PCOS Natural Alternatives
Abstract
Polycystic ovarian syndrome (PCOS) affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals. The presence of insulin resistance, hyperinsulinemia, and obesity are associated with reproductive symptoms, and these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes. Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility. Conventional treatment of PCOS is largely symptom-based with therapies aimed at these categories. While conventional pharmaceutical treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies. Numerous natural treatments exist that are commonly used as alternatives to prescription medications, such as inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence primarily indicates that natural alternatives may be used to address the insulin resistance and hyperinsulinemia seen in many patients with PCOS. Inositol has shown to be effective in improving the hormonal and metabolic profiles in PCOS. Cinnamon and chromium have shown to have benefit by improving insulin signalling and glucose control. NAC has been shown to significantly increase both ovulation rate and pregnancy rate.
Polycystic ovarian syndrome (PCOS) was first reported in 1935, when Stein and Leventhal described a series of seven women who presented with oligo/amenorrhea, hirsutism, obesity (BMI > 25), infertility, and enlarged ovaries with multiple cysts (Madnani 2013, Sirmans 2013). This condition is now recognized as a common heterogeneous disorder affecting women of reproductive age and can be hereditary (Ebejer 2013, Sirmans 2013). It affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals (Madnani 2013). Stein and Leventhal originally observed a primary ovarian defect in the women studied, classifying this disorder as polycystic ovarian disease (Madnani 2013). It has become clear in recent years that the disorder is associated with major metabolic and reproductive morbidities and as such is now known as PCOS (Gerli 2007). The presence of insulin resistance, hyperinsulinemia, and obesity are associated with the reproductive symptoms, and recent data provide evidence that these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes (Fulghesu 2002, Sirmans 2013).
Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility (Sirmans 2013). Although 30% of women with PCOS have normal menses, the majority report oligomenorrhea, amenorrhea, and prolonged erratic menstrual bleeding (Sirmans 2013). Hirsutism is a common symptom of androgen excess prevalent in up to 70% of women with PCOS. A modified Ferriman- Gallwey scoring system is used to evaluate hair growth at seven sites with a total score of eight or more being indicative of hirsutism (Sirmans 2013). More than 90% of normally menstruating women with hirsutism present with polycystic ovaries through ultrasound. Other markers of hyperandrogenism are acne, oily skin, and certain virilisation patterns such as a deep voice or alopecia (Ciotta 2011, Madnani 2013). Acne is less prevalent than hirsutism, possibly due to higher dihydrotestosterone levels resulting from the expression activity of 5α-reductase in the sebaceous glands and hair follicles (Madnani 2013).
PCOS is the most common cause of anovulatory infertility where follicular growth is halted due to disturbances in normal follicular development (Sirmans 2013). A normal ovulatory cycle comprises a complex interplay of hormones from the pituitary, hypothalamus, adrenals, and ovaries where eventually the secretion of FSH and LH target the follicles in the ovary, allowing only one to undergo maturation to become the dominant or graffian follicle (Madnani 2013). The LH surge that takes place mid-cycle then stimulates ovulation. In PCOS however, a dominant follicle does not develop and ovulation does not ensue (Sirmans 2013).
Obesity is a common feature of PCOS with 70% of these women exhibiting exaggerated insulin secretion (Fulghesu 2002). There is a decreased sensitivity to circulating insulin (possibly due to a defect in phosphorylation of tyrosine kinase in the insulin receptor), resulting in hyperinsulinemia which in turn increases androgen production (Madnani 2013). Hepatic production of sex hormone binding globulins (SHBG) is reduced thereby increasing concentrations of free androgens (Sirmans 2013). Insulin resistance occurs independently of obesity, however it is consistent with metabolic syndrome common in women with PCOS (Sirmans 2013). Impaired glucose tolerance and type 2 diabetes are also highly prevalent in these women, who are also at risk for developing dyslipidemia (Latha 2012). Studies reveal that elevated plasma insulin levels enhance VLDL synthesis and triglyceride levels, resulting in atherogenic effects in arteries (Latha 2012, Sirmans 2013).
A relationship between oxidative stress and PCOS has been shown to influence the cardiovascular system as a result of lipid peroxidation, as well as the reproductive system through its effects on oocyte maturation, ovarian steroidogenesis, corpus luteum functions and other fertilization processes (De Leo 2012, Latha 2012). Equally interesting is the finding that women with PCOS have significantly higher levels of C-reactive protein (CRP) when compared to healthy weight controls, suggesting that this is an inflammatory condition (Ebejer 2013). CRP levels can predict risk of coronary heart disease and other elevated cytokines suggesting an immune component in the pathogenesis of PCOS (Ebejer 2013).
Conventional treatment of PCOS is largely symptom-based with therapies aimed at three categories: menstruation-related disorders, androgen-related symptoms, and infertility (Madnani 2013, Sirmans 2013). Low dose combined hormonal contraceptives are the primary treatment choice for PCOS-related menstrual disorders, as well as hirsutism and acne for patients avoiding pregnancy (Sirmans 2013). Anti-androgens such as spironolactone and finesteride are also prescribed, but with great caution due to their ability to feminize a male fetus if pregnancy occurs, and so are typically combined with oral contraceptive pills (Sirmans 2013). The oral contraceptives do not correct the underlying ovulatory defect and also possibly worsen insulin sensitivity. Agents for improving insulin sensitivity include metformin and thiazolidinediones (eg. Rosiglitazone) which may also aid in restoring ovulation and improving metabolic disturbances (Ebejer 2013). Clomiphene citrate is the drug of first choice for anovulatory infertility and acts as an anti-estrogen to stimulate FSH (Ciotta 2011). Although clomiphene citrate is the gold-standard drug for ovulation induction in those with PCOS, resistance is seen in as much as 40% of women (Saha 2013). While these treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies (Madnani 2013). Numerous natural treatments exist that are commonly used as alternatives to prescription medications. These treatments include inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence for these natural therapies is reviewed.
Inositol
Mounting evidence points to the central role of insulin resistance (IR) and compensatory hyperinsulinemia in the pathogenesis of PCOS (Dona 2012, Nordio 2012). These conditions predispose patients towards the development of dyslipidemia, impaired glucose tolerance, type 2 diabetes mellitus, and cardiovascular disease (Dona 2012). Several studies show that an altered insulin transduction induces abnormal ovarian steroidogenesis (Nordio 2012). Reducing serum insulin and androgen levels and restoring ovulation are typically treated with insulin-sensitizing drugs such as metformin (Nordio 2012). Metformin is generally well tolerated, however common side effects of metformin may include reduced vitamin B12 levels and gastrointestinal upset (Sato 2013). There is a good body of evidence to suggest that inositol functions as a natural insulin sensitizer, and may improve the effectiveness of metformin.
Inositol is a six carbon polyalcohol which has also been characterized as an insulin-sensitizer, with reported improvements in glucose tolerance, ovulation and androgen concentration (Galletta 2011). It exists as nine different stereoisomers, two of which have been shown to be insulin mediators; namely myo-inositol (MI) and D-chiro-inositol (DCI) (Galletta 2011, Nordio 2012). The history of inositol treatment stems from studies performed by Larner et al. in 1993, who originally sought to unravel the causes of type 2 diabetes mellitus (Galletta 2011). Larner undeniably showed that administration of these two inositol phosphoglycans (IPG), MI and DCI reduced hyperglycemia in a dose-dependent manner (Galletta 2011). Subsequent studies suggested that a deficiency in tissue availability, or an altered metabolism of IPG mediators may contribute to insulin resistance (Dona 2012, Nordio 2012).
In 1999, Nestler et al. reported the efficacy of DCI in treating 22 obese PCOS women where 50% of subjects ovulated after four weeks of treatment (Nestler 1999). An increase in insulin sensitivity and a reduction in serum androgen levels were also reported and similar effects were produced in later studies (Galletta 2011). Inspired by the results obtained by Nestler, a research group at the AGUNCO Obstetrics and Gynecology Center in Italy began to study the effects of MI in PCOS patients and results showed a similarity in effectiveness between MI and DCI in treating metabolic disturbances and ovarian dysfunction. The study, conducted over 16 weeks, demonstrated regular menstrual cycles and a 40% pregnancy rate (Papaleo 2007). Another 16-week randomized placebo-controlled trial by Gerli et al. of 92 women with oligomenorrhea and PCOS showed a significant reduction in the mean time until the first ovulation in the myo-inositol-treated group (Gerli 2007). During the first week of treatment, a significant increase in E2 concentrations was also observed, indicating a relatively rapid effect of treatment. Considerable reductions in weight were also noted, along with lower circulating leptin and higher HDL levels (Gerli 2007).
Although MI and DCI exert similar effects on insulin resistance, a direct comparison between the two molecules has been elucidated with respect to oocyte quality and maturation (Galletta 2011, Nordio 2012). It appears that elevated concentrations of MI in follicular fluid play a specific role in follicular maturation, while DCI may be more involved with enhancing insulin response (Dona 2012). MI is converted into DCI via “epimerization”, a process that is dependent on insulin. The MI/DCI physiological ratio is specific in each tissue (Nordio 2012). In particular, DCI concentrations are present in insulin sensitive tissues that are responsible for glycogen synthesis and storage such as the liver, muscles, and fat (Galletta 2011). The ovaries however, never become insulin resistant leading to hyperinsulinemia in these organs (Nordio 2012, Galletta 2011). During insulin resistance, the MI/DCI conversion rate is affected resulting in an overproduction of DCI and a reduction of MI and this ensuing MI depletion in tissues is a possible cause for poor oocyte quality (Galletta 2011). On this basis, a combination treatment due to synergistic effects, has shown efficacy in improving the hormonal and metabolic profiles in PCOS (Nordio 2012).
Oxidative stress is another factor involved in PCOS, where reactive oxygen species are produced faster than the endogenous antioxidant systems can neutralize (Dona 2012). Hyperglycemia increases the generation of reactive oxygen species, which eventually attack certain proteins creating an inflammatory state (De Leo 2012). This in turn induces insulin resistance, hyperandrogenism and increases the risk of cardiovascular disease in women with this disorder. A dosage of 1200 mg/day of inositol has yielded therapeutic effects in lowering inflammation, serum androgens, and insulin levels (Dona 2012). Inositol belongs to the B-Complex group of vitamins and is present in phospholipids in human cells (Ciotta 2011). Increasing evidence supports its effectiveness in reducing hormonal, metabolic and oxidative abnormalities in patients with PCOS (Dona 2012). Inositol is promising as a safe and beneficial first-line and adjunctive treatment for women with this disorder.
Cinnamon and Chromium
Cinnamon (Cinnamomon cassia) and chromium are two supplemental therapies that have been studied and shown to have benefit in the treatment of PCOS (Anderson 2007). Both appear to have similar effects on insulin signalling and glucose control. In an eight-week pilot study, fifteen women with PCOS were randomized to a daily 500mg cinnamon extract or placebo (Wang 2007). The results of this study showed significant reductions in insulin resistance as measured by fasting and two-hour oral glucose tolerance tests (OGTT) in the cinnamon group as compared to the placebo group. The proposed mechanism of action is that cinnamon extract may potentiate insulin action by enhancing the insulin signaling pathways, leading to increased phosphatidylinositol 3-kinase activity, which in turn regulates insulin-stimulated glucose uptake and glycogen synthesis, as seen in in vivo rat studies (Qin 2003). In particular, the polyphenol type-A polymer procyanidin (which can be extracted from cinnamon), appears to be particularly helpful in enhancing the insulin signalling pathways. In addition, cinnamon has been demonstrated to have antioxidant effects in people with impaired fasting glucose who are overweight or obese, which may also partially explain how it benefits those with PCOS (Roussel 2009).
In a pilot study of chromium supplementation in women with PCOS, 200mcg daily of chromium picolinate improved glucose tolerance compared with placebo, but did not improve ovulatory frequency or other hormonal parameters (Lucidi 2005). In a separate trial with five obese subjects who had PCOS, trivalent chromium (also as chromium picolinate) was supplemented at a dose of 1000mcg and given without change in diet or activity level. The results showed that the chromium caused a 38% mean improvement in glucose disposal rate (as tested with a euglycemic hyperinsulinemic clamp technique) (Lydic 2006). Finally, there was a double-blind randomized clinical trial comparing 200mcg daily of chromium picolinate versus metformin for three months (Amooee 2013). The results showed that chromium significantly decreased fasting blood sugar and serum levels of fasting insulin. There were no significant differences in ovulation and pregnancy rates. In this study, only metformin was associated with decreased hyperandrogenism, but overall chromium was better tolerated. Together these studies represent the totality of recently published trials on these two supplements in the treatment of PCOS.
N-acetyl-cysteine (NAC)
There is research showing that NAC can play a role in insulin secretion in pancreatic beta-cells (Santini 1997). NAC also increases cellular levels of the antioxidant glutathione, which can itself influence insulin receptor activity (Ammon 1992). One trial used this information as justification for seeing if NAC would improve insulin sensitivity in women with PCOS (Fulghesu 2002). In this trial, 37 women with PCOS were assessed. Insulin sensitivity was measured by using the hyperinsulinemic euglycemic clamp technique and other measurements were also obtained at baseline and after treatment (including oral glucose tolerance test, lipid blood profile, and hormonal assay). Trial participants were administered 1.8g of NAC orally for five to six weeks. The results showed that although many parameters were unchanged (fasting glucose, fasting insulin, and glucose area under the curve), insulin area under the curve after the OGTT was significantly reduced and the peripheral insulin sensitivity increased. A significant improvement was observed in hyperinsulinemic subjects.
A set of trials has also examined NAC supplementation in PCOS patients who were clomiphene citrate resistant. In the earliest of these studies, 150 women undergoing therapy for infertility were assigned randomly to receive either 1.2g daily of NAC or placebo with 100mg daily of clomiphene citrate for five days starting at day 3 of the cycle (Rizk 2005). The results showed that the combination of NAC and clomiphene citrate significantly increased both ovulation rate and pregnancy rate (49.3% vs 1.3% and 21.3% vs 0%, respectively). A more recent study that included 180 PCOS infertile patients showed that NAC was safe and well-tolerated as an adjuvant therapy to clomiphene citrate (Salehpour 2012). NAC improved ovulation and pregnancy rates and may have had some beneficial impacts on endometrial thickness.
A recent review of the evidence on the topic showed that three separate studies (a 2006 prospective controlled pilot study, a 2007 prospective randomized controlled study, and a 2010 randomized controlled trial) were all unable to replicate the results found by the first study (Saha 2013). In the most recent of these studies, 192 women were similarly randomized to receive either clomiphene citrate combined with either 1.8g NAC or metformin for three treatment cycles (Abu Hashim 2010). The results of this study showed that over a three-month follow-up period, the women who received the metformin combination had higher ovulation and pregnancy rates compared to the NAC group (69.1% vs 20.0% and 22.7% vs 5.3%). The authors concluded that the efficacy of the metformin combination therapy is higher than that of NAC combination for inducing ovulation and achieving pregnancy. The evidence on NAC remains mixed, which means it may or may not help women with PCOS, but at the very least is well-tolerated.
Conclusion
PCOS is characterized by the presence of hyperandrogenism, insulin resistance, hyperinsulinemia, and obesity and is associated with an increased risk for developing cardiovascular disease and diabetes. Conventional approaches to management of PCOS often involve used of the oral contraceptive pill, which can regulate menstrual bleeding but fails to correct ovulatory defects and may worsen insulin sensitivity, and metformin, which is generally well tolerated although it may deplete vitamin B12 levels. Natural medicines such as inositol, cinnamon, chromium, and NAC have been studied as natural alternatives or adjunctive treatments. Inositol has shown efficacy in improving the hormonal and metabolic profiles in PCOS, as well as possibly providing anti-inflammatory and anti-oxidant actions. Cinnamon and chromium have shown to have benefit by purportedly improving insulin signalling and glucose control. The data on NAC is mixed but may help with ovulation and pregnancy rates. Overall, the safety profile of natural supplements is excellent and together, they provide patients with additional viable treatment options.
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