Sex Hormones & CardioMetabolic Risk:             Polycystic Ovary Syndrome

Over the past 25 years there has been exponential growth of the medical knowledge linking sex hormone disorders to cardiovascular and metabolic disease risks. This discussion focuses on the underlying metabolic dysfunction that is present in one of the most common endocrine disorders that affects women of reproductive age, Polycystic Ovary Syndrome (PCOS). PCOS is a multi-faceted disorder with unclear pathophysiology that manifests as impaired hormonal signaling at the level of the of the hypothalamic-pituitary gonadal axis resulting in abnormal ovarian hormone production, insulin resistance, and polycystic ovaries.1,2 The classic clinical presentation is characterized by menstrual irregularity, premenstrual syndrome, abnormal hair growth (hirsutism) involving the face, chest, back or buttock areas, thinning or loss of hair from the head (alopecia), oily skin or acne, weight gain, and in advanced cases, infertility.1,2 The prevalence of PCOS is generally thought to be between 3%-10% of the population but truly unknown based on the high degree of variability of expression or presentation as well as inconsistencies between different diagnostic criteria.1,2

 

The symptom presentation as it relates to the ovarian hormones is known as the “reproductive phenotype”. However it is now widely recognized that PCOS also displays a distinct “metabolic phenotype” with underlying insulin resistance as the sentinel factor or etiological process that contributes to the development and progression of the diseases or conditions of the metabolic syndrome that in turn contribute to cardiovascular disease (CVD) risk.1

 

Metabolic Syndrome refers a cluster of disease states: obesity, diabetes, dyslipidemia, and hypertension that when occurring simultaneously, exponentially increase CVD risk. These conditions are also known to be highly prevalent in PCOS with insulin resistance identified as the metabolic hallmark of this condition. In the US obesity affects 80% of women with PCOS and with the associated insulin resistance significantly increases the risk for developing prediabetes and type 2 diabetes in these women.3,4,5 Research has demonstrated that in women with PCOS the prevalence of prediabetes is 25-35% and that of type 2 diabetes is 4-10%.6,8 Studies have reported that in addition to insulin resistance the regulation of pancreatic insulin secretion may also be impaired, the two most important pathophysiologies leading to the development of type 2 diabetes. PCOS is also widely known to be associated with dyslipidemia. Due to these metabolic imbalances, women with PCOS are at increased risk for CVD.9,10,11

 

Despite the known risk factors that are associated with PCOS the American College of Obstetricians and Gynecologists (ACOG) reported that less than 20% of physicians screen women with PCOS for diabetes and dyslipidemia.12,13 Other studies have shown that about 26% of primary care physicians don’t screen for type 2 diabetes in women with PCOS.15 Consensus statements from many professional societies, such as the American Association of Clinical Endocrinologist (AACE), American College of Endocrinologist, AE-PCOS Society Endocrine Society, the Androgen Excess and PCOS Society (AEPCOS), and the Australian PCOS Alliance guidelines, recommend screening for type 2 diabetes of all women with PCOS.16,17

 

Treatment of the metabolic phenotype in women with PCOS is multifactorial. Lifestyle interventions, such as exercise and eating a balanced diet, are considered the first line to control cardiometabolic risk in PCOS, particularly in overweight and obese women. Since obesity is known to exacerbate both the reproductive and metabolic phenotypes of PCOS, lifestyle interventions can control symptoms by decreasing weight.18 In addition to diet and exercise, weight loss has been shown to ameliorate the adverse metabolic profile in women with PCOS.19

Insulin resistance plays a pivotal role in PCOS, and the use of insulin receptor sensitizers can be beneficial in decreasing cardiometabolic risk. Metformin, an oral-antidiabetic drug that decreases hepatic glucose production and improves insulin sensitivity, has been shown to improve glucose intolerance, insulin resistance, and hyperinsulinemia in women with PCOS, and is recommended in these women who have type 2 diabetes or impaired glucose tolerance.18 The newer anti-hyperglycemic agents, glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs), may also be employed to regulate pancreatic insulin secretion. Effects of GLP-1 RAs include stimulation of insulin secretion and inhibition of glucagon release when hyperglycemia is present, delay of gastric emptying, reduction of food intake with associated weight loss, and reduction of fasting and postprandial glucose.20 A study showed that the combination therapy of the GLP-1 RA liraglutide and metformin improved glucose tolerance and insulin resistance in women with PCOS compared to monotherapy, in addition to more weight loss.20-24

 

Women with PCOS are at greater risk for CVD and having PCOS is considered a risk factor for atherosclerosis.24 Studies have shown that women with PCOS have a greater prevalence of dyslipidemia compared to BMI and age matched controls with increased levels of low-density lipoprotein (LDL), very-low density lipoprotein (VLDL), and triglycerides (TG), as well as decreased levels of high-density lipoprotein (HDL).25 Statin therapy is well recognized for managing dyslipidemia and decreases CVD risk by lowering LDL-C levels. Twenty-five recent studies have shown that statins can lower LDL-C in women with PCOS and support their use for controlling CVD risk in this patient population.25

 

It is clear that the metabolic phenotype is an important component of PCOS, and experts have suggested a tight link between the metabolic and reproductive features. The high prevalence of cardiometabolic abnormalities puts women with PCOS at risk for developing insulin resistance, obesity, type 2 diabetes, and cardiovascular disease. Proper identification and screening approaches are crucial to identifying women with PCOS who are at an increased risk for metabolic imbalances. Awareness about strategies to decrease the cardiometabolic impacts of PCOS are needed, and clinicians treating PCOS should consider comprehensive and evidence-based approaches to reduce cardiometabolic risk.

 

References:

  1. Diamanti-Kandarakis, Evanthia, and Andrea Dunaif. “Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications.” Endocrine Reviews 33.6 (2012): 981-1030.

  2. El Hayek, Samer, et al. “Poly cystic ovarian syndrome: an updated overview.” Frontiers in Physiology 7 (2016): 124.

  3. Dumesic, Daniel A., et al. “Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome.” Endocrine Reviews 36.5 (2015): 487-525.

  4. Dunaif, Andrea, et al. “Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.” The Journal of Clinical Investigation 96.2 (1995): 801- 810.

  5. Dunaif, Andrea, et al. “Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS).” American Journal of Physiology- Endocrinology and Metabolism 281.2 (2001): E392-E399.

  6. Ehrmann, David A., et al. “Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.” Diabetes Care 22.1 (1999): 141-146.

  7. Legro, Richard S., et al. “Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.” The Journal of Clinical Endocrinology & Metabolism 84.1 (1999): 165-169.

  8. O’Meara, N. M., et al. “Defects in beta-cell function in functional ovarian hyperandrogenism.” The Journal of Clinical Endocrinology & Metabolism 76.5 (1993): 1241-1247.

  9. Fauser, Bart CJM, et al. “Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.” Fertility and Sterility 97.1 (2012): 28-38.

  10. Valkenburg, Olivier, et al. “A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study.” The Journal of Clinical Endocrinology & Metabolism 93.2 (2008): 470-476.

  11. Wild, Robert A., et al. “Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society.” The Journal of Clinical Endocrinology & Metabolism 95.5 (2010): 2038-2049.

  12. Teede, Helena, et al. “Polycystic ovary syndrome: perceptions and attitudes of women and primary health care physicians on features of PCOS and renaming the syndrome.” The Journal of Clinical Endocrinology & Metabolism 99.1 (2014): E107-E111.

  13. Dhesi, Amy S., et al. “Metabolic screening in patients with polycystic ovary syndrome is largely underutilized among obstetrician-gynecologists.” American Journal of Obstetrics & Gynecology 215.5 (2016): 579-e1.

  14. Gourgari, Evgenia, Elias Spanakis, and Adrian Sandra Dobs. “Pathophysiology, risk factors, and screening methods for prediabetes in women with polycystic ovary syndrome.” International Journal of Women’s Health 8 (2016): 381.

  15. Dokras, Anuja, et al. “Gaps in knowledge among physicians regarding diagnostic criteria and management of polycystic ovary syndrome.” Fertility and Sterility 107.6 (2017): 1380-1386.

  16. Ollila, M-ME, et al. “Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus—a prospective, population-based cohort study.” Human Reproduction 32.2 (2017): 423-431.

  17. Azziz, Ricardo. “Polycystic ovary syndrome: what’s in a name?.” The Journal of Clinical Endocrinology & Metabolism 99.4 (2014): 1142-1145.

  18. Legro, Richard S., et al. “Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 98.12 (2013): 4565- 4592.

  19. Butterworth, James, Jean Deguara, and Cynthia- Michelle Borg. “Bariatric surgery, polycystic ovary syndrome, and infertility.” Journal of obesity 2016 (2016).

  20. Jensterle, Mojca, Katja Goricar, and Andrej Janez. “Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved β-cell function and insulin sensitivity in metformin treated PCOS.” Endocrine Research 42.4 (2017): 261-268.

  21. Ferjan, Simona, Andrej Janez, and Mojca Jensterle. “DPP4 Inhibitor sitagliptin as a potential treatment option in metformin intolerant obese women with polycystic ovary syndrome: a pilot randomized study.” Endocrine Practice (2017).

  22. “Empagliflozin vs metformin in PCOS.” ClinicalTrials. gov identifier NCT03008551, available at https:// clinicaltrials.gov/ct2/show/NCT03008551

  23. “DAPA, EQW, DAPA/MET ER and PHEN/TPM ER in obese women with polycystic ovary syndrome (PCOS).” ClinicalTrials.gov identifier NCT02635386, available at https://clinicaltrials.gov/ct2/show/NCT02635386

  24. Jellinger, Paul S., et al. “American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.” Endocrine Practice 23.s2 (2017): 1-87.

  25. Goodman, Neil F., et al. “American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome-part 1.” Endocrine Practice 21.11 (2015): 1291-1300.