A site of Dr. Pankaj Desai

CHAPTERS CONTRIBUTED

ROLE OF STATINS IN PCOS

AUTHOR:
Pankaj D. DESAI MD (O&G)
Chief of Unit in Obgyn (VRS)
Medical College and S.S. G. Hospital Baroda
 

Co-Author
Dr. Munjal Pandya
Assistant Professor
AMC MET Medical College
Sheth L. G. Hospital
Ahmedabad
 

INTRODUCTION:

Polycystic ovarian syndrome (PCOS) is a combination of various symptoms due to an imbalance in hormonal homeostasis. Main features seen in a patient with PCOS are the result of high androgen levels, along with disturbances in lipoprotein equilibrium. Previously known as the Polycystic Ovarian Disease (PCOD), has various pathological changes, thus replacing the word ‘Disease’ with ‘Syndrome’. Also known as “Stein Leventhal Syndrome”, it has various defining criteria according to various societies. According to the National Institute of Health Criteria, hyperandrogenism and oligo/amenorrhoea are required to stamp a case as of PCOS.¹ Rotterdam criteria consists of fulfilling of any two of three criteria (hyperandrogenism, oligo/amenorrhoea, polycystic ovaries).² Androgen Access Society (2006) recommended the presence of clinical and/or biochemical hyperandrogenism and either oligo/anovulation or polycystic ovarian morphology.³ Hormonal profile of PCOS patients has derangements like high androgens, relatively increased estrogens, reduced Sex Hormone Binding Globulin (SHBG), and high insulin levels.

Co-morbidities of PCOS

High circulating insulin levels make subjects with PCOS more prone to development of gestational as well as type II diabetes. Patients with PCOS are more prone to develop an atherosclerotic disease, as compared to the common population. Low-density lipoproteins (LDL), triglycerides, and Very Low-Density Lipoproteins (VLDL) are higher while High-Density Lipoproteins (HDL) levels are lower in patients with PCOS.⁴ The risk of myocardial infarction is more in these patients owing to increased size and stiffness of the left ventricle along with increased homocysteine levels, increased androgen levels and increased chances of calcification of coronary arteries.^{3, 5} These patients are more prone to develop metabolic syndrome, along with obesity and propensity to develop diabetes.⁶

Chronic anovulation in PCOS patients makes them susceptible to endometrial hyperplasia, which may advance to endometrial adenocarcinoma. PCOS patients have hyperplasia of theca-interstitial cells, caused by increased insulin as well as oxidative stress, leading to hyperandrogenism.⁷ It is believed that this increased insulin level is responsible for hyperandrogenism, by increased production from theca-interstitial cells, as well as reduced apoptosis of the same.^{8, 9} Increased insulin levels also inhibit SHBG, thus increasing unbound free androgen levels.¹⁰

Oxidative stress has been proved to be instrumental in deranging homeostasis in subjects with PCOS, by increased generation of Reactive Oxygen Species (ROS), which leads to more of systemic inflammation, even in lean patients.¹¹ Insulin and systemic inflammatory cells are proved to increase oxidative damage independently, inducing theca cell proliferation.^{12, 13, 14} Oxidative stress also causes disturbances in insulin signalling, thus stimulating more insulin secretion, making it a vicious cycle.

Pathophysiology involved in PCOS has been explained as an algorithm in Fig. 1

Fig. 1 Pathophysiology of PCOS

What are Statins?

Any of group of drugs which act to reduce levels of cholesterol in the blood are called statins. They are also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications. Also known as hypolipidemic agents, or antihyperlipidemic agents, they are a diverse group of pharmaceuticals that are used in the treatment of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia). They are called lipid-lowering drugs. z

Statins have variety of effects, beneficial for PCOS patients, which include endothelial function improvement, increased nitric oxide, anti-oxidant effect, reduction in inflammatory markers and immunomodulation. Statins are used for improving lipid profile (reducing LDL), thus will be helpful in PCOS patients. High testosterone levels also decline with their usage, an added advantage offered.^{15, 16, 17, 18} However; studies have shown little improvement with menstrual irregularity and with hirsutism with statin monotherapy.

Mechanism of action of statins

The Mevalonate pathway is the all critical pathway in the action of statins. Mevalonate pathway causes the conversion of acetyl-CoA into isopentenyl pyrophosphate, the essential building block of all isoprenoids. It is also known as the isoprenoid pathway or HMG-CoA reductase pathway and is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, heme, vitamin K, coenzyme Q10, and all steroid hormones.

It produces mevalonate from Hydroxymethylglutaryl-CoA (HMG-CoA), the former being an essential product for cholesterol synthesis. (Fig. 2) The rate-limiting enzyme for this pathway is HMG-CoA Reductase, which is reversibly inhibited by statins, thus improving the lipid profile in PCOS patients.15 Inhibition of this enzyme leads to reduced levels of dolichol, geranyl-geranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Dolichol is essential for maturation of insulin and insulin-like growth factor-1 (IGF-1) receptors, so its reduction is helpful for PCOS patients.¹⁹ GGPP and FPP have an important role in post-transitional modification of GTPase proteins, which have an essential role in cellular mechanics.²⁰ Reduced levels of these proteins, thus, inactivates signal transduction of mitotic activity, decreasing tissue growth, along with a reduction in oxidative stress. The anti-oxidant effect seems to be due to NADPH oxidase activity inhibition as well as inhibition of oxidized LDL production and anti-free radicle action.^{21, 22}

Statins are proved to have lowered LDL cholesterol by reducing its synthesis as well as by its clearance, along with improving HDL and triglyceride levels. Inflammatory markers are seen to be reduced as well.16, 17 Statins have been effective in activating AMP-activated protein kinase (AMPK), which is important for cellular metabolic and energy homeostasis.

Fig 2: Mechanism of action of statins

Hyperandrogenism

Hirsutism is one of the most distressful features, contributing to psychological turmoil of hyperandrogenism. Statins have been promising agents in various studies with a reduction in testosterone level, improvement in LH: FSH ratio, reduction in ovarian size.²³ Cholesterol levels are reduced with statins, which again is a component for androgen production, thus correcting hyperandrogenism.

Polycystic ovaries

Statins have been effective in reducing the ovarian size, as well as in improving ovarian cycle. Improvement in LH: FSH ratio, along with a reduction in LH level contributes to unifollicular maturation, thus regularizing menstrual cycle. Insulin and IGF-1 actions on the ovary are also limited.

Obesity and Insulin resistance
PCOS patients usually have impaired insulin sensitivity and statins in a majority of the studies showed a reduction in insulin resistance. Reduced triglyceride leads to more usage of glucose, improving insulin homeostasis. Rosuvastatin showed worsening of insulin sensitivity. ²⁴

Pre-treatment with atorvastatin, followed by metformin usage, has proved to be of a synergistic effect with improvement in metabolic parameters and inflammatory markers. The study showed that 3 months treatment with atorvastatin followed by 3 months treatment of metformin leads to accumulative 33% reduction in insulin and 35% reduction in HOMA-IR.

Cardiovascular risk

Improvement in the lipid profile, inflammatory markers with statin usage reduce chances of atherosclerotic risk in PCOS patients.

Clinical Studies

Various studies have been done with statin alone, as well as with oral contraceptive pills (OC Pills), with metformin.

Simvastatin

Randomised controlled trials performed with one group on simvastatin with OC Pills and the other group on OC Pills alone, showed improvement in lipid profile, with reduction in Luteinizing Hormone (LH) level, testosterone level, inflammatory markers and hirsutism in the former group.^{25, 26} A trial using metformin, simvastatin, and combination showed the results as: reduction in cholesterol was more in patients who received simvastatin (alone and in combination groups), reduction in testosterone was better in simvastatin alone group, improvement in menstrual irregularity was more with simvastatin group. ²³ One more study divided patients into two groups, one receiving simvastatin and metformin combination and the other one receiving metformin with placebo. Reduction in testosterone, LDL, total cholesterol, LH, hirsutism was noted in former group.²⁷

Atorvastatin

Atorvastatin was found to have reduced inflammatory marker high sensitivity C-reactive protein (hs-CRP), which is a predictor of cardiovascular events.²⁸ hsCRP reduction also reduces insulin resistance in pre-diabetics. A trial comparing simvastatin with atorvastatin showed a reduction in testosterone, homocysteine, fasting insulin, LDL and LH levels in both groups. Reduction in homocysteine levels was much greater in atorvastatin group as compared to simvastatin group.²⁹

Mevastatin

Mevastatin inhibits theca-interstitial proliferation and androgenesis.³⁰ Mevastatin has been found to be having an inhibitory effect on mesenchymal cells, including smooth muscle, myocytes, mesangial cells.^{31, 32, 33, 34, 35} Mevastatin and simvastatin have been found to inhibit NADPH oxidase subunits effectively, thus decreasing steroidogenesis.³⁶ OC Pills have been very promising in improving SHBG when given for at least 3 months, much more effective than statins alone.

Adverse effects of statins:

Headache, sleep disturbances, drowsiness, nausea, vomiting, abdominal pain, bloating, constipation, skin rash are the known side effects of statins. Infrequent complications like liver toxicity may occur in patients with acute liver disease. Risk of diabetes may increase and few studies also reported reversible dementia with its usage.³⁷

Teratogenesis of statins: Statins have been rated as High-risk Category agents, thus making it compulsory for patients to use contraceptive methods along with their use. Though, statin-induced teratogenicity risk is small.

Conclusion

As PCOS is being diagnosed rampantly in today’s era, along with lifestyle and dietary modifications, Statins as potentially promising agents need to be given attention for their inclusion in routine usage guidelines, so as to benefit patients with more fruitful outcomes, to their maximum satisfaction.

References

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