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Effect of Vitamin E Supplementation on Chronic Insomnia Disorder in Postmenopausal Women

Nutrients

Chronic insomnia disorder is one of the most common problems in postmenopausal women, exacerbated by underdiagnosis and improper treatment.

This double-blinded, randomized, placebo-controlled trial was conducted to evaluate the potential of vitamin E to treat chronic insomnia as an alternative to sedative drugs and hormonal therapy.

The study enrolled 160 postmenopausal women with chronic insomnia disorder, divided randomly into two groups. The vitamin E group received 400 units of mixed tocopherol daily, while the placebo group received an identical oral capsule.

The primary outcome of this study was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI), a self-evaluated and standardized questionnaire. The secondary outcome was the percentage of participants using sedative drugs. There were no significant differences in baseline characteristics between the study groups.
However, the median PSQI score at baseline was slightly higher in the vitamin E group compared with the placebo. After one month of intervention, the PSQI score was significantly lower (indicating better sleep quality) in the vitamin E group compared with the placebo.

Moreover, the improvement score was significantly higher in the vitamin E group compared with the placebo. In addition, there was a significant reduction in the percentage of patients using sedative drugs in the vitamin E group (15%), while this reduction was not statistically significant in the placebo group (7.5%).

This study demonstrates vitamin E’s potential as an excellent alternative treatment for chronic insomnia disorder that improves sleep quality and reduces sedative drug use.

The Effects of Plasma Homocysteine in PCOS Women: A Review

Open Journal of Obstetrics and Gynecology

Abstract

Homocysteine is an intermediate substance formed during the breakdown of the amino acid methionine and may undergo remethylation to methionine or trans-sulfuration to cystathionine or cysteine. The metabolism occurs via two pathways: remethylation to methionine, which requires folate and vitamin B12; and transsulfuration to cystathionine, which requires pyridoxal-5’-phosphate.

The disturbances in the metabolic pathways lead to the accumulation of Hcy, either by insufficient transsulfuration (through CBS mutations or vitamin B6 deficiency) or by a blockage of remethylation. In the latter case, folate or vitamin B12 deficiency may be involved, as well as MTHFR.

High levels of Hcy induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque.

Hyperhomocysteinemia has become the topic of interest in recent years. It has been highly associated with increased risk for cardiovascular disorders, such as, atherosclerosis, thromboembolism and dyslipidemia.

Women with PCOS show constellation of metabolic syndromes. Obesity, hyperandrogenemia and type 2 diabetes mellitus is the hallmark of PCOS which later becomes the risk factors for cardiovascular disease. Various studies had revealed the presence of increased Hcy level in PCOS women which may or may not be associated with other biochemical parameters. Intense treatment for PCOS can influence homocysteine levels.

Introduction

Polycystic ovary syndrome (PCOS) proves as the most common endocrine disorder with a prevalence of 5% to 15% worldwide [1] , for the women of active reproductive age, but the prevalent rate varies depending on the criteria used for the diagnosis [2] [3] . According to the Rotterdam diagnostic criteria, the prevalence rate of PCOS accounts up to 18% of reproductive-aged women [2] [3] , whilst the prevalence rate is 10% when using NIH criteria for diagnosis criteria [3] but the prevalence is still unknown in children [2] [4] . Three different criteria have been implemented for the diagnosis of PCOS: the NIH criteria (1990), the Rotterdam criteria (2003) and the Androgen and PCOS society (AE-PCOS) criteria (2006) [5] [6] . Amongst the three criteria, the Rotterdam criterion was adopted as the Practice Guidelines of the Endocrine Society [2] [7] . The Rotterdam criteria comprise features as, chronic menstrual dysfunction, clinical or biochemical hyperandrogenism and polycystic ovaries confirmed by ultrasonography (≥10 follicles and ≥10 ml ovarian volume) [8] . The etiology of PCOS still remains unclear but various predisposing genes interfere with environmental and lifestyle manners [5] [9] , makes PCOS a complex genetic disorder. The constellations of symptoms significantly affect the quality of life of PCOS women and the syndrome is associated with an increased long term risk factors such as cardiovascular disease, diabetes mellitus, infertility, cancer and psychological disorders [10] .

In current years, homocysteine, a biosynthesis of methionine has proved as a major cardinal feature of PCOS. It is a non-protein a-amino acid and cysteine homologue. Its metabolic pathway encompasses either remethylation to methionine or through transsulfuration to cystathionine as shown in Figure 1 [11] . The first metabolism pathway requires folate and vitamin B12 whereas the latter requires pyridoxal-5’-phosphate. S-adenosylmethionine (SAM) augments the synthesis of both pathways which is a moderator of methylenetetrahydrofolate reductase (MTHFR) and inhibitor of cystathionine β-synthase (CBS). The metabolic pathways are interrupted by any impaired function either by insufficient transsulfuration through CBS mutation or deficiency of vitamin B6 or secondly by remethylation blockage, can lead to abnormal accumulation of plasma Hcy. In the latter case, the accumulation of homocysteine could be due to deficiency of folate or vitamin B12, as well as MTHFR [12] .

A condition that emerges from disrupted homocysteine metabolism is hyperhomocysteinemia which has been known as the most significant risk factor for cardiovascular disease and has been confirmed by recently conducted meta-analysis study by Homocysteine Studies Collaboration [13] . Deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase or enzymes involving methyl-B12 synthesis, as a result of a rare genetic defect, lead to severe hyperhomocysteinemia. In fasting status, due to mild impairment in the methylation mechanism (i.e. folate or B12 deficiencies or MTHFR thermolability), occurs mild hyperhomocysteinemia [12] . Homocysteine play a role as a mediator for endothelial damage and dysfunction [14] that subsequently impairs endothelial vasoreactivity and decrease endothelium thromboresistance. Hence, hyperhomocysteinemia associated with increased risk of atherosclerosis, thromoboembolic diseases and hyperinsulinemia is verified which is directly proportionate to increased risk of cardiovascular disorders with a strong correlation to insulin resistance. Hyperhomocysteinemia also aggravates the incidence of late pregnancy complications, such as preeclampsia, abruption placentae, preterm birth and intrauterine fetal death [15] . Hyperhomocysteinemia is also one of the major factors that leads to early miscarriages by impairing by interfering endometrial blood flow and vascular integrity [16] and also described as the sole variable resulting in recurrent pregnancy loss [17] .

According to numerous clinical studies, PCOS in women is associated with existence of endothelial and platelet dysfunction, minimal chronic inflammation, increased coronary artery calcification and carotid intima-media thickness in PCOS women [18] . PCOS women are highly susceptible to both cardiovascular risk factors, such as, obesity dyslipidemia, hypertension and type-2 diabetes mellitus, and mood disorders, such as depression and anxiety [2] .

Influence on Hcy Level Post PCOS Therapy

Insulin and Hcy have the ability to induce each other by inhibiting hepatic CBS [23] that results in hyperhomocysteinemia leading to compensatory hyperinsulinemia by inducing insulin resistance. This may impair activity of the MTHFR or CBS enzymes, leading to abnormal deposition of homocysteine in plasma [24] [51] [52] . This explains that insulin resistance may be the most important marker of metabolic disease in PCOS women [53] . Hence, metformin has always been the mainstay treatment for PCOS women with insulin resistance. With administration of metformin, some study has shown beneficial decrease in plasma Hcy level [8] [54] . Nonetheless, it is also studied that metformin monotherapy is unsatisfactory [55] . The study conducted by Vrbrikova et al. revealed that the treatment with metformin only may increase the plasma Hcy level [56] . Administration with rosiglitazone and metformin seem to decrease elevated oxidative stress compared to metformin treatment but no significant changes were observed in plasma Hcy [40] . Kilicdag et al. also reported the same result [57] . This statement can be explained by folate depletion and malabsorption of vitamin B12 [58] [59] that disturbs Hcy metabolism, thus, supplementation with folate can be preventative [57] [60] . Moreover, treatment with metformin and cyclic medroxyprogesterone acetate (MPA) also tend to increase Hcy level [55] . Stefano Palombo et al. reported that treatment with metformin can slightly reduce the Hcy level in PCOS women, but supplementation with folate has shown to increase the beneficial effect [60] . Hence, folate supplementation is the first therapeutic measure advised in obese PCOS patients that prevents rise in Hcy level during weight loss. A prospective randomized clinical study in 2010, in both obese and non-obese PCOS women, observed dramatic decrease in plasma Hcy level when treated with metformin. However, the study in the both group when treated with oral contraceptives increased the plasma Hcy level and other biochemical parameters that increased the metabolic risk [61] .

Statins have also been administered and seems to deplete serum Hcy levels in PCOS [48] [62] . In a prospective cohort study, the combination of ethinyl estradiol/drospirenone (EE-DRSP) and spironolactone treatment were given to lean and glucose tolerant patients with PCOS for 6 months, improved androgen excess but the combination increased Hcy level and CRP level [63] . Similarly, oral contraceptives containing 0.03 mg ethinyl estradiol and 0.15 mg desogestrel for 6 months had significantly decreased Hcy level in non-obese normoandrogenic PCOS patients [61] . Furthermore, oral contraceptives containing 35 µg ethinyl estradiol and 2 mg cyproterone acetate had resulted in rapid decrease in Hcy level in non-smoking PCOS women [64] [65] [66] , whereas Hcy level remains high in the smokers. It has also been studied that Hcy levels decreased after regular exercises for 6 months [67] and also have shown to decrease 3 months after ovarian surgery [68] .

Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

Cell Metabolism

Highlights

  • Transmission of PCOS traits in mice occurs via an altered DNA methylation landscape
  • Metabolic- and inflammatory-related pathways are dysregulated in models of PCOS
  • Common hypomethylation signatures occur in a mouse model of PCOS and in humans
  • Identification of a novel epigenetic-based therapeutic strategy for PCOS

Summary

Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice.

We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects.

These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.

Discussion

We speculate that a global loss of DNA methylation, particularly in promoter-TSS and upstream-promoters, could be responsible for genomic instability in the disease condition. Consistently, a genome-wide DNA methylation study on umbilical cord blood reports a prevalence of hypomethylation in women with PCOS compared with unaffected women (Lambertini et al., 2017). As genomic instability is highly correlated with DNA damage, excessive DNA demethylation could be thus associated with impaired DNA damage repair. This is in line with many reports describing a strong association between PCOS and malignancies, such as ovarian and endometrial cancer (Escobar-Morreale, 2018), and suggest that a higher predisposition to cancer detected in women with PCOS could be due to altered DNA methylation landscapes.

Remarkably, we report that several of the differentially methylated genes identified in ovarian tissues of PCOS mice of the third generation are also altered in blood samples from women with PCOS and from daughters of women with PCOS compared with healthy women. Six genes associated with DNA demethylation (TET1), axon guidance (ROBO-1), inhibition of cell proliferation (CDKN1A), inflammation (HDC), and insulin signaling (IGFBPL1, IRS4) are hypomethylated in women with PCOS as compared with controls, and three genes (ROBO-1, HDC, and IGFBPL1) are also hypomethylated in daughters diagnosed with PCOS.

Here, we examined the therapeutic potential of SAM, a known natural agent causing methylation of several genes (Chik et al., 2014). To our knowledge, this is the first direct evidence for the potential therapeutic effect of SAM in a preclinical model of PCOS. Our investigation showed that SAM treatment can rescue the major PCOS reproductive neuroendocrine and metabolic alterations of PAMH F3 mice, thus highlighting the therapeutic potential of methylating agents as promising epigenetic therapies aimed at treating women with PCOS. We provide evidence that the methylating agent restores the aberrant expression of most inflammatory genes investigated in the ovaries as well as in metabolic tissues of PAMH F3 adult mice. Numerous studies show a causal link between low-grade inflammation and metabolic diseases, including T2D (Reilly and Saltiel, 2017). Moreover, the degree of inflammation correlates well with the severity of insulin resistance, T2D, and hyperandrogenism related to PCOS (González et al., 2006; Zhao et al., 2015).

Based on our findings we can speculate that the trigger for tissue inflammations could emanate from altered DNA methylation landscapes, which can be corrected by the SAM.

Taken together, this study points to AMH excess during gestation as a detrimental factor leading to the transgenerational transmission of PCOS cardinal neuroendocrine, reproductive, and metabolic alterations and shed lights into the epigenetic modifications underlying the susceptibility of the disease while pointing to novel diagnostic tools and epigenetic-based therapeutic avenues to treat the disease.

Unveiling the Pathogenesis of Adenomyosis through Animal Models

J. Clin. Med

Adenomyosis is a common gynecological disorder traditionally viewed as “elusive”. Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power.

PubMed was exhaustively searched using the phrase “adenomyosis and animal model”, “adenomyosis and experimental model”, “adenomyosis and mouse”, and “adenomyosis and rat”, and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner.

Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial–myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill’s causality criteria. Other theories only partially satisfy Hill’s criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis.

EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.

Effect of Vitamin E on Uterine Myometrium of Adult Female Albino Rats Treated With Fluoxetine

P J M H S

Background: Vitamin E is well known for its antioxidant property and has potential role in treatment of infertility. Fluoxetine is an antidepressant from SSRI group having effect on reproductive organs by increasing oxidative stress.
Aim: To explore the role of vitamin E on uterine myometrium after treatment with fluoxetine

Methods: 8-12 weeks old female rats albino of wistar strain (n=10) were divided into three groups Group A (control), group B (experimental) and group C (protective) and were treated with distilled water, oral fluoxetine (80mg/kg) and oral fluoxetine along with vitamin E simultaneously (80mg/kg and 250mg/kg) respectively for 15 days. Gross and histological examination of uterine horns of all rats along with measurement of serum prolactin level was done on 15th day. Mean±SD, One-way ANOVA and fisher exact test was applied to analyze data

Results: Weight, volume of uterus, utero-somatic index, serum prolactin level and myometrial thickness was significantly increased (P value=0.001) along with prescence of adenomyosis in experimental group B which was given fluoxetine alone. however its was observed that in group C which was given vitamin E along with fluoxetine, ameliorated these changes and results were comparable with control group A.

Conclusion: Vitamin E has a role in protection of reproductive organs owing to its antioxidant properties when administered along with fluoxetine which produces oxidative stress related changes serum prolactin levels and uterine myometrium.

Female reproductive organs have a delicate relationship with hormonal levels. Savaskan et al., 2007 observed fluoxetine use related oxidative stress and commented on its role in alteration of histological structure of reproductive organs. Jan et al., 2008 reported hormonal imbalance in rats upon treated with fluoxetine. Mori et al., 1999 observed changes in ultra-structure of uterus caused by increase in serum prolactin levels.

The animals of group C when treated simultaneously with fluoxetine along with vitamin E, showed normal thickness and histological architecture of myometrium which is similar to findings in animals of control group A. Vitamin E has been reported to ameliorate the hormonal changes inflicted by raised level of oxidative stress in body (Yin et al., 2012) .A study done by Jalili et al. 2014 supports the observations made in current study on protective ability of vitamin E in reproductive organs because of its antioxidant properties.


Medication-induced hyperprolactinemia

Mayo Clinical Proceedings

Medication use is a common cause of hyperprolactinemia, and it is important to differentiate this cause from pathologic causes, such as prolactinomas.

To ascertain the frequency of this clinical problem and to develop treatment guidelines, the medical literature was searched by using PubMed and the reference lists of other articles dealing with hyperprolactinemia due to specific types of medications.

The medications that most commonly cause hyperprolactinemia are antipsychotic agents; however, some newer atypical antipsychotics do not cause this condition.

Other classes of medications that cause hyperprolactinemia include antidepressants, antihypertensive agents, and drugs that increase bowel motility.

Hyperprolactinemia caused by medications is commonly symptomatic, causing galactorrhea, menstrual disturbance, and impotence.

It is Important to ensure that hyperprolactinemia in an Individual patient is due to medication and not to a structural lesion in the hypothalamic/pituitary area; this can be accomplished by (1) stopping the medication temporarily to determine whether prolactin levels return to normal, (2) switching to a medication that does not cause hyperprolactinemia (in consultation with the patient’s psychiatrist for psychoactive medications), or (3) performing magnetic resonance imaging or computed tomography of the hypothalamic/pituitary area. If the patient’s hyperprolactinemia is symptomatic, treatment strategies include switching to an alternative medication that does not cause hyperprolactinemia, using estrogen or testosterone replacement, or, rarely, cautiously adding a dopamine agonist.

Medications That May Cause Hyperprolactinemia

  • Antidepressants
    • Tricyclic and tetracyclic antidepressants
    • Monoamine oxidase inhibitors
    • Selective serotonin reuptake inhibitors
    • Other
  • Opiates and cocaine
  • Antihypertensive medications
    • Verapamil
    • Methyldopa
    • Reserpine
  • Gastrointestinal medications
    • Metoclopramide
    • Domperidone
    • Histamine2 receptor blockers?
  • Protease inhibitors?
  • Estrogens

The Possible Role of Fluoxetine in Adenomyosis: An Animal Experiment with Clinical Correlations

J Clin Diagn Res.

Introduction: Fluoxetine is a commonly prescribed drug which is used in the psychiatric practice and adenomyosis is a common medical problem in women of the reproductive age group.

Objective: To explore the role of fluoxetine in the causation of adenomyosis.

Methods: Female Wistar rats (n=18) were divided into three groups (group I (the control), group II and group III) and they were treated with normal saline and oral fluoxetine (4mg/kg and 8 mg/kg) respectively for 100 days. Periodic serum prolactin measurements and histopathological examinations of the uterine horns of all the rats were done at the end. Comparison of the mean serum prolactin levels between the patients (n=15) who were diagnosed with adenomyosis, the healthy age sex matched controls and the female patients (n=20) who received fluoxetine for more than 3 months, before and after the fluoxetine administration, was done separately. Appropriate (paired or unpaired) t tests were used for the data analysis.

Results: Out of the 12 test group rats, 10 rats showed the features of adenomyosis histopathologically, along with significantly (p < 0.05) raised serum prolactin levels. The mean serum prolactin levels of the patients of adenomyosis in comparison to those of the controls and of the patients who were treated with fluoxetine (before and after the fluoxetine administration), were significantly high (p=0.001 in both the cases).

Conclusion: Fluoxetine may have some role in the causation of adenomyosis (via raising serum prolactin levels); although for a stronger evidence, the follow-up of the patients who are treated with fluoxetine on a long term basis should be ideal.

Molecular genetic and endocrine predictors of menstrual cycle regulation in patients with polycystic ovary syndrome undergoing metformin treatment

Obstetrics and Gynegology

Objective: To identify clinical, laboratory and molecular genetic predictors of menstrual circle regulation in patients with polycystic ovary syndrome (PCOS) undergoing metformin treatment.

Materials and methods: The study included 143 women with PCOS (mean age is 26.4±4.6 years, mean body mass index is 23.8 (4.8) kg/m2). The assessment of androgen profile and levels of AMH, LH, FSH was performed before and 6 months after the treatment. Also, 2-hour oral glucose tolerance test with insulin level examination and dual-energy X-ray absorptiometry were done. Single-nucleotide polymorphisms (SNPs) were genotyped using polymerase chain reaction and next generation sequencing for 45 loci. All patients were administered metformin (Glucophage Long) 1500 mg/day with dose titration for 6 months. Depending on the response to the therapy, the patients were divided into two groups:

  • group 1 included 70 (53.1%) patients whose menstrual cycle was regulated,
  • group 2 consisted of 48 (36.3%) patients without any effect of therapy;
  • 14 (10.6%) patients with partial response to therapy were not included in the analysis of predicting the effectiveness of the treatment.

Results: The following independent predictors of the effectiveness of metformin therapy in PCOS were revealed:

  • AMH level less than 13.3 ng/ml,
  • total testosterone level less than 1.81 ng/ml,
  • index of adipose tissue distribution A/G less than 0.90, as well as
  • polymorphism of loci in the genes SLCO1B1 (rs4149056), ACE (rs4340), FSHR (rs2349415), OST1 (rs113569197).

The model which was developed for predicting menstrual cycle regulation in patients with PCOS undergoing metformin therapy included the baseline level of AMH and rs2349415 SNPs of FSHR gene.

Conclusion: The most significant factors determining metformin effectiveness in PCOS patients were AMH level and genotype С/С of FSHR (rs2349415).

Clinical and metabolic effects of taurine in reproductive age women with polycystic ovarian syndrome

Obstetrics and Gynegology

Objective. To reveal taurine`s effects on metabolism, menstrual and reproductive function in women with PCOS.

Methods. A total of 44 women with PCOS were included in the study with ages ranging from 18 to 44. Patients were randomized into two groups:

1) Dibicor group, n=30;

2) Placebo group, n=14.

Thirty patients received dibicor 500 mg twice a day, fourteen patients received placebo 500 mg twice a day. Duration of the therapy was 3 months. Anthropometric measurements, content of adipose tissue, blood pressure, pulse rate, lipid levels, 3-hours oral glucose tolerance test (OGTT, 75 gr glucose), ultrasound uterine and ovarian investigations were done both before and after the therapy.

Results. In the study group systolic and diastolic blood pressures were decreased. Heart rate was decreased, while serum HDL cholesterol was significantly increased (p=0,03). Changes in glucose metabolism characterized with metabolic clearance improvement in peripheral tissue due to increasing of insulin sensitivity and beta cell function. Modulation of metabolism with taurine was accompanied by ovarian function enhancement, normalization of menstrual cycle, formation of dominate follicle in 20% of women with previous history of anovulation.

Conclusion. Administration of dibicor in women with PCOS modulates metabolic dysfunction and improves reproductive prognosis, and also has protective effects against diabetes and cardiovascular diseases.

Adding a ketogenic dietary intervention to IVF treatment in patients with polycystic ovary syndrome improves implantation and pregnancy

Reproductive Toxicology

Patients with polycystic ovary syndrome (PCOS) on a high-carbohydrate diet intrinsically suffer from exacerbated glucotoxicity, insulin resistance (IR), and infertility. Lowering the carbohydrate content has improved fertility in patients with IR and PCOS; however, the effects of a well-controlled ketogenic diet on IR and fertility in PCOS patients undergoing in vitro fertilization (IVF) have not been reported.

Twelve PCOS patients with a previous failed IVF cycle and positive for IR were retrospectively evaluated. Patients followed a ketogenic diet (50 g of total carbohydrates/1800 calories/day). Ketosis was considered when urinary concentrations were > 40 mg/dL. Once ketosis was achieved, and IR diminished, patients underwent another IVF cycle. The nutritional intervention lasted for 14 ± 11 weeks. Carbohydrate consumption decreased from 208 ± 50.5 g/day to 41.71 ± 10.1 g/day, which resulted in significant weight loss (−7.9 ± 1.1 kg). Urine ketones appeared in most patients within 13.4 ± 8.1 days. In addition, there was a decrease in fasting glucose (−11.4 ± 3.5 mg/dl), triglycerides(−43.8 ± 11.6 mg/dl), fasting insulin (−11.6 ± 3.7 mIU/mL), and HOMA-IR (−3.28 ± 1.27).

All patients underwent ovarian stimulation, and compared to the previous cycle, there was no difference in oocyte number, fertilization rate, and viable embryos produced.

However, there was a significant improvement in the implantation (83.3 vs. 8.3 %), clinical pregnancy (66.7 vs. 0 %), and ongoing pregnancy/live birth rates (66.7 vs. 0 %).

Here, restriction in carbohydrate consumption in PCOS patients induced ketosis, improved key metabolic parameters, and decreased IR. Even though this did not affect oocyte or embryo quality or quantity, the subsequent IVF cycle significantly improved embryo implantation and pregnancy rates.

Whey Protein Supplementation Improves the Glycemic Response and May Reduce Non-Alcoholic Fatty Liver Disease Related Biomarkers in Women with Polycystic Ovary Syndrome (PCOS)

Nutrients

Polycystic ovary syndrome (PCOS) increases type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) with insulin resistance. We hypothesized that a 35 g whey preload would improve insulin sensitivity and glucose handling while reducing biomarkers associated with NAFLD.

Twenty-nine age-matched women (CON = 15, PCOS = 14) completed oral glycemic tolerance tests following baseline (Day 0) as well as an acute (Day 1) and short-term whey supplementation (Day 7). Whey had an interaction effect on glucose (p = 0.02) and insulin (p = 0.03), with glucose remaining stable and insulin increasing with whey supplementation.

Insulin sensitivity (p < 0.01) improved with whey associated with increased glucagon secretion (p < 0.01). Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) remained unchanged, but “day” had an effect on the AST:ALT ratio (p = 0.04), whereas triglycerides and sex hormone binding globulin overall were greater in the PCOS group (p < 0.05). Total cholesterol decreased in PCOS (by 13%) and CON (by 8%) (NS). HepG2 cells treated with plasma from participants before and after whey decreased lipid accumulation in the PCOS group after whey (p < 0.05).

Whey provided an insulinogenic and glycemic homeostatic effect in women with PCOS with the potential to combat NAFLD-consequences.

Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome

Nutrients

To date, the involvement of α-Lactalbumin (α-LA) in the management of polycystic ovary syndrome (PCOS) refers to its ability to improve intestinal absorption of natural molecules like inositols, overcoming the inositol resistance. However, due to its own aminoacidic building blocks, α-LA is involved in various biological processes that can open new additional applications.

A great portion of women with PCOS exhibit gastrointestinal dysbiosis, which is in turn one of the triggering mechanisms of the syndrome. Due to its prebiotic effect, α-LA can recover dysbiosis, also improving the insulin resistance, obesity and intestinal inflammation frequently associated with PCOS. Further observations suggest that altered gut microbiota negatively influence mental wellbeing.

Depressive mood and low serotonin levels are indeed common features of women with PCOS. Thanks to its content of tryptophan, which is the precursor of serotonin, and considering the strict link between gut and brain, using α-LA contributes to preserving mental well-being by maintaining high levels of serotonin.

In addition, considering women with PCOS seeking pregnancy, both altered microbiota and serotonin levels can induce later consequences in the offspring. Therefore, a deeper knowledge of potential applications of α-LA is required to transition to preclinical and clinical studies extending its therapeutic advantages in PCOS.

NOTE: α-LA is high in whey protein

Exploration of the Relationship Between Gut Microbiota and Polycystic Ovary Syndrome (PCOS): a Review

Geburtshilfe Frauenheilkd

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic syndrome (MS) with a complex etiology, and its pathogenesis is not yet clear. In recent years, the correlation between gut microbiota (GM) and metabolic disease has become a hot topic in research, leading to a number of new ideas about the etiology and pathological mechanisms of PCOS.

The literature shows that GM can cause insulin resistance, hyperandrogenism, chronic inflammation and metabolic syndrome (obesity, diabetes) and may contribute to the development of PCOS by influencing energy absorption, the pathways of short chain fatty acids (SCFA), lipopolysaccharides, choline and bile acids, intestinal permeability and the brain–gut axis.

As part of the treatment of PCOS, fecal microbiota transplantation, supplementation with prebiotics and traditional Chinese medicine can be used to regulate GM and treat disorders.

This article reviews possible mechanisms and treatment options for PCOS, based on methods which target the GM, and offers new ideas for the treatment of PCOS.

Pause menopause with Rhodiola rosea, a natural selective estrogen receptor modulator

Phytomedicine

Menopause is associated with increased risks for cardiovascular disease, osteoporosis, and cancer. Many women experience declining energy, mood, cognitive function and memory during
menopause.

Rhodiola rosea extracts have been shown to enhance mood, cognitive function, and memory. Moreover, these extracts possess anti-stress, neuroprotective, cardiovascular-protective, and anticarcinogenic properties, which are particularly valuable to counteract some of the common health risks seen in women as they age. R. rosea is low in side effects compared to synthetic selective estrogen receptor modulators (SERMS).

Preclinical and clinical studies suggest that R. rosea extracts provide a combination of effects that could counteract the adverse consequences of estrogen decline by improving neurological, endothelial, and cardiovascular functions.

As a natural SERM, R. rosea could alleviate menopause-related symptoms while conferring additional neuro-protective, cardio-protective, anti-stress, anti-fatigue, osteoprotective, and other health benefits.

Unlike HRT, preliminary evidence indicates that orally ingested R. rosea extracts are unlikely to cause estrogenic effects or increased the risk of cancer in hormone sensitive tissues. R. rosea extracts and salidroside do not significantly stimulate, but rather inhibit growth of human breast cancer in vitro and in vivo in some studies. Human studies are needed to verify the safety of R. rosea in postmenopausal women who are at increased risk or who are being treated for breast cancer.

Further research on the use of R. rosea alone and in combination with other adaptogens during menopause would enable development of this promising alternative SERM.

Total flavonoids of Astragalus Ameliorated Bile Acid Metabolism Dysfunction in Diabetes Mellitus

Evid Based Complement Alternat Med.

Astragalus Radix is one of the common traditional Chinese medicines used to treat diabetes. However, the underlying mechanism is not fully understood.

Flavones are a class of active components that have been reported to exert various activities. Existing evidence suggests that flavones from Astragalus Radix may be pivotal in modulating progression of diabetes.

In this study, total flavones from Astragalus Radix (TFA) were studied to observe its effects on metabolism of bile acids both in vivo and in vitro. C57BL/6J mice were treated with STZ and high-fat feeding to construct diabetic model, and HepG2 cell line was applied to investigate the influence of TFA on liver cells.

We found a serious disturbance of bile acids and lipid metabolism in diabetic mice, and oral administration or cell incubation with TFA significantly reduced the production of total cholesterol (TCHO), total triglyceride, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and low-density lipoprotein (LDL-C), while it increased the level of high-density lipoprotein (HDL-C). The expression of glucose transporter 2 (GLUT2) and cholesterol 7α-hydroxylase (CYP7A1) was significantly upregulated on TFA treatment, and FXR and TGR5 play pivotal role in modulating bile acid and lipid metabolism.

This study supplied a novel understanding towards the mechanism of Astragalus Radix on controlling diabetes.

Natural Products Targeting Liver X Receptors or Farnesoid X Receptor

Front. Pharmacol

Nuclear receptors (NRs) are a superfamily of transcription factors induced by ligands and also function as integrators of hormonal and nutritional signals. Among NRs, the liver X receptors (LXRs) and farnesoid X receptor (FXR) have been of significance as targets for the treatment of metabolic syndrome-related diseases. In recent years, natural products targeting LXRs and FXR have received remarkable interests as a valuable source of novel ligands encompassing diverse chemical structures and bioactive properties. This review aims to survey natural products, originating from terrestrial plants and microorganisms, marine organisms, and marine-derived microorganisms, which could influence LXRs and FXR. In the recent two decades (2000–2020), 261 natural products were discovered from natural resources such as LXRs/FXR modulators, 109 agonists and 38 antagonists targeting LXRs, and 72 agonists and 55 antagonists targeting FXR. The docking evaluation of desired natural products targeted LXRs/FXR is finally discussed. This comprehensive overview will provide a reference for future study of novel LXRs and FXR agonists and antagonists to target human diseases, and attract an increasing number of professional scholars majoring in pharmacy and biology with more in-depth discussion.
 

Astragalus:
Astragalus membranaceus (Fisch.) Bunge, widespread in Europe and Asia, is beneficial to the treatment of diabetes, hyperlipidemia, atherosclerosis, and cancers, with its key constituents like astragaloside IV and cycloastragenol (164). Compound 164 stimulated FXR transcription activities and regulated the expression of FXR target gene in HepG2 cells as a potential candidate for NAFLD. Meanwhile, it improved metabolic profiles, ameliorated hepatic steatosis, altered BA composition, and activated FXR signaling and feedback loops in diet-induced obesity mice, further confirming the promise in ameliorating NAFLD. Besides, 164 also alleviated hepatic steatosis in methionine and choline-deficient L-amino acid diet-induced NASH mice (Gu et al., 2017b).

Guggulsterone:
Guggulsterone, existing in two isomeric forms, namely, E-guggulsterone (234) and Z-guggulsterone (235), is the active agent isolated from the resin of Commiphora mukul (Arn.) Bhandari, responsible for antihyperlipidemic effect. E/Z-guggulsterones 234 and 235 have been identified as FXR antagonists directly, to decrease hepatic cholesterol levels in rodent models. Moreover, Z-guggulsterone (235) exhibited remarkable FXR antagonism with an IC50 of 1–5 μM in HepG2 cells, increased the cholesterol CYP7A1, and further decreased the circulating cholesterol level (Urizar et al., 2002; Urizar and Moore, 2003; Bhutani et al., 2007; Yu et al., 2009; Singh and Sashidhara, 2017).

Hesperidin:
A flavanone glycoside abundantly found in lemons and oranges is hesperidin (183), treatment with which prevented cholestatic liver injury and reduced BA toxicity in HepaRG cells via activating FXR. Compound 183 dose-dependently protected against 75 mg/kg dose of ANIT-induced cholestasis and liver injury as reversing increases in the liver index, biliary index, serum AST, ALT, alkaline phosphatase, and total bilirubin, functioning as an effective agent for the prevention and therapy of cholestatic liver disease (Zhang et al., 2020a).

Betaine:
Betaine (104), a natural trimethyl glycine in common foods, including wheat products, spinach, pretzels, and shrimp, has been used for the therapy of NAFLD via upregulating hepatic expression of LXRα and PPARα, along with attenuating the changes in their associated target genes in fructose-induced rat models. 101 also ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through a battery of determinations, further confirming potential mechanisms involved in the treatment of NAFLD (Ge et al., 2016; Chen Q. et al., 2017).

Allicin:
Allicin (105) is an essential ingredient of garlic, responsible for its favor, and its pharmacological activities range from anti-inflammatory to antioxidative stress and antihypertensive activities. 105 has also been confirmed to attenuate inflammation via increasing the expression of LXRα in a dose-dependent manner (Zhang et al., 2017).

Taurine:
Taurine (106), known as 2-aminoethanesulfonic acid is synthesized in the liver to a small extent, which is also isolated from seafood. Macrophage cells incubated with 106 inhibited cholesterol accumulation and regulated genes expression involved in RCT as an LXRα agonist (Hoang et al., 2012c).

Luteolin:
Luteolin (118), occurring in a broad range of vegetables, fruits, and grains like carrots, peppers, celery, parsley, and spinach, is a common dietary flavonoid exerting numerous biological activities including antioxidant, anticancer, antimicrobial, antiallergic, and antiinflammatory effects. It abrogated agonist-induced LXRα/β transcriptional activity and suppressed the expression of related target genes serving as an LXRα/β antagonist (Francisco et al., 2016). Treatment with 118 inhibited LXR activation in HepG2 cells and eliminated lipid accumulation induced by LXR-SREBP-1c activation, thereby decreasing TG accumulation and primary hepatocytes. Overall, lipid accumulation induced by LXRs-SREBP-1c activation was abolished both in vivo and in vitro after treatment with 118, indicating the potential as a therapeutic agent for treating NAFLD (Yin et al., 2017). Besides, 118 in combination with cisplatin could potentially be used as a new regimen for the treatment of ovarian cancer (Wang et al., 2018c). It exhibited that 118 could upregulate LXRα and downstream target gene expression to control cholesterol metabolism (Park et al., 2020).

Curcumin:
Curcumin (133), an active phenol derivative obtained from Curcuma longa L., could suppress the hepatic overexpression of LXRα, PPARγ, and fatty acid synthase. An immunoblot analysis also verified that 133 decreased the protein expression of LXRα and SREBP1c in the liver. Moreover, histological and serum biochemical analyses indicated that 133 apparently attenuated the hepatic lipid accumulation and decreased TG, TC, and nonesterified fatty acid levels in NAFLD mice model on account of the role for the prevention and treatment of NAFLD (Maithilikarpagaselvi et al., 2016; Chen et al., 2017b; Auger et al., 2018).

Bile acid metabolism and the pathogenesis of type 2 diabetes

Curr Diab Rep.

T2D is a growing health problem world-wide, but the currently available strategies for therapy and prevention are insufficient. Recent observations indicate that bile acid homeostasis is altered in T2D. Bile acids are metabolic regulators that act as signaling molecules through receptor-dependent and -independent pathways. The most prominent signaling molecules mediating bile acid signaling are the nuclear receptor FXR and the membrane receptor TGR5. Both are implicated in the regulation of lipid, glucose and energy metabolism. Dysregulation of these pathways might contribute to the development of T2D and associated metabolic complications. Interestingly, data from studies with bile acids or bile acid sequestrants indicate that the manipulation of bile acid homeostasis might be an attractive approach for T2D therapy. In this review, we summarize the mechanisms of bile-acid-mediated metabolic control that might be of relevance in the pathogenesis of T2D.
Keywords: Animals, Bile Acids and Salts, metabolism, Diabetes Mellitus, Type 2, metabolism, physiopathology, Dyslipidemias, metabolism, physiopathology, Humans, Obesity, metabolism, physiopathology

Keywords: Bile acids, T2D, FXR, TGR5, bile acid sequestrants, obesity, dyslipidemia, NAFL

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Diabetes and metabolism Journal

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease.

Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5.

Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size.

Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity.

Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Keywords: Bile acids and salts, Gastrointestinal microbiome, Non-alcoholic fatty liver disease, Receptors, cytoplasmic and nuclear, Receptors, G-protein-coupled

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

International Journal of Molecular Sciences

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms.

In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.

Keywords: liver X receptors, cholesterol, female reproduction, breast cancer, ovarian hyperstimulation syndrome

Content retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121373/.

Intestinal Flora is a Key Factor in Insulin Resistance and Contributes to the Development of Polycystic Ovary Syndrome

Endocrinology

The key gut microbial biomarkers for polycystic ovarian syndrome (PCOS) and how dysbiosis causes insulin resistance and PCOS remain unclear.

Objective: To assess the characteristics of intestinal flora in PCOS and explore whether abnormal intestinal flora can affect insulin resistance and promote PCOS and whether chenodeoxycholic acid (CDCA) can activate intestinal farnesoid X receptor (FXR), improving glucose metabolism in PCOS.

Results: Bacteroides was significantly enriched in treatment-naïve PCOS patients. The enrichment in Bacteroides was reproduced in the PCOS mouse model. Gut microbiota removal ameliorated the PCOS phenotype and insulin resistance and increased relative FXR mRNA levels in the ileum and serum fibroblast growth factor 15 levels. PCOS stool-transplanted mice exhibited insulin resistance at 10 weeks but not PCOS. Treating the PCOS mouse model with CDCA improved glucose metabolism.

Conclusions: Bacteroides is a key microbial biomarker in PCOS and shows diagnostic value. Gut dysbiosis can cause insulin resistance. FXR activation might play a beneficial rather than detrimental role in glucose metabolism in PCOS.

Oxidative stress is implicated as a major factor involved in the pathophysiology of endometriosis

Endometriosis is a chronic gynecologic disease process with multifactorial etiology. Increased oxidative stress, a result of increased production of free radicals or depletion of the body’s endogenous antioxidant defense, has been implicated in its pathogenesis. Oxidative stress is thought to promote angiogenesis and the growth and proliferation of endometriotic implants. Oxidative stress in the reproductive [...]

Endometriosis is a chronic gynecologic disease process with multifactorial etiology. Increased oxidative stress, a result of increased production of free radicals or depletion of the body’s endogenous antioxidant defense, has been implicated in its pathogenesis. Oxidative stress is thought to promote angiogenesis and the growth and proliferation of endometriotic implants. Oxidative stress in the reproductive tract microenvironment is known to negatively affect sperm count and quality and may also arrest fertilized egg division leading to embryo death. Increased DNA damage in sperm, oocytes, and resultant embryos may account for the increase in miscarriages and fertilization and implantation failures seen in patients with endometriosis.

The evidence linking endometriosis and infertility to endogenous pro-oxidant imbalance provides a rationale for the empiric use of antioxidant therapy. Vitamin C and E deficiency has been demonstrated in women with endometriosis. Observational and randomized controlled studies have shown vitamin C and E combination therapy to decrease markers of oxidative stress.

SOURCE: Studies on Women’s Health

Similarities in Pathogenetic Mechanisms Underlying the Bidirectional Relationship between Endometriosis and Pelvic Inflammatory Disease

Diagnostics

Background:

Endometriosis is a common inflammatory disease characterized by the presence of endometrial cells outside of the uterine cavity. Endometriosis affects 10% of women of reproductive age and significantly reduces their quality of life as a result of chronic pelvic pain and infertility. Biologic mechanisms, including persistent inflammation, immune dysfunction, and epigenetic modifications, have been proposed as the pathogenesis of endometriosis. In addition, endometriosis can potentially be associated with an increased risk of pelvic inflammatory disease (PID). Changes in the vaginal microbiota associated with bacterial vaginosis (BV) result in PID or a severe form of abscess formation, tubo-ovarian abscess (TOA). This review aims to summarize the pathophysiology of endometriosis and PID and to discuss whether endometriosis may predispose to PID and vice versa.

Methods:

Papers published between 2000 and 2022 in the PubMed and Google Scholar databases were included.

Results: Available evidence supports that women with endometriosis are at increased risk of comorbid PID and vice versa, supporting that endometriosis and PID are likely to coexist. There is a bidirectional relationship between endometriosis and PID that shares a similar pathophysiology, which includes the distorted anatomy favorable to bacteria proliferation, hemorrhage from endometriotic lesions, alterations to the reproductive tract microbiome, and impaired immune response modulated by aberrant epigenetic processes. However, whether endometriosis predisposes to PID or vice versa has not been identified.

Conclusions:

This review summarizes our current understanding of the pathogenesis of endometriosis and PID and discusses the similarities between them.

Content retrieved from: https://www.mdpi.com/2075-4418/13/5/868/pdf.

Cyclical changes in calcium metabolism across the menstrual cycle in women with premenstrual dysphoric disorder

J Clin Endocrinol Metab.

Calcium-regulating hormones varied significantly across the menstrual cycle in both groups. Total serum, ionized and urine calcium, pH, intact PTH, and 1,25-dihydroxyvitamin D varied significantly over the menstrual cycle. The PMDD group, when compared with controls, had significantly lower ionized calcium at phase 1 (menses), significantly lower urine calcium excretion at three of the five phases (late follicular phase 2, midcycle phase 3, and early luteal phase 4), and significantly lower 1,25(OH)(2)D at luteal phase 4.

Source: Cyclical changes in calcium metabolism across the menstrual cycle in women with premenstrual dysphoric disorder – PubMed

Oxidative stress is implicated as a major factor involved in the pathophysiology of endometriosis

Studies on Women’s Health

Endometriosis is a chronic gynecologic disease process with multifactorial etiology. Increased oxidative stress, a result of increased production of free radicals or depletion of the body’s endogenous antioxidant defense, has been implicated in its pathogenesis. Oxidative stress is thought to promote angiogenesis and the growth and proliferation of endometriotic implants. Oxidative stress in the reproductive tract microenvironment is known to negatively affect sperm count and quality and may also arrest fertilized egg division leading to embryo death. Increased DNA damage in sperm, oocytes, and resultant embryos may account for the increase in miscarriages and fertilization and implantation failures seen in patients with endometriosis.

The evidence linking endometriosis and infertility to endogenous pro-oxidant imbalance provides a rationale for the empiric use of antioxidant therapy. Vitamin C and E deficiency has been demonstrated in women with endometriosis. Observational and randomized controlled studies have shown vitamin C and E combination therapy to decrease markers of oxidative stress.

Repeated miscarriages and multiple IVF failures may point to ‘silent endometriosis’

Endofound

…We know also that inflammation is a very important part of endometriosis and whether the inflammation causes endometriosis or whether endometriosis causes inflammation, and I think it is both, but this all plays a part in why patients end up in our practice with infertility. The majority of these patients as I said have not a single painful symptom of endometriosis. In fact, one of the first symptoms that we see is infertility and recurrent pregnancy loss and pregnancy complications.

…What we found in these situations are that young women with low ovarian reserve typically have one of three reasons; it is familial, it is genetic and we see that. The mother went into menopause early, they may do that, it is genetic. The second is it is autoimmune that there is an autoimmune attack against the follicles called autoimmune oophoritis and we can easily identify that. But number three is almost always endometriosis. It is an inflammatory environment in the pelvis and we all know these peritoneal fluids are saturated with inflammatory cytokines. We know that the follicles that are generated during IVF when they look inside the follicular fluid they have very high levels of prodigal reactive oxygen species, a by-product of oxidative stress, a by-product of all these elevated cytokines in the pelvis, and we know this affects eggs.

Dopamine receptor D2 genotype is associated with moderate/ severe endometriosis in infertile women in Brazil

Fert Sert

An excess of DRD2 polymorphism 2 was found in exon 7 in women with peritoneal moderate/severe endometriosis. The presence of polymorphism 2 could cause a defect in a post-receptor
signaling mechanism, resulting in a mild increase in serum prolactin levels. Thus, the potential angiogenic role of prolactin may play a role in the implantation of ectopic endometriosis tissue.

Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia

Fert Sert

Dopamine receptor agonist Quinagolide induced a 69.5% reduction in the size of the lesions, with 35% vanishing completely. Histologic analysis showed tissue degeneration, which was supported by down-regulation of VEGF/VEGFR2, three proangiogenic cytokines (CCL2, RUNX1, and AGGF1) and plasminogen activator inhibitor (PAI) 1, a potent inhibitor of fibrinolysis in the L2 lesions.

By interfering with angiogenesis, enhancing fibrinolysis, and reducing inflammation, quinagolide reduces or eliminates peritoneal endometriotic lesions in women with endometriosis.

Citrus fruits lower the risk of endometriosis

Hum Reprod

Endometriosis is a painful condition of the female reproductive organs that can result in heavy bleeding, scarring, fatigue, infertility, and more.

A study published in April 2018 using data collected from 70,835 premenopausal women has examined if there is a connection between fruit and vegetable consumption and endometriosis. While there didn’t appear to be an association between total vegetable intake and risk of endometriosis, citrus fruits were associated with a lower risk of the disease. Based on data from food frequency questionnaires every four years between 1991 to 2013, women consuming ≥1 servings of citrus fruits per day had a 22% lower endometriosis risk compared to those consuming <1 serving per week.

The researchers concluded, “Our findings suggest that a higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis, and beta-cryptoxanthin in these foods may partially explain this association.”

2018

Dietary supplements for treatment of endometriosis: A review

Acta Biomed

As search for optimal therapy continues for endometriosis, aid of dietary supplements is gaining attention. Supplements can be used for their anti-inflammatory, anti-oxidant, anti-proliferative and immune modulatory characteristics. We reviewed the literature, evaluated and synthesized effects of vitamin D, zinc, magnesium, omega 3, propolis, quercetin, curcumin, N-acetylcysteine, probiotics, resveratrol, alpha lipoic acid, vitamin C, vitamin E, selenium and epigallocatechin-3-gallate. Based on results of in vitro, animal and human studies, it might be safe to say that dietary supplements can be used as a complementary treatment for endometriosis.

2021

“The pill” suppresses adolescent bone growth, no matter the estrogen dose

Canadian Medical Association Journal

… a prospective, population-based, 2-year observational study of Canadian adolescents aged 16–19 years showed that those who used combined hormonal contraceptives (CHC) had decreased gains in femoral bone mineral density compared with those who did not use CHC. Loss of bone mineral density on CHC was unrelated to dose of ethinyl estradiol. Earlier data had already shown the lack of a dose effect from CHC estrogen on bone; patients on 20–35 μg ethinyl estradiol CHC formulations all had suppressed markers of bone remodelling. Our recent meta-analysis comparing adolescents who did and did not use CHC also showed impaired accrual of bone mineral density among CHC users across a wide range of doses.

Why might adolescents taking CHC have lower gains toward peak bone mineral density than those not taking CHC? Bone resorption and formation are tightly coupled physiologic processes. As with the lower doses of estrogen in menopausal hormone therapy, CHC suppress bone resorption and therefore prevent the necessary bone growth that adolescents require to reach peak bone mineral density.

NAC + L-arginine lower insulin resistance by 39% and restore ovulation in PCOS

J Endocrinol Invest

Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months.

Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored.

Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment.

Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment.

In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.

Endometriosis pathogenesis : role played by the oxidative stress due to MTHFR mutations

FertStert

Endometriosis can be explained by MTHFR mutations.

On the one hand, polymorphisms of MTHFR induces oxidative stress through the increased homocysteine level (Guo, 2016).

On the other hand, the oxidative stress is implicated in the pathophysiology of endometriosis by causing a general inflammatory response in the peritoneal cavity (Augoulea, 2009) and therefore impairs the fertility of the female patients.

To our knowledge, these preliminary results are the first in the literature showing the role played by MTHFR in the endometriosis genesis of infertile patients.

Therefore, by improving the methylation and decreasing the oxidative stress of the endometriosis patients, treating MTHFR mutation carriers improves the quality of the gametes and their ART (Assisted Reproductive Technologies) outcomes.

Curative Treatment of Period Pain

Indian J Med Res

To prove the efficacy of oral vitamin B1 administration for the treatment of primary dysmenorrhoea, a randomised, double-blind, placebo-controlled study was carried out on 556 girls aged 12-21 yr, having moderate to very severe spasmodic dysmenorrhoea.

Thiamine hydrochloride (vitamin B1) was given in a dose of 100 mg orally, daily for 90 days.

The combined final results of both the ‘active treatment first’ group and the ‘placebo first’ group, after 90 days of vitamin B1 administration, were

  • 87 per cent completely cured,
  • 8 per cent relieved (pain almost nil to reduced)
  • 5 per cent showed no effect whatsoever.

The results remained the same two months later as well when no drug was administered. Unlike all the current treatments which are suppression-oriented, this curative treatment directly treats the cause, is free from side effects, is inexpensive and easy to administer.

[PMID: 8935744]

Evaluation of the relationship between endometriosis and omega-3 and omega-6 polyunsaturated fatty acids

Iran Biomed J

Endometriosis is a common chronic inflammation causing major problems including infertility. The role of omega-3 and omega-6 fatty acids as their potential anti-inflammatory effects in endometriosis needs to be further explored. The objective of this study was to compare serum phospholipid fatty acid profile in endometriosis patients with controls, and to explore the correlation of this profile with the severity of the disease. 

Methods:

Sixty-four endometriosis patients and 74 control women, in reproductive age, participated in this study. Among the endometriosis patients, 19 cases were in stage I, 27 cases in stage II, 8 cases in stage III, and 10 cases in stage IV. Each patient underwent laparoscopy. Before surgery, 5 ml of blood was obtained. After extraction of the total lipids, serum total phospholipid fraction was isolated by thin layer chromatography. Fatty acid composition of the phospholipid fraction was determined by gas chromatography and the resulted profile was compared in endometriosis patients and controls. The profile was also compared in the endometriosis group based on the severity of disease. 

Results: 

Stearic acid was significantly lower in the endometriosis group as compared to controls (P= 0.030). No other fatty acid compositions were significantly different between patients and controls. Serum ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) was in reasonable correlation with the severity of endometriosis (r = 0.34, P = 0.006). 

Conclusion:

According to these findings, levels of fatty acids in serum total phospholipids seem not to be a marker for endometriosis, but the EPA to AA ratio was a relevant factor indicating severity of illness.

[PMC3614254]

——

EPA is hypothesized to reduce disease severity through their anti-inflammatory and immunomodulatory effects [25]. EPA is the most important component of omega-3 and AA, an omega-6 fatty acid and plays an important role in biological systems. AA has a substrate role for production of certain mediators such as PGE2 and leukotriene (LTB4). PGE2 and LTB4 are initiators for endometriosis and pain [24]. On the other hand, EPA plays a role in biosynthesis of LTB5 and PGE3 which have less inflammatory effect compared with PGE2 and LTB4 [24]. EPA is a competitive inhibitor in conversion of AA to LTB4 and PGE2 [26]. Irrespective of study design, our results were in agreement, in part, with the in vitro experiments by Gazvani et al. [20] that showed a high ratio of omega-3 to omega-6 in endometrial cell culture from endometriosis patients induce higher concentrations of IL-8 productions in cell supernatant. IL-8 as a pro-inflammatory and angiogenic cytokine has a significant role in endometriosis [27].

A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by n-acetylcysteine

Evidence-Based Complementary and Alternative Medicine

NAC (N-acetylcysteine) treatment or no treatment was offered to 92 consecutive Italian women referred to our university hospital with ultrasound confirmed diagnosis of ovarian endometriosis and scheduled to undergo laparoscopy 3 months later.

According to patients acceptance or refusal, NAC-treated and untreated groups finally comprised 73 and 72 endometriomas, respectively.

After 3 months, within NAC-treated patients cyst mean diameter was slightly reduced (−1.5 mm) versus a significant increase (+6.6 mm) in untreated patients (P = 0.001).

Particularly, during NAC treatment, more cysts reduced and fewer cysts increased their size.

Our results are better than those reported after hormonal treatments.

Twenty-four NAC-treated patients—versus 1 within controls—cancelled scheduled laparoscopy due to cysts decrease/disappearance and/or relevant pain reduction (21 cases) or pregnancy (1 case).

Eight pregnancies occurred in NAC-treated patients and 6 in untreated patients.

We can conclude that NAC actually represents a simple effective treatment for endometriosis, without side effects, and a suitable approach for women desiring a pregnancy

Effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome

Menopause

Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women.

The aim of this study was to evaluate whether myo-inositol, an insulin-sensitizing substance, may improve some features of metabolic syndrome in postmenopausal women.

Methods: 

Eighty postmenopausal women affected by the metabolic syndrome were enrolled prospectively in the study and treated with diet plus supplementation of myo-inositol (2 g BID plus diet: intervention group) or with diet plus placebo (control group) for 6 months. They were evaluated at baseline and after 6 months for insulin resistance (homeostasis model assessment ratio [HOMA] insulin resistance), lipid profile, and blood pressure.

Results: 

Myo-inositol plus diet improved systolic and diastolic blood pressure, HOMA index, cholesterol, and triglyceride serum levels with highly significant differences, compared with the groups treated only with diet and placebo. In the group treated with myo-inositol, a decrease in diastolic blood pressure (−11%), HOMA index (−75%), and serum triglycerides (−20%) and an improvement in high-density lipoprotein cholesterol (22%) were shown.

Conclusions: 

Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women.

Roles of different n-3/n-6 PUFA ratios in ovarian cell development and steroidogenesis in PCOS rats

The Royal Society of Chemistry

Polycystic ovary syndrome (PCOS) is a complex and common endocrine disorder characterized by hyperandrogenism, which is accompanied by follicle growth arrest at the small antral stage, minimal granulosa cell proliferation, and chronic anovulation.

Polyunsaturated fatty acids (PUFAs) are necessary for the body’s metabolism, growth and development. Although PUFAs play an important role in the regulation of female reproduction, their role in ovarian development in PCOS is still unclear.

The present study was conducted to investigate the effects of different ratios of n-3/n-6 PUFAs (omega-3/omega-6) on ovary development in PCOS rats. Serum levels of reproductive hormones and enzymes related to steroidogenesis were assessed.

The results indicated that PUFAs (n-3/n-6: 1/15) significantly increased ovarian weight and improved the ovarian structure although they had no significant effect on body weight in PCOS rats.

Meanwhile, apoptosis was attenuated accompanied by increased cell proliferation by PUFAs (n-3/n-6: 1/15). Moreover, serum levels of hormones (FSH and E2) were also significantly increased by PUFAs (n-3/n-6: 1/15) accompanied by decreased T levels.

To investigate whether PUFAs regulate the expression of enzymes related to hormone synthesis, western blotting was used to determine the protein levels of CYP51, CYP19, StAR and 3β-HSD.

The results showed that PUFAs significantly increased the protein levels of all of these enzymes. These results indicate that PUFAs enhance the reproductive performance of PCOS by increasing the expression of steroidogenesis enzymes, which are related to hormone secretion and ovarian functions.

These findings provide evidence that a balanced n-3/n-6 PUFA ratio is beneficial for PCOS reproduction.

Lactic Acid Bacteria Alleviate Polycystic Ovarian Syndrome by Regulating Sex Hormone Related Gut Microbiota

Royal Society of Chemistry

Polycystic ovarian syndrome (PCOS) is a common endocrine disease across the world. Because gut microbiota play a key role in the pathogenesis of PCOS, probiotics may alleviate PCOS symptoms through the regulation of intestinal flora. The effects of 8 lactic acid bacterial strains on PCOS were investigated. Letrozole was used to produce a PCOS rat model and a 4-week-strain-intervention was performed. Diane-35, as a clinical PCOS treatment medicine, was effective in attenuating rats’ reproductive disorders.

Lactobacillus plantarum HL2 was protective against ovary pathological changes and restored luteinizing hormone, follicle stimulating hormone and testosterone levels.

Bifidobacterium longum HB3 also alleviated ovary abnormalities and decreased testosterone levels.

Administration of lactic acid bacteria up-regulated short-chain fatty acid levels.

Based on 16S rRNA sequencing, lactic acid bacteria improved letrozole induced gut microbiota dysbiosis with different degrees.

Akkermansia, Roseburia, Prevotella, Staphylococcus and Lactobacillus genera were correlated with sex hormone levels. Some of the sex hormone-related gut microbiota were restored by treatment with the strains.

These results demonstrated that lactic acid bacteria alleviated PCOS in a rat model by regulating sex hormone related gut microbiota. Modifying gut microbiota by probiotic interventions may thus be a promising therapeutic option for PCOS.

Gut microbial metabolites in depression: understanding the biochemical mechanisms

Microbial Cell

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products.

Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism.

This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play in the context of emotional behaviour.

The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behaviour.

We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behaviour: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation.

Elucidating these mechanisms is essential to expand our understanding of the aetiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules.

Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.

 

Gut microbiota–bile acid–IL22 axis orchestrates PCOS

Nature

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2.

The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4.

This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels.

Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility.

Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype.

This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers

Psychopharmacology

There is now compelling evidence for a link between enteric microbiota and brain function. The ingestion of probiotics modulates the processing of information that is strongly linked to anxiety and depression, and influences the neuroendocrine stress response. 

This study found that taking a prebiotic called galactooligosaccharides for three weeks significantly reduced the amount of cortisol, a primary stress hormone in the body.

Catechol-O-methyltransferase Features

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Catechol-O-Methyltransferase (COMT) is one of the several enzymes that degrade dopamine, epinephrine, and norepinephrine. COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive or executive function (prefrontal cortex).

COMT helps break down estrogen byproducts that have the potential to cause DNA mutations and cause cancer. 

If you have higher COMT levels:

  • Mucuna  to increase dopamine,
  • Tyrosine to increase dopamine,
  • EGCG/Tea (COMT inhibitor),
  • Epicatechins/Chocolate (COMT inhibitor),
  • Luteolin 

If you have lower levels of COMT, the following may counteract some of the effects of the gene:

  • SAM-e – however, this can increase dopamine levels in people who already have high dopamine.
  • Methyl Guard Plus to ensure adequate B6, B12, folate and betaine to support the formation of S-adenosylmethionine and prevent elevated homocysteine; S-adenosylhomocysteine inhibits COMT activity.
  • Ensure adequate anti-oxidants to prevent oxidation of dopamine and pro-carcinogenic 4-hydroxyestrogens,
  • Magnesium Citrate (magnesium is a cofactor)
  • Be careful of the following supplements that are the targets of COMT: quercetin, rutin, luteolin, EGCG, catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol
  • Avoid excessive alcohol consumption.  Since alcohol-induced euphoria is associated with the rapid release of dopamine in limbic areas, low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of alcohol dependence.
  • Avoid stimulants, especially amphetamines.  Amphetamines may do worse with people who are AA, but later studies did not replicate this.  It could be differences in study design.
  • Avoid chronic stress (stress hormones require COMT for degradation and compete with estrogens),

Catechol Estrogens, Cancer and Autoimmunity

Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones. Catechol estrogens can break DNA and cause cancer and autoimmune conditions. COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols). The products of COMT methylation are 2- and 4-o-methylethers, which are less harmful and excreted in the urine (they have anti-estrogen properties). However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working. 4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumour model, whereas 2-hydroxylated metabolites were without activity. 4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurination adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA. Estrone and estradiol are oxidized to a lesser amount to 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent .

It has been observed that tissue concentration of 4-hydroxyestradiol is highest in malignant cancer tissue, out of all the estrogens. The concentration of these Catechol Estrogens in the hypothalamus and pituitary are at least ten times higher than parent estrogens. Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary).

Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle-stimulating hormone (FSH) and prolactin. Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes.

Other possible mechanisms of inactivation of these catechol estrogens include conjugation by glucuronidation and sulphation. High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucuronide or sulfate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations. The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage. In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing an important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis. The abilities of the estrogens to induce DNA mutations were ranked as follows: 4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone.

Catechol-O-methyltransferase polymorphism is associated with increased uterine fibroid risk in different ethnic groups.

J Soc Gynecol Investig

Fibroids – uterine leiomyomas (ULMs) – are estrogen-dependent tumors that are more common in African American women. The aetiology for such ethnic disparity is currently unknown. Catechol-O-methyltransferase (COMT) is an essential enzyme in estrogen metabolism.

Women with the high-activity COMT genotype are 2.5 times more likely to develop ULMs than women with other genotypes. The prevalence of this genotype was significantly higher in African American women (47%) compared with white (19%) or Hispanic (30%) women. Myometrial cell lines expressing the Val/Val genotype exhibited significantly enhanced responses to estrogen in proliferation and in estrogen-responsive element reporter assays. COMT-specific inhibitors reversed such a response and induced apoptosis. Myometrial specimens from Val/Val women demonstrated distinct estrogen-regulated gene expression that was consistent with enhanced proliferation and decreased apoptosis.

The results provide a possible explanation for the higher prevalence of ULMs among African American women and offer a potential new target for nonsurgical treatment using COMT inhibitors.

Berberine inhibits the proliferation of human uterine fibroid cells

Fertil Steril.

Berberine inhibits the proliferation of human uterine fibroid cells

Treatment of fibroid cells with berberine inhibited cell proliferation by approximately 60%.

COX-2 is a critical enzyme that converts arachidonic acid into prostaglandin E2 (PGE2) and is commonly overexpressed in many solid tumors, including colorectal, breast, prostate, and ovarian neoplasms.

Increased expression of COX-2 and the associated PGE2 production have been demonstrated to significantly enhance carcinogenesis. Ke et al. reported that COX-2 expression was significantly up-regulated in uterine fibroids and that the inhibition of COX-2 activity significantly reduced the proliferation of the uterine fibroids smooth muscle cells, which suggests that COX-2 is involved in the pathogenesis of uterine fibroids.

In turn, berberine has been reported to induce cancer cell apoptosis and suppress cancer cell migration in many neoplastic cell lines, including melanoma, non–small cell lung cancer (40), and oral cancer, an effect mediated through the reduced expression of COX-2.

Consistent with these observations, our data indicate that BBR significantly reduced COX-2 expression in uterine cells, which suggests that COX-2 may also play a role in mediating BBR-induced apoptosis in human uterine cells.

Berberine inhibits the proliferation of human uterine fibroid cells

https://www.fertstert.org/article/S0015-0282(15)00047-3/pdf

Carbohydrate Intake and Risk of Metabolic Syndrome.

Pub Med

Metabolic syndrome is a cluster of conditions that occur together, including

  • increased blood pressure
  • high blood sugar
  • excess body fat around the waist, and
  • abnormal cholesterol or triglyceride levels.

Having just one of these conditions doesn’t mean you have metabolic syndrome but as you develop more of these conditions, your risk of complications such as type 2 diabetes and heart disease, rises higher and higher.

Research shows that the more carbohydrates you eat, the more likely you are to have metabolic syndrome:

  • for every 5% intake of energy from carbohydrates, the increase in the risk of metabolic syndrome goes up by 2.6%.

 

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Sandra Ishkanes
Functional Medicine Practitioner
BSc MA DipION

sandra@gynecologic.dream.press
Brighton, UK

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