Therefore, this study hypothesized that long-term dietary CLA ibalances enhances hormonap but has CLA and hormonal imbalances negative impact on male reproduction in rabbit bucks. Mouse estrous cycle identification tool and images. Results are expressed as ± s. Lauridsen C, Mu H, and Henckel P. Effects of Conjugated Linoleic Acid CLA on Hormones and Factors Involved in Murine Ovulation Vol. Ciarloni L, Mallepell S, Brisken C.

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Signs of Hormonal Imbalance in Women

CLA and hormonal imbalances -

isolated from intestine [ ] could efficiently produce 9-CLA from LA, probably though the mediation of VA in tissues or hydroxy octadeceinoic acid [ ], as occurring in ruminal biohydorgenation.

In addition to 9-CLA, Lactobacillus spp. also synthesizes CLA and trans -9, trans- CLA [ ]. From this, it is evident that a portion of LA in placebo oil would be biohydogenated by the bacteria residing in GI tract as in rumen into CLA through the mediation of VA.

Irrespective of this fact, most of the clinical studies use the aforesaid vegetable oils as placebo, neglecting their effects on human health; especially their supposed supplementary and complementary effects.

The dietary intake of the precursor VA was found to have some major effects on heart health, blood lipid profile and immunity, and also protective against fatal ischemic heart disease [ — ].

This would lead to the misinterpretation of the results, i. Therefore, during clinical studies, the composition of FA in placebo and its effects on human health need to be addressed with due respect, and independently for getting reliable results.

The clinical studies with CLA lack a common protocol for selecting the subjects. Description of the subjects including gender and age, medical treatments given prior to intervention are the critical factors to be considered while selecting the subjects.

Medical history of the subjects should also be recorded before concluding the safety and efficacy concerns of CLA consumption. In most of the studies, the subjects selected were categorized and designated as normal, healthy obese, with metabolic syndrome, with insulin resistance, etc.

This arbitrary classification for the convenience of the investigator poses a question i. Is it with the designation normal, obese, immune-compromised subjects with metabolic syndrome or with other diseases?

Another factor to be considered in clinical studies is the continental, racial and gender differences among the subjects; for instance, literature shows that most of the clinical studies on CLA were performed in North America and Europe.

The reproducibility of such results in racially and continently separated populations all over the world, especially in Asia, Africa and South America is another point of concern, which has to be verified before accepting the nutritional status of CLA in modulating biological functions.

Other factors of concern are the composition, dosage and duration of CLA consumption. If not otherwise stated, composition and purity of CLA are meant for 9- and 10 CLAs. Generally, human studies use a CLA mixture about of 9- and CLAs; and proportion of CLA isomers depends mainly on the nature of substrate, mode of synthesis production , physico-chemical parameters involved in synthesis, and purification strategies adopted [ , ].

Most of clinical studies evaluated the effects of CLA consumption for a short period, usually of 4—12 wk. But Gaullier et al. Generally, in these studies, CLA isomer or mixture dosages varied from 0. The dosage of CLA administration in humans is also very low, compared to animal studies in terms of body weight ; thus the results in pre-clinical animal studies high dose may not be comparable with the real clinical studies.

Therefore, CLA dose intake may be considered based on energy percentage. Two people with the same body weight may have a very different body composition e.

men; body builder vs. obese person , which in turn impacts the metabolism differently. Another crucial question is the retention of the so-called good effects for a long time; of course, one might expect that CLA should be consumed as if drugs are taken for chronic diseases.

Unlike in mechanistic in vitro studies, the criss-crossed signaling pathway through which CLA induce its effects has to be elucidated clearly in clinical studies. Moreover, the biological effects of individual CLA isomers, mainly 9- and CLA, their synergistic interactions and even the possible opposition between the isomers have to be unveiled.

Effect of CLA consumption along with various adjuncts is another area of clinical research that has to be studied evidently. Some studies showed the positive health benefits of CLA are related to heart health and body fat reduction on consumption along with calcium, VA, whey proteins and oryzanol [ 49 , 68 , ].

CLA consumption along with other PUFA was found to have protective effect against renal carcinoma [ ]. Therefore, an effective combination of CLA along with other supplements or with ω -3 FAs has to be addressed to reveal the possible real effects of CLA consumption on human health.

As far as the voluminous literature on CLA is concerned, only a few studies to date examined the effects of CLA in humans in vivo. However, results of these studies do not reflect the dramatic and consistent data demonstrated in animal studies.

Thus, these disappointing results in humans demand more precise experimentations with humans. The interest in CLA research still persists, and hence, many questions related to the safety and efficacy on the consumption CLA have to be answered scientifically.

Hence, it is imperative to critically evaluate and consolidate prominent findings on human consumption of CLA, i. One of the major limitations in human studies is that most of the studies depend only on the blood cells or plasma, and fat deposition. Thus, majority of the clinical studies failed to provide conclusive evidences for the effectiveness of CLA on human health, except for anti-obesitic properties which offered a little hope to prevent body weight regain though fat deposition, nevertheless increased oxidative stress and insulin resistance due to such over-consumption of CLA poses contradictory concerns.

Moreover, age, gender, genetic polymorphism and immune status of the subject, role of other nutrients present in the diet, and extend of absorption of individual isomers to different tissues have to be well addressed during the intervention period — so as to evaluate the safety and efficacy of CLA consumption on human health.

As far as human consumption of CLA is concerned, a definite conclusion for safety and efficacy has not been reached yet. At this context, we strongly recommend the need for more precise and well-designed long-term intervention studies with controlled food intake and activity level to assess the effectiveness of CLA on human health.

Moreover, such studies need to be duplicated in other laboratories giving emphasis to men and women, age group, ethnic background, food style, continental and even national uniqueness, cultural and geographic barriers, etc.

without comparing data from animal studies — i. In toto , clinical evidences indicate a possible link of supplemental CLA per se toward negative or inconclusive outcomes; thus, inclusion of CLA in the Codex Alimentarius Book of Food — which describes internationally recognized standards of food — may be considered.

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J Agric Food Chem , 52 16 : — Download references. The authors gratefully acknowledge the Department of Biotechnology DBT , Ministry of Science and Technology, Government of India, for a research grant No. Biotechnology Division, Department of Botany, Enzyme Technology Laboratory, University of Calicut, Kerala, , India.

School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, , USA. Department of Molecular Biosciences, University of Graz, Heinrichstrasse 31, , Graz, Austria. You can also search for this author in PubMed Google Scholar. Correspondence to Sailas Benjamin.

SB designed and wrote the manuscript, and contributed substantially to discussion, PP and SS collected literature and structured the reference, FS and AGW edited it with interpretation.

All authors read and approved the final manuscript. This article is published under license to BioMed Central Ltd. Reprints and permissions. Benjamin, S. et al. Pros and cons of CLA consumption: an insight from clinical evidences.

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they are not luteinized but LH responsive with high LH receptors. As studied in detail earlier, at this stage day 4 , if cells were treated with LH, LH downregulates almost all gene in the same fashion, as LH surge downregulates the gene in vivo Monga et al.

Considering these studies, we treated the cells up to day 4, as they exhibit phenotypic characteristic features of preovulatory follicle, which were subsequently followed by their tendency to get luteinized in the succeeding days. We are comparing this in vitro -standardized model with in vivo system that day 4 cultured cells have gene expression characteristic of a dominant follicle.

This stage of follicle undergoes subsequent transition from high proliferative and less steroidogenic to less proliferative and high steroidogenic form in response to LH, which is the trigger of ovulation and luteinization Mitwally et al.

In this phase, CYP19A1 expression goes down and PTEN level increases, which is a prerequisite for dominant follicle to ovulate. However, we cannot exactly correlate the present findings with the preovulatory follicle status in postpartum animal, as they are likely to differ in their proliferative potential and kind of lipid profile in follicular fluid, which further depend on the nutritional status of animal.

However, problem remains of sampling from the animals falling in the category of negative energy balance after first calving. Therefore, further studies using granulosa cells from these animals and also profiling their lipid composition in follicular fluid reveal detailed functional evaluation of exogenously administered or nutritionally supplemented CLA.

Polycystic ovarian syndrome PCOS is the leading cause of infertility and menstrual irregularities in women of reproductive age and is characterized by chronic hyperandrogenic anovulation Rimon et al.

This disorder is mainly characterized with instances of insulin resistance. Thiazolidinediones TZDs rosiglitazone or pioglitazone have been shown to improve insulin sensitivity in PCOS Ehrmann et al. TZDs are exogenous ligand of PPARG. Hereby, it can be suggested that natural dietary CLA can also be used as a substitute to these synthetic ligands, as rosiglitazone and pioglitazone are currently listed as a Pregnancy Category C drug i.

not tested for use during human pregnancy. Some side effects of TZD administration are weight gain, fluid retention Rubenstrunk et al. Present report demonstrates the serum-free cultured buffalo granulosa cell as a model to determine the functional significance of CLA in ovary.

These cells share the same characteristic features as shown by human ovarian granulosa cells. And hence, we can relate these studies with the mammalian system including human.

Therefore, a better experimental approach is required to clarify the role of CLA in fertility considering a lot many aspects of this molecule not only as a mixture but also as a individual isomer.

Moreover, PTEN and PPARG inhibitor studies symbolize that CLA takes PPARG-dependent pathway to execute its downstream signaling effects. However, PPARG-independent effects also cannot be denied completely as PUFAs are known to take PPAR-independent pathways Derecka et al. To the best of our knowledge, as proposed Fig.

These findings showed that CLA, therefore, can be a key regulatory molecule of granulosa cell functioning in preovulatory follicles.

Further studies are required to achieve detailed functional analysis of CLA in ovary during different pathophysiological conditions. CLA binds to nuclear receptor PPARG and induced its expression, which further increased the expression of PTEN and upregulated PTEN, which intervenes IGF1 signaling by two ways: A decreasing IGF1 mRNA and B dephosphorylating PIP3 to PIP2, which leads to downregulation of p-Akt.

Buffalo ovaries were collected from commercial abattoir, Delhi. Just after killing animals, ovaries were placed in chilled normal saline 0. Healthy developing follicles were assessed by the presence of vascularized theca externa and clear amber follicular fluid with no debris.

Cell number and viability were estimated in hemocytometer using trypan blue exclusion method. All the culture reagents were purchased from Sigma—Aldrich, Inc. Cells were seeded in well tissue culture plates Nunc, Roskilde, Denmark at a density of 2×10 5 viable cells in 1.

At this stage, cells were either left untreated or treated with different doses of CLA and antagonist GW as indicated in the figure legends.

In a similar set of experiments, for cell proliferation assay, cells were plated as in well plates, but other aspects of the experimental treatments remained the same. After treatment, spent media were removed and cells from triplicate wells were collected separately and pooled for immunoblotting of p-Akt and PTEN.

Growing cells were observed microscopically. Cell proliferation was assayed using Cell Titer 96 Aqueous One Solution Cell Proliferation Assay Promega as described earlier Murugan et al.

The absorbance was directly proportional to the number of living cells in culture. Each treatment for the assay was performed in triplicate. Total RNA was isolated using TRIzol Sigma—Aldrich Co.

The RNA was quantified using nanophotometer, and RNA integrity was evaluated by denaturing agarose gel electrophoresis. cDNA synthesis was performed using the first-strand cDNA synthesis kit Fermentas, St. Leon-Rot, Germany using random hexamer primers. The prepared cDNA was then analyzed using PCR.

Gene-specific primers were used for amplification Table 2. The primers were designed using NCBI database and the Primer 3 Software Whitehead Institute for Biomedical Research, Cambridge, MI, USA.

PTEN , phosphatase and tensin homolog deleted on chromosome 10; PPARG, peroxisome proliferator-activated receptor-γ; CYP19A1 , cytochrome P aromatase; IGF1 , insulin-like growth factor 1.

Melting peaks were determined using melting curve analysis in order to ensure the amplification and thus generation of single product. Also, agarose gel electrophoresis analysis 1.

Cloned PCR products were used to generate standard curves ranging over eight orders of magnitude 2. Quantification Software, March Weihenstephaner, Freising-Weihenstephaner, Germany. Amplification efficiency was determined from the slope of the log-linear portion of the calibration curve, i.

Copy number was calculated relative to the amount of RNA that was subjected to cDNA preparation. PCR reaction with all the PCR reagents other than the added cDNA was used as a negative control.

The concentration of E 2 was determined using ELISA Omega Diagnostics, Scotland, UK. The intra- and interassay coefficients of variation for E 2 assay were 3.

Each treatment was performed in triplicate upon each batch of cells and media from each well were assayed individually. Cells were washed with ice-cold PBS pH 7. Then, lysis buffer The cells were scraped from the culture wells into 1.

A chemiluminescent signal was generated using ECL reagent ECL, Pierce, Rockford, IL, USA and membranes were exposed to X-ray film Kodak biomax light film, Sigma.

The housekeeping gene β-actin was used as a positive loading control. Normal mouse IgG was used as a negative control. A one-way ANOVA test was performed to determine the effect of significance followed by Tukey's test to find out the significance of each effect level.

All experimental data were presented as the mean± s. All statistical analysis was performed using SAS System Software copyright , SAS Institute, Inc.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This work was supported by NDRI SRF Fellowship to I Sharma and Institute's laboratory contingency grant. The authors thank the Director of National Dairy Research Institute, Karnal, for providing necessary facilities for this work.

Journal of Dairy Science 62 — S 80 Belury MA Inhibition of carcinogenesis by conjugated linoleic acid: potential mechanisms of action. Journal of Nutritional Biochemistry — Immunology and Cell Biology 77 — Acta Pharmacologica Sinica 6 — Domestic Animal Endocrinology 38 — Molecular and Cellular Endocrinology 65 — Biochemical Society Transactions 29 — Journal of Clinical Endocrinology and Metabolism 82 — Molecular and Cellular Endocrinology — Molecular and Cellular Biology 19 — Biochemical and Biophysical Research Communications — Substrate specificity and inhibition of linoleate δ cis , δ trans -isomerase from Butyrivibrio fibrisolvens.

Journal of Biological Chemistry — Journal of Nutrition — Komar CM Peroxisome proliferator-activated receptors PPARs and ovarian function — implications for regulating steroidogenesis, differentiation, and tissue remodeling.

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Article Type: Research Article Online Publication Date: Sep Copyright: © Society for Reproduction and Fertility Free access. Download PDF. Check for updates. Abstract Conjugated linoleic acid CLA has drawn much interest in last two decades in the area ranging from anticancer activity to obesity.

Introduction Conjugated linoleic acid CLA is the common element that belongs to a group of C18 fatty acids with two double bonds exhibiting strong nutritional benefits in a variety of animal models Belury Results Inhibition of FSH- and IGF1-induced cell proliferation by CLA treatment Cell proliferation assay using 3- 4,5-dimethylthiazolyl -2,5-diphenyl tetrazolium bromide MTT was carried out in cells treated as described in the Materials and methods section.

Table 1 Cell proliferation assay. Treatment Absorbance Control 1. Dose- and time-dependent effect of CLA on PPARG and PTEN expression in primary cultured buffalo granulosa cell Dose- and time-dependent effect of CLA on the expression of PPARG and PTEN has been shown in Fig.

Figure 1 Effects of CLA on PPARG and PTEN transcripts level in cultured buffalo granulosa cell. Figure 2 Dose-dependent induction of PPARG and PTEN in cultured buffalo granulosa cells. Figure 3 Effect of CLA, FSH, IGF1, and GW on PPARG A and PTEN B transcripts in cultured buffalo granulosa cells.

Figure 4 Effect of CLA, FSH, IGF1, and GW on IGF1 A , CYP19A1 B , and GATA4 C transcripts in cultured buffalo granulosa cells. Figure 5 Effect of CLA on estradiolβ content. Figure 6 Phosphorylation of Akt and induction of PTEN in cultured buffalo granulosa cells.

Figure 7 Phosphorylation of Akt and induction of PTEN in cultured buffalo granulosa cells in vitro. Discussion In this study, we have demonstrated that CLA increased PTEN expression through activation of PPARG in granulosa cells, which further attenuated the phosphorylation of Akt and thereby regulating granulosa cell functioning proliferation and steroidogenesis.

Materials and Methods Collection of buffalo ovaries and isolation of granulosa cells Buffalo ovaries were collected from commercial abattoir, Delhi. Culture and treatment of granulosa cell All the culture reagents were purchased from Sigma—Aldrich, Inc.

Cell proliferation assay Growing cells were observed microscopically. RNA isolation and RT Total RNA was isolated using TRIzol Sigma—Aldrich Co. Table 2 Primer used for real-time PCR. Measurement of E 2 The concentration of E 2 was determined using ELISA Omega Diagnostics, Scotland, UK.

Immunoblotting Cells were washed with ice-cold PBS pH 7. Statistical analysis A one-way ANOVA test was performed to determine the effect of significance followed by Tukey's test to find out the significance of each effect level.

Conjugated linoleic acid Snd has drawn much interest imbalwnces last two imbslances in the area ranging from anticancer activity to CLA and hormonal imbalances. A ibalances of research papers have been published recently hor,onal CLA and hormonal imbalances to Imba,ances additional biological Beetroot juice benefits as reproductive benefits. However, not much is known how this mixture of isomeric compounds mediates its beneficial effects particularly on fertility. In this study, we demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i. FSH and IGF1, on buffalo granulosa cell function proliferation and steroidogenesis. Western blot analysis of total cell lysates revealed that CLA intervenes the IGF1 signaling by decreasing p-Akt. In addition, CLA was found to upregulate peroxisome proliferator-activated receptor-gamma PPARG and phosphatase and tensin homolog PTEN level in granulosa cells.