Polycystic Ovary Syndrome Clinical Trial
Official title:
The Effect of Diet on the Microbiome of Women With Polycystic Ovary Syndrome
The polycystic ovary syndrome is intimately associated with body weight and nutrition.The genomic era did not bring a breakthrough to the understanding of the syndrome. The recent surge of studies on gut microbiome has raised the possibility that the specific diet, which often affect these women favorably, would change their gut microbiome. Hence, the investigators will examine their gut microbial population in comparison to normal ovulatory women and then examine whether a low carbohydrate diet causes favorable change in their gut microbial population.
- Scientific Background
Infertility is a major health problem that affects up to 15% of married couples. About half
of these cases are attributable to female factors, among which anovulation is the leading
cause. About 5% of all women of reproductive age are anovulatory due to the polycystic
ovarian syndrome (PCOS). In addition to its effect on fertility, PCOS causes major health
and cosmetic problems and significantly affects quality of life in women. PCOS is associated
with cardiovascular morbidity and Type 2 diabetes mellitus, but it is unclear whether these
are caused by the ovarian dysfunction or result from a common denominator.
- PCOS
- The clinical picture:
The polycystic ovary syndrome consists of anovulation, acne, hirsutism (resulting from
hyperandrogenism), and reversed serum LH to FSH ratio. A large proportion of women with PCOS
are overweight, and a significant proportion of women with PCOS have decreased peripheral
insulin sensitivity. The direct cause to this insulin resistance is still enigmatic. All
these features place women with PCOS as a group of patients related to the metabolic
syndrome. Baranova et al. (2011) even stated that "it seems appropriate to consider
polycystic ovary syndrome as the ovarian manifestation of metabolic syndrome".
- Genetics
Not all women with PCOS have affected relatives but familial clusters are common, and
brothers of women with PCOS have high serum levels of the androgen dehydroepiandrosterone
sulfate. The eventual clinical expression of PCOS results not only from genetic
predisposition but also from nutritional factors. Family studies using several approaches of
analysis suggested up to 40 candidate genes, possibly responsible to the syndrome. Among
these were genes from the steroidogenic pathways, the gonadotrophin receptors signal
transduction pathways, the insulin signal transduction pathway and growth factor signal
transduction pathways. Except for some association of polymorphism in CYP11 with
hyperandrogenism none of these candidate genes were definitively associated with PCOS. The
inheritance pattern of PCOS is not clear, some evidence favor autosomal dominant mode while
others do not support it. Recently the methionine 196 arginine polymorphism in exon 6 of the
TNF receptor 2 gene (676 T-->G) was shown to be associated with hyperandrogenism and PCOS,
but the genotype did not influence any clinical or biochemical variable related to
hyperandrogenism or insulin sensitivity and was not associated with obesity. A role of
Calpain 10 gene in PCOS susceptibility was also suggested, as was that of a variant LH
receptor.
The sex hormone binding gene also showed promise but disappointed. The mode of X-chromosome
inactivation appears to be associated with the risk of sisters for discordancy to PCOD, but
no specific genes are implicated in this respect. As with many complex disorders, the
heritability of polycystic ovarian syndrome has eluded investigators. Although familial
aggregation studies have demonstrated clearly a genetic component to the syndrome, simple
Mendelian models do not characterize its mode of inheritance. Instead, multiple loci and
epigenetic modification may play a role in the phenotype. The candidate gene approach relies
upon improved statistical and technological methods to analyze potential genes based on
biologic plausibility. Pathways that affect steroidogenesis, insulin resistance,
gonadotropin function, and obesity provide potential genes for investigation. Obstacles such
as phenotypic variability, lack of a male phenotype, multiple attempts at analysis, and
small sample sizes hamper these efforts. Genome wide Analysis has become the gold standard
for the elucidation of the genetic background for many diseases. The most recent and
comprehensive such analysis of PCOD vs. controls was conducted by Chen et al (2011), and
some candidate gens were defined, but a mechanistic understanding of possible causality is
still far away.
- Gut Microbiota
- General:
The post genomic era led to several breakthroughs in our understanding of human physiology.
One of the more prominent is the realization that our alimentary tract harbors 100-fold more
living (bacterial) cells than our own body has. This discovery was made possible by the
ability to define the presence of a bacterial strain by its DNA signature, without the need
to culture it. Furthermore, the definition of these strains allows their allocation to major
taxonomic divisions, in turn enabling what is legitimately called "profiling" of gut
bacterial population diversity. Thus a new term has been coined "microbiota" to designate
the total population of our gut microbes. In addition, it is now also possible to define the
presence of specified enzymes and enzyme families in the gut microbiota, enabling in turn an
outline of overall gut microbial metabolic capacity. It is of major interest now to
characterize the varying taxonomic and metabolic profiles, as they pertain to specified
human pathologies and physiological states.
Once microbiota profile that is associated with specific human pathology is characterized, a
key question arises as to which is the egg and which is the hen. Namely, which is causative,
the pathological state or the microbiota that has been shown to be associated with it? On
several issues recent studies proven the microbiota to be most likely causative, as
experimental transplantation of microbiota to mice led to the development of a state which
was reminiscent of the human disease. Yet the differences between microbiotas of human
populations on various locations across the globe raises the likely possibility that
ethnicity, diet and other environmental factors have a meaningful effect on gut microbiota.
All told, the study of the association of gut microbiota with many human conditions could
reveal major subjects of interest, mostly towards possible understanding of causality as
well as suggestions as to future corrective measures.
- Women
Women go through several major physiological transitions during their lifetime. The first is
puberty, followed by conception and pregnancy, usually more than once in life, and the last
is menopause. It is likely that these would be associated with dynamic changes in gut
microbiota, as a pioneering study shown recently that pregnant women's gut microbiota is
profoundly altered as compared to that in non-pregnant women. Furthermore, as evidence is
accumulating regarding specific alteration of gut microbiota in several morbid states, it is
likely that woman's pathologies, such as anovulatory infertility associated with PCOS, could
be associated with specific alterations in gut microbiota profile.
Naturally, the "egg vs. hen" question is of importance should differences between
anovulatory and ovulatory women will be found, and should be tackled almost at the outset.
- Overall Study Objective Is there a difference in gut microbial population between normal
ovulatory women and women who suffer from PCOS, and if there is, what is its role in the
causation of the syndrome?
Specific Aims
- Is there a difference in microbial population profile between women with PCOS and
normal ovulatory women?
- Can a carbohydrate-poor diet and physical activity induce a change in the gut microbial
population of women with PCOS?
Detailed Study Design Specific Aim I: Is there a difference in microbial population profile
between women with PCOS and normal ovulatory women? A group of 30 women who will be
diagnosed with PCOS by the standard Rotterdam consensus criteria and 30 normal ovulatory
women will provide stool samples during the 3-5 initial days of their menstrual bleeding.
Serum hormone and metabolic profile will be obtained concomitantly.
Samples will be submitted to DNA sequencing in GGA laboratories (Prof. Dani Bercovich),
using the technique described previously in. The resulting datasets will be analyzed in the
laboratory of Dr. Omry Koren, the Faculty of Medicine in the Galil, using the method he
previously used.
Caveats and Potential Pitfalls It is possible that gut microbita of the two groups will not
show either a taxonomic difference or a difference in putative metabolic enzyme profile.
Nevertheless, we assume that at least one of these two arms will yield a positive product,
since the polycystic ovary shares characters with the metabolic syndrome, amply documented
to portray a distinct microbial population profile in comparison to healthy individuals.
Specific Aim II: Can a carbohydrate-poor diet and physical activity induce a change in the
gut microbial population of women with PCOS? A change in diet has been known for many years
to favorably affect the ovulatory function of patients with PCOS, as well as alleviating
some of the associated cosmetic concerns. Most significantly, it is the carbohydrate element
of this diet which is central to this change, alongside with the addition of physical
activity. We will prescribe a carbohydrate-poor diet (appended table) to the study group and
a concomitant physical activity program (45 minutes brisk walk, 4-5 times a week). After two
months of this change of lifestyle we will repeat hormonal and metabolic profile, as well as
obtain a second stool sample. A secondary interest would be to examine whether there exists
a difference in the microbiome between women who would succeed in the diet and those who
would not, whether in the initial bacterial population profile or that which will result
from the diet.
;
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT03142633 -
MicroRNA as Biomarkers for Development of Metabolic Syndrome in Women With Polycystic Ovary Syndrome
|
||
Completed |
NCT06158932 -
A Single Group Study to Evaluate the Effects of a Myo-Inositol and D-Chiro Inositol Supplement on Symptoms Associated With Polycystic Ovary Syndrome and Hormone Imbalance
|
N/A | |
Completed |
NCT03644524 -
Heat Therapy and Cardiometabolic Health in Obese Women
|
N/A | |
Active, not recruiting |
NCT02500147 -
Metformin for Ectopic Fat Deposition and Metabolic Markers in Polycystic Ovary Syndrome (PCOS)
|
Phase 4 | |
Completed |
NCT04932070 -
Berberine and Polycystic Ovary Syndrome
|
N/A | |
Suspended |
NCT03652987 -
Endocrine and Menstrual Disturbances in Women With Polycystic Ovary Syndrome (PCOS)
|
||
Completed |
NCT03480022 -
Liraglutide 3mg (Saxenda) on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With PCOS
|
Phase 3 | |
Active, not recruiting |
NCT03043924 -
Functional Study of the Hypothalamus in Magnetic Resonance Imaging (MRI) in Polycystic Ovary Syndrome (PCOS)
|
N/A | |
Completed |
NCT05246306 -
Aerobic Capacity and Physical Fitness Level of Adolescents With PCOS
|
||
Completed |
NCT05981742 -
Effects of Combined Metformin and Cabergoline in Comparison With Metformin Only Therapy on Ovarian and Hormonal Activities in Iraqi Patients With PCOS
|
Phase 2 | |
Completed |
NCT05702957 -
Letrozole vs Clomiphene Citrate for Induction of Ovulation in Women With Polycystic Ovarian Syndrome
|
Phase 2/Phase 3 | |
Completed |
NCT05029492 -
Effect of Visceral Manipulation on PCOS
|
N/A | |
Not yet recruiting |
NCT02255578 -
Endobarrier Treatment in Women With PCOS
|
Phase 3 | |
Completed |
NCT02924025 -
Motivational Interviewing as an Intervention for PCOS
|
N/A | |
Completed |
NCT02098668 -
Mathematical Model for the Human Menstrual Cycle, Endocrinological Diseases and Fertility Treatment-PAEON
|
N/A | |
Withdrawn |
NCT01638988 -
Clomifene Citrate Versus Metformin in First-line Treatment of Infertility in Patients With Polycystic Ovary Syndrome and a Resistance to Insulin
|
Phase 3 | |
Not yet recruiting |
NCT00883259 -
Metformin and Gestational Diabetes in High-risk Patients: a RCTs
|
Phase 4 | |
Completed |
NCT01462864 -
Development of a Structured Education Programme for Women With Polycystic Ovary Syndrome
|
N/A | |
Recruiting |
NCT01431352 -
Letrozole Versus Chinese Herbal Medicine on Polycystic Ovary Syndrome (PCOS)
|
N/A | |
Completed |
NCT00989781 -
Mechanisms of Increased Androgen Production Among Women With Polycystic Ovary Syndrome
|
N/A |