Pharmacy and Wellness Review

Volume 2 Issue 1 Article 6

March 2011

Polycystic Ovarian Syndrome and Hyperinsulinemia: Overview and Treatment

Amanda M. Meyer Ohio Northern University

Lauren D. Bajbus Ohio Northern University

Sarah E. Drake Ohio Northern University

Kristen M. Quertinmont Ohio Northern University

Ashley Overy Ohio Northern University

See next page for additional authors

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Part of the Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Female Urogenital Diseases and Pregnancy Complications Commons, Obstetrics and Gynecology Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutics and Drug Design Commons, Therapeutics Commons, and the Women's Health Commons

This Article is brought to you for free and open access by the ONU Journals and Publications at DigitalCommons@ONU. It has been accepted for inclusion in Pharmacy and Wellness Review by an authorized editor of DigitalCommons@ONU. For more information, please contact [email protected]. Polycystic Ovarian Syndrome and Hyperinsulinemia: Overview and Treatment

Authors Amanda M. Meyer, Lauren D. Bajbus, Sarah E. Drake, Kristen M. Quertinmont, Ashley Overy, and Anne Gentry

This article is available in Pharmacy and Wellness Review: https://digitalcommons.onu.edu/paw_review/vol2/iss1/6 Women's Heafth

Polycystic Ovarian Syndrome and Hyperinsulinemia: Overview and Treatment

Amanda M. Meyer, fourth-year pharmacy student from Dublin, Ohio, Lauren D. Bajbus, fourth-year pharmacy student from Parma, Ohio. Ssrah E. Drake, fifth-year pharmacy student from Fairfield, Ohio, Kosten M. Quertinmont, fifth-year pharmacy student from Carmel, Ind.. Ashley Overy, fifth-year pharmacy student from Grafton, Ohio. Anne Gentry, PharmD, assistant director of the Drug lnformabOn Center and advisor for The Pharmacy and Wellness Review

Abstract Hyperinsulinemia Hypennsuhnemia and insulin resistance are commonly associated with Polycysbc ovary syndrome is a prevalent issue in women's health that 1s associated with hypennsJllnemia and insulin resistance and PCOS. Hyperinsulinemia increases production of already elevated can lead to long-term health problems. The most highly recom­ androgens, worsening PCOS symptoms. ThlS IS accomplished by mended treatments are diet and lifestyle changes. If these changes overproduction of ovarian androstenedt0ne ard adrenal dehydroepi­ alone are oot eoough pharmac:ilogic treatments may be employed androsterone (DHEA), which leads to excess estrogen m the periphery. which include melformin, spironolactone or th1azolldinediones , Elevated estrogen increases the ratio of lute1raing hormone (LH) secreted by the anterior pituitary gland to secret10n of follicle stimulating although more research IS neeoed to fully rea hze their role. The role 1 of the pharmacist in this disease state includes counseling patients hormone (FSH). Increased LH secretions lead to amenorrhea, infertility, on healthy lifestyle changes, consulting with the phys1c1an about anovulaaon and hyperandrogenism. prescribing the best medication for each pa tient, and momtonng The hypothalam1c-p1tu1tary axis also 1s affected by excess release of therapy adherence in the pat1ert adreoocort1cotropic hormone (ACTH) in response to cortJCOtropm·re· leasing hormone (CRH). 1 ACTH samulates hJX)prote1n uptake by cortical Introduction cells, which can lead to higher cholesterol levels. This dysregulatlon of PolycysllC ovanan syndrome (PCOS) 1s a prevalent disorder affecting cholesterol levels correlates to the finding that many women with PCOS 6-15 percent of women of reprodoct1ve age. 1 PCOS 1s a ple10tropic are obese. Hyperinsulinemia also may possibly contnbute to this weight syndrome that can have delete nous effects on the ent1re body. Hyper­ gain Overall, insulin resistance and compensatory hypennsulinemia are insullnem1a IS one of the main concerns associated with this syndrome contnbutmg factors for anovulation, hyperandrogen1Sm, infertility and because rt can increase the risk for many other disease states in a earty pregnancy loss associated with PCOS paoents (Figure 1). woman with PCOS. There are few treatment options for PCOS at this time; but by understanding the safety and efficacy of the available op­ t10ns, pharmacists can help their patients better understand the disease state and medications. Pharmacists ca n further ta ke an active role by prov1d1ng screenings and educanrg patients on preventative measures for women who are at nsk of developing this disease.

PCOS PolycystJC ovanan syndrome IS the most common endocnne disorder Ooosny among premenopausal women 1 The symptoms of this disorder are vaned and extend beyond reproductive system problems. Along with menstrual 1rregulanties, chronic anovulation and possible infertlhty, wom­ en with PCOS often develop hirsutism, acne , hyperandrogenism and inappropnate gonadotropin secretJon. 14 While some of the symptoms may only be frustrating or uncomfortable for the patient, a woman with PCOS 1s at nsk for developing other cond itions that are not as benign. A PCOS diagnosis means the patient is at an increased ris k for insulin resistance. hyperinsulinemia, dysl pidemia, hypertension, gestational and type 2 diabetes, systemic inflammatlOn, endothelial dysfunction, Figure 1. Detrimental ettects of PCOS-induced hyperinsulinemia and cardiac events such as myocardial infarction or cerebral vascular accidents Although PCOS is a common problem, its pathogenesis Non-phannacologic Treatment Options remains unknown. It 1s not merely a structural disorder, rather, it has The most hghly recommended way to treat PCOS is artenng the diet to definite ties to problems with horrrones, genetics, and even potentlally include healthier opaons, such as whole grains and fresh produce, and altered central nervous system (CNS) function.6 There are theories reduce the 1n1ake of hghly processed foods and foods high 1n fat or sodium. that PCOS has a genetic component due to a gene mutation in ova rian lncorporanng exercise into daily life also is recommended.7 Eating foods that and adrenal androgen synthesis as evidenced by a higher incidence of help decrease LDLs and increase HDLs, such as high fi~r foods and foods PCOS among f1rst-<1egree relatives. CNS problems such as epilepsy and con1a1mng omega-3 fatty acids (fish and nuts), can~ ~neflCial dietary btpolar disorder may also play a role in PCOS but more research needs modlfcaoons.' Achieving Ideal body weight and exercis1119 at least five umes to be done before a more concrete conclust0n 1s reached regarding this per week can JX)tentially alleviate many symplOrns assoc10.ted with PCOS as potential relationship. wel as reveise the progression of concurrem dlS98se states.

2 1 THE P HAIWAc• AND WELLNEss AEvtew Volume two. Issue one March 2011 Polycystic Ovarian Syndrome and Hyperins ulinemia: Overview and Treatment Women's Health

A diet that has recenUy received significant media and patient attention is test parameters or insulin sensitivity when patents received a 50 mg/day the human chononic gonadotrop1n (hCG) diet. Human chononic gonado· dose of spironolactone.16 However, there was a significant improvement tropin 1s a hormone produced by tl'e trophoblastic cells of the placenta m menstruation cycle, hirsutism and androgen levels. While spirono­ dunng pregnancy.' The hCG diet supposedly mobilizes fat stored in the lactone was supe rior in helping with hirsutism and patient acceptance, abdomen, h1~ and thighs while keeping the patient feeling satiated. The metformin was more effective at improving glucose tolerance and insulin diet involves three "gorging days," to build up calories in the body, followed sensitivity. Although spironolactone 1s an option in the treatment of by a :-;Lrict, ve1y low-cato1ie diet of 500 calorie:; a day while receiving hCG PCOS, 1t iS not µrefe11 ed becau:;e it doe:; not cause sig11mca11t irnprove­ as injgctions, subbngual dro~ or lozenges. Despite some clinical trials ment in glucose tolerance and insulin sensitivity. showing benefits, the FDA denies that hCG has any benefit in treating obesity.1°CurrenUy, the only FDA-approved use for hCG is for fe rtility treat­ Another pharmacologic option is a TZD such as rosiglitazone or piogli­ ment 11 The diet is not recommended for weight loss in most patients, but tazone. Both of these drugs are agonists of the peroxisome-proliferator­ it may be used as a last resort for patie nts who desperate ly need to lose activated receptors {PPARs ), which, when activated, influence the weight Pharmacists can counsel p.i.tients about the risks associated with production of proteins invo lved in glucose and lipid metabolism. 15 This the diet, monitor its correct use and ensure the safety of the patients. improves response to insulin without influencing the amount of insulin that 1s secreted by the pancreas. In a randomized , two-armed, head-to­ Pharrn acologic Treatment Options head study of96 patients, it was found that ros1glitazone was more ef­ There are limited pharmaceutical opttons that can be utilized; however, fective than metformin at red ucing female hirsutism, but it was not found because of the underlying problem with hyperinsulinemia, insuhn-sens1uz­ to be more beneficial at red ucing insulin levels , even though there was a ing agents may be beneficial in treating PCOS. 12 The three products that s1gnif1cant reduction in fasting insulin levels in the use of rosightazone.2 currently are used in the treatment of PCOS are metformin, sp1ronolactone Although these resu lts sou nd promising, due ro a recent change in the and th1azohd1nediones (TZDs). These medications all have different mech­ FDA Black Box Warning regarding increased nsk of cardiac events, anisms of acoon and treat PCOS ma variety of ways. Further resesarch is rosightazone should not be used in PCOS patents because they are necessary prior to widespread use of these agents. predisposed to such events.

Metformin is a commonly used and studied treatment of PCOS in patients Pioglitazone has also been studied in the treatment of PCOS. A random­ with hyperinsulinemia. There are various potential mechanisms by which ized controlled trial of 52 patients found that a six-month administration metformin may lower insulin levels, including the inhibition of gluconeo­ of pioglitazone in obese women was as effective as metformin in reduc­ genic enzymes, reduced uptake of enzymes needed for hepatic gluconeo­ ing fasting insulin levels without drastically changing glucose conce n­ gensis, increased phosphorylation 0f insulin receptor and insulin receptor tration.17 There also was a significant reduction in hirsutism and serum substrates, and inhibition of mitochondrial respi ration, which can reduce concentrations of testosterone and androgens. Pioglitazone use may the energy supply needed for gluconeogenesis. 13 In patients with PCOS, cause an increased risk of bladder cancer as indicated by the FDA Black the lowering of insulin levels can lead to improved ovarian function as Box Warning. This risk should be taken into consideration when choos­ well as improved glucose metabolism.14 Lowering insulin levels also may ing a treatment, and patients should be monitored. Due to the Black Box reverse the dysfuncoon in the hypothalamic·pituitary-ovanan axis, causing warnings, and because there's no significant benefit over metform1n or a decrease in androgen levels. 13 Add1nonally, mettorm1n has effects on sp1ronolactone, the use of TZDs in women with PCOS IS not recom· free fatty acid syntheslS, which indi'ectly lowers gluconeogenesis acovtty. mended as a first choice of therapy m the treatment of PCOS. It does this through antagon1Sm of acetyl·CoA ca rboxylase act1v1ty so that there is decreased fatty acid synthesis and increased mitochondrial Conclusion fatty acid oxidation. These two effects on the body lead to a reduction Pharmacists can assume an active role when ass1Sting with the treat­ in hepatic lipid levels and lowered plasma triglyceride levels. While the ment of hyperinsulinemia in PCOS. Awareness of the treatment options effects of metformin seem to be beneficial in women with PCOS, there available can allow pharmacis ts to ensure that prescribers are utiliz- are side effects to consider that may deter patient use of this medication. ing the optimum treatment plan for the patient Metformin is generally The most common issues are gastrointes tinal-related, such as nausea, the first-choice option in the treatment of hyperinsulinemia in PCOS. vomiting and diarrhea. 13 These are typically resolved in a few days or Since there are several negative side effects associated with the drug, weeks and can be minimized by taking metformin with meals and follow­ the pharmacist can communicate with the prescriber about a titration ing a gradual titration schedule. 13 A change in diet and exercise patterns, schedule in order to make the patient more comfortable. Spironolactone along with the use of metformin, can improve cardiometabolic irregulari­ is not as effective as metformin in treating hy~rinsulinem1a , but it does ties and may even restore ovanan function. treat the problems caused by excess androgens. TZDs are not recom­ mended in the treatment of PCOS because of the Black Box warnings Spironolactone IS another treatment option for women with PCOS. Along and concerns of patient sa fety: however, patients already taking a TZD with diurebc properties. spironolactone may be used as an antiandrogen should be counseled on correct and safe use. Aside from counseling for female h1rsut1Sm. Though the nechanism 1s unknown, it is thought the patients on their prescnbed medications, pharmac1Sts can help with to block androgen receptors and nay decrease the overall productlon.3 screenings to track patient progress. Such screenings include glucose According to a randomized, open-label study of 69 PCOS patients com­ screenings, lipid panel screenings, and body mass index va lues. Becom· paring sp1ronolactone and mettorn1n treatment, there was no significant 1ng involved 1n the outpatient setting can allow pharmacists to alert effect on BMI, waist-to-hip ratio, blood µre:;s ure , oral glucose tolerance patients to any concerning lab values or assis t patients with plans and

March 2011 Volume two. Issue one THE P HARMAc1 AND W ELLNESS R Ev1Ew 22 Women's Health Polycystic Ovarian Syndrome and Hyperinsulinemia: Overview and Treatment tracking of lifestyle changes. Because of the complexity of PCOS, it is 14. Sahin I, Serter R, Karakurt F, Demirbas B, Culha C, Taskapan C, important to treat each patient based on individual symptoms and needs. Kosar F, Aral Y. Metfo rmin versus nutamlde mthe treatment of Due to the access1b1hty of pharmacists, counseling PCOS patients is a metabolic consequences of non-obese young women with polycysuc pos111ve opportunity to take on an integral role in helping patients man­ ovary syndrome. a ra ndomized prospective study. Gynecol Endo­ age and improve the symptoms of this disease state. cnnol. 2004;19'115·124. 15. Lexi-Comp [database on line]. Hudson, OH: Lexi-Comp, Inc. 2010. References Availal>le al u11line.lexi.<.:u111/c1lsql/:;ervleVcrlo11li11e. A<.:ce:;:;ed OcL 1. Romualdi D, Giuliani M, Draisci G, Costantini B, Cristello F, Lanzone 29, 2010. A, Guido M. Pioglitazone reduces the adrenal androgen respo nse 16. Ganie MA, Khurana ML, Eunice M, Gupta N, Gulati M, Dwivedi SN, to corticotropin-releasing facto r without changes m ACTH release Ammini AC. Comparison of efficacy of spironolactone with metformin in hyperinsulinemic women with polycystic ovary syndrome. Fertil in the management of po lycystic ovary syndrome: an open-labeled Steril. 2007;88(1):131-138. study. J Clin Endocrinol Metab. 2004;89(6):2756-2762. 2. Yilmaz M, Karakoc A, Toruner FB, Cakir N, Tiras B, Ayvaz G, Arslan 17. Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P, M. The effects of rosiglitazone and metformin on menstrual cyclicity Arteaga-Troncoso G, Parra A. Responses of serum androgen and and hirsullsm in polycystic ovary syndrome. Gynecol Endocrinol. insulin resistance to metformin and pioglitazone m obese, insulin­ 2005 ; 21 (3)' 154-160. resistant women with polycys tic ovary syndrome. J Chn Endocnnol 3. Bhatia V. Insulin resistance in po lycystic ovarian disease. Southern Metab. 2005;90(3):1360- 1365. Medical Assoc1at10n. 2005; 98(9):902-909. 4. Fulghesu AM, Ciampell1 M, Guido M, Murgia F, Garuso A, Mancuso S, Lanzone A. Role of op101d tone in the pathophysiology of hyper­ msuhnem1a and insulin resistance m polycystic ovarian disease. Metabolism. 1998. 47 158· 162. 5. Banaszewska B, Pawelczyk L, Spaczynski RZ, Ouleba AJ. Compan­ son of s1mvastatin and metformin in treatment of polycystic ovary syndrome: prospective ra ndomized trial. J Clin Endocrinol Metab. 2009: 94(12): 4938-4945. 6. Abbott Laboratories. Understanding Obesity and Polycystic Ovary Syndrome: 2006. Abbott Park, IL. 7. Insulin Resistance and Hyperinsulinemia. Jewish Hospital Cincin­ nati, Catholic Healthcare Partne rs. 2010. Available at www. ~wish­ hospitalcincinnati.com/cholesterol/Research/insulin resistance.html. Accessed Oct 29, 2010. 8. HDL cholesterol How to boost your "good" choles terol. Mayo Foun­ dacion for Medical Educacion and Research. 2010. Available at www.mayochnte.com/health/hdl-cholesterol/CL00030/ NSECTIONGROUP=2. Accessed Oct. 29 . 2010. 9. BellusclO 00, R1pamonte L, and Wolansky M. Utility of an Oral Pre­ sentatJon of hCG (Human Choriogonadotropin) for the Management of Obesity. A Double Blind Study. The Orig inal Internist. 2009: 197· 211. 10. Robb-N icholson C. By the Way , Doctor I've been trying to lose weight for a long time and nothing see ms to work. What do you know about the HCG diet? Harv Wome ns Health Watch. 20 10;17:8. 11. Scheve T. How the HCG Diet Works. Discovery Communications Inc. 2010. Available at health.howstuffworks.com/wellness/diet­ fitness/weight-loss/hcg-diet3.htm. Accessed Oct. 29, 2010. 12. Cheang Kl , Sharma ST, Nestler JE. Is Metform in a primary ovulatory agent m pallents with polycystic ovary syndrome? Gynecol Endo­ crinol. 2006;22(11):595-604. 13. Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C. Mecformin in polycystic ovary syndrome. Ann NY Acad Sci. 2010'1205 192-198.

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