Am J Physiol Endocrinol Metab. 2011 Jul; 301(1): E1–E10.Published online 2011 Apr 12. doi: 10.1152/ajpendo.00667.2010

PMCID: PMC4459923

The physiological basis of complementary and alternative medicines forpolycystic ovary syndromeNazia Raja-Khan, Elisabet Stener-Victorin, XiaoKe Wu, and Richard S. Legro

Division of Endocrinology, Diabetes, and Metabolism, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center,Hershey, Pennsylvania;

Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg,Sweden;

Department of Obstetrics and Gynecology, National Key Discipline and Clinical Base, Heilongjiang University of Chinese Medicine, Harbin,China; and

Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, M. S. Hershey Medical Center, Hershey,Pennsylvania

Corresponding author.Address for reprint requests and other correspondence: N. Raja-Khan, Division of Endocrinology, Diabetes, & Metabolism, Penn State Univ.College of Medicine, M. S. Hershey Medical Center, 500 University Dr., H044, Hershey, PA 17033 (e-mail: nrajakhan@psu.edu).

Received 2010 Dec 6; Accepted 2011 Apr 7.

Copyright © 2011 the American Physiological Society

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronichyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility.Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance,obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, currenttreatments for PCOS are only moderately effective at controlling symptoms and preventing complications.This article describes how the physiological effects of major complementary and alternative medicine(CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduceshyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects aremediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulationof the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolicfunctions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficialphysiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe andeffective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychologicaldistress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. Inconclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects inPCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled.Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms ofCAM treatments for PCOS.

Keywords: acupuncture, mindfulness meditation, herbs, dietary supplements, traditional Chinesemedicine

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POLYCYSTIC OVARY SYNDROME (PCOS), a common endocrine disorder that affects 5–10% of reproductive-age women, is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism,acne, irregular menses, and infertility (86). The exact etiology of PCOS remains unclear, but it is believedto result from complex interactions between genetic, behavioral, and environmental factors. Multiplemetabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance (IR),obesity, type 2 diabetes (DM-2), hypertension, dyslipidemia, inflammation, and subclinical cardiovasculardisease (32, 62, 63, 87, 107). Anxiety, depression, and reduced quality of life are also common in PCOS(5, 19, 45, 107).

Current treatments for PCOS are only moderately effective at controlling symptoms and preventingcomplications. In fact, when 648 women were asked, “If your PCOS could be safely and effectively helpedby something else besides fertility drugs or birth control pills, would that interest you?”, 99% respondedyes (95). Although the prevalence of complementary and alternative medicine (CAM) used by womenwith PCOS is not known, a landmark study showed that one in three Americans use CAM (23). Recentstudies suggest that several CAM treatments could be beneficial as an adjunct to conventional medicalmanagement of PCOS. This article describes how the physiological effects of CAM treatments couldreduce the severity of PCOS and its endocrine, cardiometabolic, and reproductive complications.

Acupuncture

Acupuncture is a form of sensory stimulation in which thin needles are placed in the skin and muscles. It isof great importance to describe the needling “dose”, because the intensity, frequency, and type ofstimulation, manual or electrical, with high or low frequency, and the interval between stimulationsdirectly influence the kind of receptors activated and thus the therapeutic effect (114). Patients'expectations may also influence the results, as acupuncture may have strong psychological effects (94).

The primary mechanism for acupuncture's clinical effects is activation of somatic afferent nervesinnervating the skin and muscles, which may modulate somatic and autonomic nervous system activityand endocrine and metabolic functions. The efficacy of acupuncture in treating pain and disease has beenstudied from a Western scientific perspective. Systematic reviews have concluded that there is no evidencefor acupuncture point specificity and suggest that needles can be inserted anywhere in appropriatesegments (80, 122). Here, we will use a neurophysiological approach to describe how acupuncture,specifically electro-acupuncture (EA), where needles are electrically stimulated, may work in women withPCOS, because it has good support from experimental and clinical studies (36, 79).

Etiology of PCOS.

The etiology of PCOS is poorly understood (83). Ovarian hyperandrogenemia, the most consistentendocrine feature, probably plays a key role (30), but hyperinsulinemia/insulin resistance and abdominalobesity are also thought to be important (4). Whether hyperandrogenism results from the hyperinsulinemiaof IR or vice versa is unclear (91). Moreover, neuroendocrine defects can contribute to persistently rapidluteinizing hormone (LH) pulsatility and increased amplitude, which further augment ovarian androgenproduction (7). In addition, PCOS women have high sympathetic nervous system activity compared withcontrols, and circulating testosterone is the strongest factor explaining the high activity (105).Furthermore, high activity in the sympathetic neurons innervating the ovaries precedes the development ofovarian cysts in rats (58), and women with PCOS may have increased ovarian nerve fiber density (37).

Clinical effects of acupuncture in PCOS.

The clinical effect of acupuncture on menstrual dysfunction in PCOS has been evaluated in several casecontrol studies (12, 29, 101, 117) and in one randomized controlled trial (RCT) (n = 84) (44). In the RCT,women were randomized in a 2:2:1 ratio to receive 14 treatments with low-frequency EA (n = 33) for 16wk or physical exercise (n = 34) at least three times per week for 16 wk, or no intervention during thestudy period, which served as a control group (n = 17). This RCT demonstrated that low-frequency EAwas superior to physical exercise and improved hyperandrogenism and menstrual frequency moreeffectively than no intervention (44). Whether the improved menstrual frequency reflected ovulationinduction remains to be elucidated.

The effect of acupuncture (manual or electrical stimulation) on metabolic variables in women with PCOShas never been evaluated in clinical trials. Low-frequency EA, with repetitive muscle contraction, mayactivate physiological processes similar to those resulting from physical exercise and could influencemetabolic variables. Experimental evidence is described below.

The effect of acupuncture on mental health and health-related quality of life in women with PCOS has notbeen evaluated in clinical trials. Acupuncture has been used to treat depressive disorders, but itseffectiveness and safety are not well defined (124). Because women with PCOS are prone to developsymptoms of anxiety and depression and decreased health-related quality of life, this is an important areafor exploration.

Placebo and limitations in acupuncture studies.

Acupuncture treatment is associated with particularly potent placebo effects, and there are indications thatacupuncture treatment may be associated with larger effects than pharmacological and other physicalplacebos (52, 53, 67). The characteristics of acupuncture treatment are relevant in the context of placeboeffects, including frequent patient-practitioner contacts and the procedure of needling (51). Placebo effectsresult in true psychobiological events and exist in clinical practice (27).

Acupuncture studies are difficult to design for many reasons, including the variety of sham procedures, thenumber of acupuncture points used, the number and duration of acupuncture treatments, and differences instimulation techniques (114). Studies involving acupuncture in which both the patient and the therapist areunaware of the treatment are practically impossible to conduct. Thus, many variables affect the outcome ofan acupuncture study. The so called placebo-acupuncture needle (102) has been used in many trials, andmost often it has similar effects to true acupuncture but is superior to no treatment if a no-treatment groupis included. Thus, the placebo-acupuncture needle is not inert and may not be used as a sham (72). Instead,it is of importance to control for the increased amount of attention, and the control/comparison groupshould meet with a therapist the same amount of times as in the acupuncture group.

With this in mind, standardized study protocols to increase the validity of acupuncture studies by followingthe new revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA)checklist in conjunction with CONSORT will improve critical appraisal, analysis, and replication of trials(73). Furthermore, given the uncertainties about physiological effects of sham controls and the question ofenhanced placebo effects, it is crucial that direct, head-to-head comparisons of acupuncture and gold-standard treatment be conducted.

Physiological basis of acupuncture in PCOS: peripheral mechanisms.

Insertion and manual or electrical stimulation of needles in skin and muscle activates Aα, β, δ, and C fibers(49). In particular, activation of Aδ and C fibers may be essential for modulating autonomic nervoussystem activity (90). Manual and probably electrical stimulation causes release of neuropeptides from

peripheral nerve terminals into the area surrounding the needle, increasing blood flow (42). Low-frequency(2 Hz) EA also increases skeletal muscle glucose uptake (39). In insulin-resistant rats withdihydrotestosterone (DHT)-induced PCOS, peripheral insulin sensitivity is improved by low-frequency EAfor 4–5 wk with three treatments per week (75) and normalized by five treatments per week (47). Thisnormalization may reflect increased expression of soleus muscle glucose transporter (GLUT)4 protein,including the plasma membrane of muscle cells (47). Moreover, there is a dose-response relationshipbetween the number of EA treatments and improvement in insulin sensitivity (74, 75). Similarly, in ratswith prednisolone-induced IR, low-frequency EA acutely increases protein expression of insulin receptorsubstrate-1 and GLUT4 in skeletal muscle (65). Low-frequency EA improved insulin sensitivity in DM-2db/db mice, and the effect was mediated, at least partly, via regulation of skeletal muscle Sirtuin-1 (SIRT1)and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (64). The increased peripheralblood flow and glucose uptake in skeletal muscle are most likely mediated by a reflex response frommuscle twitches during manual or electrical stimulation, as the response is abolished after transection ofsomatic afferent nerve fibers (38) (Fig. 1).

Segmental (spinal) mechanisms.

Needles in abdominal and leg muscles with somatic innervations corresponding to the sympatheticinnervations of the ovaries, so-called segmental acupuncture points, may alter ovarian function bymodulating sympathetic efferent activity (96, 98, 100). This is of particular interest since the PCOS ovaryhas been shown to have denser innervation (37) and high concentrations of nerve growth factor (NGF), amarker of sympathetic activity (20). Needles placed in the abdominal and hindlimb muscles of female ratsand stimulated with low-frequency EA modulate the activity of ovarian sympathetic nerves, as reflected byincreased ovarian blood flow (96, 98, 99). The response was demonstrated to be mediated by ovariansympathetic nerves as a reflex response and was controlled by supraspinal pathways [i.e., central nervoussystem (CNS)] (96, 98). Further evidence that low-frequency EA modulates ovarian sympathetic nerveactivity comes from studies in estradiol valerate-induced PCOS. Gene and protein expression of markersof sympathetic activity (α -, α -, α -, and β -adrenoceptors, NGF, the p75 neurotropin receptor, andtyrosine hydroxylase) were normalized after 4 wk of low-frequency EA (76, 100). In rats with DHT-induced PCOS, ovarian morphology was improved by thrice weekly treatment for 4–5 wk, as reflected bya higher proportion of healthy antral follicles and a thinner theca interna cell layer than in untreated PCOSrats (74, 75). When treatment was increased to five times per week, low-frequency EA normalized estruscyclicity, indicating a clear dose-response relationship (25). It is not known whether manual stimulation ofacupuncture needles induces similar effects.

Central mechanisms of acupuncture.

When needles are placed, the peripheral nervous system transfers signals to the brain, which contributes tothe effect of acupuncture. Since the CNS regulates pituitary hormone release, acupuncture may alsomodulate endocrine and metabolic function.

Many brain areas, especially the hypothalamic nucleus, are involved in the effect of acupuncture.Acupuncture-induced release of CNS neuropeptides seems to be essential for inducing functional changesin organ systems (36). The central hypothalamic β-endorphin system is a key mediator of changes inautonomic functions, such as effects on the vasomotor center, which decreases sympathetic tone and ismanifested as improved blood pressure regulation and decreased muscle sympathetic nerve activity (120).Both exercise and low-frequency EA increase hypothalamic β-endorphin secretion and decrease bloodpressure and sympathetic nerve activity; these effects are reversed by µ-opiod receptor antagonists (48).

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Interestingly, repeated low-frequency EA plus physical exercise significantly decrease high sympatheticnerve activity measured by microneurography in women with PCOS (97). Decreased sympathetic nerveactivity, possibly mediated by modulation of hypothalamic β-endorphin secretion, may partly explain thedecrease in circulating testosterone and improved menstrual frequency after low-frequency EA plusphysical exercise in women with PCOS (44).

Hypothalamic β-endorphin interacts with the hypothalamic-pituitary-ovarian axis by exerting a tonicinhibitory effect on the gonadotropin-releasing hormone (GnRH) pulse generator and on pituitary LHrelease (46). In PCOS, growing evidence suggests that the opioid system is dysregulated both centrally andperipherally, with complex interactions (24). Indeed, opioid receptor antagonists improve menstrualcyclicity, induce ovulation, and decrease testosterone, insulin, and LH levels and the LH/FSH ratio (1, 15,28). Acupuncture might affect the hypothalamic-pituitary-ovarian axis by modulating central β-endorphinproduction and secretion, thereby influencing release of hypothalamic GnRH and pituitary secretion ofgonadotropins, as shown by the decrease in LH/FSH ratio after low-frequency EA (101). Furthermore, inrats with DHT-induced PCOS, five low-frequency EA treatments per week for 4–5 wk restored highhypothalamic androgen receptor and GnRH protein expression, which may help explain the beneficialneuroendocrine effects of low-frequency EA in women with PCOS (25).

β-Endorphin is also released into peripheral blood from the hypothalamus via the anterior pituitary, aprocess regulated by CRF. Circulating β-endorphin is thought to be related to the hyperinsulinemicresponse (70). It may also decrease hyperinsulinemia by lowering high concentrations of circulating β-endorphin (101). Interestingly, low-frequency EA lowers high circulating β-endorphin concentrations inwomen with PCOS and may decrease hyperinsulinemia and increase insulin clearance or insulinsensitivity (12, 101).

In sum, clinical and experimental evidence indicates that acupuncture with electrical muscle stimulationmay be a suitable alternative or complement to improving endocrine and reproductive function in womenwith PCOS without adverse side effects. More experimental mechanistic studies and RCTs to furtherexplore the use of acupuncture to treat PCOS-related symptoms are warranted.

Chinese Herbal Medicine

Chinese herbal medicine (CHM) is an integral part of traditional Chinese medicine (TCM). In China today,TCM is often administered as a complement to Western medicine. While TCM traces its roots backthousands of years, it rests, from the view of evidence-based medicine, more on a philosophy than ascience. Much of the central philosophy involves maintaining the balanced flow of life energy (qi). TCMviews organ systems as contributing to mind-body states and tries to address imbalances of these organsystems. TCM views PCOS as linked to disorders of the kidneys, liver, and spleen. Reproductiveabnormalities, especially anovulation, are believed to be linked to the kidney, and a deficit in kidney isviewed as the primary problem in PCOS (82, 110).

Traditionally, CHMs are combined in varying preparations. Although some preparations are regulated bythe government, there remains concern about quality control of individual formulations, given thevariation in plant quality from harvest to harvest, and concerns about harmful supplements or byproductsof preparation such as heavy metals, herbicides, pesticides, microorganisms, mycotoxins, insects,pharmaceuticals, etc. (6, 68). The FDA has published guidelines to ensure better quality control ofmanufactured products from plants, but many of these products fall outside of regulation by the FDA, asthey are not pharmaceuticals. CHMs also include many animal byproducts that we will not discuss indetail in this review. For example, a common preparation used to induce ovulation in women with PCOS is

Di Long (Earth Dragon), which is made from abdominal extracts of the red earthworm Lumbricusrubellus.

Safety and efficacy of CHMs.

Unfortunately, there is minimal evidence that CHMs are safe and efficacious. Most of the trials have beensmall and thus inadequately powered to detect true differences. Most, not surprisingly, have beenconducted mainly in Chinese populations and published in Chinese and thus are not easily accessible. Thestudies have also tested a large number of varying preparations (most containing multiple components),and thus there has been little to no replication for individual preparations. Above all, the studies have beenof poor methodological quality without adherence to CONSORT guidelines.

This is well illustrated by systematic reviews of CHM in subfertile women with PCOS (123) and patientswith impaired glucose tolerance (IGT) (34) and DM-2 (68), disorders related to PCOS because of thecommon underlying link of IR (Table 1).

Here, we also review the evidence for CHM in IGT and DM-2 because women with PCOS are at markedlyincreased risk for both IGT and DM-2 due to IR (63). Furthermore, these disorders of glucosedysregulation may represent later stages in the pathophysiological progression of PCOS. Finally, manydrugs used to prevent or treat PCOS have been borrowed from DM-2, most notably metformin, but alsothe thiazolidinediones, acarbose, but also newer agents such as incretin mimetics such as exenatide.Similarly, many of the CHMs used to treat DM-2 may be useful for PCOS. However, the evidence for thebenefit of CHM in all three disorders is weak (Table 1).

There are the fewest articles for PCOS, which is perhaps understandable from a public health perspective,as IGT and DM-2 are more prevalent than PCOS. The large drop-off from published articles to thosemeeting the minimum quality standard for a systematic review is staggering. None of the studiesdocumented allocation concealment (the method by which the order of treatment assignment wasgenerated and implemented in the study) or blinding, none of the studies used an intention to treat methodanalysis, a standard method to account for drop-out in a randomized trial (123).

The authors of the review of CHM in PCOS (123) did note that in two studies where multiple formulationsof Chinese herbs were given as adjuvant therapy to clomiphene, there was a significantly increased odds ofpregnancy with CHM (OR 2.97, 95% CI 1.71 to 5.17) (123). The reviews (34, 68, 123) share a commontheme, a hint of efficacy clouded by poor methodology and lack of replication. But all reviews were eagerto see larger better designed studies carried out.

There are multiple hurdles to adapting CHM into Western medicine. One is the lack of scientificjustification from a hypothesis-driven perspective for the use of these medications. Many herbs containmultiple active substances, and combinations are exponentially more problematic for determining what isdoing what to what. Much research currently is focusing on compound analysis through such technologiesas high-performance liquid chromatography-mass spectrometry to identify specific bioactive agents.

Physiological mechanisms of CHMs.

Currently, the physiological mechanisms for efficacy of most CHMs are unknown in PCOS. Table 2 listsseveral CHMs used in PCOS and their proposed mechanism of action. Many may have selectiveestrogenic effects and function like clomiphene to induce ovulation. Risks, however, must be carefullydetermined, and these have not been well delineated. Gancao or licorice, given chronically or in excess,can cause an acquired form of apparent mineralocorticoid excess, as it is a potent inhibitor of 11β-

hydroxysteroid dehydrogenease. This enzyme inactivates cortisol to cortisone, and decreased inactivation,especially in the kidney, can lead to excess cortisol cross-reacting with the mineralocorticoid receptor,which induces fluid retention, hypokalemia, and hypertension (66). In addition, CHMs may interfere withthe metabolism of other drugs used to treat PCOS. For example, plantain has been proposed to interferewith many commonly prescribed medications such as digitoxin and tricyclic antidepressants, although atleast one study shows no clinical interactions (17).

Mechanisms of action should be explored in cell culture and animal models by basic scientists. Forexample, Rhizoma alismatis has been found in an in vitro tissue model to inhibit intestinal glucoseabsorption and stimulate glucose uptake in fibroblasts and adipocytes (59). Furthermore, in astreptozotocin-induced diabetes mouse model, it lowers plasma glucose and triglycerides and improvesinsulin levels (119). Other CHMs, such as Radix notoginseng, have been found to have similar antidiabeticeffects in mouse models, improving not only glucose tolerance and insulin action in a dose-responsefashion but also ameliorating obesity (13). Similarly, Salvia miltiorrhiza Bunge has been shown tosignificantly improve glucose tolerance in a prenatally androgenized rat model of PCOS and to favorablyimpact insulin signaling in treated animals (118). Berberine, a component of Rhizoma coptidis, has beenshown to improve glucose uptake and insuln action in human thecal cells with dexamethasone-inducedinsulin resistance (125). These favorable changes in glucose metabolism have also been shown tofavorably alter sex steroid feedback or production, ameliorating hyperandrogenism in these models (22,125). Additionally, antioxidant activity has been noted in vitro for a number of these substances (61, 116).

Furthermore, extensive investigation of promising drugs should be established in preliminary studies, firstexploring safety and secondarily exploring proof of concept through larger dose ranging studies. This iscertainly the FDA model for new drugs; i.e., begin with Phase I studies, progress to dose ranging andfurther safety Phase II studies, and finally choose a dose and perform a large-scale, adequately poweredand designed Phase III efficacy study. Second, there remains, at least in the US, a great gulf betweenpractitioners of TCM and allopathic physicians and a general skepticism of the Weltanschauung of theother. Along these lines, there is a lack of adequately trained investigators who are familiar both withCHM and with the design and implementation of RCTs. This latter element is especially lacking in China,where most of these trials are conducted, as the systematic reviews document.

A group of international authors has recognized the unique challenges of RCTs of CHMs and made thefollowing summary recommendations to improve the quality of these trials by ensuring the stability,consistency, and purity of CHMs. These suggested guidelines, replicated here, are a positive step towardthe exploration of CHMs for the treatment of PCOS and related disorders. At present, their potential isuntapped, although this represents a tremendous opportunity for researchers on both sides of the ocean.

Dietary Supplements

Several dietary supplements may have benefical effects on PCOS. However, most studies are small oruncontrolled. Therefore, larger, better-designed studies are needed to further evaluate the risks and benefitsof these supplements in PCOS. In addition, it is important to note that the supplements discussed here arenot FDA approved for the treatment of PCOS.

Vitamin D.

Accumulating evidence suggests that vitamin D deficiency may be a causal factor in the pathogenesis ofIR and the metabolic syndrome in PCOS (35). Furthermore, 25-hydroxyvitamin D levels are closelyassociated with impaired β-cell function, IGT, and the metabolic syndrome in PCOS women (113). Two

small, uncontrolled studies demonstrate that vitamin D may improve IR and lipid profiles in PCOSpatients (56, 92). One of these studies demonstrated a significant reduction in homeostatic modelassessment of insulin resistance (HOMA-IR) 3 wk after a single oral vitamin D dose of 300,000 IU in 11obese, insulin-resistant women with PCOS (56, 92). Moreover, vitamin D supplementation may alsoimprove anovulation in PCOS. A pilot RCT of 60 infertile PCOS patients showed that the number ofdominant follicles (≥14 mm) during 2–3 mo of follow-up was higher in the calcium (1,000 mg/day) plusvitamin D (400/day) plus metformin (1,500 mg/day) group than in the calcium + vitamin D-only group orthe metformin-only group (88).

Vitamin B and folate.

Two recent studies suggest that B vitamins may be important in PCOS. In the first study, IR, obesity, andelevated homocysteine were associated with lower serum vitamin B concentrations in PCOS patients(55). The second study was a nonrandomized, placebo-controlled, double-blind trial that demonstrated thatsupplementation with folate (400 µg daily) for 6 mo increases the beneficial effect of metformin on thevascular endothelium in women with PCOS (84). However, the mechanisms are still unclear.

Green tea and spearmint tea.

Tea, next only to water, is the most popularly consumed beverage in the world, with a per capitaconsumption of 120 ml/day (78). Green tea has been shown to exert beneficial effects on glucose and lipidmetabolism (11, 21) and the hormonal system (26, 50) in rats and humans, which are all very relevant inthe management of PCOS patients. In addition, herbal tea reduces body weight and induced ovulation inandrogen-sterilized rats (103). However, there are only two RCTs of herbal tea in PCOS, one using greentea (10) and the other spearmint tea (33).

The principal component of green tea, (−)-epigallocatechin-3-gallate (EGCG), significantly reduced bodyweight and circulating testosterone, estradiol, leptin, insulin, IGF-I, LH, glucose, cholesterol, andtriglyceride in Sprague-Dawley rats and lean and obese Zucker rats (50). In vitro studies demonstrate thatgreen tea extract and EGCG inhibit basal and stimulated testosterone production in rat Leydig cells. Themechanisms underlying the effects of EGCG involve the in vitro inhibition of the PKA/PKC signalingpathways as well as the inhibition of P-450 side-chain cleavage enzyme and 17β-hydroxysteroiddehydrogenase function during testicular steroidogenesis (26).

In an RCT of 34 obese Chinese women with PCOS, the body weight of the green tea capsule group (540mg EGCG/day) decreased by a nonsignificant 2.4% after treatment, whereas the body weight, body massindex (BMI), and body fat content of the control group were significantly higher after 3 mo (10). However,there were no significant differences in glucose, lipid metabolism, or any of the hormone levels betweenthe two groups. The lack of a positive finding in this study may be due to an inadequate dose of green teaand the small sample size of the study. Furthermore, the response to EGCG may be greater in other ethnicgroups, especially those groups who do not already have a strong habit of taking tea in their daily lives(121).

In regard to spearmint tea, an RCT of 41 PCOS women showed that spearmint tea twice a day for 1 mosignificantly decreased free and total testosterone levels, improved patients' subjective assessments of theirhirsutism, and increased LH and FSH compared with a placebo herbal tea (33). Further studies are neededto confirm these findings and further elucidate the mechanisms underlying the antiandrogenic effects ofspearmint tea.

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Cinnamon extract.

Cinnamon extract (a traditional herb) has been shown to potentiate the insulin effect through upregulationof glucose uptake in cultured adipocytes (3, 8, 43). Cinnamon extract also improves insulin action viaincreasing glucose uptake in vivo, as it has been shown to enhance the insulin-signaling pathway inskeletal muscle in rats (85). An RCT of 15 women with PCOS showed significant reductions in IR in thecinnamon group (333 mg of cinnamon extract, 3 times a day) but not in the placebo group (111).

ω-3 and other polyunsaturated fatty acids.

A small RCT of 25 PCOS women demonstrated that dietary supplementation with ω -3 fatty acid 4 g/day(4 × 1,000-mg capsules of 56% docosahexaenoic acid and 27% eicosapentaenoic acid; Ocean Nutrition,Halifax, NS, Canada) for 8 wk has beneficial effects on liver fat content and other cardiovascular riskfactors in women with PCOS (16). Another small study, of 17 women with PCOS, showed that increaseddietary polyunsaturated fatty acid (PUFA) intake from walnuts (48 g walnuts per 800 kcal energy intake)for 3 mo increased glucose levels in women with PCOS (54). Forty-eight grams of walnuts contain 311kcal (70 kcal from 30 g fat, 28 kcal from 7 g protein, and 36 kcal from 9 g carbohydrates) and provide 19 gof linolenic acid and 3.3 g of α-linolenic acid. Further studies are needed to determine the risks andbenefits of ω-3 fatty acids and other PUFAs in PCOS.

Qi Gong and Tai Chi

Exercise is an important component of a healthy lifestyle, and it reduces metabolic and reproductivedisturbances in PCOS. Qi gong and Tai chi are the two most popular Chinese medical exercisesworldwide. Qi gong may be beneficial for individuals with DM-2 or metabolic syndrome, for its favorableeffects on hemoglobin (Hb) A , glucose levels, and insulin sensitivity, reported by several RCTs (69, 104,109). Tai chi has been shown to have similar energy expenditure to other moderate-intensity activities,such as walking at a speed of 6 km/h (2). It also has favorable effects on glucose control, lipid profile, andanxiety in patients with DM-2 (41, 108, 112). Therefore, Qi gong and Tai chi may be effective adjuncttreatments for PCOS women. However, to date no studies have evaluated the effects of Qi gong or Tai chiin PCOS.

Mindfulness Meditation

Mindfulness, a component of ancient meditative practices such as Vipassana meditation and Zenmeditation, is increasingly being applied to Western medicine to enhance psychological health and overallwell-being (14, 71). In contemporary Western psychology, mindfulness has been described as theawareness that emerges through intentionally paying attention to one's present thoughts, emotions, andbodily sensations moment to moment in a nonjudgmental manner (93). Mindfulness has not beeninvestigated in women with PCOS; however, studies in non-PCOS populations, including patients withDM-2 (89), suggest that mindfulness has psychological and physiological effects that could be beneficialin PCOS. Mindfulness-based stress reduction (MBSR), the most researched mindfulness-based program,reduces psychological distress (71) and may also reduce blood pressure, glucose, and inflammation (9, 77,89, 115). These physiological effects appear to be mediated by changes in brain activity (18, 31) andstructure (40, 60) leading to improvements in the autonomic nervous system (57, 81, 106) andhypothalamic-pituitary-adrenal (HPA) axis (9, 77, 115). It is hypothesized that these beneficial effects ofmindfulness might ultimately lower the risk for diabetes and cardiovascular disease in PCOS. However,most of the evidence comes from small, uncontrolled, nonrandomized studies in non-PCOS populations.Therefore, well-designed RCTs of mindfulness in women with PCOS are needed before definitive

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conclusions can be drawn regarding the effects and mechanisms of mindfulness in PCOS.

Conclusions

In conclusion, several CAM treatments may have beneficial endocrine, cardiometabolic, and reproductiveeffects in women with PCOS. However, most studies are small, nonrandomized, or uncontrolled.Therefore, larger, well-designed RCTs are needed to further evaluate the safety, effectiveness, andmechanisms of CAM treatments for PCOS.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

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Figures and Tables

Fig. 1.

Stimulation of needles activates Aδ and C fibers and causes release of neuropeptides from peripheral nerve terminals,increasing blood flow locally. Low-frequency electro-acupuncture (EA) caused muscle contraction and increased GLUT4expression and most likely translocation to plasma membrane. Low-frequency EA also increased Sirtuin-1 (SIRT1) andperoxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).

Table 1.

List of systematic reviews of CHM for treatment of PCOS and disorders of glucose metabolism includingtype 2 diabetes

Topic Total No.

of Studies

Retrieved

Total

Studies

Included

in

Cochrane

Review

Total

No. of

Studies

in

Chinese

Total

No. of

Subjects

in

Included

Studies

Total No. of

Preparations

Tested in

Trials

Main Conclusions

SubfertilePCOS (123)

267 4 4 334 6 Limited evidence that addition of CHMto clomiphene is associated withimproved clinical pregnancy outcomesand no other evidence of any other effect.Methodology of RCTs was notadequately reported.

Impairedfastingglucose (IFG)or impairedglucosetolerance(IGT) (34)

1,926 16 15 1,391 15 Some positive evidence favors CHM fortreatment of IGT or IFG. Limited by thefollowing factors: lack of trials that testedthe same herbal medicine, lack of detailson cointerventions, unclear methods ofrandomization, poor reporting, and otherrisks of bias

Type 2diabetes (68)

713 66 61 8,302 69 Some herbal medicines showhypoglycemic effect in type 2 diabetes.However, these findings are limited bylow methodological quality, small samplesize, and limited number of trials.

PCOS, polycystic ovary syndrome; CHM, Chinese herbal medicine; RCT, randomized controlled trial.Nos. in parentheses are references.

Table 2.

Partial list of CHMs used to treat PCOS, their proposed mechanisms of action, and their reported sideeffects

Mechanism Chinese

Name

Latin Name English Name Adverse Effects

Improve insulin sensitivity Baishao Radix paeoniaeAlba

White peonyroot

Uterine contractions, interfere with bloodclotting

Danggui RadixangelicaeSinensis

Angelica Uterine contractions

Danshen SalviamiltiorrhizaBunge

Red sage May interact and potentiate effects ofwarfarin

HuangLian

Rhizomacoptidis

Goldenthread Hypertension, respiratory failure, paresthesias

Induce ovulation (throughestrogenic effects)

Luole Ocimumbasilicum

Basil Contains a chemical, estragole, which hascaused liver cancer in mice

Sanqi Radix no-toginseng

Panaxpseudoginseng

Dry mouth, flushed skin, nervousness, sleepproblems, nausea, and vomiting.

Zelan Herba lycopi Bugleweed Enlarged thyroid gland, hypoglycemia

Zexie Rhizomaalismatis

Water plantain Fresh rootstock may be poisonous

Inhibit androgen synthesis Gancao Radixglycytthizae

Licorice Hypertension, fluid retention, hypokalemia,exacerbate kidney disease

Articles from American Journal of Physiology - Endocrinology and Metabolism are provided here courtesy of

American Physiological Society