Roseff, S., & Montenegro, M. (2020). Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary. International journal of endocrinology, 2020, 6461254. https://doi.org/10.1155/2020/6461254
Roseff S, Montenegro M. Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary. International journal of endocrinology. 2020;2020:6461254. doi:10.1155/2020/6461254
Roseff, S., and M. Montenegro. "Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary." International journal of endocrinology, vol. 2020, 2020, pp. 6461254.
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RRM Academy Synopsis
Reviewers back one inositol ratio for PCOS ovulation over others
A 2020 review of studies in women with PCOS argues that the 40 : 1 inositol ratio is the best supported for restoring ovulation. The authors call most other mixes and added ingredients poorly supported.
Key Findings
A meta-analysis of nine randomized trials (247 cases, 249 controls) of myo-inositol, alone or with D-chiro-inositol, found lower fasting insulin (standardized mean difference −1.021, 95% CI −1.791 to −0.251, P=0.009).
The pooled analysis also found a lower HOMA index, a marker of insulin resistance (standardized mean difference −0.585, 95% CI −1.145 to −0.025, P=0.041).
A 2019 trial gave 56 patients, 8 per group, one of seven inositol ratios for 3 months. The authors report the 40 : 1 ratio was best for restoring ovulation.
In the first controlled trial (1999, 44 obese women with PCOS), 19 of 22 (86%) women taking D-chiro-inositol ovulated, against 6 of 22 (27%) on placebo.
In 18 healthy volunteers given single doses, myo-inositol total absorption (AUC) was 19.1% lower with D-chiro-inositol and 31.8% lower with phlorizin plus other compounds.
Interpretation
This is a narrative review. The authors describe a MEDLINE search and a survey of supplement products, without listing selection steps. Support for the 40 : 1 ratio rests on a 2019 trial with 8 patients per group, a mouse study, and a meta-analysis with fasting insulin as its main outcome. The absorption results come from healthy volunteers, and the D-chiro-inositol findings on granulosa cells come from cell cultures. The authors describe an unpublished high-dose trial without data. Their judgments about products, including that added ingredients look like marketing, are opinion.
RRM Context
RRM clinicians approach PCOS, now named PMOS (Polyendocrine Metabolic Ovarian Syndrome), as an ovulation problem with an underlying cause. Evaluation comes before any product. Inositol is a supplement, so the trial record behind a formulation sets its weight. The review counts ovulation as success, which fits the restorative aim of ovulatory cycles.
Our editorial summary of this paper, not the article's abstract.
Abstract
The aim of this paper is to critically analyze the composition of many inositol-based products currently used to treat Polycystic Ovary Syndrome (PCOS). Several different combinations of myo-inositol and D-chiro-inositol, with and without additional compounds such as micro- and macroelements, vitamins, and alpha-lipoic acid, have been formulated over the years. Such therapeutic proposals do not take various features of inositol stereoisomers into consideration. As an example, it is important to know that D-chiro-inositol treatment may be beneficial when administered in low doses, yet the progressive increase of its dosage results in the loss of its advantageous effects on the reproductive performance of women and a deterioration in the quality of blastocysts created via in vitro fertilization (IVF). In addition, we have to consider that the intestinal absorption of myo-inositol is reduced by the simultaneous administration of D-chiro-inositol since the two stereoisomers compete with each other for the same transporter that has similar affinity for each of them. A decrease in myo-inositol absorption is also found when it is coadministered with inhibitors of sugar intestinal absorption and/or types of sugars such as sorbitol, maltodextrin, and sucralose. The combination of these may require higher amounts of myo-inositol in order to reach a therapeutic dosage compared to inositol administration alone, a particularly important fact when physicians strive to obtain a specific plasma level of the stereoisomer. Finally, we must point out that D-chiro-inositol was found to be an aromatase inhibitor which increases androgens and may have harmful consequences for women. Therefore, the inositol supplements used in PCOS treatment must be carefully defined. Clinical evidence has demonstrated that the 40 : 1 ratio between myo-inositol and D-chiro-inositol is the optimal combination to restore ovulation in PCOS women. Therefore, it is quite surprising to find that inositol-based treatments for PCOS seem to be randomly chosen and are often combined with useless or even counterproductive molecules, all of which can weaken myo-inositol's efficacy. Such treatments clearly lack therapeutic rationale.
Greff D et al., 2023·Reprod Biol Endocrinol·Free full text on PubMed Central
Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. PROSPERO registration number: CRD42021283275.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Celentano C et al., 2018·J Matern Fetal Neonatal Med
To identify the effects of different dietary inositol stereoisomers on insulin resistance and the development of gestational diabetes mellitus (GDM) in women at high risk for this disorder.Design: A preliminary, prospective, randomized, placebo controlled clinical trial. Nonobese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy. Supplementation with myo-inositol, d-chiro-inositol, combined myoand d-chiro-inositol or placebo.Main Development of GDM on a 75 grams oral glucose tolerance test at 24-28 weeks' gestation. Secondary outcome measures were increase in BMI, need for maternal insulin therapy, macrosomia, polyhydramnios, neonatal birthweight and hypoglycemia. The group of women allocated to receive myo-inositol alone had a lower incidence of abnormal oral glucose tolerance test (OGTT). Nine women in the control group (C), one of the myo-inositol (MI), five in d-chiro-inositol (DCI), three in the myo-inositol/D-chiro-inositol group (MI/DCI) required insulin (p = .134). Basal, 1-hour, and 2 hours glycemic controls were significantly lower in exposed groups (p < .001, .011, and .037, respectively). The relative risk reduction related to primary outcome was 0.083, 0.559, and 0.621 for MI, DCI, and MI/DCI groups. This study compared the different inositol stereoisomers in pregnancy to prevent GDM. Noninferiority analysis demonstrated the largest benefit in the myo-inositol group. The relevance of our findings is mainly related to the possibility of an effective approach in GDM. Our study confirmed the efficacy of inositol supplementation in pregnant women at risk for GDM.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Laganà AS et al., 2017·Int J Endocrinol Metab·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS)’s rate is about 6% to10% among the reproductive aged women; it is characterized by menstrual cycle irregularity with oligo-anovulation, hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. Despite the fact that the last two elements are present in a large percentage of PCOS women, they are not mandatory for the diagnosis; in order to explain the pathogenesis in these patients, it was supposed that ovarian theca cells got higher insulin sensitivity probably related to the mechanism of intracellular signalling transduction (1). Corroborating this view, it was previously demonstrated that diazoxid, which has the well-known effect of decreasing insulin levels, reduced hyperandrogenism in lean women affected by PCOS, even in the cases of normal insulin level and insulin sensitivity (2). Based on the detrimental role of insulin resistance, several insulin sensitizer drugs have been used to ameliorate PCOS symptoms and signs. Although metformin has represented the landmark of PCOS therapy in the recent past, to date several studies have tested the efficacy of Inositols, a carbocyclic polyols. Two stereoisomers, in particular Myo-inositol (MI) and D-Dhiro-inositol (DCI) showed a clinical efficacy and safety during PCOS. MI is converted in DCI by epimerase, an enzyme regulated also by insulin action. In the form of inositol-phosphoglycans (IPGs), they are involved in a non-classical insulin signalling cascade: insulin receptor is coupled by G-protein which can activate phospholipase, allowing the release of second messengers (DCI-glycan), which is able to stimulate pyruvate dehydrogenase and glycogen synthase activities, the enzyme involved in the oxidative and the non-oxidative glucose metabolism (3). On one hand, MI-IPG is able to inhibit cyclic adenosine monophosphate (cAMP) kinase and adenylyl cyclase, both involved in free fatty acid metabolism. On the other hand, DCI-IPG play a pivotal role during the binding of insulin to its receptor on cell membrane where it stimulates IPG release and starts signalling cascade. In addition, Inositols are incorporated in membrane phospholipids as phosphoinositides. Phosphatidylinositol 4, 5 bisphosphate (PtdIns-4, 5P) and phosphatidylinositol 4P (PtdIns-4P), in particular, are involved in the regulation of the cytoskeleton structure and in the regulation of cellular motility, which account also the beneficial effects of Inositol administration on sperm parameters. PtdIns-4, 5P plays a key role in controlling calcium-mediated intracellular signalling which is mandatory to address the oocytes maturation and fecundation (4).
Thyroid and Metabolic Function · Insulin and Metabolism
Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. In the 22 women given D-chiro-inositol, the mean (+/-SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417+/-11,572 to 5158+/-6714 microU per milliliter per minute (81+/-69 to 31+/-40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1+/-0.8 to 0.5+/-0.5 ng per deciliter (38+/-7 to 17+/-3 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women's diastolic and systolic blood pressure decreased by 4 mm Hg (P<0.001 and P=0.05, respectively, for the comparisons with the changes in the placebo group), and their plasma triglyceride concentrations decreased from 184+/-88 to 110+/-61 mg per deciliter (2.1+/-0.2 to 1.2+/-0.1 mmol per liter) (P=0.002 for the comparison with the change in the placebo group). None of these variables changed appreciably in the placebo group. Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001). D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.
Therapeutics › Metabolic and Endocrine Agents › Insulin Sensitizing Agents
PMID 32308679 32308679 DOI 10.1155/2020/6461254 10.1155/2020/6461254 Roseff et al. 2020, Roseff 2020
Cite this article
Roseff, S., & Montenegro, M. (2020). Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary. International journal of endocrinology, 2020, 6461254. https://doi.org/10.1155/2020/6461254
Roseff S, Montenegro M. Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary. International journal of endocrinology. 2020;2020:6461254. doi:10.1155/2020/6461254
Roseff, S., and M. Montenegro. "Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary." International journal of endocrinology, vol. 2020, 2020, pp. 6461254.