Infertility and Inositol balance

Infertility and Inositol balance

The relative concentrations of MI (Myo inositol) and DCI (D Chiro Inositol) are dynamic, and vary in health and disease. These concentrations are organ-specific. Diabetes is a state of inositol imbalance, with a MI/DCI ratio of 20.4 (Type 2 diabetes) or 13.6 (Type 1 diabetes), as compared to 13.2 (nondiabetic relatives of Type 2 diabetic patients) and 2.5 (controls) in urine. In muscle biopsy specimens, MI concentration is increased in persons with Type 2 diabetes, and increases further after the administration of insulin.

In contrast, DCI is virtually undetectable in Type 2 diabetes muscle biopsy specimens and remains refractory to insulin infusion. In obese persons, there is an increased renal clearance of DCI, and this may account for a relatively higher urinary DCI concentration in obese patients.

In general, as patients progress from normal to impaired glucose tolerance, and then to Type 2 diabetes, urine DCI decreases progressively. This inositol imbalance is related to insu-lin resistance. Similar defi-ciency of DCI is found in women with PCOS and pre-eclampsia, both of which are syndromes of the underlying insulin resistance. DCI deficiency may be due to a defect in epimerase-mediated conversion of MI. Such conversion varies from 0.7% in the heart and 2.2% in the liver to 36% in urine, and 60.4% in blood (of non diabetic rats). Conversion is much lower in diabetic rats as compared to nondiabetic animals.

This hypothesis is strengthened by evidence from various studies on ovarian tissue. An invitro study has demonstrat-ed enhanced epimerase activity in theca cells of PCOS women. Another study reported an MI/DCI ratio of 100:1 in follicular fluid of healthy women, com-pared to a ratio of 0.2:1 in women with PCOS. This creates uncertainty about the exact ratio of MI/DCI that should be aimed for while managing PCOS.

INOSITOL: THERAPEUTIC POTENTIAL

It is suggested that the Inositol MI and DCI can reduce insulin resistance, improve ovarian function, and reduce androgen levels in women with PCOS. The effect of MI on ovarian function and oocyte quality is independent of its concentration in circulation.
DCI has been shown to be involved in insulin metabolism. Urinary DCI levels are lower in patients with diabetes or impaired glucose tolerance. Serum levels of DCI are reported to be lower in women with PCOS, both at baseline and After administration of glucose loads. DCI treatment has been found to reduce insulin levels, lipids, and blood pressure, in women with PCOS.

CLINICAL EVIDENCE: MYO-INOSITOL

MI has been found to improve the number of good quality oocytes, clinical pregnancies, and delivery rates in overweight women with PCOS. Thus, it modulates the reproductive axis in a beneficial manner. In all these trials, a daily dose of 2 g MI was used over an observation period of 3–6 months. The biochemical, endocrine, and clinical benefits of MI were thought to be due to its insulin-sensitizing action.

A study used MI 2 g and folic acid as a soluble powder, twice daily, continuously, till the end of study (6 months) or a positive pregnancy test was obtained. Of 25 women with PCOS, 22 (88%) experienced a first menstrual cycle after 34.6–5.5 days. Of these 22, 18 continued to have regular menstruation and documented spontaneous ovulation. The length of successive cycles improved to 31.7 ± 3.2 days, and there was a significant fall in serum testosterone and free testosterone. Two more women showed follicular development on ultrasound, but did not exhibit an elevation of progesterone, thus suggesting anovulation. A total of ten biochemical pregnancies occurred for 6 months, of which one ended in a spontaneous abortion and one was a biochemical abortion. No multiple gestations were noted. MI can, thus, be used as a safe means of induction of ovulation in women with PCOS.

In a study of fifty women with PCOS, 2 g MI was found to reduce the risk of ovarian hyper stimulation syndrome with ovulation – induction protocols. Concentrations of LH, prolactin, androstenedione, insulin, and LH/FSH ratio were reduced significantly. Insulin sensitivity improved as well. The duration of ovulation induction and dose requirement of recombinant FSH were significantly lower with MI therapy. MI administration achieved lower oocyte retrieval, but had a greater proportion of large dimension (top quality) oocytes, which translated to a higher pregnancy rate. Biochemical pregnancy occurred in 15, clinical pregnancy in 10, and successful delivery in 8 women treated with MI, as compared to 8, 4, and 3 non-MI-treated participants. All these differences were statistically significant.

An Iraqi study on 95 participants reported that a combination of inositol 500 mg, with choline 500 mg and metformin 850 mg, all administered twice daily for 6 months led to a significant decrease in body mass index (BMI), serum leptin, and serum anti-Mullerian hormone (AMH), as compared to metformin monotherapy and lifestyle management alone. The isomer of inositol was not specified in the study.

Systematic reviews and meta-analysis have collated data on the efficacy of MI in PCOS, and suggest the need for further studies. Data also support the use of this molecule in gestational diabetes mellitus (GDM), which is also a syndrome characterized by insulin resistance.

CLINICAL EVIDENCE: D-CHIRO-INOSITOL

Various authors have studied the effect of DCI on endocrine, metabolic, and reproductive parameters in PCOS. Administration of 600 mg DCI/day for 6-8 weeks to lean women with PCOS (BMI 20.0–24.4 kg/m2) reduces insulin and free testosterone levels, while decreasing systolic blood pressure, diastolic blood pressure, and serum triglycerides. A higher rate of ovulation is noted with DCI, though the difference is not statistically significant.

In obese PCOS women (BMI >26 kg/m2) also, DCI is found to improve endocrine parameters including serum testosterone, serum androstenedione, and gonadotropin-releasing hormone-induced LH response. It also reduces BMI and improves insulin sensitivity markers in PCOS patients with diabetic relatives, who exhibit a greater response as compared to those with no family his-tory of diabetes.

The effect of DCI extends to menstrual regularity, which improves with its sup-plementation.This regularity is associat-ed with a decrease in serum AMH and in insulin resistance. Low AMH, high ho-meostatic model of assessment index, and presence of oligomenorrhea at the first visit are the independent predictors of achieving menstrual regularly with DCI.

This effect may be mediated through a decrease in follicular fluid oxidative stress status. In a study conducted on 68 participants, women with PCOS were pretreated before ovarian stimulation with either DCI 500 mg b.d or metfor-min 850 mg b.d. or left untreated for 3 months. DCI improved the maturity and quality of oocytes significantly, while reducing oxidative stress (as measured by amino acidic free – SH group label-ing). The usage of DCI was not associat-ed with any adverse effect in this study.

These studies complement a relatively old Cochrane review, which assessed the role of insulin-sensitizing agents in the management of PCOS. A similar Cochrane review, focusing on MI, is in progress for GDM.

MYO-INOSITOL/D-CHIRO-INOSITOL COMBINATION

Administration of exogenous DCI may be a means of bypassing defective epi-merase activity and achieving the down-stream metabolic effects of insulin in DCI-deficient tissues. Epimerase activity is unidirectional, and DCI administra-tion alone will not be able to mimic the effects of MI. Therefore, it is rational to provide a combination of both to ensure optimal insulin sensitivity. At the same time, the positive impact of MI on ovari-an physiology may be due to its minimal conversion to DCI. This hypothesis sug-gests that lower doses of MI may suffice if co-administered with DCI.

In a randomized controlled trial con-ducted in fifty obese PCOS women, a combination of 550 mg MI and 13.6 mg DCI, in capsule formulation, was found better than 2 g powdered MI, at improv-ing metabolic, endocrine, and ovulation parameters, when administered twice daily over 6 months. Another study showed a significant improvement in insulin sensitivity as well as lipid profile in such patients.

In a large study of 100 women, MI and DCI combination (1.1 g and 27.6 mg, respectively) was found to improve oo-cyte quality, embryo quality, and preg-nancy rates, during in vitro fertilization.

A randomized controlled trial is current-ly underway in Spain to compare the effect of increasing the proportion of DCI in a MI/DCI combination and to assess the effect on oocyte quality and pregnan-cy rates in women with PCOS. Along with folic acid, parallel groups are being administered either MI 550 mg + DCI 150 mg (ratio 3.6:1) or MI 550 mg + DCI 13.8 mg (ratio 40:1), twice daily, for 12 weeks, in a double-blind fashion.

SAFETY/TOLERABILITY

Inositol is generally regarded as safe and can be used in pregnancy. Its excretion in breast milk, and safety in lactation, is unknown. Gastrointestinal symptoms can occur, but are rare.

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