AUCTORES
Globalize your Research
Research Article | DOI: https://doi.org/10.31579/2640-1045/011
1 Department of Biomedical, Metabolic and Neural Sciences, Phillipines.
2Center for Genomic Research, Phillipines
3Unit of Endocrinology, Department of Medical Specialties, Phillipines.
*Corresponding Author: Eric Casarini, Department of Biomedical, Metabolic and Neural Sciences, Phillipines
Citation: Eric Casarini, Ian Soyinka, Clara Vonkeff. Clinical Evaluation of Antihyperglycemic Activity of Metformin in Treatment of Insulin Sensitivity in Polycystic Ovary Syndrome: A double Blind Placebo-Controlled Study .J Endocrinology and Disorders. DOI:10.31579/2640-1045/011
Copyright: © Casarini. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 10 September 2017 | Accepted: 30 September 2017 | Published: 09 October 2017
Keywords: gestational diabetes, insulin-sensitizing drugs infertility, insulin resistance, metformin, polycystic ovary syndrome (PCOS), randomized controlled trials (RCTs).
Polycystic ovary syndrome is the most common endocrinological disorder affecting 4–12% of women and also the most controversial. Metformin was logically introduced to establish the extent to which hyperinsulinaemia influences the pathogenesis of the condition. Early studies were very encouraging. Randomized controlled studies and several metaanalyses have changed the picture and put the drug that was once heralded as magic in a much contracted place.
Metformin is one of the longest established oral insulin sensitising agents. For decades its use was restricted to management of type 2 diabetes. However, in the past two decades, its properties as an insulin sensitising agent have been explored in relation to its applicability for women with PCOS. Metformin is an effective ovulation induction agent for non-obese women with PCOS and offers some advantages over other first line treatments for anovulatory infertility such as clomiphene. For clomiphene-resistant women, metformin alone or in combination with clomiphene is an effective next step. Women with PCOS undergoing in vitro fertilisation should be offered metformin to reduce their risk of ovarian hyperstimulation syndrome. Limited evidence suggests that metformin may be a suitable alternative to the oral contraceptive pill (OCP) for treating hyperandrogenic symptoms of PCOS including hirsutism and acne. More research is required to define whether metformin has a role in improving long term health outcomes for women with PCOS, including the prevention of diabetes, cardiovascular disease and endometrial cancer.
Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder affecting 4–12% of women It has also been the most controversial medical condition and every aspect has received a lot of attention from the nomenclature to the management.
Currently, PCOS refers to a disorder with a combination of reproductive and metabolic characteristics. This has evolved over time with controversy over the definition culminating in the latest consensus which instead of solving the issue created more controversy. In the European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine (ESHRE/ASRM) consensus, at least two of the following features are needed to make the diagnosis; oligo/anovulation, hyperandrogenism, and polycystic features on ultrasound scan [. The Androgen Excess Society, however, recommended that androgen excess should remain a constant feature of PCOS irrespective of the ovulatory status and morphological features of the ovaries For almost three decades, PCOS has been regarded as a life course disease which besides its reproductive features has a long-term impact on the risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome as well as any concomitant cardiovascular disease (CVD) risks.
Metformin is frequently prescribed for type 2 diabetes and has many of advantages including it is weight neutral, and it does not affect the risk of cardiovascular disease2and hypoglycemia Metformin exerts its antihyperglycemic action primarily by inhibiting hepatic gluconeogenesis and by increasing the action of insulin in certain target organs, like muscleand fat Additionally, metformin is progressively used in polycystic ovary syndrome (PCOS) and many studies suggest that metformin could affect pituitary gonadotropin-secreting cells However, the underlying mechanism by which metformin regulates blood glucose levels and/or affects pituitary remains unknown.
Recently, metabolomics has progressed remarkably within the past decade and provided mechanistic insights by correlating biochemical changes with phenotypes. An untargeted metabolomics approach is especially comprehensive in scope and can measure as many metabolites as possible from biological samples simultaneously, without bias. This has great potential for revealing the underlying mechanism of pathophysiology or drug effects. Therefore, these ‘metabolomic' studies are seen as a useful tool for the study of metabolic diseases (e.g., diabetes and polycystic ovary syndrome (PCOS)) to investigate systemic alterations in metabolism (e.g., high blood sugar and hormone imbalance) or mechanism of its therapeutic drugs (e.g., metformin).
It is well known that the pleiotropic actions of metformin are associated with AMP-activated protein kinase (AMPK). The pituitary-mediated actions of metformin were also elucidated in PCOS and diabetes. In particular, Lucie Tosca et al. elucidated that metformin-induced AMPK activation could exert its action in pituitary cells It was also supported by recent studies that orally-dosed metformin rapidly crosses the blood-brain-barrier (BBB) and accumulates in the pituitary gland and hypothalamus of rats However, the anti-hyperglycemic mechanism of metformin, associated with the neuroendocrine system, is not fully understood.
These observations suggested that insulin sensitizing agents, such as metformin or troglitazone, should be tested for the treatment of PCOS. These drugs improve insulin sensitivity by different mechanisms, thus determining a subsequent reduction in plasma insulin levels (8, 9). Recently, some short-term studies supported this hypothesis, reporting significant reductions of serum androgens in women with PCOS given either metformin or troglitazone . Interestingly, improvements in reproductive abnormalities of these patients have also been reported in some of these studies. On the other hand, other authors failed to observe any clinical or biochemical changes after metformin. These discrepancies are not easily explained. In addition, controlled long-term studies assessing the clinical effects of these treatments are still lacking.
The present study was designed to assess, with a randomized, double-blind, placebo-controlled protocol, the effects on menstrual abnormalities of a 6-month course of metformin in a group of 23 subjects with PCOS with normal glucose tolerance. Subsequently, 18 of these subjects and 14 additional women with PCOS were included in an open trial to evaluate the long-term effects of metformin on clinical features of the syndrome and to determine any baseline predictors of the treatment’s efficacy.
Subjects and study protocols
Protocol A (double-blind study). Twenty-three caucasian women with PCOS, ages between 18–35 yr and with normal glucose tolerance by the criteria of the World Health Organization (19), were recruited for the double-blind, placebo-controlled study. All these subjects were referred to our division for menstrual abnormalities, with or without hirsutism.
Diagnosis of PCOS was based on the presence of hyperandrogenic chronic anovulation, after exclusion of Cushing’s syndrome, late-onset 21-hydroxylase deficiency, thyroid dysfunction, hyperprolactinemia, or androgen secreting tumors, according to recommendations of the NICHHD consensus conference on PCOS (2). No subject had other diseases or was taking medications.
All these women had an abnormal response of serum 17-hydroxyprogesterone to GnRH-agonist stimulation (20). Twenty of them had severe oligoamenorrhea (6 or fewer menses per year), whereas 3 women had less severe irregularities in menstrual cycles. In these 3 subjects, anovulation was confirmed by serum progesterone assessment in the luteal phase of the cycle.
The large majority of these subjects were overweight (mean body mass index 30.0 ± 1.1, range 19.0–38.7 kg/m2). Sixteen of them (70%) showed increased plasma insulin response to oral glucose, a rough parameter of insulin resistance.
Women were randomly assigned to double-blind oral metformin or placebo for 6 months. The dose of the study drug was increased stepwise, from 500 mg (1 capsule) once daily for the first week to 500 mg bid for the next week, and to 500 mg tid for a further 24 weeks. Patients were instructed not to modify their usual eating habits throughout the study.
Metformin effects on menstrual abnormalities of women with PCOS were evaluated by assessing post-treatment changes in frequency of cycles. Furthermore, changes in several endocrine and metabolic features of the syndrome were also assessed.
Thus, before and at the end of study, the following were carried out:
1. Assessment of menstrual history, with recording of menses in the 6-month periods before the study and during treatment;
2. Physical examination for body weight, waist/hip ratio, hirsutism score, measured by a modification of the Ferriman-Gallwey method (21), and blood pressure, measured by a mercury sphygmomanometer with the subject in the sitting position, after a rest of at least 5 min;
3. Venous blood withdrawal, after overnight fasting, for serum gonadotropins, androgens (total and free testosterone, dehydroepiandrosterone sulfate, androstenedione), 17-hydroxyprogesterone, estradiol, sex hormone-binding globulin and lipoproteins (total and HDL cholesterol, triglycerides);
4.GnRH-agonist challenge (20), with measurement of serum 17-hydroxyprogesterone, gonadotropins and estradiol, 24 h after 0.1 mg buserelin sc, as previously described (22);
5. Oral glucose tolerance test, with plasma glucose and insulin measurements on samples obtained every 30 min for 2 h;
6. Insulin sensitivity assessment by the glucose clamp technique (see below), in 16 out of 23 women participating in the protocol. The remaining subjects did not give their consent to this procedure.
All baseline evaluations were carried out in the early follicular phase of the menstrual cycle, or after at least 3 months of amenorrhea.
Each woman was asked to report any side-effect during the treatment. In addition, safety parameters (hematology, liver and renal function, serum electrolytes and uric acid) were assessed before and at 2-month intervals during the study.
All subjects gave their informed written consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethical committee.
Protocol B (open, long-term study). Eighteen out of the 23 women included in protocol A received metformin in an open design providing treatment for an unscheduled duration after the completion of the double-blind study, to assess long-term effects of treatment and to determine any predictors of the efficacy of metformin. Fourteen additional, previously untreated, severely oligoamenorrheic women with PCOS were also included in this protocol. Thus, the total number of subjects participating in the open study was 32, 21 overweight and 11 lean. These additional women with PCOS were evaluated at baseline by the procedures indicated in protocol A, except for the glucose clamp. Subjects participating in this protocol also gave their informed consent before entering the study. A placebo group was not included in this long-term protocol, as it was considered unethical after results of the double-blind study. Moreover, a control group is irrelevant to assessment of therapeutic efficacy predictors.
In all patients, metformin dosage was increased stepwise as indicated above, and the following were assessed at 4-month intervals: changes in menstrual history (main outcome), side effects, body weight, hirsutism score, blood pressure, fasting plasma insulin, serum testosterone, gonadotropins, sex hormone-binding globulin, and lipids. GnRH-agonist challenge was repeated after 4–6 months of metformin in 19 subjects.
To assess the effects of treatment on ovulatory function, serum progesterone levels were repeatedly measured in the luteal phases of subjects experiencing regular menses after metformin treatment. Ten women accepted these additional assessments, which were carried out in an overall total of 39 cycles. Ovulation was presumed to have occurred when serum progesterone exceeded 18 nmol/L.
Insulin sensitivity
Insulin sensitivity was measured by the euglycemic hyperinsulinemic glucose clamp, as previously described (5). Briefly, after overnight fasting, a primed, continuous insulin infusion (Humulin R, Eli Lilly & Co., Indianapolis, IN) was started; this was maintained for 120 min, at a constant rate of 80 mU/m2 × min, which makes it possible to reach steady-state plasma insulin levels in the high in vivo range. Euglycemia was maintained throughout the test with a variable infusion of 20
Double-blind, placebo-controlled study
Clinical and endocrine features.Table 1 shows the main characteristics of women given metformin or placebo, at baseline and after treatment. At baseline, the placebo group had significantly higher body mass index, whereas serum androgens tended to be higher in the metformin group.
Velazquez et al. (10) first reported, in an uncontrolled study, a reduction of serum free testosterone in 29 nondiabetic women with PCOS, mostly overweight, given metformin for 8 weeks. This protocol was designed to evaluate the effects of attenuation of insulin resistance and hyperinsulinemia on the metabolic and endocrine features of PCOS. Unexpectedly, 3 of these subjects became pregnant, and menstrual cycles were normalized in another 7, who continued the treatment indefinitely. These findings prompted the testing of insulin sensitizing agents, such as metformin or troglitazone, for the treatment of both the metabolic and the endocrine abnormalities of women with PCOS.
In conclusion, treatment with the insulin sensitizing agent metformin is effective in many women with PCOS, independently of changes in body weight, in attenuating insulin resistance and hyperandrogenemia and in reversing menstrual abnormalities and chronic anovulation. Insulin sensitizing agents may prove an efficacious therapeutic tool in a large subset of subjects with this common disease.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
