NATURAMedicatrix will be present ESHRE virtual 37th Annual Meeting, 26 June - 1 July 2021
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Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder. As the name indicates, PCOS is a syndrome and not a disease, meaning it is a set of signs and symptoms with no known, specific aetiology and for which no single test can be used for diagnosis.
PCOS is one of the most frequent endocrine pathologies encountered in women of reproductive age and it is the principal cause of sterility and anovulation. It affects up to 10% of women of reproductive age in which hyperandrogenism, enlarged cystic ovaries, and chronic anovulation often coexist in close relation with metabolic syndrome (obesity, hypertension, dyslipidemia, and glucose metabolism alterations), which makes it a serious threat to public health.
Women with PCOS have often a higher body mass index (BMI) than the general population while a reduction in weight has been shown to improve insulin resistance and PCOS symptoms1. The long term consequences of PCOS include cardiovascular disease (CVD), type II diabetes mellitus (DM2), sleep apnoea, psychological complications and low self-esteem as well as reproductive, fertility and pregnancy complications2. PCOS itself accounts for 19 to 28% of DM2 in reproductive aged women3.
The pathophysiology of PCOS is complex (figure 1) with its aetiology remaining unclear but likely genetic, being influenced later by environmental factors such as nutrition, lifestyle or obesity. Insulin resistance (IR) and compensatory hyperinsulinemia are known to be key components of the syndrome, affecting 75% of lean PCOS affected individuals and 95% of obese individuals1,4. The degree of IR experienced by women with PCOS has also been shown to be above what would be expected given their BMI1. IR affects both hyperandrogenaemia and ovulation by acting on the pituitary and ovaries arresting follicular development and increasing androgen production5,6 Insulin further inhibits the production of hepatic sex hormone binding globulin (SHBG) at the liver contributing to the higher serum concentration of free androgens commonly seen in PCOS7. Decreasing IR through weight loss, lifestyle interventions or with insulin sensitising agents improves the clinical features of PCOS while excess weight worsens IR and symptom severity1.
The clinical manifestations of this syndrome are polymorphous and vary according to the age and characteristics of each patient. Within this range of presentations, we can find:
The risk of complications during pregnancy for these women is increased. The miscarriage rate is 20 to 40% higher than with normal women21.
Women with PCOS also present a greater risk of hypertensive disorders of pregnancy, preeclampsia, gestational diabetes, foetal macrosomia, intrauterine growth retardation, preterm birth, the need for caesarean section, and their children are at a higher risk of needing admission to neonatal intensive care units22.
|NIH/NICHD-1990||ESHRE/ ASRM Rotterdam 2003||AE-PCOS Society 2006|
|Exclusion of other disorders that cause excessive androgen secretion||Exclusion of other disorders that cause excessive androgen secretion||Exclusion of other disorders that cause excessive androgen secretion|
|Clinical hyperandrogenism and/or biochemistry||Clinical hyperandrogenism and/or biochemistry||Clinical hyperandrogenism and/or biochemistry|
(Both criteria are necessary)
|Oligovulation or anovulation
Ultrasound: polycystic ovaries
(Two of the three criteria are necessary)
| Ovarian dys-function and/or Ultrasound: polycystic ovaries
(Both criteria are necessary)
Accoring to The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group Revised 2003 consensus on diagnostic criteria and long-term health risks related to poly-cystic ovary syndrome (PCOS). Hum-Reprod. 2004;19:41-7.
Where classical treatment of infertility in PCOS patients for a long time was based on Myo-Inositol, modern treatments have the potential to improve all symptoms, signs, and laboratory anomalies of PCOS. They should be able to correct systemic insulin resistance treating the metabolic features of PCOS. Simultaneously, they will create a healthy intra-ovarian milieu, which will correct hyperandrogenism, improve menstrual regularity, and promote ovulation and fertility.
The first step in a treatment often is to lose weight, specifically for obese or overweight patients. Weight loss of 2 to 5% can improve hyperinsulinemia as well as hyperandrogenism23,24,25 which at their turn improve the metabolic level and is also related with increased rates of ovulation recovery and pregnancy26,27.
More than 50% of PCOS patients present resistance to insulin and insulinaemia which justifies the use of insulin sensitizers increasing cellular susceptibility to insulin, improving endocrine functions and restoring follicle producing cycle and ovulation. Classical insulin sensitizer is metformin which is recommended in cases of patients with glucose intolerance or type 2 diabetes and in cases of Clomiphene citrate therapy which often fails in PCOS patients.
The Inositol isomers are a group of insulin sensitizing agents derived from vitamin B8. These substances are naturally present in the cell membranes and exist in nine isomers with Myo-Inositol (MYO) and D-Chiro-Inositol (DCI) as most frequent. Inositol is, among a lot of other functions, facilitating the metabolization of fat in the liver and contributes to a proper function of muscles and nervous system.
MYO is the most abundant inositol in the human body and naturally converts into DCI.
The role of both substances as well as single ingredients as well in combination are well investigated in relation to PCOS.
MYO and DCI act by increasing the cell’s insulin sensitivity by activating the enzymes that control glucose metabolism. In patients with PCOS and insulin resistance, a defect in tissue bioavailability or in the metabolism of inositol can favour the maintenance of this insulin resistance. Administering inositols in PCOS patients results in an increased sensitivity to insulin at the cellular level, which translates to an improvement in ovulatory function and hyperandrogenism.
Supplementation with MYO In patients with PCOS, improves levels of prolactine (PRL), testosterone, LH and insulin. It also produces a variation of the FSH/LH quotient, improves insulin resistance and restores cycles in amenorrheic patients28. Both MYO and DCI have been shown to improve metabolic factors in women with PCOS, reducing insulin resistance, improving ovarian function, and reducing androgen levels.
Supplementation with MYO has been demonstrated to improve oocyte and embryo quality in patients treated with in vitro fertilisation (IVF). And it has achieved lower requirements of recombinant FHS and fewer canceled cycles29,30. Effective doses for MYO are as high as 4g/day as being demonstrated in various clinical trials31,32,33,34.
Supplementation with DCI in PCOS patients appears to improve levels of progesterone by 35%, increase the ovulation rate 3 times versus a placebo35, and regulate cycles in 64% of patients after six cycles of DCI36. DCI supplements reduce levels of LH by 55% and improve the FSH/ LH ratio by 44% in patients with PCOS. They also appear to reduce oxidative stress within the ovarian follicles.
In patients with diabetes mellitus type 2, the DCI/MYO ratio and the synthesis of DCI are lower due to the lesser activity of the epimerase converting MYO to DCI, except in the ovary where cells do not develop insulin resistance. As a result, there is an increase in the epimerisation of MYO into DCI. This phenomenon has been described as the “DCI paradox”37. High intraovarian concentrations of DCI seem to negatively affect oocyte quality38. Supplementation with DCI also led to a decrease in hirsutism by 12%, measured using the Ferriman-Gallwey scale.
As for the glycaemic profile, DCI decrease hyperinsulinemia by lowering levels in blood and improves resistance by 48%35. It seems to improve cell sensitivity to insulin by 71% and the glucose/insulin ratio by 43%39.
By improving cellular sensitivity to glucose, a decrease in cardiovascular risk, along with a decrease of total cholesterol by 27% against a placebo and a reduction of tryglycerides by 41%, are achieved38.
Comparing the action of MYO supplements with DCI in patients subjected to IVF, MYO supplements appear to be more effective40.
According to clinical trials, combination inositol therapy (MYO and DCI) has the potential to improve all symptoms, signs, and laboratory anomalies of PCOS. Both inositols, prescribed together, should be able to improve the required inositol concentrations in both systemic circulation and the ovary, thus addressing the ovary inositol paradox. The correction of systemic insulin resistance by MYO will treat the metabolic features of PCOS. Simultaneously, adequate DCI levels will create a healthy intra-ovarian milieu, which will correct hyperandrogenism, improve menstrual regularity, and promote ovulation and fertility.
Recent studies have indeed confirmed the superiority of combined use of MYO and DCI rather than MYO alone for the treatment of PCOS41,42,43. These studies propose a very low proportion of DCI, with a ratio of 40:1, based on the proportion found in the human body.
However in an overview article of Barthi Kalra in the Indian Journal of Endocrinology44, she remarked that current evidence is still inadequate to provide a definite answer regarding the optimal MYO/DCI ratio. While MYO is necessary for metabolic management, DCI is equally important for menstrual, ovulatory, and cutaneous hyperandrogenic resolution. Therefore, the ratio may be less important than the absolute concentrations of both inositols. It is clear, therefore, that a high concentration of DCI is necessary to circumvent epimerase deficiency and ensure adequate levels in the ovary. Most actual pharmaceutical preparations provide very low amounts of DCI, which are insufficient to achieve adequate levels in the ovary. Hence, formulations with relatively higher levels of DCI are preferred. In 2019, very recently a new study was reported using a ratio of 3.6:1. However more important is the absolute concentration which is used in this trial (300 mg DCI)45.
A Natural Comprehensive Approach for Women with Polycystic Ovary Syndrome
“INODYS FERTILITY” is a novel combination of high MYO and high DCI combination. According to experts these are the absolute concentrations of MYO and DCI which are more important than the physiological ratio. The suggested actual dosage of 40:1 is not enough to get the maximum benefit to the use of inositols for improvement of fertility in women suffering PCOS.
“INODYS FERTILITY” contains 1.100 mg MYO and 300 mg DCI, or expressed as a ratio: 3,6:1
This results in a strong increase in numbers of pregnancies in a comparative clinical trial between these ratios45:
This clearly demonstrates the superiority of the 3.6:1 ratio over the physiological 40:1 ratio, presenting the 3.6:1 ratio as most advanced treatment for PCOS infertility.
– D-Chiro Inositol
|200 µg||Folic acid (as Quatrefolic)|
|5 µg||Vitamin D3|
Presented in a box of 60 tablets.
Quatrefolic® is the glucosamine salt of (6S)-5- methyltetrahydrofolate and is structurally analogous to the reduced and active form of folic acid so Quadefolic® completely bypasses the «damaged»
MTHFR conversion step and delivers a «finished» folate the body can immediately use without any kind of metabolization. Many studies have shown synergy between inositol and folic acid in PCOS (Raffone et al, 2010).
Vitamin D is most crucial in PCOS. Vitamin D acts in the body as a hormone and has receptors in about every organ. Vitamin D has been shown to play a role in egg quality, development, and overall fertility.
INODYS FERTILITY product contains glutathione for better efficacy. Glutathione is one of the body’s greatest antioxidants, protecting cells from attack by free radicals.
Zinc contributes to normal fertility and reproduction. Inodys Fertlity contains zinc as bisglycinate form which shows a vastly superior bioavailability in comparaison with other forms of zinc.