WELCOME TO THE CLINICAL CENTER GRAND ROUNDS, A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN BETHESDA, MD. THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING TOMORROW'S CURES. LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV WE HAVE SPECIAL GRAND ROUNDS WITH TWO COLLEAGUES WHO WILL REPRESENT THE NIDDK AND NIMH, AND WILL SHARE UPDATES ON THEIR RESEARCH RELATED TO THE ENDOWCIP. SO OUR FIRST SPEAKER, LYNETTE NIEMAN WHO IS A SENIOR INVESTIGATOR IN THE DIABETES ENDOCRINOLOGY AND OBESITY BRANCH IN NIDDK. GRADUATEDFROM COLLEGE, EARNING HER MEDICAL DEGREE FROM BUFFALO, COMPLETED AN INTERNAL MEDICAL RESIDENCY IN ENDOCRINOLOGY FELLOWSHIP. HER FIRST NIH APPOINTMENT WAS AN ENDOCRINOLOGY FELLOW AT THE NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, SERVES AS THAT INSTITUTE'S -- SERVED AS THAT INSTITUTE'S CLINICAL DIRECTOR FROM 1994 UNTIL 2001. NOW SHE'S THE DIRECTOR OF THE OFFICE OF HUMAN SUBJECTS RESEARCH PROTECTION FOR INTRAMURAL RESEARCH AT NIH, A POSITION SHE'S HELD SENSE 2011. ALSO HEAD OF THE ENDOCRINOLOGY CONSULTATION SERVICE. FOCUSES ON DEVELOPMENT OF ANTIPROGESTINS, TREATMENT OF REPRODUCTIVE DISORDERS. ALSO STUDIES CLINICAL DESORDERS OF COURTSAL. HAS NUMEROUS AWARDS, INCLUDING THE DISTINGUISHED CLINICAL TEACHER AWARD, IN 2005, FROM NIH. AND IN 2009 HONORED AS A DISTINGUISHED PHYSICIAN AWARD BY THE ENDOCRINOLOGY SOCIETY. SHE HAS SERVED AS A MEMBER OF THE AMERICAN BOARD OF INTERNAL MEDICINE ENDOCRINOLOGIOLOGY AND METASTASES SUBCOMMITTEE 2007 TO 2013ENED A THE THE PER ELECT DIGNITY OF THE ENEPSOCIETY. TODAY, SHE'S GOING TO PRESENT TO US THE TITLE OF HER TALK, CORTISOL, TOO MUCH? TOO LITTLE? OR JUST RIGHT? WELCOME. [APPLAUSE] >> THANK YOU VERY MUCH. IT'S A PLEASURE TO BE HERE. AND TO SEE SO MANY OF YOU IN THE AUDIENCE. HOPEFULLY ON VIDEO CAST. I'M GOING TO DO SOMETHING A LITTLE UNUSUAL TODAY WHICH IS THAT I'M NOT GOING TO TALK ABOUT A LOT OF CLASSICAL ENDOCRINOLOGY. I'M NOT GOING TO PRESENT A LOT OF DATA THAT DEFINITELY ESTABLISHED AS FACT. I'M GOING TO LEAD YOU ON A ROAD OF SPECULATION, I HOPE. SO I HOPE THAT THAT WILL BE GOOD FOR EVERYBODY. SO I HAVE A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT WITH HRA PHARMA FOR DEVELOPMENT OF THE -- REFERRING TO ENONE SLIDE. RU486. A SECTION AUDITer AND AUTHOR IN THE ADRENAL SECTION UP-TO-DATE AND I'M THE PRESIDENT ELECT DIGNITY DESIGNATE. NONE OF THE VIEW ARE FROM THE SOCIETY. AFTER ATTENDING THE LECTURE THE PARTICIPANTS WILL DEMONSTRATE THE ABILITY TO DESCRIBE PHYSIOLOGIC REGULATION OF CORTISOL SECRETION AND ACTION AND DISTINGUISH BETWEEN ADRENAL FATIGUE AND ADRENAL INSUFFICIENCY. THIS IS WHAT I'M GOING TO TALK ABOUT. GOING TO GO THROUGH A LITTLE BIT OF BACKGROUND ON CORTISOL REGULATION, NUCLEAR RECEPTORS iAND COREGULATERS, CORTISOL ACTION, PATHOI DIDN'T SEOLOGY, TOO MUCH OR TOO LITTLE. MYTH OF ADRENAL FATIGUE AND FINISH UP WITH A QUESTION OF WHETHER OR NOT A NORMAL CORTISOL IS PATHOPHYSIOLOGIC. THIS IS A FAMILY OF INTRACELLER MOLECULES. THIS FAMILY MEDIATES THE BIOLOGICAL ACTIVITY OF MOLECULES SUCH AS STEROIDS, GLUCOCORTICOIDS, THE TOPIC OFF MY TALK. THEY FUNCTION AS LIGAND DEPENDENT TRANSCRIPTION FACTORS. HERE WE HAVE A CARTOON THAT SHOWS HOW THIS WORKS. IN TERMS OF NUCLEAR RECEPTORS BINDING, A FILLED IN DOT, RECRUITING A VARIETY OF COREGULATERS AND CHROMATIN MODULATORS TO THE COMPLEX WHICH INTERACTS WITH RNA POLYMERASE AND ALLOWS FOR TRANSCRIPTION. AND INITIATION OF ACTION OF THE LIGAND HEAR, CORTISOL. SO HOW IS CORTISOL REGULATES? THE NORMAL ASSIST IS SHOWN HEAR. WHAT YOU CAN SEE IS THAT THE HYPOTHALAMUS MAKES RELEASING HORMONE, TRAVELING DOWN THE STOCK TO THE PITUITARY GLAND, STIMULATING THE SECRETION. TH TRAVELS INTO THE BLOOD, STIMULATING THE PRODUCTION OF CORTISOL. ONE OF THE MOST IMPORTANT PIECES OF THIS SYSTEM IS THAT THERE IS A VERY ROBUST NIH FEEDBACK OF CRAIG'S LIST ON CRH SECRETION AND A -- CORTISOL ON SECRETION, SO THAT THE BODY SENSES WHEN THERE IS ENOUGH CORTISOL AND TURNS THE SYSTEM OFF AND WHEN THERE IS TOO LITTLE, THE SYSTEM IS TURNED BACK ON. WE USE THIS PROPERTY OF NEGATIVE FEEDBACK OF CORTISOL TO TEST THE AXIS TO SEE WHETHER IT WILL RESPOND NORMALLY TO A HIGH POTENCYGLUCO-- THIS IS TO SHOW IT'S NOT REGULATED BY ACTA H. SO CORTISOL ITSELF IS MADE BY THE ADRENAL GLANDS FROM STEROIDS. IT'S SECRETED IN PULSES. IT HAS A SURE CADIAN DAILY RHYTHM, SHOWN HEAR. INCREASE IN CORTISOL IN THE EARLY MORNING HOURS OF THOSE PEOPLE WHO SLEEP DURING THE NIGHT. IT'S REVERSED WHEN YOU SLEEP DURING THE DAY. AND THE PULSES BUILD UP IN FREQUENCY, SO THAT WE HAVE HIGHEST LEVELS EARLY IN THE MORNING, AND THEN THESE PULSES DECREASE AND WE HAVE WITHIN AN HOUR OF GOING TOUSLED TO SLEEP AT NIGHT. CORTISOL IS CARRIED AROUND IN THE BLOOD STREAM BY PROTEINS, CBG. AND BIOLOGICAL FREE FRACTION IS IMPORTANT AND DELIVERED TO THE TISSUERS VIA THESE CARRIER PROTEINS. AND THERE IS INTERCONVERSION IN SOME TISSUES VIA 11 BETA HYDROXY STEROID. THIS IS VERY IMPORTANT IN THE KIDNEY WHERE THE CORTISOL IS INACTIVATED, SO IT DOESN'T ACT ON THE RECEPTOR AND ALSO IS REGENERATED IN A VARIETY OF TISSUES AND I'LL SPEAK MORE ON THAT LATER. AS I MENTIONED EARLIER, IT BINDS TO THE RECEPTOR TO MODULATE TRANSCRIPTION DIRECT LAR OTHER INDIRECTLY. IT'S METABILOUSED AND EXCREATED. WE CAN MEASURE CIRCULATING AS A TOTAL VALUE IN THE BLOOD FANCY MANIPULATION, WE CAN MESHTER FREE FRACTION IN THE BLOOD AND MEASURE THE FREE FRACTION THAT'S SECRETED IN SALIVA AND EXCRETED IN THE URINE. WE HAVE A NIM OF TOOLS THAT WE CAN JUDGE CORTISOL CONCENTRATED. SO I WANT TO JUST MENTION ABOUT WHAT WE KNOW ABOUT WHEN THERE IS TOO MUCH OR TOO LITTLE CORTISOLS. THE RIGHT AMOUNT IS REALLY IMPORTANT. ONE OF THE HORMONES YOU CAN'T LIVE WITHOUT, BUT NOT HAPPY WITH TOO MUCH. THIS IS THE GOLDY LOCKS AND 3 BEARS TRANSLATION HERE. CUSHINGS SYNDROME IS ON THE LEFT. TOO MUCH CORTISOL LEADS TO DEATH, IF IT'S NOT TREATED. AND ON THE RIGHT WHEN YOU HAVE TOO LITTLE, YOU HAVE ADRENAL INSUFFICIENCY, LEADING TO DEATH IF UNDEREATED. THESE ARE VERY IMPORTANT ENDOCRINE DISORDERS TO DESIGNATE IN A TIMELY WAY. DIAGNOSE IN A TIMELY WAY. CUSHINGS WAS DESCRIBED BY HARVEY IN THE 1900S, AND IT'S A SYMPTOM COMPLEX THAT REFLECTS EXCESSIVE TISSUE EXPOSURE TO CORTISOL. ONE OF HIS FIRST PATIENTS IS DESCRIBED BY HIM IN HIS MONO GRAPH SHOWN ON THE LEFT A PATIENT OF MINE IS ON THE RIGHT. AND EACH OF THEM EXHIBITS CLASSIC FEATURES, PHYSICAL FEATURES OF CUSHING'S SYNDROME. THERE ARE MANY PATIENTS, THOUGH, WHO HAVE EXCESSIVE CORTISOL CIRCULATING THAT HAVE CUSHING'S, AND NOT AS OVERTLY ABNORMAL. WE KNOW IF THIS IS NOT TREATED THERE IS INCREASED MORTALITY. FROM PULL MONEY. BOW LIMP, MYOCARDIAL INFARCTION, STROKE, ANY KIND OF INFECTION. AS WELL AS INFECTIONS THAT WE SEE IN IMMUNOCOMPROMISED INDIVIDUALS. SO AS A SYNDROME, THERE ARE MULTIPLE SYMPTOMS THAT ARE POSSIBLE TO BE FOUND. AND THEY'RE LISTED HERE. WHAT I'VE DONE IS TO HIGHLIGHT IN PINK THOSE SYMPTOMS WHICH ARE CONSISTENT WITH THE METABOLIC SYNDROME, I'M GOING TO SPEAK TO THAT LATER ON. THERE IS A WHOLE VARIETY OF MANIFESTATIONS OF THIS CONDITION. NOW, I WANT TO TURN TO THE OPPOSITE, SO UNTREATED COMPLETE [TECHNICAL DIFFICULTIES]. WE DIAGNOSE THIS BY BASAL OR STIMULATED CORTISOL LEVELS. THE SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENTTY ARE SHOWN HERE. IN PEPPING ARE THOSE THAT ARE SEEN IN -- IN PINK ARE TOSS THAT ARE SEEN IN PATIENTS WHO HAVE A PRIMARY DISORDER OF THE ADRENAL GLAND. IN YELLOW THOSE ARE FOUND IN SECONDARY ADRENAL INSUFFICIENCY WHERE THE HYPOTHALAMUS OR PITUITARY GLAND ARE INCAPABLE OF [INDISCERNIBLE]. IN THE GRAY BOX ARE THE SYMPTOMS BEST DISTINGUISHED BETWEEN THE TWO CAUSES OF ADRENAL INSUFFICIENCY. SO I WANT TO TURN NOW TO SOMETHING WHICH IS VERY COMMON IN THE LAY PRESS. I WAS AT BROWN A COUPLE WEEKS AGO GIVING A TALK ON ADRENAL INSUFFICIENCY. I SPOKE ABOUT THIS. AND I ASKED THE AUDIENCE WHO HAD HEARD ABOUT ADRENAL FATIGUE. I WAS SURPRISED VERY FEW PEOPLERACIED THEIR HAND. WE'LL TRY IT AGAIN. HOW MANY HAVE HEARD OF THIS CONCEPT OF ADRENAL FATIGUE? SOME OF THE -- ENDOCRINOLOGISTS AND SOME OF THE FOLKS IN THE FRONT ROW HERE. THIS IS PROBLEMATIC, I WOULD SAY, FOR US BECAUSE PEOPLE READ THE INTERNET AND THEY'VE DECIDED THEY HAVE IT. SO I THOUGHT IT MIGHT BE USEFUL TO GO OVER THIS FOR THE ENDOCRINOLOGISTS IN THE AUDIENCE AS WELL AS SORT OF A INTERESTING TOPIC FOR OTHERS. SO HERE WE HAVE A NUMBER OF BOOKS AND WEBSITES AND MEDICATIONS WHICH ARE TOUTED TO TREAT THIS PARTICULAR CONDITION. AND I MUST RIGHT AT THE OUTSET SAY WE DO NOT CONSIDER THIS TO BE AN ENDOCRINE DISORDER. NOW YOU SEE THE GENESIS OF THE PROBLEM FOR US. PEOPLE COME IN, THEY THINK THEY HAVE SOMETHING THAT WE SAY NO THERE IS NO SUCH THING. AND THERE IS A CONFLICT BETWEEN THE PATIENT AND THE PHYSICIAN. SO I WANT TO TAKE SOME WORDS FROM THE WEBSITES, SO THAT YOU GET A FLAVOR FOR THIS. SO IT'S A COLLECTION OF NON SPECIFIC SYMPTOMS SUCH AS BODY ACHES, FATIGUE, NERVOUSNESSTIOUS SLEEP DISTURBANCES AND GIINVESTIVE PROBLEMS. A MILD FORM CAUSED BY CHRONIC STRESS, THE ADRENAL GLANDS ARE UNABLE TO KEEP PACE WITH THE DEMANDS OF FIGHT OR FLIGHT AROUSAL, DRAWING ON THE CONCEPT OF THE RESPONSE TO STRESS. IT'S USUALLY DIAGNOSED BY A QUESTIONNAIRE SAMPLES. AND CONVENTIONAL TESTS TO MY KNOWLEDGE HAVE NEVER BEEN DONE IN ANY PATIENTS PURPORTED TO HAVE THIS PARTICULAR CONDITION, SO IT'S SAID TO BE A FORM OF ADRENAL INSUFFICIENCY, BUT THAT'S NEVER BEEN ESTABLISHED IN THE USUAL WAY WE ADDRESS THAT QUESTION. SO HERE FROM A WEBSITE ABOUT THIS ARE THE QUESTIONS. SO YOU MAY BE EXPERIENCING ADRENAL FATIGUE IF YOU REGULARLY NOTICE ONE OR MORE OF THE FOLLOWING. YOU FEEL TIRED FOR NO REASON. [LAUGHTER] YOU HAVE TROUBLE GETTING UP IN THE MORNING. EVEN WHEN YOU GO TO BED AT A REASONABLE HOUR. YOU'RE FEELING RUN DOWN OR OVERWHELMED. YOU HAVE DIFFICULTY BROWNING BACK FROM STRESS OR ILLNESS OR SNOW SHOVELING. [LAUGHTER] I GRAVE CRAVE SALTY SNACKS. YOU FEEL MORE AWAKE ALERT AND ENERGETIC AFTER 6:00 P.M. THAN YOU DO ALL DAY LONG. HOW MANY PEOPLE WOULD SAY I HAVETH! SO YOU CAN SEE WHY THIS IS SO APPEALING TO OUR PATIENTS. THIS IS ANOTHER PICTURE WHICH I LOVE. IT'S SHOWING US THE CAUSES OF ADRENAL FATIGUE. PRESCRIPTION DRUGS ARE BAD FOR YOU, TRIANGLES IN MIDDLE TO BE VERY SAD. CAFFEINE, COFFEE, SURING, LACK OF GOOD FOOD, WHITE FLOUR, LACK OF RELAXATION OR EXCESSIVE EXERCISE, LACK OF SLEEP, OVEREXERTION, UNWANTED UNEMPLOYMENT, FINANCIAL PRESSURES. THIS IS DESCRIBING PEOPLE'S DAILY LIVES. SO MANY FOLKS FEEL THAT THEY ARE SUFFERING BECAUSE THESE EXTERNAL VOLUNTEERS HAVE LED TO THEIR ADRENAL GLANDS BEING UNABLE TO COPY. THERE ARE TREATMENTS. SO I'M NOT SURE YOU'RE ALL GLAD TO HEAR THAT. YOU ALL FEEL THAT YOU HAVE IT. SO WHAT ARE THETREMES? SUPPLEMENTS FOR ADRENAL GLAND SUPPORT. THIS BECOMES PROBLEMATIC, BECAUSE SOME OF THESE DO HAVE ADRENAL GLAND HORMONES IN THIS. WHICH CAN THEN LEAD TO CUSHING'S SYNDROME. PLUS, 2-5-GRAMS OF VITAMIN C, CALCIUM, MAG KNEE SEIUM, LICK WRIST ROT EXTRACT, VITAMIN E DIET. REGULAR MEALS, SLOW CARBS, NO JUNK FOOD. 5-6 VEGGIES PER DAY AND SEA SALT. VITAMIN E, B COMPLEX. THIS IS A GOOD ONE FOR ALL OF YOU HERE. LYING DOWN DURING WORK BREAKS, PREFERLY AT 10:00 A.M. AND BETWEEN 3 AND 5:00 P.M. SLEEP IN UNTIL 9 OF. OFTEN. LIVING, DOING SOMETHING FUN EVERY DAY. EXERCISING. THIS IS MY FIRST FAVORITE. NO, NOT QUITE. MINIMIZING STRESS. NOT MY FIRST FAVORITE. TAKING THE NEGATIVE PEOPLE OUT OF YOUR LIFE. [LAUGHTER] WHEN PEOPLE COME IN TO TELL ME THEY HAVE ADRENAL FATIGUE, I TELL THEM WE DON'T CONSIDER THIS TO BE A REAL CONDITION BUT ALL THE TREATMENTS PROBABLY NOT A BAD THING TO DO EXCEPT THE SUPPLEMENTS, IF YOU SLEEP DURING THE DAY AT YOUR WORKPLACE. [LAUGHTER] SO THE BOTTOM LINE THAT I WANTED TO LEAVE YOU WITH IS THAT WE DON'T BELIEVE THERE IS SUCH A THING AS ADRENAL FATIGUE. WE THINK THAT THERE IS SUCH A THING AS ADRENAL INSUFFICIENCY. IF PEOPLE COME IN WITH REAL SYMPTOMS AS SHOWN ON THE EARLY, SLIDE, GI SYMPTOMS, AND NAUSEA, WEIGHT LOSS, WE WOULD TEST THEM AND WE -- BUT WE WOULD ENDORSE A GOOD DIET AND ALL THOSE THINGS THAT ADRENAL FATIGUE PATIENTS THINK THEY NEED. I WANT TO SPEND THE REST OF THE TIME ABOUT THE QUESTION OF WHICH NORMAL CORTISOL -- THIS IS THE SPECULATIVE PIECE OF THE TALK ALSO NOT ROOTED IN CLASSICAL ENDOCRINOLOGY TEACHING AT THIS TIME. I THINK THIS IS WITH THE FIELD WILL BE GOING ONCE WE DEVELOP BETTER TOOLS. ASK CORTISOL PATH LOGIC IN THE ABSENCE OF CUSHING'S SYNDROME. IS IT PLAUSIBLE? YES, AND THERE ARE SOME EVIDENCE AND SOME POSSIBLE MECHANISMS. ONE IS THAT GLUCOCORTICOIDS THEMSELVES ARE INCREASED WITHIN THE NORMAL RANGE. THAT THERE HAS BEEN FETAL REPROGRAMMING OF THE HPA AXIS. I'M NOT GOING TO HAVE TIME TO TALK ABOUT THAT, BUT REALLY LOVELY PAPERS THAT SPEAK TO THAT. IT'S A REAL POSSIBILITY. I'M GOING TO TOUCH ON A LITTLE BIT, POSSIBILITIES OF POLYMORPHISMS AND HAPLOTYPE AFFECTING OUR ABILITY TO RESPOND TO CIRCULATING GLUCOCORTICOIDS. AND THE QUESTION OF WHETHER THERE IS AN INCREASED CONVERSION OF CORTISONE INTO CORTISOL IN APPOST TISSUE THAT MIGHT UNDER LIE THE CONCEPT. SO IN THE BODYEM HERE I'M SHOWING A PICTURE A CAR TUNE OF THE STRESS TEST CONSISTING ON 15 MINUTES OF PEOPLE LOOKING AT YOU, ASKING YOU TO PREPARE TO GIVE A JOB INTERVIEW, THEN ASKING YOU TO COUNT BACKWARDS FROM 1,022 BY 13, INCREMENTS. IF YOU MAKE A MISTAKE YOU HAVE TO START OVER AGAIN. AND SO THIS IS ONE OF THE WELL DEFINED PARADIGMS TO LOOK AT STRESS. AND WHAT WE KNOW THERE THE LITERATURE, VARIOUS KINDS OF STRESS INCREASED URINE FREE CORTISOL SERUM, NOT ENOUGH SLEEP, OTHER PARADIGMS. WHITE COAT HYPERTENSION. AND MEN WHO WERE PARTICIPATING IN GOLF TOURNAMENTS. SO ALL OF THESE SITUATIONS CAN INCREASE VARIOUS OF THESE PARAMETERS, OF COURSE GOLF. AND WE KNOW THAT THERE IS A CHRONIC INCREASE IN SERUM VALUES GENERALLY WITHIN THE NORMAL RANGE OR JUST MILDLY ABOVE THE NORMAL RANGE IN PEOPLE WHO ARE ALCOHOL DEPENDENT, AND CAREGIVERS IN FOLKS WITH JOB STRAIN OF BOTH GENDERS, AND IN PATIENTS THAT -- SORRY, IN MEN WHO ARE OVERCOMMITTED TO THEIR JOBS. WHY WOMEN DON'T HAVE IT, I DON'T KNOW THE ANSWER. ONLY MEN. THERE ARE VARIABLES EFFECTS. SO HERE IS DATA FROM A LARGE GROUP OF -- 65-YEAR OLDS, ALMOST 900, SHOWING THAT THE 0S RATIO INCREASED FOR METABOLIC SYNDROME IF PATIENTS ARE DEPRESSED WITH VERY HIGH USC -- UCS, THIS GROUP RIGHT HERE. AGAIN SHOWING AN ASSOCIATION. THIS GRAPH DEPICTING SURVIVAL CURVES OF PATIENTS WITH A SUPPOSEDLY NON FUNCTIONINGADRINE ALADENOMA, WHO DON'T HAVE A HIGH UFC, DO NOT HAVE NORMAL SUPPRESSION TO DEXAIRE METH ZONE. REMEMBER I WAS TALKING HOW YOU CAN USE DEX AMETH ZONE TO LOOK AT THE NEGATIVE FEEDBACK OF THE AX AXIS. THIS IS A DRAMATIC AND IMPRESSIVE DECREASE IN SURVIVAL, BUT SEEM TO HAVE ABNORMAL FEEDBACK OF THEIR AXIS. THIS IS A SLIDE SHOWING THE EFFECT OF THE CRITERION THAT ONE USED FOR WHAT'S NORMAL OR ABNORMAL. THE EFFECT OF AGE, AND AGE WAS I BELIEVE 65. IF I'M GETTING CLOSER TO THAT, I THINK THAT'S AN UNFAIR DEPICTION, 65 IS WHAT THEY CONSIDERED TO BE AGED. THOSE WHO HAD DIABETES AND HYPERTENSION, AND THESE ARE A BUNCH OF -- A LARGE NUMBER OF VETERANS FROM PALO ALTO. WHAT WE'RE LOOKING AT, THE LATE NIGHT SALIVARY CORTISOL LEVEL. THE VALUE, UPPER LIMIT OF NORMAL IN THIS ESSAY, 4.3. I SHOULD SAY THAT A ROT OF THESE ISSUES HAVE TO DO WITH HOW TO SET A NORMAL RANGE. THIS NORMAL RANGE HAPPENED TO BE SET WITH MOSTLY YOUNG PEOPLE. ALL LESS THAN 40. IF YOU LOOK AT EVERYBODY AND YOU LOOK AT THIS VERY CONSERVATIVE CUT OFF POINT OR -- THAT YOU GET 20% OF THESE PEOPLE HAD ABNORMAL RESULTS, AND EVEN AS YOU INCREASED THE -- DECREASED THE STRIGANCY OF THE CUT OFF POINT TO MORE THAN 2 TIMES, WHAT IS CONSIDERED TO BE UPPER REFERENCE RANGE, YOU STILL HAVE ABNORMAL PEOPLE. AS YOU ADD CO-MORBIDITIES AND AGE, YOU GET UP TO 43% OF PEOPLE WITH AN ABNORMAL RESULT. AGAIN, SAYING WHAT'S NORMAL, WHAT'S NOT, AS WE ARE OLDER AND AS WE HAVE SICKNESS AND IS THERE ANY KIND OF RECIPROCAL RELATIONSHIP HERE. SO HERE IS THE STUDY LOOKING AT OPTIMISM. WHAT THEY DID IS TO SAMPLE SALIVARY CORTISOL 4 TIMES DURING THE TIME. LOOKED AT THE -- AT THIS AFFECT SCALE, DETERMINING HOW WHETHER PEOPLE WHO ARE HAPPY OR NOT HAPPY, AND YOU CAN SEE, I THINK, THAT THE PEOPLE WHO WERE NOT HAPPY HAD HIGHER CORTISOLS AT ALL THESE TIME POINTS. AND I THINK THIS IS WHAT WE'RE LEFT WITH WITH A A LOT OF THESE DATA. THERE ARE PERHAPS THE STUDIES ARE NOT DONE AS WELL THEY MIGHT BE. IT'S DIFFICULT TO MEASURE LONG TERM. SUBTLE CHANGES IN CORTISOL. AND WE CONTINUE REALLY KNOW WHETHER THIS IS A CAUSE OR AN EFFECT OF THE CONDITIONS. AND WE DON'T HAVE VERY GOOD DISEASE OUTCOMES IN PEOPLE WHERE WE KNOW THERE IS SUBTLE INCREASE IN CORTISOL. SO JUST TO TURN NOW TO THE CONCEPT OF POLYMORPHISMS IN THE GLUCOCORTICOID RECEPTOR, THESE DATA ARE WELL ESTABLISHES, ARE CONSIDERED TO BE INDICATIVE OF REAL CLINICAL LIFE. THIS IS FROM THE NETHERLANDS. LOOKING AT 3 DIFFERENT POLLY MORISMS, TWO OF WHICH THEY'VE LABELED PATIENTS AS BEING GLUCOCORTICOID HYPER SENSITIVE. THEY HAVE, DESPITE NORMAL LEVELS OF CORTISOL, HAVE MORE OF A RESPONSE. THEY LOOK MORE CUSHING, HAVE MORE BODY FAT, LESS LEAN MASS. INSULIN -- THEY HAVE HIGH INSULIN LEVELS. AND INCREASE CHOLESTEROL. AS OPPOSED TO THE PEOPLE WHO HAVE THIS VARIANCE, WHICH THEY TERMED GLUCOCORTICOID RESISTANCE. AT THE SAME LEVELS THEY HAVE BETTER BODY COMPOSITION, BETTER SURVIVAL AND INTERESTINGLY, A RISK OF DEMENTIA. HIGH CORTISOLS HAVE BEEN SOUTHERED WITH AN INCREASED RISK OF ALZHEIMER'S. AND JUST TO FINISH UP ABOUT THE PLAUSIBLE MECHANISMS BY WHICH WE MIGHT HAVE A PATHOPHYSIOLOGIC RESPONSE TO CORTISOL, WHAT ABOUT TISSUE CONVERSION? AS I MENTIONED EARLIER, 11 BETA HSD TWO CONCERTS CORTISOL TO CORTISONE AND THE KIDNEY INACTIVATES IT. THE BABY IS NOT EXPOSED FROM THE MOTHER AND THE KIDNEYS RA NOT EXPOSED TO HIGH LEVELS THAT WOULD ALLOW THEM TO ACT AS -- YOU'LL RECALL IT CIRCULATES, MASSESIVE AMOUNTS THAT IF CORTISOL WERE NOT INACTIVATED WE WOULD ALL BE IN HYPERTENSIVE CRISIS ALL THE TIME. SO 11 BETA HSD1 ACTS AS A REDUCT TASTE. REGENERATES CORTISOL FROM CORTISONE. THIS IS FOUND IN THE LIVER, BONE, EYE, AND SUBCAN YOUTAINIOUS FAT, SKELETAL MUSCLES AND JOINTS. SO THE -- THE ISSUE HERE IS WHETHER IN CERTAIN CONDITIONS, AND WHAT'S BEEN PROPOSED, OBESITY, AND METABOLIC SYNDROME, 11 BETA HSD1 IS OVERACTIVE, ARE WE DELIVERING MORE CORTISOL TO THE LIVER? SO THIS IS A NICE STUDY PUBLISHED IN GOOD JOURNALS LOOKING AT RATS WHO WERE PUT INTO COLD WATER, AND THIS IS A STRESSFUL PARADIGM FOR RATS. INDUCED OBESITY ONLY WHEN THERE WAS A HIGH FAT AND HIGH SUGAR DIET. INTRODUCING ANOTHER CONCEPT OF HOW THE ENVIRONMENT MAY INTERACT WITH THE INCREASE IN GLUCOCORTICOID. THIS WAS BLOCKED BY [INDISCERNIBLE], SOME THIS IS TELLING US THAT YOKO CORTICOIDS ARE SOMEHOW INVOLVED. THE Y LEVELS WERE INCREASEED. [INDISCERNIBLE] IT BECAME NORMAL. AND 11 BETA HSD1 WAS INCREASED IN ABDOMINAL FAT. AGAIN, WAS THERE AN INCREASED REGENERATION OF CORTICO COSTERONE IN THE FAT, IN THESE ANIMALS. BASICALLY, THIS IS JUST A SCHEMATIC OF WHAT HAPPENED. LOOKING AT TISSUE EXPANSION OF THE WHEAT ADIPOSE TISSUE, POTENTIALLY AFFECTING ANGIO GENESIS AND MACROPHAGE INFILTRATING, IMPLICATING GLUCOCORTICOIDS, DIET, IN THIS STRESS CONDITION INDUCED OBESITY. I BELIEVE THIS IS MY FINAL SLIDE. AND THIS WAS A STUDY IN WHICH 11 BETA KNOCKOUT WAS PERFORMED, SO WHAT WAS DONE HERE WAS THAT THERE WAS -- RATS WERE -- MICE WERE -- KNOCKOUTS WERE PERFORMED. THERE WAS WILDTYPES AS WTs, KNOCKOUTS, AND TREATED WITH VEHICLE OR WITH CORTICO COSTERONE, DENOTED AS COURT HERE. AND WHAT YOU CAN SEE IS THAT IN THE VEHICLE TREATMENT THE KNOCKOUT DIDN'T MAKE ANY DIFFERENCE. IN THE -- WHEN WE WERE -- THE MICE WERE TREATED WITH CORTICO COSTERONE, GLUCOSE TOLERANCE WAS EFFECTED, WAS AMEALIER RATED BY THE KNOCKOUT, AS WAS FASTING GLUCOSE LEVEL. THE FASTING INSULIN LEVEL. THE IR, A MEASURE OF INSULIN RESISTANCE, AND SYSTOLIC BLOB, SO THAT -- BLOOD PRESSURE, SO THAT WE HAVE A SENSE THAT 11 BETA HSD1 IS AN IMPORTANT PLAYER IN INDUCING METABOLIC SYNDROME OR METABOLIC FEATURES, AND THAT THIS 43 BE RELATED -- THIS MAY BE RELATED IN A SENSE TO THE WAY WE'RE METABOLIZING CORTISOL. I THINK THIS OPENS UP SOME INTERESTING AREAS FOR RESEARCH AND PEOPLE, WHICH THE KINDS OF THINGS WE CAN DO HERE AT THE CLINICAL CENTER AND HARD TO DO OTHER PLACES. SO THIS IS WHAT I'VE TALKED ABOUT. I'M GOING TO CLOSE NOW. I THINK I'M JUST ABOUT ON TIME. AND THANK YOU, AND HAPPY TO TAKE E-MAILS OR QUESTIONS. [APPLAUSE] >> WE HAVE A FEW MOMENTS FOR QUESTIONS. PLEASE USE THE MICROPHONE. >> IT WAS A BEAUTIFUL TALK. ENDING ON THE 11 BETA HSD SUBJECT, WHERE ARE WE WITH PHARMACOLOGIC INTERVENTIONS, ESPECIALLY FOR THE TREATMENT OF OBESITY. >> WE'RE NO PLACE, AS FAR AS I KNOW. INTENSE ACTIVITY, TO MY KNOWLEDGE, ALL OF THE COMPOUNDS HAVE BEEN PUBLISHED ON. THERE MAY BE SOME THAT AREN'T PUBLISHED BECAUSE THEY'RE WORKING. THE ONES THAT ARE PUBLISHED HAVE INTERACTION WITH 1 AND 2, SO IT'S A NON SPECIFIC TREATMENT. SO FAR. SO IT WOULD BE A WAY OF TESTING THE HYPOTHESIS. IN THE PLEASURE HAVE 0 INTRODUCING OUR SECOND SPEAKER, DR. PETER SCHMIDT, CHIEF OF THE BEHAVIORIAL EPENBRANCH AT THE NATIONAL INSTITUTE OF MENTAL HEALTH. HE EARNED HIS BACHELOR OF MEDICINE AND SURGERY DEGREE FROM THE ROYAL CLEM OF VIRGINS IN THE UNIVERSITY OF [INDISCERNIBLE]. COMPLETED HIS INTERMSHIP AND RESIDENCY IN PSYCHIATRY AT THE UNIVERSITY OF TORONTO IN CANADA, AND IN 1986 JOINED THE NIMH AS -- ONTARIO MENTAL HEALTH HEALTH FOUNDATION FELLOW. AFTER COMPLETING HIS RESEARCH FELLOWSHIP, HE SERVE AS THE ASSOCIATE DIRECTOR AND THEN DIRECTOR OF THE NATIONAL INSTITUTE OF MENTAL HEALTH PSYCHIATRY CONSULTATION SERVICE FROM 188 TO 1995. HE CONTINUED TO SERVE AS THE SENIOR CONSULTANT PSYCHIATRY CONSULTATION FROM 1995 TO 2006. ALSO ACTIC CHIEF FROM 2005 TO 11, SERVED AS DIRECTOR OF THE NATIONAL MENTAL INSTITUTE'S OUTPATIENT CLINIC SINCE 1991. HIS RESEARCH FOCUSES ON THE NEURO BEHAVIORAL EFFECTS OF STEROIDS IN HUMANS, INCLUDING THE ROLES OF STEROIDS IN MOOD STATE REGULATION IN WOMEN, AND MENSTRUAL RELATED MOOD DISORDERS, PERIMENOPAUSE RELATED DEPRESSION AND PERIPHERAL DEPRESSION. SERVED AS THE ATHLETICS CONSULTANT -- ETHNICS COULD BE SULANT SINCE 2008. AND TODAY HE'S GOING TO PRESENT HIS TALK TITLED SUBSTRATES FOR DIFFERENTIALer DIFFERTUAL RESPONSIVITY IN WOMAN. DR. SCHMID. [APPLAUSE] >> THANK YOU FOR THAT INTRODUCTION. CAN EVERYBODY HEAR ME OKAY? I HAVE NOTHING TO DISCLOSE. AND THIS WILL BE THE MAIN OBJECTIVE IS TO DISCUSS THE ROLE OF OVARIAN STEROIDS IN WOMEN WITH MOOD DISORDERS. SO THERE IS A LARGE GAP BETWEEN THE EXPLOSION OF FINDINGS THAT HAVE COME UP RECENTLY IN THE FIELD OF REPRODUCTIVE NEUROSCIENCE, BASIC CLINICAL STUDIES AND OUR ABILITY TO TRANSLATE THESE FINDINGS INTO A BET YOU ARE UNDERSTANDING OF THE PATHOSIZOLOGY OF DEPRESSION IN WOMEN. SO THE WORK OF OUR GROUP AND COLLABORATORS HAS BEEN TO TRY TO CLOSE SOME OF THOSE GAPS. AS DR. GALLIN DESCRIBE IN THE INTRODUCTION, THESE ARE THE CONDITIONS WE STUDY. THEY'RE IMPORTANT. THEY OCCUR WITH WOMEN AS DIFFERENT FACES OF LIFE CYCLE, PREVALENT AND SOUTHERED WITH CONSIDERABLE MORBIDITY. IN STUDIES WE TAKE ADVANTAGES OF THE EXPERIMENTS OF NATURE THAT THESE CONDITIONS REPRESENT AS THEY PROVIDE US WITH A WINDOW INTO THE NEURO REGULATORY EFFECTS OF OVARIAN STEROIDS IN WOMEN. WE STUDY ALL 3 CONDITIONS, BECAUSE THEY -- WE FEEL THAT THE EFFECTS ARE THE EFFECTS OF SEX STEROIDS ON THE BRAIN, WILL DIFFER AS THE FACTOR OR FUNCTION OF A NUMBER OF CONTEXTUAL VARIABLES INCLUDING AGE, PAST EXPERIENCE, INCLUDING EARLY LIFE TRAUMA, AS WELL AS DIFFERENT BILL SUBSTRATES. THESE ARE THE -- BIOLOGICAL SUBSTRATES. THESE ARE THE QUESTIONS WE HAVE TRIED TO ANSWER, HOW DO THEY TRIGGER NEGATIVE MOOD STATES OR AFFECTIVE DESTABILIZATION. WHY THEY DO SO ONLY IN A SMALL SUBGROUP OF WOMEN. THEN HOW CAN THE HYPOTHESIS ABOUT THE PATHOGENESIS OF THESE CONDITIONS TRANSLATE INTO NOVEL THERAPEUTICS? THESE ARE OUR STUDY OBJECTIVES. SO IN THE FIRST ONE, WE'VE EMPLOYED STEROID RECEPTOR AGONISTS AND APTAGNISTS TO BLOCK HORMONAL EVENTS THAT WE THINK ARE CRITICAL FOR TRIGGERING THE ON SET. SEND, WE'VE TRIED TO INVESTIGATE IN COLLABORATION WITH KAREN'S GROUP, SHE BROUGHT TO THE PICTURE OUR ABILITY TO LOOK AT NEURO IMAGING MEASURES, TO TRY TO IDENTIFY SOME OF THE PHYSIOLOGIC SYSTEMS THAT MAY BE DIFFER ALLY REGULATED. I WON'T BE TALKING WITHOUT -- ABOUT THEM, BUT COLUMBUS -- [TECHNICAL DIFFICULTIES]. FINALLY, BOTH IN COLLABORATION WITH KAREN'S GROUP AND DAVID GOLDMAN'S, TRY TO UNDERSTAND ONE OF THE SUBSTRATES OF VULNERABILITY. WHAT IS IT ABOUT THE BIOLOGY OF THESE WOMEN THAT PUTS THEM AT INCREASED RISK OF NEGATIVE MOOD STATE DURING THE TIME OF HORMONAL CHANGE. I'M GOING TO FOCUS ON ONE CONDITION, ALTHOUGH WE HAVE DONE SIMILAR STUDIES IN THE OTHER TWO CONDITIONS. LOOK AT SOME OF OUR WORK ON WOMEN WITH SEVERE PRIMENESS TRAL DISFORIC DISORDERS, SPECIFICALLY EFFECTS OF SUPPRESSING THE OVARIAN FUNCTION AND ADDING BACK LEVELS OF STEROIDS. SO JUST AS BACKGROUND, THIS IS A CONDITION ePMDD RECENTLY EXCEPTED INTO THE DSM5, INCLUDED AS A LEGITIMATE CONDITION THAT PSYCHIATRISTS NEED TO UNDERSTAND. JUST AS BACKGROUND, LEVELS OF STEROIDS RA NOT ABNORMAL, SO IN CONTRAST TO WHAT WAS TALKED ABOUT WITH RESPECT TO COUCHING'S OR ADRENAL INSUFFICIENTTY, THE SEQUELI OF THOSE CONDITIONS A FUNCTION OF TOO MUCH OR TOO LEGAL CORTISOL, THERE IS NO SIMILAR STORY IN THIS CONDITION. NO STUDY HAS SHOWN ANY ABNORMALITY OF ANY STEROID OR OTHER HORMONE THAT WOULD DISTINGUISH A WOMAN WHO HAS SEVERE PRIMENESS CENTRAL DISFORIC DISORDER FROM A WITH WOMAN WITH NO SYMPTOMS. MANY YEARS AGO, WE EMPLOYED THE AG TAGNIST TO ELIMINATE THE MAJORITY OF THE PHASE AND FOUND SYMPTOMS OCCURRED BY THE CALENDAR. SO THAT SUGGESTED THAT THEY WERE INDEPENDENT EVENTS OR SOMETHING EARLIER. THAT IN IS MENSTRUAL CYCLE TRIGGERED SYMPTOMS, WHERE SOME OF OUR NEXT STUDIES WERE INFORMED BY PEOPLE WHO HAD TEMPORARILY SUPPRESSED OVARIAN FUNCTION, AND FOUND THAT THAT LED TO THE ELIMINATION OF PMDD SYMPTOMS. SO AFTER CONFIRMING THE DIAGNOSIS OF PMTD, SYMPTOMS OCCURRED DURING THE WILL YOU TEAL FACED, THEN -- LUTEAL PHASE, THEN THEY WERE PLACED ON AN AGONIST. THIS ESSENTIALLY IS A SUPER AGONIST. GIVE BEEN ONCE A MONTH AFTER INITIAL FLARE OF THE AXIS WILL SUPPRESS OVARIAN FUNCTION, LEVELS OF ESTRADIOL WILL BE DOWN COMPARE TO THOSE DURING MENOPAUSE, AND A STABLE SUPPRESSED OVARIAN FUNCTION IS MAINTAINED AS LONG AS MEDICATION IS GIVEN ON A REGULAR BASIS. SO THEM WE LOOKED FOR THE WOMEN WHO RESPONDED TO THIS. MEANING THAT THEIR SYMPTOMS, PMDD AFFECTIVE SYMPTOMS DISAPPEARED, AND THAT SYMPTOMS WAS ELIMINATED, 70% OF THE SAMPLE. THEY WERE CONTINUED FOR AN ADDITIONAL 3 MONTHS ON [INDISCERNIBLE], WHICH TIME WE ADDED BACK LEVELS OF ESTRO DIAL, COMPARABLE TO WHAT WE SEE DURING THE MID FOLIC CAN YOU LAR PHASE, OR PROGESTERONE LEVELS, OR THE SAME HORMONES IN REVERSE ORDER. EACH HISTOGRAM REPRESENTS 7 DAY AVERAGES FOR THE DAILYING RATICS, OVER THE 8 -- LAST 8 WEEKS, AND THE 4 WEEKS OF HORMONE REPLACEMENT. THIS IS A SCALE, HIGHER SCALE REPRESENTS MORE SEVERE SYMPTOMS. WE FOUND DURING THE LUPRON, THAT SYMPTOMS REMITTED, AND THAT THERE WAS THE ELIMINATION OF SYMPTOMS SUNSHINE. WITHIN A 2 OR 3 WEEK PERIOD OF ADDING BACK PHYSIOLOGICAL LEVELS, THESE WOMEN DESCRIBED A RECURRENCE IN THE RANGE OF SYMPTOMS IFCLUDING AFFECTIVE AS WELL AS SOME PHYSICAL SYMPTOMS. NOW, WE ALSO ADDED PLACEBO, FOUND NO CHANGE IN SYMPTOMS IN PEOPLE ANTICIPATING THE HORMONES WOULD BE ADDED BACK. WE ALSO ASKED WHETHER IS THIS JUST A FUNCTION OF THE HORMONE MANIPULATION THAT WE'RE PRODUCING. AND SO WE RECRUITED CONTROLS. THESE ARE WOMEN, ASYMPTOMATIC WOMEN WITH NO, NO, SIGNIFICANT BEHAVIORAL SYMPTOMS IN RELATION TO MENSTRUAL CYCLE. THEY WENT THROUGH THE STUDY AND REALLY NO DIFFERENCE IN SYMPTOM LEVELS DURING THE LUPRON, BUT STRIKING DIFFERENCE WHEN WE ADDED BACK PHYSICIANSLOGIC LEVELS OF ESTROGEN OR PROGESTERONE. WHAT THESING IS, THERE WAS -- WHAT THIS SUGGESTED, THERE WAS A DIFFER CHALLENGE BEHAVIORAL RESPONSE. BECAUSE BOTH GROUPS WERE IN THE SAME MANIPULATION, THE SAME DOSES OFF ESTRADIOL AND PROTEST JER REASON. WHAT THAT SUGGESTED, THERE WAS SOMETHING THAT DISTINGUISHED THESE WOMEN WITH MPDD FROM THE CONTROLS, BUT THAT THE TRIGGER SUGGESTED THAT IT WAS THE EXPOSURE. IT WAS STILL AMBIGUOUS. IT WASN'T CLEAR WHETHER THE CHANGE IN AFFECTIVE STATE WAS DETERMINED BY THE INITIAL EXPOSURE OR THE CHANGE IN OVARIAN STEROID, OR WHETHER WE HAD EXCEEDED SOME CRITICAL THRESH HOLD OF STEROID LEVEL. SO THAT'S WHERE WE DID THE SECOND STUDY TO -- SCHEMATIC OF THAT. IF THESE ARE SYMPTOMS RECURRING, DURING LUTEAL FACE, IF IT LOOKED TO BE OMITTED DURING THE LUPRON. IF LONGER PERIOD, HORMONE LEVELS WERE STABLE, WE WOULD JUST SEE ONE EPISODE OF SYMPTOMS RECURRING. THEN WHEN HORMONE LEVELS WERE STABLE WE WOULD SEE REMISSION OF SYMPTOMS IN FACT IS SIMILAR TO WHAT THEN WOMEN DESCRIBED DURING PREGNANCY. SYMPTOMSGO AWAY. IN OVARIAN STEROIDS PLAYED A PURCHASE MISSIVE ROLE AND ALLOWED FOR THE EXPRESSION OF PACE MAKER WITHIN THE BRAIN THAT WOULD BE EXPRESSED AFTER WE HAD ACHIEVED A CERTAIN LEVEL OF CNS HORMONE, WE WOULD SEE A MORE RECURRENT PATTERN OF EPISODE, DESPITE THE STABLE LEVELS OF THE HORMONE. THIS IS WHAT WE SAW. THIS IS THE SIGN THAT WE DID. WOMEN WITH MPDD WERE -- RECEIVED [INDISCERNIBLE]. ONCE WE DETERMINED THAT THEY WERE RESPONDERS, WHICH AGAIN WE SAW ABOUT 70% RESPONSE RATE, THEY RECEIVED A SINGLE ONE MONTH SINGLE BLIND PLACEBO, TO TEST IF THEY WERE RESPONDING TO KIND OF THE PERCEPTION THAT THEY WERE GETTING HORMONES BACK. AND THEN THEY RECEIVED 3 MONTHS OF STABLE LEVELS OF ESTRADIOL AND PROGESTERONE, THE SAME DOSES IN THE FIRST STUDY. THIS WAS THE PATTERN. THESE WERE CROSS SECTIONAL RATING SCALE THAT ASKED ABOUT TYPICAL AFFECTIVE AND PHYSICAL AND BEHAVIORAL SYMPTOMS THAT THESE WOMEN EXPERIENCED. THE -- THESE ARE THE SCORES. THE YELLOW IS BASELINE PRIOR TO THE STUDY. IN THE WHITE, DURING LUPRONE THERE WAS ELIMINATION OF SYMPTOMS. FO CHANGE ON PLACEBO. HOWEVER, DURING THE FIRST MONTH WHEN WE ADDED BACK COMBINED ESTROGEN AND PROGESTERONE, WE SAY INCREASE IN SYMPTOMS, THOSE DIS APPEARED WHEN WE LANGUAGE A -- LARGELY, WHEN HORMONE LEVELS WERE STABILIZED DURING THE SECOND AND THIRD MONTH. WE THINK THESE DATA NOW SHOW THAT IT IS THE EXPOSURE TO THE HORMONE OR A METAP LIGHT OF THE HORMONE, AND SO FOR THE NEXT PHASE OF THE STUDY WE'RE GOING TO BE LOOKING AT TRYING TO DISENTANGLE WHETHER IT'S ESTRADIOL, PROGESTERONE OR BOTH. THESE DATA SUGGEST IT'S CHANGE IN HORMONES, IN CONTRAST TO -- AND MARRY DALMAN HAS DESCRIBED SOMETHING SIMILAR THAT DETERMINES CORTISOL NEGATIVE FEEDBACK EFFECT. MARY WAS ONE OF THE STUDIES SHOWN. SO IT SEEMS TO BE THE CHANGE IN HORMONE. SIMILAR STUDIES IN THESE OTHER CONDITIONS WITH PREAMP CENTRAL DISORDER SEEMS TO BE -- PREMENSTRUAL DISORDER SEEMS TO BE THE EXPOSURE TO ESTROGEN. OR IT WAS THE WITHDRAWAL FROM ESTROGEN OR PROGESTERONE. AND WE ESTABLISHED RECENTLY SHOWING A PAPER SHOWING IN WOMEN WHO HAD A PAST PERIMENO PAUSAL DEPRESSION IT WAS THE WITHDRAWAL FROM ESTROGEN. THEY DON'T SEEM TO BE ALL THE SAME CONDITION. THE TRIGGER SEEMS TO DIFFER ACROSS THE 3 CONDITIONS. SO, GETTING TO THE NEXT PART OF THE TALK, IN -- AS I MENTIONED IN COLLABORATION WITH KAREN, WE HAVE BEEN ABLE TO ASK SOME OF QUESTIONS RELATED TO WHAT BRAIN CIRCUIT MIGHT BE DIFFERENTIALLY REGULATED BY THE SIGNAL IN THESE CONDITIONS. AND WE ASKED THE QUESTION OF WE OVARIAN STEROIDS MODULATE BRAIN NEURO CIRCUITRY IN PMTD. WE EMPLOYED THE LUPRON STUDY TO ANSWER THESE QUESTIONS. FOR A NUMBER OF REASONS. SO REMIND YOU, THIS IS 6 MONTHS WHERE OVARIAN SUPPRESSION IS MAINTAINED. AFTER 3 MONTHS WE ADD BACK PHYSIOLOGIC LEVELS OF ESTRADIOL OR PROGESTERONE FOR FOUR WEEKS. THE REASON WE PICKED THIS STUDY, IT PROVIDES US WITH A BASELINE. LIKE MANY OF THE BASIC SCIENCE CITIES HAVE WHERE HORMONE LEVELS ARE SUPPRESSED. AND CONVENIENTLY, ALSO, SYMPTOMS ARE ABSENCE IN WOMEN WITH PMDD. THEN WE ADD BACK ESTRADIOL AND PROGESTERONE, SO ONCE SYMPTOMS COME BACK IN TFSS,ENED SUBPOENA SAID ABREUS US [TECHNICAL DIFFICULTIES] 4 SO THIS IS WORK DONE BY [INDISCERNIBLE], WHO IS A POST-DOC IN KAREN'S LAB. AND WHAT THEY DID, DURING THE LUPRON STUDY SHE PERFORMED 3 SCANS DURING THE 3 HORMONE CONDITIONS. IN THIS CASE SHE USED 015 PET SCANS. THIS WAS RESTING STATE. PEOPLE ARE -- WOMEN ARE ASKED JUST TO FIX ON A CROSS HAIR ON THE SCREEN. THERE IS NO COGNITIVE ACTIVATION. WHAT SHE FOUND, THERE IS A SIGNIFICANT DIAGNOSIS BY HORMONE INTERACTION IN AN AREA BA25, AS WELL AS IN ANOTHER BRAIN AREA OF THE MEDIAL OR FRONTAL CORE TEXT. FOCUSING ON THE AREA BA25, THESE ARE MEASURES OF REGIONAL BLOOD FLOW, SO BRAIN ACTIVATION. IN THE CONTROLS YOU CAN SEE IN THE 32 CONTROLS ACROSS ALL 3 HORMONAL STATES, THERE WAS NO CHANGE RELATED TO HORMONE CONDITION IN ANY OF THESE WOMEN. IN THAT AREA. WHEREAS IN THE PATIENTS, COMPARED TO THE LUPRON WHEN THEY WERE NOT SYMPTOMATIC, BOTH ESTRADIOL AND PROGESTERONE WERE ASSOCIATED WITH REDUCTIONS IN THE ACTIVATION OF THIS REGION. NOW, THIS IS IMPORTANT, STRUCTURAL AND FUNCTIONAL ABNORMALITIES HAVE BEEN IDENTIFIED IN DEPRESSION. IT ALSO HAPPENS TO BE ONE OF THE ORIGINAL TARGETS FOR BRAIN -- FOR DEEP BRAIN STIMULATION. IT ALSO CONTAINS THE LARGEST -- ONE OF THE LARGEST CONCENTRATIONS OF SEROTONIN IN YOUR ONS. SINCE THIS IS UNIQUELY RESPONSIVE TO SERO TONEN UPTAKE INHIBITORS, IT SEEMED TO HAVE A LOT OF PATHOPHYSIOLOGIC RELEVANCE. NOW, WHAT DO WE THINK THIS REFLECTS? FIRST, IT COULD REFLECT MERELY A REACTION, HOMEOSTATIC EFFORT ON PART OF THE BRAIN IN RESPONSE TO THE PRESENCE OF SYMPTOMS. SO THAT THE DIFFERENCE IN ADDITION TO THE BRAIN ACTIVITY IS THAT THESE WOMEN STARTING TO BECOME SYMPTOMATIC ON BOTH ESTRADIOL AND PROGESTERONE, AND MAY REFLECT A SEQUELI OF THAT. ALTLY, I GUESS FOR THE HOPEFUL MEMBERS OF THE GROUP, THAT COULD BE DEFINING A LOCUST THAT IS DIFFERENTIALLY REGULATED BY STEROIDS, AND MAY DIRECTLY MEDIATE CHANGES IN BEHAVIOR AND AFFECTIVE STATE THAT WE SEE IN THIS CONDITION. THAT REMAINS TO BE TO BE DETERMINED. WHAT WE HAVE IS A DIFFERENTIAL BEHAVIOR RESPONSE. WE HAVE A POTENTIAL LOCUST IN THE BRAIN OF -- HUB IN THE BRAIN THAT MAY BE DIFFERENTIALLY REGULATED BY STEROIDS IN THESE WOMEN. THE QUESTION, I THINK, THAT NEEDS TO BE ANSWERED IS WHAT MIGHT BE UNDER LYING THIS DIFFERENTIAL RESPONSE. WHY DO WOMEN WITH PMDD RESPOND WITH A NEGATIVE AFFECTIVE STATE AS THE CONTROLS? SO JUST AS A PRELIMINARY DATA, GOING BACK TO WORK, SHE LOOKED AT WHETHER FUNCTIONAL VARIANCE IN SOME GENES THAT WERE RELEVANT TO BRAIN FUNCTION, MAY BE ARE INDUCED DIFFERENTIAL SENSITIVITY TO SEX STEROIDS IN THE CONTROL. THESE ARE NOT WOMEN WITH PMDD. ONE OF THE GENES SHE HOOKED AT WAS THE TRANSFERIS JEEP. THERE ARE MULTIPLE, MULTIPLE INTERACTIONS IDENTIFIED. THERE IS [INDISCERNIBLE] RESPONSE ELEMENT ON THE GENE. [INDISCERNIBLE], ESTROGENS, GAINED MORE RELEVANCE IN TERMS OF THE ONCOLOGY PEALED. SUBSTRATES FOR COMT. WITH RESPECT TO NEUROSCIENCE, THE PRINCIPLE REGULATOR DOPAMINE IN THE FREE FRONTAL CORTEX. THERE ARE VERY FEW TRANSPORTERS SO IT'S REALLY THE CONTROLLER OF DOPAMINE. IN HUMANS THERE SEEMS TO BE UNIQUELY HUMAN, THERE IS A FUNCTIONAL POLY MOREMISM, IN THE COMT WHICH WAS IDENTIFIED HERE BY JULIE AXELROD WHERE [INDISCERNIBLE] IS SUBSTITUTED IN THE GENE. AND THAT THAT ENZYME THAT RESULTS THERE THAT POLYMORPHISM IS ABOUT 50%, MAYBE BETWEEN 30 AND 50% LESS FUNCTIONAL AT BODY TEMPERATURE. SO THE ALLELE IS MAINTAINED FUNCTIONALITY, THE VAL HAS A DECREASED -- SORRY. THE MET ALLELE IS LEGAL FUNCTIONAL, RESULTS IN POTENTIALLY HIGHER PREFRONTAL DOPAMINE LEVELS THAN THE VAL HOMOZYGOUS. SO THERE WAS A FAIRLY -- A STUDY SHE LOOKED TO GAIN AT USING 015 PET STUDIES. THE IT WAS A COGNITIVE ACTIVATION PERFORMED USING THE TASK, WHICH IS A TASK THAT TRIES TO STIMULATE, A TEST OF WORKING MEMORY FUNCTION. SO THE 0 BACK PEOPLE ARE JUST ASKED TO REPEAT THE NUMBER THAT THEY SEE UP ON THE SLIDE. THE TWO BACK, THEY HAVE TO REMEMBER NOT ONLY THE NUMBER THEY SAW, BUT THE NUMBER THEY SAW BEFORE THAT. AND THEN AT THE TIME THAT THEY SEE THE NEW NUMBER, THEY HAVE TO REPORT THE NUMBER THEY SAW 2 BACK. SO I CAN'T EVEN EXBRAIN IT TO YOU. SO LET ALONE THE [INDISCERNIBLE] MY PERFORMANCE WASN'T PARTICULARLY GOOD. BUT IT'S THE WORKING MEMORY TASK. THE 0 BACK IS REALLY THE BASELINE. AND SHE DID THIS IN 39 NORMAL CONTROLS, WHO WENT THROUGH THE LUPRON STUDY. OVER 100 SCANS WORTH OF DATA THAT SHE ACCUMULATED IN THIS STUDY. SHE FOUND A SIGNIFICANT INTERACTION BETWEEN A SEX STEROID AND GENOTYPE IN THE DORSAL LATERAL PREFRONTAL CORTICAL AREA, ONE OF THE AREAS IN THE BRAIN INVOLVED IN PERFORMING THIS TASK. AND SO WHAT SHE IDENTIFIED IS THAT WHEN SHE SPLIT PEOPLE UP BY GENOTYPES, THE VAL, VAL, HOMO ZYGOTES, HETEROZYGOTES, AND THE MET ARE THERE, DURING WILL YOU PLEASE PRONE, THERE WAS NO -- LUPRONE, THERE WAS NO DIFFERENCE. DURING ESTRADIOL, THE HORMONE WE HYPOTHESIZED THERE MAY BE SOME INTERACTION WITH, WE SAY SIGNIFICANT DIFFERENCE IN THE BRAIN ACTIVATION DEPENDING, REALLY, AS ALMOST LIKE A DOSE DEPENDENT BETWEEN THE DECREASED ACTIVATION OF THE VAL HOMO SAN DIEGOAL, AND THE INCREASED IN THE MET. SO WHAT DOES THIS MEAN? I THINK SHE'LL BE LOOKING AT THIS IN THE PATIENTS BUT IT DOES SUGGEST THAT A SAMPLE VARIATION IN A -- SIMPLE VARIATION IN ONE GENE MAY HAVE A VERY IMPORTANT EFFECT ON BRAIN ACTIVATION IN THE CONTEXT OF A CHANGE IN SEX STEROID. AND CONVEY A DIFFERENT SENSITIVITY. IT MAY EXPLAIN THE INDIVIDUAL DIFFERENCES WE SEE IN PEOPLE'S RESPONSE TO SEX STEROIDS, WHETHER IT'S DURING THE POST MENOPAUSE OR AT OTHER TIME'S IN A WOMEN'S LIFE. SOME WOMEN CLAIM THAT ESTROGEN HAS A WONDERFUL EFFECT ON BRAIN FUNCTION, OTHERS REALLY NO DIFFERENT. IT DID LEAD US, THOUGH, TO THEN DOING THIS COLLABORATION WITH DAVID GOLDMAN'S LAB. WE HAD IDENTIFIED A PHENOTYPE THAT SEEMED TO BE -- HAVE AN OVARIAN STEROID TRIGGER BEHAVIORAL PHENOTYPE THAT WE COULD CONFIRM DURING OUR STUDY. AND THAT WE KNEW THAT THE EXPOSURE TO THE HORMONES TRIG TRIGGERED SYMPTOMS THAT LED US TO LOOK AT WHETHER WE COULD IDENTIFY A DIFFERENCE ON A CELLULAR LEVEL. AND SO THIS WAS WORK DONE AT DAVID'S LAB BY INITIALLY STARTED BY [INDISCERNIBLE], NOW BACK IN INDIA, CARRIED ON BY JESSICA HOFF MPDD. AND WE TOOK -- DEVELOPED -- HOFFMAN. WE DEVELOPED CELL LINES FROM THE ASYMPTOMATIC CONTROLS THAT WENT THROUGH THE STUDY AND WOMEN WITH MPDD WHO CONFIRMED THEY SHOWED A REMISSION OF SYMPTOMS ON [INDISCERNIBLE], BUT THE RETURN OF SYMPTOMS WHEN WE ADD BACK ESTRADIOL OR PROGESTERONE. WE FIRST HAD TO FIGURE OUT WHETHER THESE LYMPHOBLAST TOYED CELLS -- WE BOTH MESSAGE AND PROTEIN FROM THE 2 ESTROGEN RELATIONSHIPERS. WE DID NOT FIND THE -- WE FIND A MEMBRANE COMPONENT. IT SEEMED TO HAVE THE MACHINERY, AT LEAST, THAT PEOPLE HAVE RESUMED TO BE NECESSARY FOR SEX STEROIDS TO COMMUNICATE WITH THEM. THEN THERE WAS TWO GROUPS IN EACH ONE WAS TREATED IN -- AND DEVELOPED IN SEX STEROIDS KNOCKOUT OR STEROID FREE MEDIA. AND THEN IN A DIFFERENT GROUP FROM THE SAME SAMPLES, WE TREATED DOWN TO 24 HOUR EXPOSURE TO ESTRADIOL OR ANOTHER GROUP TO 24 HOUR EXPOSURE TO PROGESTERONE. THIS WAS DONE IN PATIENTS AND CONTROLS. WE, THEN, DID TRANSCRIPTOMY RNA SEEK AND SUBMITTED THAT TO A PATH AWAY ANALYSIS. ONE OF THE PATHWAYS THAT EMERGED IN THIS, THAT DIFFERED BETWEEN THE PATIENTS AND CONTROLS, WASTH ESC, EASY PATHWAY. NOW, IT WAS ONE OF THE TOP HITS IN THE GROUP. THIS IS A INTERESTING PATHWAY, IT CONTAINED A SMALL NUMBER OF GENES. 13 GENES SO WE FELT THAT WE COULD STUDY IT IN MORE DETAIL. IT IS A MAJOR EPIGENETIC MODIFIER, METHYLATES THE LYSINE RESIDUE ON HISTORY TONE 3, AND RESPONSIBLE FOR SUPPRESSING LARGE COMPONENTS OF THE GENOME. IT'S BEEN IDENTIFIED TO BE RELEVANT IN NUMBER OF AFFECTIVE DISORDERS, AS WELL AS CANCER. AND IT ALSO IS REGULATED BY BOTH ESTRADIOL AND PROGESTERONE, AND CAN REGULATE THE SIGNALING OF ESTROGEN PROGESTERONE. SO IT SEEMED TO HAVE PATHOPHYSIOLOGIC RELEVANCE. WE FURTHER LOOKED INTO THIS, AND THESE ARE THE RESULTS FROM THE RNA SEEK. RELATIVE TO CONTROLS. JUST TO KEEP THINGS ON THE SAME SCALES. RELATIVE TO THE QPCR. WE FOUND ABOUT 50% OF THE 13 GENES IN THIS PATHWAY WERE INCREASED IN THE PATIENTS COMPARED TO THE CONTROLS. WE, THEN, REPLICATED AND EXPANDED THIS WITH THE LARGER GROUP OF 30 CONTROLS, 29 WOMEN WITH PMDD AND FOUND A SIMILAR PROFILE OF INCREASED mRNA EXPRESSION. BY PCR, INSTUDY -- THE RESULT OF THE RNA SEEMING. AGAIN, ABOUT 50% OF THE GENES SHOWED A SIGNIFICANT INCREASE IN THE PATIENTS. NOW, PARADOXICALLY, WHEN JESSICA HOFFMAN DID THE PROTEIN EVALUATION, THAT IN CONTRAST WE FOUND THAT PROTEIN EXPRESSION WAS DECREASED IN THE PATIENTS RELATIVE TO THE CONTROLS. SUGGESTING EITHER SOME POST TRANSCRIPTIONAL MODIFICATIONS THAT COULD OCCUR, OR PERHAPS MEDIATED BY MICRORNAS, VERY INVOLVED IN THIS COMPLEX WHICH IS PART OF THE REPRESSER COMPLEX, INVOLVED IN ONE OF THE SWITCHERS FOR PUBERTY, AS WELL AS OTHER PHYSIOLOGIC EVENTS. WHEN WE LOOKED AT WHAT THE EFFECTS WERE OF EXPOSING THE CELLS TO HORMONES, WE SAW THAT NOT ONLY WAS THERE DIFFERENCES AT BASELINE, BUT THAT THIS SYSTEM ALSO WAS DIFFERENTIALLY REGULATED IN THE PATIENTS COMPARED TO THE CONTROLS. FOR A NUMBER OF GENES THAT MAKE UP THE 13 GENE COMPLEX INCLUDING [INDISCERNIBLE] AND THE MTF2. SO WHAT WE THINK WE'VE IDENTIFIED NOW IN THIS OTHERWISE COMPLEX, CERTAIN ONES VERY INVOLVED, BEEN REPORTED FOR A NUMBER OF CONDITIONS, H VAC 3, INVOLVED IN SOCIAL BEHAVIOR, ALSO IN AFFECTIVE BEHAVIORS. THAT WE THINK WE HAVE NOW AN INTRINSIC CELLULAR DIFFERENCE THAT IS ALSO DIFFERENTIALLY RESPONSIVE TO SEX STEROIDS. SO UNFORTUNATELY WE DON'T UNDERSTAND ENOUGH ABOUT THE BIOLOGICAL, WHAT GENES THIS SYSTEM ACTS ON. HOW ESTROGEN AND PROGESTERONE ARE REGULATING THIS SYSTEM. THOSE ARE SUBJECTS THAT ARE BEING PURSUED WITH DAVID. JUST TO END, I THINK THESE SIMILAR FINDINGS WE'RE COMING UP WITH AND THE TARGET, POSTPARTUM DEPRESSION, VERY SEVERE CONDITION. AND RECEIVING A LOT OF ATTENTION THESE DAYS. ALL OF THESE CONDITIONS, I THINK, ARE IMPORTANT TO STUDY BUT ARE GENERALLY -- NOT RECEIVED A LOT OF ATTENTION. I THINK THEY'RE IMPORTANT CONDITIONS BECAUSE THEY ALLOW US TO ASK QUESTIONS THAT WE COULDN'T OTHERWISE ASK IN STUDYING DEPRESSION, IN WOMEN, GEM. LIKE CLASSICAL DEPRESSION. FIRST WE CAN TRY TO UNDERSTAND THE TRIGGER THAT MAY BE CAUSING THE AFFECTIVE DYSREGULATION. WE CAN, THEN, TRY TO RECAPULATE THAT TRIGGER. AND UNDERSTAND WHAT'S GOING ON IN BRAIN AND OTHER PHYSIOLOGIC SYSTEMS BETTER. AND THEN FINALLY, I THINK THEY LEAD 250 HELPING US UNDERSTAND WHAT'S PROBABLY THE MOST IMPORTANT QUESTION, PSYCHIATRY, IS WHY DO PEOPLE RESPOND TO A -- DIFFERENTLY TO THE SAME BIOLOGICAL EVENT? AND I THINK THAT'S HOPEFULLY WHAT WE'LL BE ON TO IN OUR CURRENT STUDIES. [APPLAUSE] TO ACKNOWLEDGE THE GROUP, MANY ARE HERE. [LIST OF NAMES] >> THANK YOU. TIME FOR A FEW QUESTIONS. IF YOU WOULD USE THE MICROPHONE. IF YOU HAVE ANY. YES. ONE QUESTION. >> PETER, IS THIS ANY CORRELATE IN MEN WITH CASTRATION FOR PROSTATE CANCER, ET CETERA? I YOU USED TO DO SOME WORK IN THIS AREA IN THE PAST. >> YEAH. THE -- IN TERMS OF CORRELATES, THERE IS OBVIOUSLY NOT THE SAME MAGNITUDE OR DEGREE OF CHANGE IN SEX STEROIDS DURING A MAN'S REPRODUCTIVE LIFE COMPARED TO WOMEN. I THINK THE ASSOCIATION WOULD BE THAT ONE WE HAVE MEASURE -- WE HAVE DIFFICULTIES MEASURING TEST TOST ROPE. USING THE CURRENT LEVELS THIS SEEMS TO BE VERY DIFFERENT RESPONSE TO -- WITHIN MEN. A LOT OF INDIVIDUAL VARIABILITY IN BOTH THE EFFECTS OF HYPO[INDISCERNIBLE] ON MOOD OR COGNITION. AND THE BENEFICIAL EFFECTS OF TEST TOST ERR REASON -- TESTOSTERONE OR OTHER THERAPIES. SO THE APDOCTOR GENDEPRIVATION THERAPY, MOST MEN GETS HOT FLUSHES, A SMALL PROPORTION WILL DEVELOP A DEPRESSION. SO THAT, I THINK, IS KIND OF THE ASSOCIATED FINDING CLINICALLY WITH WOMEN. AND THEN PEOPLE TALK ABOUT WITH AGE RELATED ANDROGENS, START DECLINING IN THEIR 30s. WE DON'T KNOW, THERE IS APPARENTLY -- I THINK THERE IS A LOT OF VARIATION IN PEOPLE'S ANDROGEN LEVELS. SOME MEN MAY GO THROUGH 50% DECLINE WITH AGING, IF THEY STARTED OUT WITH A LOW LEVEL, IT MAY GET DOWN BELOW SOME THRESHOLD. CLINICALLY, PEOPLE DO DESCRIBE THE POTENTIAL FOR THIS APDOCTOR GENINSUFFICIENTCY IN MEN. LIKE ADRENAL FATIGUE. A LOT MORE PEOPLE SUBSCRIBE TO IT ON THE INTERNET THAN SEEM TO HAVE A REAL CONDITION. ONE OF THE PROBLEMS IT'S VERY HARD TO MEMBER TESTOSTERONE LEVELS WHEN THEY GET LOW. THEY GET DOWN TO LIMITS OF DETECTABILITY AND IT'S A RANDOM NUMBER GAME AT THAT POINT. BUT WHEN YOU DO TREAT SOME OF THESE MEN, THEY SEEM TO RESPOND AS IF THIS IS THE GREATEST THING SINCE SLICED BREAD. SO I THINK THOSE ARE THE ANALOGOUS SITUATIONS. AND I THINK IT'S COMMON THROUGH ALL OF ENDOCRINOLOGY THAT I THINK THERE ARE GROUPS OF PEOPLE WHO SEEM TO BE DIFFERENTIALLY RESPONSIVE TO SOME OF THESE 40th MOANS. PARTICULARLY IN -- HORMONES, PARTICULARLY IN STEROIDS. >> THANK YOU TO BOTH SPEAKERS. THANK YOU. THAT WAS GREAT. [APPLAUSE]