465-72. • Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999 Aug 7;354(9177):447-55.

35. References (2 of 3) Elevated CRP • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421. • Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000 Mar 23;342(12):836-43. Vitamin D Deficiency • Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168(12):1340-1349. • Giovannucci E, Liu Y, Hollis B, Rimm E. 25-hydroxyvitamin d and risk of myocardial infarction in men. Arch Intern Med. 2008;168(11):1174-1180. • Michos E and Blumenthal R. Vitamin D Supplementation and Cardiovascular Disease Risk. Circulation. 2007;115(7):827-828. • Hathcock J, Shao A, Vieth R, et al. Risk assessment for vitamin D. Am J ClinNutr. 2007;85:6-18. • Holick M. Vitamin D Deficiency. N Engl J Med. 2007;357:266-81. .

36. References (3 of 3) PCOS • HarborneL, Fleming R, Lyall H, et al. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet. 2003 May 31;361(9372):1849-901. • Brettenthaler N, De Geyter C, Huber PR, et al. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J ClinEndrocrinolMetab. 2004 Aug;89(8):3835-40.