Metformin & Myo-inositol: Management of Insulin Resistance in Women with PCOS

Student Scholarship – Second Place Research Review 

LIQAA ESSAM NASER, ND, MBCHB, CCT  

KRIS SOMOL, ND 

According to the United States Department of Health & Human Services, polycystic ovary syndrome (PCOS) affects 1 in 10 women of childbearing age and can result in infertility.¹ PCOS is a polygenic and multifactorial problem characterized by excess androgens, often accompanied by dysregulation of other reproductive hormones.^2,3 It typically results in disruption of endocrine, reproductive, and metabolic systems, and can be accompanied by systemic, low-grade inflammation.^2,3 Common signs and symptoms of PCOS include hyperandrogenism (hirsutism, acne), weight gain, irregular menses, and difficulty conceiving (due to anovulation).³ Primarily a result of hormone dysregulation, patients with PCOS are also at an increased risk for endometrial cancer, metabolic syndrome, type II diabetes, nonalcoholic steatohepatitis, and cardiovascular disease.^3,4 According the Rotterdam Criteria, a diagnosis of PCOS is made for patients that exhibit any 2 of the following features: hyperandrogenism (physical or biochemical), ovulatory dysfunction, or polycystic ovarian morphology (on ultrasound).³  

Insulin Sensitizers 

One of the most important aspects of the pathology of PCOS is the development of insulin resistance (IR). Changes in glucose management, due to underlying hormonal imbalances, result in IR, which then leads to hyperinsulinemia.³ Because excess insulin increases ovarian androgen synthesis, a positive feedback loop is created – androgen synthesis, as well as the downstream sequelae of hormonal and metabolic dysregulation, are then perpetuated.³ As a result, IR is considered part of the pathogenesis of PCOS and is a primary target for treatment. 

Metformin 

Metformin is a biguanide commonly prescribed for the treatment of type II diabetes. As an insulin sensitizer, metformin has shown promise in the treatment of PCOS. Despite initially inconclusive results,^5,6 more recent studies have shown that by addressing IR with metformin, symptoms of acne, hirsutism, menstrual irregularities, anovulatory infertility, androgen profile, BMI, and incidence of diabetes can be improved.^7,8 One of the limitations of metformin’s use for PCOS patients is that its efficacy may depend on the specific phenotypic expression of the disorder, and researchers have yet to be able to predict who will benefit most.^6,7 Additionally, metformin has a well-established side effect profile that includes gastrointestinal complaints (nausea, diarrhea, abdominal pain), vitamin B12 deficiency, and lactic acidosis, all of which may prevent some women from tolerating the medication. 

Myo-inositol 

Myo-inositol, which is an isomerized and dephosphorylated precursor of glucose-6-phosphate, has also been shown to act as an insulin sensitizer.⁹ In relation to PCOS, researchers have further investigated the possibility that an intracellular deficiency of D-chiro-inositol (DCI), a myo-inositol metabolite found in muscle, fat, and theca cells, may contribute to IR development.^10,11 DCI is responsible for the formation of inositol phosphoglycan (IPG), which is a facilitator of insulin activity.¹¹ Women with PCOS and IR have been shown to have an increased urinary clearance of DCI, accompanied by impaired DCI-IPG release in response to insulin.¹² Supplementation with myo-inositol and/or DCI may therefore address multiple factors related to the development of IR in PCOS patients, leading to improved treatment outcomes. 

A Comparison Study 

Several studies have been completed comparing the efficacy of metformin and myo-inositol for the treatment of PCOS. A 2018 meta-analysis by Facchinetti et al found 6 randomized clinical trials (RCTs) conducted between 1994 and 2017.¹³ The results of the meta-analysis showed no significant differences between the 2 treatment methods on fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), testosterone, sex hormone binding globulin (SHBG), or BMI of the participants.¹³ Perhaps the most important difference between treatment methods was that, of the 355 women identified across all of the studies, those receiving treatment with metformin had a significantly increased risk of adverse events.¹³  

In order to highlight the importance of researching and comparing these 2 potential therapies for PCOS, the following is an in-depth examination of 1 of the 6 studies identified in the 2018 meta-analysis. Though it is still considered “off-label” use, metformin is the most commonly prescribed pharmacological agent for the treatment of IR in PCOS patients.¹⁴ Some patients may desire a non-pharmacologic approach, and as such, it is imperative to understand and evaluate current research to determine the safest and most effective treatment options available.  

Study Parameters 

Fruzetti et al conducted their study from among patients referred to the Outpatient Clinic of Reproductive Endocrinology of the University of Pisa between 2014 and 2015.¹⁵ The age group selected for the study, 18-28, is within the age range when PCOS generally presents, and women referred to the study had all been treated for oligomenorrhea and/or hyperandrogenism. A diagnosis of PCOS was made using the Rotterdam Criteria, and a total of 50 women were selected for the 2 treatment groups. An additional 30 healthy women, ages 18-28, with no symptoms of menstrual irregularity or hirsutism, were included as a control group. To minimize confounding factors, all women were screened and excluded if other endocrine disorders were suspected. Additionally, any women taking medication that could affect endocrine or metabolic biomarkers were excluded. All women in the treatment group were also screened and only included if they had either IR or hyperinsulinemia.¹⁵ 

Allocation of the treatment sequence was completed by a third-party.¹⁵ The subjects of the treatment groups were randomized to either metformin 1500 mg/day or myo-inositol 4 g/day plus folic acid 400 mcg/day. The authors did not mention if patients or providers were blinded to the study; however, the randomization appeared adequate. Women were evaluated and treated over a 6-month period, with all measurements taking place during the follicular phase (days 3-7 after menstrual bleeding) of the menstrual cycle. Study parameters included measurements of BMI, hirsutism, average cycle length, LH, FSH, prolactin, estradiol, 17-hydroxyprogesterone (17-OHP), total testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, cortisol, glucose, insulin, and ovarian morphology. Relative insulin resistance was calculated using HOMA-IR, hyperinsulinemia was calculated using area under the curve plasma insulin concentrations (AUC-insulin), and insulin sensitivity was calculated using the Matsuda index.¹⁵ 

Results 

A significant difference in baseline measurements was noted between the control group and the treatment groups concerning most PCOS markers, except for BMI, FSH, estradiol, prolactin, cortisol, and 17-OHP.¹⁵ After 6 months of treatment and evaluation, BMI, HOMA-IR, AUC-insulin, and Matsuda scores improved significantly in both the metformin and myo-inositol groups. The percent change between both groups was similar. Mean cycle length also improved with both forms of treatment, and 53% of the women in the metformin group and 44% of the women in the inositol group reported a normal cycle length at the end of the 6 months. No significant changes in androgen levels were observed in either group, though there were slight improvements in hirsutism and acne in some of the women. The authors concluded that both metformin and myo-inositol were equally effective in improving insulin resistance, inducing weight loss, and improving menstrual cycle length in PCOS patients with IR.¹⁵ 

Discussion 

Fruzetti et al completed a well-designed RCT study that measured a broad range of biomarkers relevant to PCOS and IR pathology.¹⁵ Furthermore, their randomization, statistical analysis, and lack of stated conflicts bolster the weight of their results. The authors did acknowledge several limitations of the study, however, including the fact that neither metformin nor myo-inositol appeared to improve the overall hormonal profile (other than insulin) of the participants. Additionally, they did not gather additional data, and therefore could not determine, if the improvements to menstrual cycle length experienced by some of the women translated into improved or resumed ovulation.¹⁵  

There were, unfortunately, a few important weaknesses of the study that the authors failed to mention. The study was limited to women ages 18-28, which limits extrapolation of the results to older women. Additionally, all women in the study were told to eat a “Mediterranean Diet;” however, the authors failed to discuss any information related to dietary guidelines.¹⁵ With this parameter left undefined, it remains unclear whether there was a calorie restriction, if women were given a specific list of foods to choose from, or what the relative adherence was to the diet. Because changes in BMI in both treatment groups were significant, it is important to evaluate what impacts any dietary changes may have had on the data.  

The authors did note that 3 women dropped out of the metformin group due to side effects, and 1 woman dropped out of the inositol group.¹⁵ It is relevant, especially in the age range that was being studied, to note that metformin is a class C drug, and that some women with PCOS may seek treatment to help with fertility issues. In addition to metformin’s side effect profile, the fact that it is a class C drug makes it less appealing as a long-term treatment option when compared to the relative safety and lack of side effects of myo-inositol. The authors did state, however, that treatment costs for myo-inositol are substantially higher.¹⁵ 

Conclusion 

Despite the limitations of the study analyzed, Fruzetti et al demonstrated that myo-inositol can lower BMI, reduce insulin resistance, and help normalize the menstrual cycle in women with PCOS and IR.¹⁵ Their data are in agreement with similar research, including other studies examined by Facchinetti et al in their 2018 meta-analysis.¹³ Because metformin showed similar results, it should not be discounted as a potential therapy for PCOS. The efficacy of metformin also supports IR as a general treatment target for managing PCOS pathology. The lower costs for metformin use are potentially outweighed by its side effect profile, however, including concerns over its use during pregnancy. 

One of the benefits of taking the time to review and analyze not only results, but study parameters and design, is that more is often revealed about the data gathered. In the study by Fruzetti et al, an important piece of information that could be overlooked is the fact that, though they were unable to show a significant change in androgen levels with either treatment, these results were only obtained when using myo-inositol as a stand-alone therapy.¹⁵ Other research on the use of inositols has noted that cellular concentration ratios of myo-inositol to DCI are altered in PCOS patients, specifically in theca cells.^11,12 Researchers are still attempting to understand the underlying physiology of these changes, but it has been proposed that the most effective therapeutic use of inositols for PCOS includes a ratio of myo-inositol to DCI given simultaneously.^10-12 The results by Fruzetti et al primarily show myo-inositol affecting glucose management, without significantly impacting hormonal profiles.¹⁵ It is unfortunate that they did not include an additional treatment group that received a combination of myo-inositol and DCI in a 40:1 ratio, as has been proposed,¹⁰ to evaluate if adding DCI could improve androgen levels. More studies are needed in this evolving area of research. In the meantime, myo-inositol represents an important alternative to metformin for the treatment of IR in women with PCOS. 

References

1. US Department of Health & Human Services. Polycystic Ovary Syndrome. Last updated April 1, 2019. Available at: https://www.womenshealth.gov/a-z-topics/polycystic-ovary-syndrome. Accessed November 17, 2021. 

2. Patel S. Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy. J Steroid Biochem Mol Biol. 2018;182:27-36. 

3. Rocha AL, Oliveira FR, Azevedo RC, et al. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res. 2019;8:F1000 Faculty Rev-565. 

4. Ali AT. Polycystic ovary syndrome and metabolic syndrome. Ceska Gynekol. 2015;80(4):279-289. 

5. Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2(6):56. 

6. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2010;1(3):117-128. 

7. Jensterle M, Kravos NA, Ferjan S, et al. Long-term efficacy of metformin in overweight-obese PCOS: longitudinal follow-up of retrospective cohort. Endocr Connect. 2020;9(1):44-54. 

8. Artani M, Iftikhar MF, Khan S. Effects of Metformin on Symptoms of Polycystic Ovarian Syndrome Among Women of Reproductive Age. Cureus. 2018;10(8):e3203. 

9. Bevilacqua A, Bizzarri M. Inositols in Insulin Signaling and Glucose Metabolism. Int J Endocrinol. 2018;2018:1968450. 

10. Pintaudi B, Di Vieste G, Bonomo M. The Effectiveness of Myo-Inositol and D-Chiro Inositol Treatment in Type 2 Diabetes. Int J Endocrinol. 2016;2016:9132052. 

11. Heimark D, McAllister J, Larner J. Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocr J. 2014;61(2):111-117. 

12. Baillargeon JP, Diamanti-Kandarakis E, Ostlund RE Jr, et al. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care. 2006;29(2):300-305. 

13. Facchinetti F, Orrù B, Grandi G, Unfer V. Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials. Gynecol Endocrinol. 2019;35(3):198-206. 

14. Liu Y, Shao Y, Xie J, et al. The efficacy and safety of metformin combined with simvastatin in the treatment of polycystic ovary syndrome: A meta-analysis and systematic review. Medicine (Baltimore). 2021;100(31):e26622. 

15. Fruzzetti F, Perini D, Russo M, et al. Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017;33(1):39-42. 

Liqaa Essam Naser, ND, MBChB, CCT was a 4th-year student at Bastyr University at the time of this writing; she has since completed her naturopathic degree. She began her medical career in 2004 after graduating from Mosul Medical School in Iraq. She initially specialized pediatrics. After moving to the United States and struggling with her own health issues, Dr Liqaa discovered the field of naturopathic medicine. Dr Liqaa is still pursuing her master’s degree in East Asian medicine and acupuncture at Bastyr. She plans to use her considerable skills to help the underserved communities in Washington state and to participate in the field of integrative medicine research. Dr Liqaa also serves as a board member for both the Naturopathic Association of Primary Care Physicians and the Gastroenterology Association of Naturopathic Medicine.

Kris Somol, ND graduated from Bastyr University in 2005. She completed a 2-year residency at the Bastyr Center for Natural Health (BCNH) before beginning her practice in Seattle, Washington. As an adjunct faculty member at Bastyr, Dr Somol instructs students in introductory and advanced gynecology classes. Dr Somol leads the naturopathic profession through advanced lectures, support of student research, and practicums including IUD placement, pelvic myofascial release, and intrauterine insemination. She also brought the Washington Breast and Cervical Health Program to BCNH. Dr Somol’s private practice focuses on preventive care, health collaboration with adolescents, and women’s health.