THERAPEUTIC USE OF RESVERATROL IN THE TREATMENT OF NEUROLOGICAL AND ENDOCRINOLOGICAL PATIENTS.

The article represents the data characterizing the use of resveratrol in the treatment of various diseases, including endocrinological and neurological. It was shown that resveratrol is widely used in the treatment of various diseases due to its ability to actively suppress the inflammatory process. At the same time, in autoimmune diseases resveratrol inhibits the function of the entire population of T-cells, but when it comes to the neoplastic process, it only inhibits the activity of a subpopulation of T-cells (Treg). Thus, resveratrol can be recommended in the treatment of any diseases associated with the activation of the T-cell immunity.

Novel Role of the SIRT1 in Endocrine and Metabolic Diseases.

Silent information regulator 1 (SIRT1), a highly conserved NAD+-dependent deacetylase, is a cellular regulator that has received extensive attention in recent years and regarded as a sensor of cellular energy and metabolism. The accumulated evidence suggests that SIRT1 is involved in the development of endocrine and metabolic diseases. In a variety of organisms, SIRT1 regulates gene expression through the deacetylation of histone, transcription factors, and lysine residues of other modified proteins including several metabolic and endocrine signal transcription factors, thereby enhancing the therapeutic effects of endocrine and metabolic diseases. These evidences indicate that targeting SIRT1 has promising applications in the treatment of endocrine and metabolic diseases. This review focuses on the role of SIRT1 in endocrine and metabolic diseases. First, we describe the background and structure of SIRT1. Then, we outline the role of SIRT1 in endocrine and metabolic diseases such as hyperuricemia, diabetes, hypertension, hyperlipidemia, osteoporosis, and polycystic ovarian syndrome. Subsequently, the SIRT1 agonists and inhibitors in the above diseases are summarized and future research directions are proposed. Overall, the information presents here may highlight the potential of SIRT1 as a future biomarker and therapeutic target for endocrine and metabolic diseases.

Growth and Growth Hormone through the Ages: Art and Science.

BACKGROUND: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. SUMMARY: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. KEY MESSAGES: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

Real-World Experience of Monitoring Practice of Endocrinopathies Associated with the Use of Novel Targeted Therapies among Patients with Solid Tumors.

BACKGROUND: Cancer treatments have gradually evolved into targeted molecular therapies characterized by a unique mechanism of action instead of non-specific cytotoxic chemotherapies. However, they have unique safety concerns. For instance, endocrinopathies, which are defined as unfavorable metabolic alterations including thyroid disorders, hyperglycemia, dyslipidemia, and adrenal insufficiency necessitate additional monitoring. The aim of this study was to assess the prevalence of monitoring errors and develop strategies for monitoring cancer patients who receive targeted therapies. METHOD: A retrospective chart review was used to assess the prevalence of monitoring errors of endocrinopathies among cancer patients who received targeted therapies over one year. All of the adult cancer patients diagnosed with a solid tumor who received targeted therapies were included. The primary outcome was to determine the prevalence of monitoring errors of endocrinopathies. The secondary outcomes were to assess the incidences of endocrinopathies and referral practice to endocrinology services. RESULTS: A total of 128 adult patients with solid tumors were involved. The primary outcome revealed a total of 148 monitoring errors of endocrinopathies. Monitoring errors of the lipid profile and thyroid functions were the most common error types in 94% and 92.6% of the patients treated with novel targeted therapies, respectively. Subsequently, 57% of the monitoring errors in the blood glucose measures were identified. Targeted therapies caused 63 events of endocrinopathies, hyperglycemia in 32% of the patients, thyroid disorders in 15.6% of them and dyslipidemia in 1.5% of the patients. CONCLUSION: Our study showed a high prevalence of monitoring errors among the cancer patients who received targeted therapies which led to endocrinopathies. It emphasizes the importance of adhering to monitoring strategies and following up on the appropriate referral process.

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

Combined Therapy with Ixazomib, Lenalidomide, and Dexamethasone for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome.

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report.

BACKGROUND: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. CASE PRESENTATION: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 µg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. CONCLUSION: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.

[Endocrinopathies Associated with Immune Checkpoint Inhibitors]. / Endocrinopatias Associadas ao Tratamento com Inibidores do Checkpoint Imunológico.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that increase the efficiency of the immune system in the destruction of neoplastic cells. In recent years, these drugs have been increasingly used in the treatment of many neoplasms in advanced stages. However, the change in the regulation of the immune system induced by these drugs has the potential adverse effect of inducing autoimmunity in practically all organ systems. Endocrinopathies are one of the most common autoimmune adverse eventsof these drugs. MATERIAL AND METHODS: Non-systematic review of endocrinopathies reported in the context of treatment with ICIs. A search was carried out on PubMed until January 31st, 2020, and articles were selected based on their relevance and excluded in case of redundant content. The following search terms were used: "immune checkpoint inhibitor" and "endocrinopathy" / "endocrine system diseases" / "pituitary" / "thyroid" / "diabetes" / "adrenal" / "parathyroid". RESULTS: Endocrinopathies with all classes of ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) have been reported. Thyroid dysfunction is the most frequently reported endocrinopathy, mainly with anti-PD-1 and anti-PD-L1. Hypophysitis is the most prevalent with anti-CTLA-4. The incidence of autoimmune diabetes in this context is increasing, mainly with anti-PD-1 and anti-PD-L1. Rare cases of primary adrenal insufficiency, Graves' disease and primary hypoparathyroidism have also been reported. CONCLUSION: Knowing the spectrum of endocrinopathies triggered by ICI, as well as their clinical features, diagnosis and treatment criteria is essential, given its high prevalence and the increasing number of cancer patients treated with these new drugs.

Introdução: Os inibidores do checkpoint imunológico (ICI) são anticorpos monoclonais que permitem aumentar a eficiência do sistema imunitário na destruição das células neoplásicas. Nos últimos anos, estes fármacos têm sido cada vez mais utilizados no tratamento de muitas neoplasias em estadios avançados. Contudo, a alteração da regulação do sistema imunitário induzida por estes fármacos tem como potencial efeito adverso o aparecimento de autoimunidade em praticamente todos os órgãos. As endocrinopatias são um dos eventos adversos autoimunes mais frequentes com estes fármacos.Material e Métodos: Revisão não sistemática sobre as endocrinopatias reportadas em contexto de tratamento com ICI. Foram pesquisados artigos publicados na PubMed até 31 de janeiro de 2020, selecionados com base na sua relevância e excluídos em caso de conteúdo redundante. Foram utilizados os seguintes termos de pesquisa: "immune checkpoint inhibitor" e "endocrinopathy" / "endocrine system diseases" / "pituitary" / "thyroid" / "diabetes" / "adrenal" / "parathyroid".Resultados: Foram já reportadas endocrinopatias com todas as classes de ICI (anti-CTLA-4, anti-PD-1, anti-PD-L1). A disfunção tiroideia é a endocrinopatia mais frequentemente reportada, principalmente sob anti-PD-1 e anti-PD-L1. A hipofisite é a mais prevalente sob anti-CTLA-4. É crescente a incidência de diabetes autoimune neste contexto, principalmente sob anti-PD-1 e anti-PD-L1. Foram reportados também casos raros de insuficiência suprarrenal primária, doença de Graves e hipoparatiroidismo primário.Conclusão: O conhecimento do espectro de endocrinopatias desencadeadas pela terapêutica com ICI, assim como as suas manifestações clínicas, critérios de diagnóstico e tratamento, é essencial, dada a sua elevada prevalência e o cada vez maior número de doentes oncológicos tratados com estes novos fármacos.

MANAGEMENT OF ENDOCRINE DISEASE: Papillary thyroid microcarcinoma: toward an active surveillance strategy.

In the last decades, the incidence of thyroid cancer (TC) has more than doubled, but the disease-specific mortality rate was stable. To date, 30-40% of all TC is represented by papillary microcarcinomas (mPTC), an indolent tumor, that probably remained undiagnosed before routine ultrasound use. In 1993, Miyauchi was the first who hypothesized a conservative approach for low-risk mPTC and introduced the concept of active surveillance (AS) in its clinical management. The progression rate of mPTC during AS was low and delaying surgery did not impact the efficacy of treatment or outcome. Since then, several authors from all over the world have reported their experience of AS in mPTCs. As suggested by current guidelines, AS can be considered as an alternative to immediate surgery to avoid overtreatment in low-risk mPTC and may be the strategy to avoid complications from unnecessary surgery. In the last years, AS inclusion criteria have been extended to both bigger tumors and to younger/healthier patients. The adoption of AS should take into consideration not only tumor characteristics but also patient psychological profiles and medical team expertise. Its safety and efficacy have been demonstrated in long-term outcome studies and in other types of tumors; however, skepticism in patients, families and physicians should be overcome by strong recommendations coming from scientific guidelines. This review analyses the several and different experiences of AS and the potential obstacles in implementing it as a routine approach in mPTC patients.

Changes in clinical trials of endocrine disorder and metabolism and nutrition disorder drugs in mainland China over 2010-2019.

With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self-evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.

Diagnosis and management of secondary causes of steatohepatitis.

The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.

The side effects of immune checkpoint inhibitor therapy on the endocrine system.

Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte-associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary-adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary-adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.

DIAGNOSIS OF ENDOCRINE DISEASE: Sex steroid action in adolescence: too much, too little; too early, too late.

ABSTRACT: This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient's motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

MANAGEMENT OF ENDOCRINE DISEASE: Male osteoporosis: diagnosis and management - should the treatment and the target be the same as for female osteoporosis?

Male osteoporosis has been neglected for too long time and there is need for a change. This condition is clearly under-estimated, under-diagnosed and under-treated. The diagnosis is often made late in the natural history of the pathology or even after a fracture event. Guidelines on screening politics do not agree whether and when men should be considered, and clinical trials are far less performed in men with respect to women. Actually, most of our knowledge on male osteoporosis, especially regarding treatment, is extrapolate from the female counterpart. Male osteoporosis is frequently secondary to other conditions and often associated with comorbidities. Therefore, identification of specific causes of male osteoporosis is essential to drive a correct and personalized treatment. Moreover, men have more osteoporosis-related complications and higher mortality rate associated with fractures. Furthermore, not only fewer men receive a correct and timely diagnosis, but also fewer men receive adequate treatment, and adherence to therapy is far less in men than in women. Of note, very few studies assessed the effect of antiosteoporotic treatments in men and most of them considered only bone density as primary endpoint. This review focuses on the areas that are still nebulous in male osteoporosis field, from identification of subjects who need to be evaluated for osteoporosis and screening programs dealing with primary prevention to diagnostic procedures for good estimates of bone quantity and quality and precise calculation of fracture risk and personalized treatment that take into account the pathophysiology of osteoporosis.

Management of endocrine conditions at the end of life.

An important facet to end-of-life care is deprescribing. This can be challenging when reviewing life-sustaining endocrine medications but, unlike for diabetes, there is no national guidance to support patients and clinicians faced with care planning. This article reviews the limited current evidence to highlight areas for further discussion and research with the aim of moving towards consensus opinion. Discontinuation of certain endocrine medications, including corticosteroids, desmopressin and levothyroxine, is likely to precipitate an 'endocrine-driven mechanism of death', while it may be reasonable to discontinue other endocrine medications without the risk of hastening death or causing unnecessary symptoms. However, the over-arching theme should be that early discussion with patients regarding conversion or discontinuation of endocrine medications or monitoring is central to care planning.

Isolated Adrenocorticotropic Hormone Deficiency and Primary Hypothyroidism in a Patient Undergoing Long-Term Hemodialysis: A Case Report and Literature Review.

BACKGROUND Patients with end-stage renal disease undergoing long-term maintenance hemodialysis are more likely than the general population to exhibit primary hypothyroidism. Only a few cases of isolated adrenocorticotropic hormone deficiency (IAD) among hemodialysis patients have been reported. We herein report an unusual case of a patient undergoing long-term hemodialysis who exhibited both IAD and primary hypothyroidism. CASE REPORT A 82-year-old male with end-stage renal disease secondary to immunoglobulin A nephropathy, undergoing hemodialysis for 20 years, was found to have primary hypothyroidism without obvious symptoms and consequently began thyroid hormone replacement therapy with oral levothyroxine. At 84 years of age, he developed anorexia, fatigue, and lethargy. A systemic workup using computed tomography and gastrointestinal endoscopy detected no abnormalities. He did not exhibit electrolyte imbalances, such as hyponatremia or hyperkalemia, and had normal morning blood levels of cortisol and adrenocorticotropic hormone. However, he exhibited hypoglycemic coma 4 months later. Detailed endocrinological examinations using dynamic function tests indicated IAD. After commencement of corticosteroid replacement therapy, his symptoms resolved without complications. CONCLUSIONS To our knowledge, this is the first report of a hemodialysis patient with both IAD and primary hypothyroidism. This case highlights the importance of regular assessments of thyroid function for primary hypothyroidism in hemodialysis patients, even when they are asymptomatic. Furthermore, timely dynamic endocrine testing of hypothalamic-pituitary-adrenal function is needed to diagnose possible IAD in hemodialysis patients with symptoms suggestive of adrenal insufficiency, even in the absence of abnormal laboratory findings such as electrolyte imbalances or low morning blood levels of cortisol or adrenocorticotropic hormone.

The Pharmacological Activity of Camellia sinensis ( L. ) Kuntze on Metabolic and Endocrine Disorders: A Systematic Review.

Tea made from Camellia sinensis leaves is one of the most consumed beverages worldwide. This systematic review aims to update Camellia sinensis pharmacological activity on metabolic and endocrine disorders. Inclusion criteria were preclinical and clinical studies of tea extracts and isolated compounds on osteoporosis, hypertension, diabetes, metabolic syndrome, hypercholesterolemia, and obesity written in English between 2014 and 2019 and published in Pubmed, Science Direct, and Scopus. From a total of 1384 studies, 80 reports met inclusion criteria. Most papers were published in 2015 (29.3%) and 2017 (20.6%), conducted in China (28.75%), US (12.5%), and South Korea (10%) and carried out with extracts (67.5%, especially green tea) and isolated compounds (41.25%, especially epigallocatechin gallate). Most pharmacological studies were in vitro and in vivo studies focused on diabetes and obesity. Clinical trials, although they have demonstrated promising results, are very limited. Future research should be aimed at providing more clinical evidence on less studied pathologies such as osteoporosis, hypertension, and metabolic syndrome. Given the close relationship among all endocrine disorders, it would be of interest to find a standard dose of tea or their bioactive constituents that would be beneficial for all of them.