Health Communication Research Institute. American Red Cross. This course is a general discussion of the clinical presentation of primary immunodeficiency diseases and how to make the diagnosis. Before starting, you will download a special "installer. Click this icon to start the course. ConferenceSeek Last visited College of American Pathologists, Rush-Presbyterian. The fee courses require that you register and pay in advance. Thomas R. Beam, Jr. Text-and-Graphics, Text-Only. Bristol-Myers Squibb. Each issue of this online journal presents a photograph and accompanying clinical information for two patients.
The program asks you to select a diagnosis from a list of possibilities, then follows with a didactic presentation based on the correct diagnosis. You must complete both cases in each issue to earn one hour of CME credit. You will also find 6 text-only symposia on various topics in pdf format. ONC, General Interest. National Cancer Institute. This tutorial is intended for use by those involved in the design and conduct of research involving human participants.
The tutorial presents "common concepts, principles, and issues related to protection of human participants. It is intended to act as a companion piece to your institutional policy, as well as local, state, and federal regulations applicable to human research. The tutorial will help you and your team identify research activities that involve human participants, and help you understand how to protect the rights and welfare of all human participants involved in research.
CBC Biomed. Payment in advance. This is a set of webcasts from a live meeting. The course provides a comprehensive update of the diagnosis, monitoring, and management of the critically ill patient. It is intended to help you prepare for the critical care subspecialty examination of the American Board of Internal Medicine. You may view a free demo prior to registering. To receive credit, mail the completed posttest and evaluation. Cyberounds Last visited Also accredited by the American Osteopathic Association.
Albert Einstein College of Medicine. Cyberounds was the first producer of online CME, beginning in There are programs in 15 specialties, developed by a panel of academic clinicians from 15 U. Forest Pharmaceuticals. Diabetes Roundtable Last visited Washington Hospital Center. American College of Radiology. Cardinal Health. Some recent courses include: MRI joins CT in modern evaluation of stroke; Adding PET to a practice requires clinical and business acumen; Digital mammography: interpretation challenges, data capture advantages; CT angiography offers noninvasive evaluation of renal arteries; and Unique considerations in pediatric MDCT require specific programs.
Digiscript Last visited It is not possible to count the courses or hours, but there appear to be many hundreds. Multiple Sponsors. Slide-Audio and Slide-Video-lectures. Multiple Specialties. Digiscript contains many hundreds of audio and video slide lectures recorded at medical meetings. Some courses offer CME and some do not. It is not possible to give an accurate count. However the site is searchable by medical topic and by sponsoring organization. You may have to pay an additional fee for CME credit by any individual sponsor. Discovery International Last visited Discovery International.
Most are Text-Only pdf ; one video course; some slide-audio. Two slide-audio courses on the use of Cox-2 inhibitors in arthritis; one pdf course on hormone replacement therapy; seven pdf courses on breast cancer therapy; four pdf courses on the use of leukotrienes in asthma; and one video presentation on Myofascial Pain Syndromes, showing techniques for trigger point injections using Botulinum toxin. University of Minnesota. A separate Slide-and-Text module for each disease state and a pdf monograph discussing all of the disease states.
After studying this course, you should be able to discuss the epidemiology of acute myocardial infarction, stroke, deep vein thrombosis, peripheral arterial occlusion, hemodialysis access, catheter clearance, pulmonary embolism, and nonvascular disease, such as empyema and pleural effusions, and explain the rationale for using fibrinolytic therapy in each of these conditions. CME certificates will be mailed to you. Doctors Guide Webcasts Last visited Many different medical schools. This site offers links to about "webcasts" which were created within the past three years.
The courses listed at Doctor's Guide Webcasts are located at the sponsoring sites, but Doctor's Guide offers a convenient jumping off place for these courses. You may search the database by subject or by date added. You may also personalize the site so that the courses in your specialty are automatically presented when you visit. Drexel University College of Medicine. Various Pharmas. There are 76 lectures on general internal medicine and medical subspecialty areas. This site has 12 monographs on various internal medicine topics.
Some of the monographs are quite old , but the content has been reviewed and CME credit for all courses has been extended until December 31, Quiz answers may be submitted on line, or by mail or fax, but you must send your check or credit card information by surface mail. Duke University School of Medicine.
Quality of the Body Cell Mass
One hour for each 10 questions answered correctly Total of This site offers a set of questions and discussions in 22 different specialties, aimed at primary care physicians. You receive immediate feedback on how your first answer compares to the first answers of fellow participants.
One hour of credit is available for each 10 questions correctly answered. You will also find 23 topic areas which can also be searched by specialty for non-primary care physicians. Weill Medical College of Cornell University. This site features three courses from Cornell's Hospital for Special Surgery. Ed Credits Last visited Infusion, Inc. Not Stated. This site contains 11 courses, created to satisfy licensing requirements for the state of Florida, although all physicians may obtain credit through these offerings.
Some courses are A. S Review , Domestic Violence , O. This site offers 2 articles per month for a total of 26 possible CME credits per year. Read the article and take a short quiz. Incorrect answers will return you to the appropriate section of the article and give you another try to answer correctly. Typically 1. University of Nebraska Medical Center.
All Specialties. Each article is like a textbook chapter on a single disease, written in outline style. There are two ways to receive continuing education credits. You can read an article, answer six questions correctly and receive 1. Or you can read and correctly answer several questions in a subspecialty area correctly and receive 1. If you subscribe to the email notification service, you will receive notice of free courses, presently about 40 courses. Most of the eMedicine courses are available without charge at CEMedicus. The Endocrine Society Last visited Baylor College of Medicine.
One nine credit-hour course: Hot Topics in Endocrinology. Free to North Carolina MDs. EPIC is a faculty development curriculum in clinical teaching for community practitioners who serve as preceptors to health professions students. The course is divided into 10 modules which may be studied independently but are really part of a whole. The program makes good use of brief audio clips illustrating typical patient student preceptor scenarios. The course is highly interactive and requests the user to answer questions and give opinions before proceeding.
- Rues Redemption.
- Blonde Ambition?
- Commitment to Privacy.
- Commitment to Privacy - Virginia Commonwealth University.
- Top Authors.
- multi-frequency bioelectrical impedance: Topics by cosenefuno.tk?
The site has four kinds of instruction: Image Quiz Last visited American Academy of Family Physicians. Image Question and Answer. Earn CME credit while advancing your skills at identifying clinical images. The program presents you with multiple choice questions related to 39 clinical images. If you answer the question correctly, you will continue on to the next question. If you answer incorrectly, the answer summary is presented for your reference.
In-Training Exams Last visited The CME consists of Lifecycle of Obesity Diagnosis and Management Last visited Abbott Laboratories. Slide-Audio or Slide-Video lectures Last visited Slide-Video-Lecture and one case-based-interactive. Financial Support lectures only Teen Smoking Cessation Cases Last visited FP, PED. Illinois Public Agencies. This course combines didactic material with case-based-interactive instruction. The cases will help you hone your interviewing skills through interactive dialogue with two young patients.
After completing this course, you should be able to define the prevalence of tobacco use among adolescents today; identify the risk factors for and characteristics of adolescent tobacco use; understand the process of change as applied to adolescent tobacco use and treatment; and develop and implement effective tobacco-cessation interventions for adolescents. Family Practice Update Last visited Professional Education Services Group. This series presents new information on a variety of subjects including allergy and immunology, osteoporosis, infectious disease and diabetes.
Florida Medical Association. Two courses are part of the licensure requirements for Florida physicians. They may also be taken for credit by non-Florida physicians. Foundation for Better Health Care. Slide-Only or Text-Only. Many pharmaceutical companies. There are five courses. A fifth is Enhancing Care Through Communication.
This new site offers free CME for many medical specialties and in many medical topics. The site allows you to search for courses in your specialty or area of interest. It is designed to help geriatric caregivers assess and sharpen their diagnostic and clinical management skills. Players face more than clinical challenges and earn "Longevity Points" as they guide their patients through the health care system, from the ICU to Assisted Living.
You may play by yourself or in a group. There is also a shorter game, "Longevity FP," intended for non-geriatric specialists. To receive your CME credit, print and mail your certificate of completion. Geriatric Times Last visited CME, Inc. Geriatrics CME Last visited Mount Sinai School of Medicine. Expiration of CME Credit Each issue of this online journal contains one article in pdf format, which you can download and read. The Year features articles about heart disease. The quiz must be printed and mailed along with your payment within 6 months of the publication date. Various pharmaceutical companies.
Create and download your own PowerPoint presentations. Hepatitis C Training Last visited After completing this course you will be able to: describe the natural history of HCV infection; describe the risk factors for acquiring HCV infection; describe serologic and laboratory tests to diagnose and evaluate patients with HCV infection; discuss treatment options for patients who have chronic hepatitis C; and discuss the most effective methods to counsel patients who have HCV infection.
University of South Dakota School of Medicine. Six lectures on various aspects of depression. Educational material last updated.. You will find 24 lectures, covering the full range of rheumatology topics. You must register and pay before viewing each lecture. Medical Education Collaborative. Cytyc Corporation. After completing this activity, you should be able to understand the epidemiology, etiology, and impact of cervical disease; understand how the identification of HSIL high-grade squamous intraepithelial lesion on Pap testing relates to cervical disease; and recognize the benefits of new technologies.
Thomson American Health Consultants. Text-Only html or pdf. CME Credit Expires You may read online or download as a pdf file 55 pages , print and read. InforMed Last visited Medical Society of Virginia. Amgen, Lilly. Institute for Advanced Medical Education Last visited Institute for Advanced Medical Education. GE Ultrasound. Some nice pictures of black-and-white and color Doppler images. Interactive Grand Rounds from Medsite Last visited Total of 26 hours available. Question-and-Answer based on a Text-Only review article.
Each course consists of a very brief case presentation followed by 10 multiple choice questions. The answers to the questions are found in an article that reviews the medical condition discussed. You will need a high speed connection to access these courses online. Dartmouth-Hitchcock Medical Center. The program features four simulated patients who have, or may develop, diseases where your decisions about, clinical genetics can affect outcomes.
You can visit the Learning Resources Room and attend lectures, listen to interviews, engage in activities, and search the World Wide Web for relevant information. Up to 8. Pfizer, Simon and Schuster. The interactive video, sound, and graphics move you through a "virtual clinic" that includes an orientation, a learning resources room, and encounters with a virtual patient.
This site consists of questions and answers on psychiatric topics. Each of seven modules contains 30 board-style questions. You read and answer each question, submit the answers, and the program gives you immediate feedback. Although the material has apparently not been updated since , CME credit is still available. Four courses for AIDS specialists. After a brief text-based introduction, you are presented with cases and must make decisions as you move through each case. Texas Academy of Family Physicians. You may download and print the slides and follow along with the presentation.
Text-only or slides-only. Jefferson Medical College. Johns Hopkins. Text-Only or PowerPoint. Expiration of CME credit Click on CME Courses to get started. Text-Only pdf Target Audiences Johns Hopkins Arthritis Last visited Up to 9. McNeill, Nutramax. The course is divided into three sections. The first section presents medical, non-surgical approaches for the treatment of OA.
The third section focuses on novel tissue-engineered products for cartilage repair. Centocor, Genentech. Joslin Diabetes Center. Text-Only Disease-Based Interactive. You will find 6 courses offering credit. They cover various aspects of the diagnosis and management of diabetes. All versions are accessed through the same URL. Journalbytes Chest Medicine Last visited Most is Text-Only; some Audio.
Educational material updated monthly. Two years after date of publication. Journalbytes Gastroenterology Last visited Journalbytes General Surgery Last visited Journalbytes Integrative Medicine Last visited Journalbytes Internal Medicine Last visited Journalbytes Pathology Last visited Journalbytes Pediatrics Last visited Journalbytes Radiology Last visited University of Medicine and Dentistry of New Jersey. RAD Educational material updated monthly. Journalbytes Urology Last visited American Urological Association. Three years after date of publication.
Journal of Clinical Outcomes Management Last visited Wayne State University School of Medicine. Many Physicians. One year after date of publication. The Journal of Clinical Outcomes Management is a peer-reviewed journal dedicated to helping physicians and managed care decision makers improve outcomes of care.
Each online issue of this journal contains an article offering one hour of CME credit. Some recent subjects are: Hospital acquired acute renal failure - what hospitalists need to know; Glycemic control in the hospitalized patient with diabetes mellitus; Inpatient evaluation and management of acute decompensated heart failure; and Adolescent substance use: prevention and management by primary care clinicians. Fax or mail the evaluation form to receive credit.
Many activities have financial support from pharmaceutical companies. Register for the Journal by joining the NetSociety free. This gives you access to most of the CME activities. Audiograph Series Last visited Total of Physicians Postgraduate Press. Text-and-Audio or Slide-Video. There are now 7 courses, each offering 2 hours.
Download the pdf description and print or view online ; then choose the mp3 or Windows Media Player version to hear the audio. Print and mail the quiz along with your check to receive CME credit. Last visited Each issue contains two articles each offering one hour of CME credit. Print and mail the quiz along with check to receive CME credit. Some are on the same topics and have the same faculty as Audiographs or newsletters.
JCP Visuals Last visited PDF versions of published newsletters. PCC Visuals Last visited FP, IM, Educ. This newsletter is geared toward primary care physicians who treat psychiatric disorders or who are interested in learning more about them. Online Insights Last visited CNS Discourses Last visited PDF files of published newsletters.
George Chrousos | National & Kapodistrian University of Athens - cosenefuno.tk
There is currently one credit available: Update on the Treatment of Anxiety Disorders. Journal Watch Psychiatry Last visited Massachusetts Medical Society. Each exam includes questions from 50 brief articles on psychiatric topics posted in the 6 months before the exam is due. The exam is in pencil and paper form and must be mailed before each six-month deadline. Journal Watch Women's Health Last visited Each exam includes questions from 50 brief articles on women's health topics posted in the 6 months before the exam is due.
Total of 13 hours. To receive credit, print and mail the answer sheet along with your check. Legal Medicine Last visited Total of 50 hours available. Armed Forces Institute of Pathology. This site contains articles concerning legal aspects of medical practice. You will find yearly issues back to ; credit is offered for all issues. I suggest you print and read the pdf files offline. LipidHealth Last visited Thomson Professional Postgraduate Services.
Case-Based-Interactive and others. This site offers four ways to earn CME credits. Interactive Case Studies has 8 modules; each module concerns two patients with lipid disorders and awards one hour of credit. Virtual Case Studies offers one series of two cases. Eight courses, from 0. Total of 5. April 30, Canadian System.
The Canadian medical university that develops the course. Osteoporosis course is free.
Case-Based-Interactive with online facilitator. GP, FP. The primary emphasis on helping rural MDs to maintain medical competence. Courses offer credit for US physicians as well as those in Canada. Courses are offered in specific time periods and involve interaction with other students and an instructor. This is a 3-Step continuing medical education program. In Step 1, Lectures, you are presented with a lecture by experts followed by a posttest. In Step 2, Simulated Patient Encounters, you complete a number of simulated patient encounters with two pediatric and two adult cases and complete a short survey outlining the key points learned.
In Step 3, From Theory to Practice, you list up to five future improvements you will implement into your practice based on the information learned in Steps 1 and 2. Each month you will reflect on this list and your experiences with patients. Additional learning activities will be provided each month through clinical vignettes. You work through an encounter, from initial presentation through the creation of a treatment plan. Three case simulations followed by expert slide-audio discussion.
The cases are: A year-old white man with a history of smoking presents with shortness of breath; A year-old white man presents to the emergency department with a productive cough and worsening shortness of breath; and A year-old black man presents with cough and dyspnea. Two case simulations: a 5-month-old girl with newly diagnosed cystic fibrosis, failure to thrive and cough; and an year-old boy with cystic fibrosis and worsening cough.
The cases are: A year-old Hispanic man with a history of known COPD presents with increasing dyspnea, fatigue, and productive cough; A year-old white woman with a history of mild hypertension, extensive prior tobacco use, and COPD complains of fatigue and increasing dyspnea on exertion; and A year-old white man complains of a cough productive of whitish sputum. One case simulation: A year-old diabetic man presents with persistently elevated blood pressure.
Improving Erectile Function Last visited MedCases, Inc. Case-Based-Interactive Target Audiences Bayer, GlaxoSmithKline. Eight case simulations of men with erectile dysfunction. After studying these cases, you will be able to recognize erectile dysfunction as a manifestation of underlying medical disease; obtain an appropriate sexual history in the general medical evaluation; identify modifiable risk factors for erectile dysfunction; select appropriate diagnostic testing for erectile dysfunction; and discuss the latest advances in erectile dysfunction management.
Insomnia: The Scope of the Problem Last visited One case at present, although 3 additional cases are promised. Sanofi-Synthelabo, Inc. Upon completion of all components of the program, you should be able to obtain a thorough sleep history; identify the most common etiologies for insomnia; distinguish between insomnia as a presenting symptom and other conditions; recommend appropriate pharmacologic and nonpharmacologic approaches to treatment; and recognize when and how to use hypnotic agents.
Three simulated patient encounters: A year-old white woman presents complaining of abdominal pain, constipation, and bloating; A year-old African American man presents complaining of abdominal pain, diarrhea, and urgency since returning from a trip to Mexico 3 months ago; and A year-old woman presents with severe, alternating diarrhea and constipation. Most courses offer 1. Indiana State Medical Association. Slide-Audio You also have the option of a text-only version. Most courses will expire in December ; some expire in About half the courses are on clinical topics, and about half concern practice management.
MedEd Interactive Ultrasound Last visited Excerpta Medica, Inc. A set of courses for physicians with special interest in ultrasound. Courses are organized into these groups: cardiovascular , abdomen this is actually tyroid , women's health , and emergency medicine. Texas Department of Health. A discussion of the importance of filling out death certificates correctly. Some of the reasons for doing so are to "assess the general health of the population; examine medical problems which may be found among specific groups of people; indicate areas in which medical research may have the greatest impact on reducing mortality; allocate medical services, funding, and other resources; evaluate prenatal care services and obstetrical programs; and study the causes of adverse pregnancy outcomes in the case of fetal deaths.
About 8 hours. Medical Programs Inc. MedicalRounds Last visited Generally one hour per lecture, total of hours at present. Credit Type Slide-Audio-Lecture or you can choose slides and text. MedicalRounds webcasts multimedia presentations and conferences for many contributing medical groups. Many Canadian medical schools have contributed lectures to this series. All talks were originally presented at grand rounds of quality educational institutions or at accredited medical meetings. In addition, the website maintains an extensive database of hyperlinks to other free multimedia medical presentations available on the web.
Although the courses on this site do NOT offer AMA Category I credit, I have included the site on this list because of the very extensive array of high quality lectures, searchable by medical topic or specialty. MediCom Worldwide Last visited Janssen and Boehringer Ingelheim. There are now 4 courses in pain management, 21 courses in psychiatry mostly about treatment of psychosis and 6 in gastroenterology primarily about GERD. Each quarterly issue of Bipolar Disorders Letter every third issue of Psychiatric Times contains a set of readings on bipolar disorder.
You must read and answer questions on each article to earn CME credit. Psychiatric Times Last visited Some not all issues of Psychiatric Times contain articles that you can read online for credit. MedRisk Online Last visited Medical Risk Management, Inc. Thirteen programs on reducing malpractice risk in various practice settings. Medscape Last visited Vary according to the course.
Presently activities offering about CME hours. Many different sponsoring organizations, including Medscape. Most Specialties New activities posted each month. Many academic, specialty, and commercial sources as well as WebMD. Credit for most activities expires one year after posting.
Medscape's CME activities are divided into four groups: Conference Coverage : Medical experts provide coverage of presentations from major medical conferences across target specialties. This typically includes news stories, articles for CME credit, posters and abstracts, and links to meeting satellite symposia content.
Medscape Professional Education : These activities are reviews of new therapies or presentations of results of clinical studies. News CME: Each weekday, you will find an abstract, offering 0. When you first register with Medscape, you are asked for your specialty. After that, whenever you log in, the program directs you to those medical and CME areas that should be of most interest to you. Instruction is by interactive text.
American Academy of Pain Management. This is a set of 50 pdf articles, organized into 5 groups of 10 articles each. Some titles are What Is Anti-Aging? Case-Based Interactive. National Institute on Drug Abuse. Advanced Practice in Spasticity Management Last visited This course is designed for clinicians with significant experience in utilizing intrathecal baclofen therapy for their patients with severe spasticity.
It provides the opportunity to expand your knowledge of the use of intrathecal baclofen therapy for management of severe spasticity of cerebral origin in the adult and pediatric populations. All phases of intrathecal baclofen therapy are addressed: patient selection, screening, and ongoing management. To receive credit, complete and mail the quiz to the address shown. About Mostly Text-and-Graphics; there is one slide-audio program.
Esai, Pfizer. ADvantage has four sections. Note: Use Code Number "" to log in unless you have already received different instructions from the site managers. National Institute on Alcohol Abuse and Alcoholism. After taking this course, you will be better able to identify patients in your practice who are at risk or currently experiencing alcohol use problems. Pfizer, UCB Pharma. Upon completion of this activity, you should be able to describe new clinical data supporting the potential role of antihistamines in the treatment of mild to moderate asthma; select optimal therapy based on pharmacologic and practical considerations; and evaluate current and future potential therapies for better treatment.
Preventive Services Task Force. You may view the slide-video lectures; you may view a slide show without sound; or you may download the slides for later viewing. In addition to the video presentation, each course offers a monograph as a pdf document text and graphics. Free members only. The content of the monograph is identical to the paper version. American Family Physician Journal Last visited Credit hours.. Each month's issue of this online journal contains a series of articles concerning clinical issues in primary care and a quiz with questions relating to those articles.
Members of the AAFP may submit the answers to quizzes online, while nonmembers must complete and mail in the tear-out card found in the paper version of the journal. Case Studies in Pain Management Last visited Purdue Pharma. This series of simulated patient encounters highlights areas of particular clinical concern including the proper assessment of pain syndromes, the appropriate use of opioids, and the prevention of medication diversion. After completing these cases, you will be able to: recognize common pain scenarios encountered in clinical practice, identify the features of an appropriate pain assessment, with attention to historical and physical findings, describe limitations associated with the use of available assessment tools.
CME Bulletin Last visited This new section offers evidence based CME. Family Practice Management Last visited Each month's issue of this online journal contains a series of articles concerning management issues in primary care and questions relating to those articles. You will also find a half-day course, Introduction to Neuro-Urology. American Academy of Ophthalmology.
The site offers Lifelong Education for the Ophthalmologist LEO , a total approach to the educational needs of the ophthalmologist. There are presently about 12 courses. Learning Center Last visited Text-and-Graphics or Case-Based-Interactive. Self Assessment Center Last visited Nine special interests examinations, consisting of questions each, in orthopaedic specialty areas. Examinations are updated every three years and each examination grants up to 10 Category 1 credits.
A Professional Affairs examination ethics, professional liability, and occupational health provides up to 5 Category 1 credits. American Academy of Pediatrics PediaLink. AAP PediaLink offers 3 kinds of instruction:. American Academy of Pediatrics. Case-Based-Interactive with group discussions. The PREP Self-Assessment Exercise offers multiple choice questions including critiques; links to many of the references; and search capabilities.
Other AAP online courses Last visited About 11 courses offering about 40 hours of credit. You will find six shorter journal articles 1. There is also a single free course on bioterrorism and biological weapons of mass destruction. Archived webcasts: total of 15 hours. American College of Cardiology Foundation. Free to members of ACC. The Blended Learning Community combines many interactive learning tools, including live webcasts, archived webcasts, case studies, reference material, pre-tests, and CME Tests.
You also have the opportunity to interact and communicate with featured speakers and other professional colleagues. Archived webcasts are on various cardiology topics with a heavy emphasis on echocardiography. Pricing depends on membership in ACC and level of subscription. American College of Cardiology Foundation Cardiosource should fill many of the educational needs of cardiologists.
Those sections offering online CME are described below. Features of ACCSAP V include 21 chapters of information; practice examination with more than peer-reviewed self-assessment questions and answers based on the American Board of Internal Medicine model; electronic score submission; audio interviews with chapter editors; expanded panel of authors more than experts ; and updated and expanded database of clinical trials. CARD Educ. Some areas covered in this course are basic concepts in cardiac catheterization; clinical applications in coronary artery disease; and clinical applications in noncoronary heart disease.
You will also find a literature review with more than selected abstracts, figures, and tables; a practice examination featuring simulated ABIM questions; and clinical trial summaries. This program offers a self-assessment tool in electrocardiography that provides immediate feedback on your current skills in single ECG tracing interpretations, overreading of computer ECG interpretations, electrocardiographic clinical correlations, interpretation of serial ECG tracings and stress test interpretations.
The course is intended to improve your interpretive skills and your understanding of electrocardiography and help you identify the specific areas in ECG interpretation in which you may be deficient. Free with Cardiosource Premium subscription. This self-assessment program covers basic cardiac electrophysiology and developments in the field that have occurred during the last several years. Topics include sinus node dysfunction, atrioventricular conduction disturbances, and syncope; supraventricular tachycardia; atrial fibrillation; ventricular arrhythmias and sudden cardiac death; pharmacokinetics, antiarrhythmic drugs and proarrhythmia; cardiac pacing; and implantable cardioverter-defibrillators.
The programs are linked from the main page , Online CME, midway down the right side of the page. Chest Presentations Online Last visited American College of Chest Physicians. Slide-Audio Lectures. This pdf monograph, for physicians who treat COPD, was adapted from a live presentation in This online journal is intended for the pulmonary and critical care specialist. Each month provides two lessons on pulmonary and critical care topics.
Actelion Pharmaceuticals. This symposium provides an overview of the etiology, pathogenesis and and diagnosis of pulmonary arterial hypertension PAH secondary to systemic sclerosis; updates on the uses of conventional therapies for PAH and clinical-trial results of newer treatment options; and case-based approaches to apply in individual patients. Text-Only Target Audience You should view this site using Internet Explorer. Two presentations: Credentialing Part I: A Return to Basics and Beyond, discusses "the core process for determining a candidate's qualifications for the initial and subsequent granting of membership and privileges.
Forty-eight interactive cases aimed at internists. You begin by assessing the patient's condition, form differential diagnoses, make treatment decisions, order tests and follow patients through the resolution of their problems. As you complete each step in the process of solving patient problems, the program's interactive features allow you to compare your clinical decisions to those of expert authors. Before registering, you may try one of two demonstration cases, "A 54 year old white man presents for prostate cancer screening," or "83 year old woman with vague periumbilical and epigastric pain.
American Diabetes Association. This site features highlights of the meeting held in June Each one unit course represents summaries of one day of the meeting.
American Heart Association. This site features highlights of the four day November meeting. You may earn credit by either reading and answering questions based on the summaries of each day's proceedings or by reading and answering questions based on 4 subject areas: basic science, clinical science, population science or lipids.
Center for Bio-Medical Communication. GlaxoSmithKline and Novartis. To receive CME credit, print the information sheet, posttest, and evaluation form and mail it in with your fee. American Medical Association Online Courses are described in 4 sections:. October Some of the instruction uses sample cases, while other pieces are largely didactic. In addition to text and pictures, there are some very nice narrated animations of bone growth and resorption.
There are also online "forums," through which you can ask questions and receive answers from experts in the field. This course is based on the manuals of the Family Violence Prevention Fund. It is mostly text with a few graphics, but there are also optional audio or video clips of victims of domestic violence. One nice feature is that there is a brief quiz after each section, and you may answer the quiz questions repeatedly until you get them right.
American Psychiatric Association Last visited American Psychiatric Association. Many Pharmaceutical Companies. There are two courses are on the use of buprenorphine for the treatment of opiate addiction. None stated. There are presently 13 courses offering CME credit. Another 14 courses are available for viewing with credit to be awarded later. Anesoft Medical Simulation Software Last visited Anesoft Corporation.
You can see a demo of each course before ordering. Anesthesiology Online Last visited Dannemiller Memorial Educational Foundation. Text-Only and three slide-shows. There are 3 new modules each month. There are 7 articles available for credit. This course reviews the research literature and provides guidelines to treat PONV. The course is given in monograph format and slide-audio format. You may obtain credit for studying one or the other, but not both.
ArcMesa Educators Last visited ArcMesa Educators. Text-Only one course, Diagnostics Challenges in Radiology, is described as "interactive.
This site features courses that you can read online html format , or download and read off line pdf format. There are about 87 courses in a wide variety of topics offering a total of about CME credits. Association of Reproductive Health Professionals. Barr Laboratories. These are the first two sections, Bladder Pathology and Lesions of the Penis and Urethra of a course primarily for urologists preparing for board examinations and for practicing urologists and pathologists. Following the text, the participant sees several images with captions that illustrate the important features discussed.
With a single click on an image, the participant can see a full-size version of an image with its caption. The course has 5 modules; each module consists of eight cases with a brief case history and a set of microscopic slides of an endoscopic biopsy. Mostly Text; some audio. Although these courses were posted in and , they appear to still offer CME credit. Three years after posting. Each month, two new courses are posted.
Although the extreme length of the polyglutamine repeat does determine mild androgen resistance, these men usually have normal reproductive function including fertility and virilization prior to diagnosis in mid-life Furthermore, since complete androgen receptor inactivation in humans and other mammals does not cause motor neuron disease and female carriers are protected from symptomatic neurodegeneration, SBMA like other genetic polyglutamine repeat neurodegenerative diseases represents a toxic gain-of-function involving pathological protein aggregates of the mutant AR Transgenic mouse models of SBMA suggest that testosterone deprivation by medical castration using a GnRH agonist may slow progression of neuropathy and that genetic or pharmacological administration of IGF-I may slow disease progression.
However the first major clinical trial of leuprolide, a GnRH analog, failed to demonstrate neuromuscular benefit in swallowing and further studies of selected subgroups and therapeutic targets are warranted The DBD is highly conserved between steroid receptors reflecting its tightly defined function of forming the two zinc fingers that bind to DNA by intercalating between its grooves. The first zinc finger exon 2 is directly involved with the major DNA groove of the androgen response element through a proximal P-box region whereas the second zinc finger exon 3 is also responsible for enhancing receptor dimerization through its distal D-box region.
The most C terminal helix 12 seals the binding pocket and influences whether a bound ligand acts as an agonist or antagonist as well as forming a hydrophobic surface for binding of co-regulator proteins that modify transcriptional activity of the androgen target genes. The LBD also participates in receptor dimerization, nuclear localization and transactivation via its activation function AF-2 domain. The AR has a predominantly nuclear location in androgen target cells regardless of whether bound to its ligand or not, unlike other steroid receptors which are more often evenly distributed between cytoplasm and nucleus when not bound to their cognate ligands.
Androgen binding to the C-terminal LBD causes a conformational change in the androgen receptor protein and dimerization to facilitate binding of the ligand-loaded receptor to segments of DNA featuring a characteristic palindromic motif known as an androgen-response element, located in the promoter regions of androgen target genes. Ligand binding leads to shedding of heat shock proteins 70 and 90 that act as a molecular chaperone for the unliganded androgen receptor Specific binding of the dimerized, ligand-bound androgen receptor complex to tandem androgen-response elements initiates gene transcription so that the androgen receptor acts as a ligand-activated transcription factor.
Androgen receptor transcriptional activation is governed by a large number of coregulators whose tissue distribution and modulation of androgen action remain incompletely understood. As the androgen receptor is an X chromosomal gene, functionally significant AR mutations are effectively expressed in all affected males because they are hemizygous. By contrast, women bearing these mutations including the obligate heterzygote mothers of affected males are silent carriers without any overt phenotype because they have a balancing allele as well as their circulating testosterone levels never rise to post-pubertal male levels sufficient to activate AR mediated effects.
Germline AR mutations produce a very wide spectrum of effects from functionally silent polymorphisms to androgen insensitivity syndromes that display phenotypes proportionate to the impairment of AR function and, thereby, the degree of deficit in androgen action 1. These clinical manifestations extend from a complete androgen insensitivity syndrome CAIS, formerly known as testicular feminization which produces a well developed female external phenotype in a spectrum spanning across all grades of undervirilized male phenotype to, at the other extreme, a virtually normal male phenotype.
The degree of urogenital sinus derivative development together with testis descent provide clinical clues to the degree of androgen sensitivity. CAIS due to completely inactivating AR mutations results in a 46XY individual with a hormonally active testis that secretes abundant testosterone but which cannot activate AR-mediated action so no male internal or external genitalia or somatic features develop. However, testosterone aromatization to estradiol is unimpeded, leading to the development of normal female somatic features including breast and external genital development after puberty.
The clinical features usually include well developed breasts, hips and female fat pattern deposition, acne-free facial complexion with minimal axillary and pubic hair with testes located within an inguinal hernia or in the abdominal cavity. The uterus and fallopian tubes are absent and the vagina is short and blind ending reflecting unimpeded effects of testicular AMH secretion causing regression of Mullerian structures including the upper third of the vagina.
Earlier diagnosis is increasingly possible where a prenatal 46XY karyotype is discrepant from a female phenotype on ultrasound or at birth or among female infants presenting with inguinal hernia The family history may be informative with infertile maternal but not paternal aunts consistent with an X-linked inheritance.
Laboratory investigations of post-pubertal individuals show elevated blood LH, SHBG at adult female levels and testosterone at adult male levels prior to gonadectomy. The androgen sensitivity index, the product of LH and testosterone concentrations, is elevated These features reflect high amplitude and frequency LH pulses due to the absence of effective negative androgenic feedback on the hypothalamus as well as the increased LH drive to maintain high-normal male levels of testicular testosterone secretion.
In untreated individuals, failure to suppress blood SHBG with short-term, high dose androgen administration may be useful confirmation of androgen resistance After gonadectomy, blood LH and FSH increase to castrate levels but are partially suppressed by estradiol replacement therapy.
Long-term management includes a reinforcing female gender identity with counseling to cope with eventual infertility and acceptance of the genetic diagnosis, b post-pubertal gonadectomy to prevent the risk of gonadoblastoma especially if the gonad is impalpable but allowing the completion of puberty balanced against the low risks of tumour at that age and of unwanted virilization due to any residual AR function or mosaicism , and c post-gonadectomy estrogen replacement therapy to maintain bone density, breast development and quality of life.
Long-term bone density is often subnormal for age due not only to the deficit in androgen action but also inadequate post-gonadectomy estrogen replacement, often resulting from suboptimal adherence to medication , Although the long-term outcomes for AR mutations based on large prospective studies of a consistent management approach remain very limited, the clinical outcomes for individuals with CAIS reared as females are reported as successful although some gender role and psychosexual functional outcomes remain suboptimal Partial androgen insensitivity syndrome PAIS is characterized by a full range of external genital virilization and breast development from female to male phenotype, reflecting the functional severity of the AR mutation.
A simple clinical guide to the severity of the deficit in AR function is provided by the level of testis descent and phallic development. PAIS was originally recognised under a variety of eponymously named syndromes Reifenstein, Gilbert-Dreyfus, Lubs, Rosewater and only more recently clearly distinguished from other developmental disorders of 46XY individuals with incomplete virilisation especially those due to steroidogenic enzyme defects. Severe forms of PAIS with minimal AR function produce a predominantly female phenotype with clitoromegaly whereas PAIS with mutations displaying more functional AR are characterized by a male phenotype with various grades of labioscrotal formation varying from minimal posterior partial labial fusion to labioscrotal fusion and bifid, ruggose scrotum and hypospadias urinary orofice ranging from perineal aperture to hypospadia with meatus at locations along penile shaft to the corona , micropenis and gynecomastia, each in inverse proportion to the AR function.
These features have been combined into a External Masculinization Score EMS ranging from 0 female to 12 male based on degree of scrotal fusion, phallic development, location of urethral meatus and testis descent each scored The biochemical finding in PAIS are similar to those of CAIS but with a wide spectrum of severity from mildly virilized, predominantly female to an undervirilized male phenotype. The increase in blood LH and testosterone are less severe and consistent but the androgen sensitivity index may help confirm the diagnosis of androgen resistance.
Unlike CAIS, which usually presents during adolescence with failure of puberty, PAIS usually presents at birth with ambiguous genitalia requiring a crucial and decisive clinical judgement on sex of rearing to be made rapidly. The expert pediatric endocrinologist must balance the need for early genital surgery and vicarious decision-making against the risk of possible subsequent regret by the affected individual as an adult. This makes for inevitably complex, difficult and contentious choices as the available systematic prospective evidence from long-term follow-up of sex or rearing is still limited.
Genital surgery for hypospadias is often required and usually uncertainty remains about the adequacy of the potential for post-pubertal virilization due to either endogenous or exogenous testosterone. If pubertal progression is inadequate, exogenous testosterone may be useful but higher than usual dosage may be required to get satisfactory effects. Long-term follow-up of PAIS raised as males has shown apparently adequate psychosexual function despite phallic underdevelopment, limited somatic virilization and dissatisfaction with outcomes by some patients as adults , For those to be reared as females, the management is similar to that for CAIS and involves early genital surgery and pre-pubertal gonadectomy to prevent unwanted virilization.
The blood LH and testosterone concentrations are usually but not always elevated although the androgen sensitivity index, the product of serum LH and testosterone concentrations, is more consistently raised. In common with mutations in many other genes, making a clear distinction between the most minor grades of clinical pathology and a silent, functionally insignificant polymorphism is challenging and depends on reproducing experimentally the functional consequences of the mutation in an authentic biological system.
Ideally such verification is performed in vivo eg in genetically modified mouse models but, as this is laborious and expensive, it is rarely undertaken. The functional verification of putative mutations is usually undertaken by either in silico prediction of functional effects of structural protein changes from sequence data or in vitro studies of cultured cells or cell-free systems aiming to characterize protein functions. Nevertheless, although informative, the biological fidelity of these surrogate endpoints relative to the in vivo effects on androgen action may remain questionable.
All types of mutations have been reported in the AR gene including disruption of the reading frame by deletions, insertions, splice site interruption and frame-shift which usually produce major interference with function as well as the more common single base substitutions with effects ranging from nil to complete functional inactivation. In addition, mutation can produce less common mechanisms of interrupting AR function such as inefficient translation, unstable protein, or aberrant translational start sites all leading to reduced expression of functional AR protein.
Mutations occur throughout the AR gene, probably at random; however, those reported are distributed unevenly because the most important functional regions of the gene are sensitive to even minor changes in sequence whereas the more variable regions may tolerate sequence changes without functional consequences. For example, despite forming more than half the AR sequence, few functionally important mutations are reported in the NTD exon1.
Those described in exon 1 mostly represent major disruptions of the AR protein due to creation of a premature stop codon, a major deletion or frame shift mutation causing mistranslation onward from exon 1 whereas point mutations are more likely to constitute functionally insignificant silent polymorphisms. The profusion of AR mutations has created numerous experiments of Nature with multiple different mutations involving the same amino acid with the physiological consequences depending generally on how conservative is the amino acid substitution.
Nevertheless, there are exceptions to such categorization with mutations in regions other than the DBD or LBD sometimes unexpectedly affecting DNA or ligand binding properties presumably through physical interaction effects in the tertiary structure of the AR in its 3 dimensional topography. The familial occurrence of androgen insensitivity due to X-linked inheritance of mutated AR makes carrier detection and prenatal genetic diagnosis feasible.
A specific mutation detection test needs to be established usually involving PCR-based genotyping for point mutations athough other mutational mechanisms may require more complex genotyping methods. For prenatal genetic diagnosis now usually applied to chorionic villus samples, the genetic diagnosis must be rapid, reliable and efficient. However, accurate genetic counselling relies on the a consistent and predictable phenotype for any specific genotype. Discrepancies in the fidelity of phenotype within families, or between unrelated individual bearing the identical mutation, is relatively common in PAIS and may be attributable to somatic mosaicism or the effect of modifier genes that influence androgen action such as 5a reductase An exotic, complex DNA breakage repair slippage mechanism has also been described to produce mutiple mutations within a single family Wider population genetic screening for AR mutations is not currently cost-effective because, despite diminishing costs for increasingly facile genetic testing, the large number of different mutations featuring diverse mechanisms and variable phenotype which still mostly predict a normal life expectancy but a diminished quality of life that is difficult to cost or cure Acquired androgen insensitivity during life can arise either through postnatal somatic or germline AR mutations or by non-genetic, non-receptor mechanisms that hinder androgen action.
Somatic AR mutations, arising de novo postnatally in the stem cell pool of repopulating cells, are theoretically possible but have not been reported. Somatic AR mutations are relatively common in prostate cancer usually arising in late stage disease palliatively treated by androgen deprivation when AR mutations and functional splice variants are reported The switch of highly androgen dependent prostate cancer cells to an androgen deplete milieu may encourage clonal selection of androgen insensitive sublines to proliferate in the terminal stage of the disease.
Genetic instability of prostate cancer cells may also contribute to this process although somatic AR mutations are rare in other cancers such as liver or breast cancer in the absence of androgen deprivation. Somatic AR mutation in prostate cancer cells are responsible for the paradoxical anti-androgen withdrawal syndromes observed with non-steroidal flutamide, bicalutamide, nilutamide or steroidal cyproterone, megestrol treatment.
- Bestselling Series.
- Endotext [Internet]..
- Quality of the Body Cell Mass | SpringerLink.
In this state, anti-androgen withdrawal or switch-over produces remission of worsening disease attributable to the occurrence of a de novo AR mutation in prostate cancer cells which alters ligand specificity turning the non-steroidal antiandrogens into AR agonists , The LNCaP prostate cell line widely used in cancer cell biology research harbours a mutated AR TA which occurs relatively frequently in prostate cancer metastases and can cause the flutamide withdrawal syndrome After transient remission following castration, however, prostate cancers resume growth in the apparently androgen independent terminal, treatment resistant stage of the disease.
Abiraterone has proven effective and well-tolerated in treatment of late stage, apparently androgen independent prostate cancer although the blockade of glucocorticoid and mineralocorticoid synthesis requires adrenal replacement therapy. In addition, newer androgen receptor blockers also provided promising new therapeutic approaches especially for castration-resistent advanced prostate cancer Acquired androgen insensitivity may occur without AR mutations by mechanisms such as drugs including non-steroidal flutamide, bicalutamide, nilutamide and steroidal cyproterone acetate , drugs that block part of testosterone activation such as 5a reductase inhibitors finasteride, dutasteride or estrogen antagonists or aromatase inhibitors.
In addition, drugs may have physiological effects or pharmacological actions that oppose various steps in androgen action such as LH and FSH suppression by estrogens or progestins or that cause an increase in circulating SHBG which may influence testosterone transfer from blood into tissues to produce a functional phenocopy of androgen insensitivity. Acquired androgen insensitivity in various disease states is reported with hormonal findings reflecting impeded androgen action which may be reversible with alleviation of the underlying disease.
For example, in hyperthyroidism, increased blood LH and testosterone concentrations with clinical features of androgen deficiency are mediated by increased circulating SHBG due to thyroid hormone-induced hepatic SHBG secretion whereas in hypothyroidism the reduced blood testosterone and SHBG are rapidly corrected by thyroid hormone repacement therapy In epilepsy, anticonvulsant-induced increase in hepatic SHBG secretion appears to be a common denominator in the near ubiquitous reproductive endocrine abnormalities in men with epilepsy The relative contributions of impaired tissue transfer of testosterone, reduced testosterone metabolic clearance rate or direct anti-androgenic effects of valproate remain to be clarified.
Androgen therapy can be classified as physiologic replacement or pharmacologic therapy according to the dose, type of androgen and objectives of treatment. Androgen replacement therapy aims to restore tissue androgen exposure in androgen-deficient men due to pathological hypogonadism disorders of the reproductive system to levels comparable with those of eugonadal men. Using the natural androgen testosterone and a dose limited to one that maintains blood testosterone levels within the eugonadal range, androgen replacement therapy aims to restore the full spectrum of androgen effects while replicating the efficacy and safety experience of eugonadal men of similar age.
Androgen replacement therapy is unlikely to prolong life because androgen deficiency, whether due to castration or biological disorder has minimal effect in shortening life expectancy As an alternative, pharmacologic androgen therapy uses androgens without restriction on androgen type or dose but aims to produce androgen effects on muscle, bone, brain, or other tissues. In such pharmacological treatment, regardless of androgen status, an androgen is used therapeutically to exploit the anabolic or other effects of androgens on muscle, bone, and other tissues as hormonal drugs in various non-reproductive disorders.
Such pharmacological androgen therapy is neither constrained to using the natural androgen, testosterone, nor it is limited to physiological replacement doses or their equivalent. Rather, it is judged on its efficacy, safety, and relative cost-effectiveness for that specific indication just as any other hormonal or xenobiotic non-hormonal therapeutic drug. Many older uses of pharmacologic androgen therapy are now considered second-line therapies as more specific treatments are developed For example, erythropoietin has largely supplanted androgen therapy for anemia due to marrow or renal failure and improved first-line drug treatments for endometriosis, osteoporosis and advanced breast cancer have similarly relegated androgen therapy to a last resort while newer mechanism-based agents in development for hereditary angioedema may displace 17a-alkylated androgens Nevertheless in many clinical situations, pharmacological androgen therapy remains a cost-effective option with a long-established efficacy and safety profile.
Establishing a pathological basis for androgen replacement therapy requires identifying well-defined disorders of the hypothalamus, pituitary or testis which have a known and clearly defined pathological basis. The principal goal of androgen testosterone replacement therapy is to restore a physiologic pattern of net tissue androgen exposure in androgen deficient men whose damaged reproductive systems are unable to secrete adequate testosterone to levels comparable with those of eugonadal men.
This treatment uses only the natural androgen, testosterone, aimed at restoring a physiologic pattern of androgen exposure using a dose limited to that which maintains blood testosterone levels within the eugonadal range. Such treatment aims to restore the full spectrum of androgen effects when endogenous testosterone production fails due to pathological disorders of the reproductive system testicular-hypthalamic-pituitary axis.
The overall goal of such replacement therapy is to replicate the efficacy and safety experience of eugonadal men of similar age by recreating the full spectrum of endogenous natural androgen effects on tissues so as to recapitulate the natural history of efficacy and safety of endogenous testosterone. Due to its variable and often subtle clinical features, androgen deficiency remains significantly underdiagnosed, thus denying sufferers simple and effective medical treatment with often striking benefits.
The testis has two physiological functions, spermatogenesis and steroidogenesis, either of which can be impaired independently, resulting in infertility or androgen deficiency, respectively, so the term hypogonadism is inherently ambiguous. However, hypogonadism of any cause may require androgen replacement therapy if the deficit in endogenous testosterone production is sufficient to cause clinical and biochemical manifestations of androgen deficiency. Androgen deficiency is a clinical diagnosis with a characteristic presentation and underlying pathological basis in hypothalamus, pituitary or testis disorder, and confirmed by blood hormone assays see Chapter 4 for details.
The clinical features of androgen deficiency vary according to the severity, chronicity, and epoch of life at presentation. These include ambiguous genitalia, microphallus, delayed puberty, sexual dysfunction, infertility, osteoporosis, anemia, flushing, muscular ache, lethargy, lack of stamina or endurance, easy fatigue, or incidental biochemical diagnosis. For each androgen deficient man, his leading clinical symptoms of androgen deficiency are distinctive, reproducible and corresponds to a specific blood testosterone threshold for any individual but both the symptom s and threshold vary between men Because the underlying disorders are mostly irreversible, lifelong treatment is usually required.
Androgen replacement therapy can rectify most clinical features of androgen deficiency apart from defective spermatogenesis When fertility is required in gonadotropin-deficient men, spermatogenesis can be initiated by treatment with pulsatile GnRH if pituitary gonadotroph function is intact or gonadotropins to substitute for pituitary gonadotropin secretion see also Endotext, Endocrinology of Male Reproduction, Chapter 5, Hypogonadotropic Hypogonadism HH and Gonadtropin Therapy. The short half-life of LH would require multi-daily injections rendering it unsuitable for gonadotrophin therapy Instead practical gonadotropin therapy uses hCG, a placental heterodimeric glycoprotein which has a much longer duration of action allowing it to be administered every two or three days.
The chorionic gonadotropin hCG consists of an identical a subunit as LH also the same as in FSH and TSH combined with a distinct b subunit that is highly homologous to the LH b subunit except for a C terminal extension of 22 amino acids which includes four O-linked sialic acid-capped, carbohydrate side chains. This C terminal extension markedly prolong the circulating half-life of hCG relative to LH thereby making it a naturally occuring long-acting LH analog.
Pharmaceutical hCG, originally purified from pregnancy urine and more recently its recombinant form, can be administered times weekly for several months. Where spermatogenesis remains persistently suboptimal, recombinant FSH may subsequently be added Once fertility is no longer required and any pregnancy has passed the 1 st trimester, androgen replacement therapy usually reverts to the simpler and cheaper use of testosterone while preserving the ability subsequently to reinitiate spermatogenesis by gonadotropin replacement The potential value of hCG therapy in gonadotropin-deficient adolescents to produce timely testis growth replicating physiologic puberty , rather than reliance on exogenous testosterone which leaves a dormant testis but remains standard management, has yet to be fully evaluated The extension of testosterone replacement therapy to men with partial, subclinical or compensated androgen deficiency states remain of unproven value.
Although such features may signify mild androgen deficiency, substantial clinical benefits from testosterone replacement therapy remain to be demonstrated Hormonal male contraception can be considered a form of androgen replacement therapy because all currently envisaged regimens aiming to suppress spermatogenesis and thereby endogenous testosterone production by inhibiting gonadotropin secretion, use testosterone either alone or with a progestin or a GnRH antagonist see also Endotext, Endocrinology of Male Reproduction, Chapter 15, Male Contraception.
As a consequence, exogenous testosterone is required to replace endogenous testosterone secretion. Schematic representation of the hypothalamo-pituitary-testicular HPT system in health left panel and in disease right panel. While these non-reproductive disorders may lead to a reduced serum testosterone, that is neither a testosterone deficiency state nor warrants testosterone treatment without convincing evidence of safety and efficacy.
Pharmacologic androgen therapy uses androgens to maximal therapeutic efficacy within adequate safety limits but without regard to androgen type, dose, duration of treatment or gender. To obtain morbidity benefits requires that androgens must modify the natural history of an underlying disease, a goal not yet achieved in any nongonadal disorder. Morbidity benefits are more achievable in aiming to improve quality of life by enhancing muscle, bone, brain, or other androgen-sensitive function including mood elevation as an adjuvant therapy in non-reproductive diseases.
Such treatment is judged by the efficacy, safety, and cost-effectiveness standards of other drugs but very few studies fulfill the requirements of adequate study design prospective design, randomization, placebo control, objective and validated end points, adequate power, and appropriate duration , Accordingly, the role of pharmacological androgen therapy is mostly relegated to an affordable but second line, supportive or adjunctive therapy The range of pharmacologic uses of androgens include: treatment of anemia due to marrow or renal failure; osteoporosis especially where estrogen therapy is contraindicated; advanced ER-positive breast cancer; hereditary angioedema C1 esterase inhibitor deficiency ; and for immunologic, pulmonary, and muscular diseases reviewed in detail In anemia due to renal or marrow failure, androgens have proven beneficial effects on morbidity by improving hemoglobin levels, reducing transfusion requirements and improving quality of life.
However, characteristically androgens do not improve mortality as they do not change the natural history of the underlying disease. In renal anemia, androgens are equally effective with erythropoeitin in maintaining hemoglobin levels and reducing transfusion requirement However, their virilizing effects in women are limiting so that the affordability and augmentation of erythropoeitin effects by androgens provides an ongoing adjuvant role in older men or where erythropoeitin is unavailable Similarly, in anemia due to marrow failure androgens reduce transfusion dependence but do not improve survival from the underlying marrow disorders.
They remain secondary line, supportive therapy for men in whom marrow transplantation is not feasible or fails. For historical reasons, pharmacologic androgen therapy has often involved synthetic, orally active 17a-alkylated androgens despite their hepatotoxicity including cholestasis, hepatitis, adenoma and peliosis Other than in treating angioedema, in which direct hepatic effects of 17a-alkyl androgens rather than androgen action per se may be crucial to increasing circulating C1 esterase inhibitor levels to prevent attacks , safer nonhepatotoxic testosterone preparations should generally be favored for long-term clinical use, although the risk-benefit balance may vary according to prognosis.
For hereditary angioedema, newer mechanism-based, more specific and costly therapies such as purified or recombinant C1 inhibitor and bradykinin or kallekrein antagonists may overtake the traditional role of 17a-alkylated androgens such as danazol for long-term prophylaxis of hereditary angioedema , or endometriosis. In most clinical applications, pharmacological androgen therapy remains a cost-effective option relative to newer, more costly therapies.
An important watershed was the proof via a well-designed, placebo-controlled randomized clinical trial that pharmacologic testosterone doses increase muscular size and strength even in eugonadal men , overturning prior belief to the contrary Testosterone has clear dose-dependent effects, extending from below to well above the physiological concentrations without evidence of a plateau, on muscle size and strength but not performance function or fatigue in young and older men with similar magnitude of ultimate effect Nevertheless, ageing reduced the responsiveness of older muscle to testosterone as the same doses produced higher blood testosterone concentrations in older men.
The higher blood testosterone concentrations are the result of decreased testosterone metabolic clearance rate due to age-related higher blood SHBG concentrations Similarly, erythropoeitic effects of testosterone are greater in older men who developed a higher rate of polycythemia Diverse androgen-sensitive effects including changes in metabolic function, cognition, mood and sexual function were minimal at physiological testosterone doses The wide dose-response to testosterone through and beyond the physiologic range suggests that androgens may have beneficial effects in reversing the frailty observed in many medical settings.
Whether such effects can be applied effectively and safely to improve frailty and quality of life in chronic disease or in male ageing remains an important challenge to be determined. Pharmacological androgen therapy for human immunodeficiency virus HIV infection in the absence of classical hypogonadism has been investigated for its effects on disease-associated morbidity, notably AIDS wasting. However pharmacologic androgen therapy does not alter the natural history of underlying disease and the objective functional benefits remain modest being confined to reversing some aspects of AIDS wasting.
Meta-analysis of randomized, placebo-controlled studies of pharmacologic androgen therapy in HIV-positive men with AIDS wasting indicate modest increase in lean and decreased fat mass with additive effects from resistance training but inconsistent improvement in quality of life Among HIV-positive men without wasting there is less improvement in body composition and none in quality of life although, in affluent countries, there is a popular subculture of androgen abuse The oral progestin, megestrol acetate, used alone as an appetite stimulant induces profound gonadotropin and testosterone suppression to castrate levels and predominanty increases fat mass rather than reversing the loss of muscle It is now well recognized that chronic use of opiates has multiple effects on the human endocrine system , including prominent mu-opioid receptor mediated effects on the hypothalamus resulting in suppression of pituitary LH secretion and thereby testicular testosterone production However, despite an open-label study suggesting quality of life benefits for testosterone replacement therapy , placebo-controlled studies show no clinically significant benefit possibly due to failure to rectify non-androgenic effects of opiates.
A special application of pharmacologic androgen treatment is its use in women with estrogen-resistant menopausal symptoms such as loss of energy or libido. The similarity of blood testosterone in women, children, and orchidectomized men indicates that the term female androgen deficiency is not meaningful in women with normal adrenal function In women with adrenal failure due to hypothalamo-pituitary or adrenal disease, DHEA replacement therapy 14 has significant but modest clinical benefits in some but not all studies with relatively frequent, mild virilizing side-effects.
Similar effects are observed using testosterone instead of DHEA Well controlled studies of testosterone administration for menopausal symptoms or sexual hypofunction in women with normal adrenal function show strong placebo effects but minimal or no consistent symptomatic benefits despite supraphysiological blood testosterone levels High-dose testosterone used at male androgen replacement therapy doses produce markedly supraphysiologic blood testosterone levels and virilization including voice changes and androgenic alopecia Lower but still supraphysiologic testosterone doses and blood levels increase bone density in menopausal women but produce virilizing adverse effects hirsutism, acne in short-term studies.
Overall the long-term efficacy and safety risks for cardiovascular disease and hormone dependent cancers breast, uterus, ovary for testosterone therapy in women remain unclear Studies of testosterone administration as a form of adjuvant pharmacologic androgen therapy in women with chronic medical disorders such as anorexia nervosa , HIV and systemic lupus erythematosus have little consistent effect on disease activity or quality of life including sexual function.
Many important questions and opportunities remain for pharmacologic androgen therapy in nongonadal disease, but careful clinical trials are essential for proper evaluation Recent well designed placebo-controlled clinical studies of pharmacologic androgen therapy in chronic disease have been reported.
In men with severe chronic obstructive pulmonary disease it produces modest increases in muscle mass and strength with improved quality of life but no effect on underlying lung function whereas oral megestrol administration had similar effects despite marked suppression of blood testosterone levels Similarly, although in an observational study chronic heart failure is associated with lower blood testosterone that is proportional to the decrease in cardiac function and which predicts survival , a placebo-controlled prospective study of testosterone administration showed improvement in effort-dependent exercise capacity but not in left ventricular function or survival This discrepancy suggests that the lowered blood testosterone is the consequence of a non-specific adaptive reaction of the reproductive hormonal axis to chronic disease ontogenic regression rather than a detrimental effect susceptible to being overcome by androgen supplementation.
Both testosterone and its non-aromatizable derivative nandrolone, produce increased bone density in men with glucocorticoid-induced osteoporosis with minimal short-term side-effects The best opportunities for future evaluation of adjuvant use of androgen therapy in men with nongonadal disease include steroid-induced osteoporosis; wasting due to AIDS or cancer cachexia; and chronic respiratory, rheumatologic, and some neuromuscular diseases.
Future studies of adjuvant androgen therapy require high-quality clinical data involving randomization and placebo controls as well as finding the optimal dose and authentic clinical, rather than surrogate, end points. After Handelsman et al. Ann Clin Biochem An observational study of older war veterans reported testosterone treatment was associated with better survival ; however, bias in the non-randomised design allowing for preferential treatment of healthier men with testosterone may explain those findings However, as observational studies cannot ascribe causality it remains likely that such reductions in blood testosterone may be a consequence rather than a cause of the increased mortality.
Interventional studies have remained too small and short-term to resolve this dilemma. Definitive evidence as to whether androgen treatment ameliorates age-related changes in bodily function and improves quality of life requires high quality, randomized placebo-controlled clinical trials using testosterone , DHT or hCG or synthetic androgens ; however, so far the only consistent changes observed in well controlled studies of at least 3 months duration have been small increases in lean muscle and decreases in fat mass. As a result, the Institute of Medicine report recommended a priority to acquire more convincing, target-defining feasibility evidence to justify a large-scale clinical trial to weight potential benefits against risks of accelerating cardiovascular and prostate disease.
The benefit in sexual function was less robust than the effects of PDE5 inhibitors and of uncertain clinical significance, insufficient to warrant initiating testosterone treatment of older men These findings do not materially change the unfavourable balance of evidence for testosterone treatment for functional causes of a low serum testosterone in the absence of pathological hypogonadism. The major hypothetical population risk from androgen therapy for male ageing remains increased cardiovascular disease as was proven unexpectedly by the WHI study for the risks of estrogen replacement for menopause Cardiovascular disease has earlier onset and greater severity in men resulting in a fold higher age-specific risks of cardiovascular death compared with women The male disadvantage in cardiovascular disease has a complex pathogenesis with androgens having apparently beneficial effects including in regulating cardiac ion channel fluxes that dictate QT interval length, cardiac ventricular repolarization and lesser risk of arrthymia as well as angiogenesis which must be integrated with other apparently deleterious effects , Prospective observational data remains conflicting, with low blood testosterone predicting subsequent cardiovascular death in some but not other studies.
Testosterone therapy for older, frail men may increase adverse cardiovascular events , side-effects that may be under reported in previous studies not reporting such hazards The latter interpretations are supported by Mendelian randomization studies which report only non-causal relationships albeit with important methodological caveats Independent critical analyses have concluded that it is not valid to extrapolate the features of pathological hypogonadism in younger men to older men with possibly age-related hypogonadism Nor did a comprehensive meta-analysis identify any valid basis for testosterone treatment of such older men Decisive testing of these alternatives requires an adequately powered, placebo-controlled, prospective, randomized clinical trial As the decisive safety and efficacy evidence on testosterone supplementation for male ageing remains distant, interim clinical guidelines have been developed by academic and professional societies ostensibly aiming to restrain the unproven testosterone prescribing which nevertheless escalated over recent decades in Australia , Europe and most dramatically in North America Consequently, more recent clinical guidelines have curbed the tacit promotion of testosterone prescribing for men without pathological hypogonadism At present, testosterone treatment cannot be recommended as routine treatment for male ageing see also Endotext, Endocrinology of Male Reproduction, Chapter 11, Age-Related Changes in the Male Reproductive Axis.
Nevertheless, androgen replacement therapy may be used cautiously even in older men with pre-existing pathological pituitary-gonadal disorders causing androgen deficiency if contraindications such as prostate cancer are excluded. Misuse of androgens involves medical prescription without a valid clinical indication and outside an approved clinical trial, and androgen abuse is the use of androgens for nonmedical purposes.
Although there is no exact boundary defining overuse, mass marketing and promotion to fend off ageing in the absence of reliable evidence are hallmarks of systemic misuse of androgens. Androgens have a mystique of youthful virility making them ideal for manipulative marketing to the wealthy, worried well as they grow older. Despite the absence of any new approved indications beyond the treatment of pathological classical hypogonadism, testosterone prescribing has displayed major and progressive increases especially since In Australia, for example, where a national health scheme provides accurate prescription data, striking differences between states, increasing use of costlier newer products and partially effective regulatory curbs on unproven testosterone prescribing were reported , A study of international trends in testosterone prescribing based on per capita sales of testosterone usage and pooling all products into standardized testosterone usage estimates per person per month , showed testosterone usage increased in every world region and for 37 of 41 countries surveyed over the 11 years The increases were most striking in North America where they rose fold in Canada and fold in the USA over only a decade.
Other estimates from the US confirm an increase in testosterone prescribing although with a lower increase when based on selective sources such as private insurance databases , or the Veterans Administration VA system These lower increases underestimate the national usage, indicating the efficacy of formulary or other restrictions constraining unjustified testosterone prescribing but implies much greater increases in testosterone usage outside those populations served by private medical insurance and the VA system.
The major factors driving these increases include direct-to-consumer advertising as part of a broad spectrum of pharmaceutical promotional activities as well as permissive clinical prescribing guidelines from professional and single-issue societies. The latter have, in concert, tacitly encouraged, facilitated, and promoted increased off-label testosterone prescribing, bypassing the requirement for high quality clinical evidence of safety and efficacy.
Nevertheless, it is highly unlikely that recent steep increases in testosterone prescribing and use can be attributed to rectifying the under-diagnosis of KS, which is generally diagnosed in young male adults. Not only does total testosterone prescribing in some countries exceed the maximal amount that could be attributed to pathological AD, there is no evidence the diagnosis of KS has increased in recent years , Androgen abuse originated in the s as a product of the Cold War whereby communist Eastern European countries could develop national programs to achieve short-term propaganda victories over the West in Olympic and international sports This form of cheating was readily taken up by individual athletes seeking personal rewards of fame and fortune in elite competitive sports.
Over decades, androgen abuse has become endemic in developed countries with sufficient affluence to support drug abuse subcultures. The myotrophic benefits of supraphysiologic androgen doses in eugonadal men were long doubted in the belief that alleged performance gains were attributable to placebo responses involving effects of motivation, training and diet, This belief was overturned by a randomized, placebo-controlled clinical study showing decisively that supraphysiologic testosterone doses mg testosterone enanthate weekly for 10 weeks increases muscular size and strength In well-controlled studies of eugonadal young and older men, testosterone shows strong linear relationships of dose with muscular size and strength throughout and beyond the physiologic range.
The additional dose-dependent increases in erythropoesis and mood may also enhance the direct myotrophic benefits of supraphysiologic androgen dose. While these studies prove the unequivocal efficacy of supraphysiological androgen dosage to increase muscle size and strength even in eugonadal men, the specific benefits for skilled athletic performance depend on the sport involved with greatest advantages evident in power sports. The overall safety of the sustained supraphysiological androgen exposure in these settings remains undefined, notably for cardiovascular and prostate disease as well as psychiatric sequelae Progressively, the epidemic of androgen abuse has spread from elite power athletes so that the majority of abusers are no longer athletes but recreational and cosmetic users wishing to augment body building or occupational users working in security-related professions A remarkable meta-analysis of papers reporting prevalence of androgen abuse within various populations comprising 2.
As an illicit activity, the extent of androgen abuse in the general community is difficult to estimate, although point estimates of prevalence are more feasible in captive populations such as high schools. Predictors of androgen abuse in high schools are consistent across many cultures include truancy, availability of disposable income, minority ethnic or migrant status and there is significant overlap with typical features of adolescent abuse of other drugs.
Voluntary self-report of androgen abuse understates prevalence of drug use among weight lifters and prisoners Abusers consume androgens from many sources including veterinary, inert, or counterfeit preparations, obtained mostly through illicit sales by underground networks with a small proportion obtained from compliant doctors. Highly sensitive urinary drug screening methods for detection of natural and synthetic androgens, standardized by the Word AntiDoping Agency WADA for international and national sporting bodies as a deterrent, has contributed to the progressive elimination of known androgens from elite sporting events.
The persistent demand for androgens as the most potent known ergogenic drugs has led to the production in unlicensed laboratories of illicit designer androgens such as norbolethone , tetrahydrogestrinone and dimethyltestosterone custom-developed for elite professional athletes to evade doping detection. The rapid identification of these designer androgens has meant that they have been seldom, if ever, used Corresponding legislation has also been introduced by some governments to regulate clinical use of androgens and to reduce illicit supply of marketed androgens.
The medical consequences of androgen abuse for the cardiovascular system have been reviewed , but only few anecdotal reports are available relating to prostate diseases However, for both, long-term consequences of androgen abuse based on anecdotal reporting are likely to be significantly underestimated due to underreporting of past androgen use and non-systematic follow-up.
Few well controlled prospective clinical studies of the cardiovascular or prostatic , , effects of high dose androgens have been reported. Most available clinical studies consist of non-randomized, observational comparisons of androgen users compared with non or discontinued users However, such retrospective observational studies suffer from ascertainment, participation and other bias so that important unrecognized determinants of outcomes may not be measured.
Given the low community prevalence of androgen abuse, well designed, sufficiently powerful retrospective case-control studies are required to define the long-term risks of cardiovascular and prostate disease The best available evidence suggests elite athletes have longer life expectancy due to reduced cardiovascular disease This benefit, however, is least evident among power athletes, the group with highest likelihood of past androgen abuse, a finding confirmed by a small study finding a greater than 4-fold increase in premature deaths from suicide, cardiovascular disease, liver failure and lymphoma among 62 former power athletes compared with population norms More definitive studies are required, but, at present, largely anecdotal information suggests that serious short-term medical danger is limited considering the extent of androgen abuse, that androgens are not physically addictive and that most androgen abusers eventually discontinue drug use.
After cessation of prolonged use of high-dose androgens, recovery of the hypothalamic-pituitary-testicular axis may be delayed for months and up to 2 years , creating a transient gonadotropin deficiency state Although hCG can induce spermatogenesis , , like exogenous testosterone, it further delays recovery of the reproductive axis and perpetuates the drug abuse cycle There remains anecdotal evidence from experienced observers that prolonged hypothalamic-pituitary suppression by high dose exogenous androgens may not always be fully reversible after even a year off exogenous androgens, resembling the incomplete reversibility of GnRH analog suppression of circulating testosterone in older men after cessation of prolonged medical castration for prostate cancer The goal of androgen replacement therapy is to replicate the physiologic actions of endogenous testosterone, usually for the remainder of life as the pathological basis of hypogonadism is usually irreversible disorders of the hypothalamus, pituitary or testis.
The ideal product for long-term androgen replacement therapy should be a safe, effective, convenient, and inexpensive form of testosterone with long-acting depot properties providing steady-state blood testosterone levels due to reproducible, zero-order release kinetics. Androgen replacement therapy usually employs testosterone rather than synthetic androgens for reasons of safety and ease of monitoring.
The aim is to maintain physiologic testosterone levels and resulting tissue androgen effects. The practical goal of androgen replacement therapy is therefore to maintain stable, physiologic testosterone levels for prolonged periods using convenient depot testosterone formulations that facilitate compliance and avoid either supranormal or excessive fluctuation of androgen levels.
The adequacy of testosterone replacement therapy is important for optimal outcomes as suboptimal testosterone regimens, whether due to inadequate dosage or poor compliance, produce suboptimal bone density compared with maintenance of age-specific norms achieved with adequate testosterone regimens , Similarly, the severity of the androgen deficiency also predicts the magnitude of the restorative effect of testosterone replacement with greatest effects early in treatment of severe androgen deficiency , whereas only minimal effects are evident for testosterone treatment of mild androgen deficiency However, this polyglutamine repeat is inversely related to ambient blood testosterone levels consistent with the reciprocal relationship between repeat lengths and AR transactivational activity.
Hence this polymorphism is only a weak modulator of tissue androgen sensitivity.