CoRTisoL, STRESS,AND HEALTH

Keeping levels ofthe stress hormone cortisol in checkmay help prevent illness and slow

By Edward R. Rosick, DO, MPH, MS

T oday, we are more stressed than ever before. Men and women are working morehours, teens are committing suicide at high rates, and physicians cannot write

enough prescriptions for antidepressant and anti-anxiety medications.

Although modern technology is light years ahead of that of our primitive forebears,our biological make-up has not changed appreciably for many thousands of years.Because of this, understanding how our bodies react to external and internal stressors isvitally important to the quest for optimal health and well-being.

While questions remain as to precisely how stress contributes to the disease process,research has shown that chronic stress causes a significant dysfunction of one ofthemost vital systems of our body—the neuroendocrine system.'"^ > > >

40 LIFE EXTENSION December 2005

The Mind-Body Connection

The study of brain-body interac-tion, or psychoneuroimmunology, isone of the most contentious fields inmedicine today. While moreresearchers and physicians believethat the mind and body are one, asignificant number of doctors stillinsist that the mind and body areseparate entities that have onlyminimal interaction.

Of course, this stubbornness isnot surprising, as Western medicinehas long held as one of its majoraxioms that the mind and body areseparate entities. By contrast,Chinese and other traditionalmedicines have always recognizedthe interconnectedness of the bodyand mind. For those who still doubtthis interplay, recent scientificresearch proves that what happensin the mind can profoundly influ-ence the body.

The Neuroendocrine Connection

Scientists are just now beginningto unravel the ways in which in themind influences the body, and viceversa. The hypothalamic-pituitary-adrenal (HPA) axis plays a majorrole in both mind and body health.The intricate connection betweenthe brain and endocrine svstembroadly influences our health, andmany researchers suggest that ourstressful, modern lifestyles are over-taxing the HPA axis.

Before we explore how aberra-tions of the HPA axis can contributeto many chronic disease states, it isimportant to understand how theHPA axis works. It starts with thehypothalamus, a specialized glan-dular area of the brain that someconsider the "master gland" ofthe neuroendocrine system. Thehypothalamus has many functions,such as controlling the body's tem-perature, water balance, thirst, andhunger. It also acts as a controller ofthe pituitary gland, a small, bean-sized structure that sits just belowthe hypothalamus. During times ofstress, the hypothalamus releasescorticotropin-releasing factor,which in turn signals the pituitarygland to release adrenocorticotrop-ic hormone, or ACTH. This hor-mone then travels through thebloodstream to the adrenals, twosmall, triangle-shaped glands locat-ed on the top of the kidneys. WhenACTH reaches the adrenals, it caus-es them to release a biochemicalknown as cortisol.

Cortisol: the Stress Hormone

Cortisol is, in many ways, a para-doxical hormone. A certain amountof cortisol is needed to maintain opti-mal health, but too much or too littlecan be deadly. Cortisol is involved inmultiple bodily functions, includingblood pressure regulation, cardiovas-cular and immunological function.

and the metabolism of fats, proteins,and carbohydrates. In stressful situa-tions, the body secretes cortisol athigher-than-normal rates to helpbreak down and use fatty acids andproteins for energy production,which is especially important foroptimal brain function. Unlike levelsof other hormones such as testos-terone and DHEA, cortisol levelsgenerally do not decrease as we getolder. In fact, some researchers nowbelieve that many age-related prob-lems may result from a ratio ofincreased cortisol and loweredDHEA as we age."

How Stress Kills

In the 1930s, the renownedendocrinologist Hans Selye discov-ered that both psychological andbiological stress can adversely affecthuman health through interactionsbetween the mind and the adrenalglands." Following his landmarkwork on the crucial link betweenstress and the HPA axis, in 1946Selye published his now-classic workon the relationship between chronicstress and disease. Selye reasonedthat living organisms, includinghumans, react in physiologicallypredictable ways to both physicaland psychological stressors, seekingto maintain homeostasis, or a con-stant, dynamic metabolic equilibri-um wherein all organ systemsfunction to maintain optimal health.He termed these often-complexphysiological and behavioralresponses to stress the "generaladaptation syndrome," or GAS.^Selye also observed that if the stres-sors were continuous, the organismwould ultimately "burn out" anddie. He devised the following three-step model to describe the process:• Step 1: alarm reaction. Faced

with an immediate stressor(either physical or psychologi-cal), there is activation of boththe "flight or fight" response

42 LIFE EXTENSION December 2005

and the HPA axis, leading tosecretion of greater amounts ofhormones such as cortisol.

• Step 2: resistance phase. If theperceived stressors are notcountered in a timely fashionand the HPA axis is in a contin-ual "on" mode in an attempt tomaintain homeostasis, adrenalhypertrophy and numerous otherdeleterious health effects beginto occur.

• Step 3: exhaustion phase. If theperceived stress is prolonged,the adrenal glands and otherorgan systems begin to "burnout" and experience a precipi-tous decline in function. If theexhaustion phase continues longenough, the organism will die.

Stress, Cortisol, and Illness

Taking their lead from Selye'soriginal work, scientists havedemonstrated that both acute andchronic levels of stress contributeto elevated levels of cortisol.""' Inaddition, high levels of stress arenow known to be significantlylinked to various illnesses, includ-ing upper respiratory infections,"exacerbation of multiple sclerosis,"and gastrointestinal disorders suchas irritable bowel syndrome.'^'"

Since the mid-1990s, scien-tists have presented provocative

evidence linking cancer, stress, andelevated cortisol levels. In a 1996case-controlled study, scientistsexamined hormone levels of thehypothalamic-pituitary-adrenal sys-tem in women with both early-stageand metastatic breast cancer." Bothgroups had statistically higher levelsof cortisol compared to womenwithout breast cancer. Further-more, those with metastatic breastcancer had higher cortisol levelsthan women with early-stage breastcancer. The authors noted, "thesedata provide evidence that breastcancer is associated with a hyperac-tive adrenal gland.'"

A more recent report in thejournal Lancet Oncology summarizedwhat is currently known about thecomplex interactions between theHPA system, stress, and cancer.According to the authors, "Evi-dence mainly from animal modelsand human studies suggests thatstress and depression result in animpairment of the immune systemand might promote the initiationand progression of some types ofcancer...Through HPA activation,the mediators released duringchronic stress suppress somenon-specific and specific parts ofthe immune response...compro-mising the most important effectorsof the immune response againsttumors.""^

While cancer is probably themost widely feared chronic disease,heart disease remains the number-one killer of Americans. MayoClinic researchers examined themedical and economic costs ofstress in heart disease patients.'' Ina study of 311 men and 70 women,the authors found that patients withthe highest stress levels hadmarkedly higher rates of rehospital-ization and reoccurrence of furtherheart disease-related problems,including heart attacks and cardiacarrest. Concluding that psychologicaldistress may adversely affect prog-nosis in heart disease patients, theauthors suggested that identifyingand treating psychological distresscould improve outcomes in thesepatients.

A more recent report in theEuropean Heart Journal supportsthe theory that stress can literally bea killer."" In this 21-year prospectivestudy of nearly 14,000 men andwomen, researchers concluded,"chronic stress is an independentrisk factor for [cardiovascular dis-ease], particularly fatal stroke."Other scientists, however, have crit-icized these data, indicating theneed for further investigation.

December 2005 LIFE EXTENSION 43

Alzheimer's disease, the mostcommon cause of dementia in thoseaged 65 or older, is characterized bya progressive decline in cognitionand memory. This debilitating con-dition currently affects over \5 mil-lion people worldwide. With therapidly aging US population—anestimated 30% of all Americans willbe 65 or older by the year 2050—projections are that 14 million peo-ple in the US alone will be affectedby Alzheimer's in the next fewdecades.-'" This represents a qua-drupling over the current preva-lence of Alzheimer's in the US.

Although scientists continue tosearch for the root cause of this dev-astating illness, new evidence sug-gests that increased levels of stress,along with high levels of cortisol,may play a significant role.Research indicates that high corti-sol levels may promote degenera-tion and death of neurons^' '̂ alongwith decreased memory function inotherwise healthy elderly men andwomen.-" Furthermore, a recentreport in the journal Neurologyshowed that chronic stress is associ-ated with the risk of developingAlzheimer's disease."' In this study,researchers found that people who

were prone to experiencing highlevels of stress had twice the risk ofdeveloping Alzheimer's as thosewho were not prone to stress. Theauthors concluded, "proneness toexperience psychological stress is arisk factor for [Alzheimer's dis-ease]."

While mainstream medicineoffers little in the way of reducingchronic stress or high cortisol levels,making behavioral changes andusing certain supplements can helpyou bring your stress load and highcortisol levels safely under control.

Exercise Counters Stress

Humans are designed to be phys-ically active. However, our typicaltwenty-first century lifestyle—sit-ting in front of a computer all day—is a far cry from the daily huntingand gathering activities of ourancestors. While it is commonknowledge that exercise can keepour muscles and bones strong andhealthy, less often recognized is thatmoderate exercise can alsodecrease stress and high cortisollevels.

A newly published study in thejournal Psychoneuroendocrinologyexamined the effects of aging andfitness on the HPA axis response to

stress.'" The study authors hypothe-sized that aging is associated with agreater HPA axis reactivity to psy-chological stress leading to highercortisol levels, and that exercisecould ameliorate this reactivity. Theresearchers subjected three groupsof women—categorized as "young-unfit" (aged 25-30). "older-unfit"(aged 64-67), and "older-fit" (aged64-68)—to a battery of psychologi-cal and physical tests meant toinduce stress. These tests includedan EKG-monitored treadmill test, amental arithmetic test, an anagramtest, and a cold pressor test, wheresubjects placed their hands in abucket of ice water for as long asthey could tolerate. While cortisollevels rose in all three groups ofwomen, those in the older-unfitgroup had the most significantincrease. The authors concludedthat "aging is associated withgreater HPA axis reactivity to psy-chological stress, and that higheraerobic fitness among older womencan attenuate these age-relatedchanges as indicated by a bluntedcortisol response to psychologicalstress. These findings suggest thatexercise training may be an effec-tive way of modifying some of theneuroendocrine changes associatedwith aging."-'

44 LIFE EXTENSION December 2005

Relaxation and Meditation

If you want to decrease stress andloweryour cortisol, then taking timeout each day to relax and meditatemay be just the solution. Consider-able scientific evidence has estab-lished that relaxation andmeditation techniques are valuabletherapeutics for optimal health.

An article in Psychoneuroen-docrinology highlighted medita-tion's effects on levels of varioushormones, including cortisol, inotherwise healthy male subjectswho were subjected to mental andphysical stressors.'" In this prospec-tive, randomized study, blood sam-ples were taken and hormone levelsanalyzed at the study's onset andagain four months later after thesubjects had learned and practiceda meditation technique. Those whohad practiced meditation had loweraverage cortisol levels compared tosubjects who had not meditated,suggesting that meditation mayhelp reverse the effects of chronicstress.-" A paper in the journal Psy-chosomatic Medicine described howwomen with stage I or II breast can-cer could decrease their perceivedlevels of stress, as well as their cor-tisol levels, by simple cognitive-behavioral stress-managementtechniques.-'"

Supplements to Combat Cortisol

Exercise and meditation are twoimportant modalities that may helpmany individuals manage stress-filled lives. In addition, studiessuggest that effective natural sup-plements, such as vitamin C, fish oil,phosphatidylserine, and herbaladaptogens, may help keep theHPA axis in equilibrium, reduce ele-vated cortisol levels, and help opti-mize health.

Vitamin C

Besides its beneficial effects inmaintaining proper immune sys-tem function, vitamin C has beenshown to help modulate high levelsof cortisol brought about by stress.A study in 2001 examined theeffects of supplemental vitamin Con high cortisol levels broughtabout by physical stress inmarathon runners." In a random-ized, placebo-controlled study,ultramarathon runners were given500 mg a day of vitamin C, 1500 mga day of vitamin C, or a placeboseven days before a marathon, theday of the race, and two days afterthe race. Researchers found thatathletes who took 1500 mg per dayof vitamin C had significantly low-er post-race cortisol levels then

those taking either 500 mg a day orplacebo."

Another study pubhshed in thejournal Psychophamiacology reviewedevidence showing that vitamin C canreduce high cortisol levels broughtabout by psychologically inducedstress.'- In a randomized, double-blind, placebo-controlled trial,researchers gave 3000 mg per day ofvitamin C or a placebo to 120 vol-unteers who were subjected to psy-chological stress through the TrierSocial Stress Test (TSST), a com-monly used assessment tool in psy-chological research that simulatespublic speaking and arithmetic teststo induce stress and raise cortisollevels. Subjects who took vitamin Chad lower blood pressure, subjec-tive stress, and cortisol measurescompared to those who were givenplacebo.

Fish Oil

In a number of clinical tests, fishoil has been shown to reduce car-diovascular risk in women and men.Preliminary research has shownthat fish oil may help individualscope with psychological stress andlower their cortisol levels. In a studypublished in 2003, researchers gaveseven study volunteers 7.2 gramsper day of fish oil for three weeksand then subjected them to a bat-tery of mental stress tests." Bloodtests showed that these psychologi-cal stressors elicited changes in thesubjects' heart rate, blood pressure,and cortisol levels. After threeweeks of fish oil supplementation,however, the rise in cortisol levelssecondary to stress testing was sig-nificantly blunted, leading theauthors to conclude that supple-mentation with omega-3 fatty acidsfrom fish oil "inhibits the adrenalactivation elicited by a mentalstress, presumably through effectsexerted at the level of the centralnervous system."'-

December 2005 LIFE EXTENSION 45

Phosphatidylserine

Another supplement that hasbeen shown to be useful in combat-ing the deleterious effects of stressis phosphatidyfserine. This phos-pholipid constitutes an essentialpart of biological cellular mem-branes. For more than 10 years,studies have shown that phos-phatidylserine is able to cut elevat-ed cortisol levels induced by mentaland physical stress. In one earlystudy, 800 mg per day given tohealthy men significantly bluntedthe rise in cortisol caused by physi-cal stress." Another paper reportedthat even small amounts of supple-mental phosphatidylserine (50-75mg administered intravenously)could blunt cortisol increases sec-ondary to physical stressors.'- In thisstudy, eight healthy men had theirblood drawn before and after phys-ical stress induced by riding a bicy-cle crgometer. While all subjectsshowed increased cortisol levels,pretreatment with the 50- or 75-mgdose of phosphatidylserine signifi-cantly blunted cortisol response tothe physical stressor."

Finally, a study published in 2004examined phosphatidylserine'seffects on endocrine and psycholog-ical responses to mental stress. *" Thestressor used was the Trier SocialStress Test (TSST), which consists of15 minutes of psychological stressinduced via a mock job interview,followed by a mental arithmeticchallenge. This double-blind studyfollowed 40 men and 40 women,aged 20-45, for three weeks. Thesubjects were given either phos-phatidylserine (either 400 or 600 mgdaily) or a placebo before taking theTSST. Phosphatidylserine was effec-tive in blunting the cortisol responseto stressors, with those taking 400mg daily (but not, surprisingly, 600mg) of phosphatidylserine showinga significantly decreased cortisolresponse. The authors concludedthat phosphatidylserine helpeddampen the effects of stress on thepituitary-adrenal axis, and may havea role in managing stress-relateddisorders.'"

Herbal Adaptogens

Plant-derived adaptogens can bea very useful in combating the men-tal and physical rigors of our modernlifestyle. Adaptogens work by modu-lating the levels and activity of hor-mones and brain neurochemicalsthat affect everything from cardiacactivity to pain perception. For anyherb or substance to be properlyclassified as an adaptogen, it should;

• produce a non-specific responseand increase an individual'sresistance to a wide range ofdeleterious stimuli

• produce a normalizingresponse in an individual whensubjected to physiological,emotional, or mental stressors

• be non-toxic and not inducechanges in the physiological,emotional, or mental state of anon-stressed individual.

One such herbal adaptogen isRhodiola rosea, or rhodiola. In tra-ditional Asian and Europeanmedicine, this herb has been usedfor centuries to increase physicalendurance and longevity, as well asto manage fatigue, depression, andimpotence. Rhodiola's positiveeffects are thought to be mediatedthrough the actions of rosavins andsalidrosides, chemical compoundsfound in the plant's roots. Multiplestudies from the former SovietUnion have demonstrated rhodio-la's effectiveness in combating bothphysically and psychologicallystressful conditions."

Another herb that serves as anadaptogen is ginseng, which hasbeen used throughout Asia sinceantiquity. It is important to notethat ginseng is the name given tothree different plants used as adap-togens. The most widely used gin-seng is Panax ginseng, also known asKorean, Chinese, or Asian ginseng.Panax quinquefolium—or Ameri-can ginseng—is also considered a"true" ginseng. However, Siberianginseng (Eleutherococcus sentico-sus), while commonly referred to asginseng, is not a true ginseng but aclosely related plant. Yet no matterwhat the genus or species, all threeof these plants have experimentalevidence backing their adaptogcnicclaims. Animal studies have shownthat ginsenosides, bioactive com-pounds in ginsengs, improve thesensitivity of the HPA axis to corti-sol.'"" In addition, studies suggestthat all three plants provide protec-tion against both physical and psy-chological stresses.'**'"

Finally, another plant thatdeserves mention as an adaptogenis ginkgo biloba. For the last 5,000years, leaves of the ginkgo tree havebeen used to treat various medicalconditions. While ginkgo is current-ly used to help combat the debili-tating effects of memory declineand dementia,""' "•- emerging evidence

46 LIFE EXTENSION December 2005

suggests that it may be useful intreating the impact of stress and ele-vated cortisol levels. A recent dou-ble-blind, placebo-controlled studypublished in the Journal of Physiol-ogy' am! Pharmacology examinedginkgo's effects in modulating cor-tisol and blood pressure levels in 70healthy male and female subjects/'When subjected to physical andmental stressors, subjects who weregiven 120 mg per day of a standard-ized ginkgo extract saw smallerincreases in their cortisol levels andblood pressure then did their coun-terparts who were given a placebo.

Raising DHEA Levels

While cortisol levels stay thesame or even increase as we age,levels of another vitally importanthormone, DHEA, decrease witheach passing year. This relationshipbetween cortisol and DHEA has ledsome to suggest that these adrenalhormones may play a significantrole in the aging process and itsassociated negative health effects.A recent paper in the EuropeanJournal of Endocrinology examinedthe pathophysiological correlates ofage-related changes in the HPAaxis." The authors showed that thecortisol/DHEA ratio increases sig-nificantly as one ages, and is evenhigher in elderly patients who sufferfrom dementia. SupplementalDHEA, however, enhances the

brain's resistance to stress-mediat-ed changes, maintains functionalabilities, and protects against age-related diseases. The authors con-cluded, "the changes of thehormonal balance [between cortisoland DHEA] occurring in aging maycontribute to the onset and pro-gression of the aging-associatedneurogenerative diseases.'"^'

Conclusion

Exercise, stress managementtechniques such as relaxation andmeditation, and nutritional supple-ments can help you manage stressand lower cortisol to promote opti-mal health and longevity. The fol-lowing are scientifically supportedtechniques that can help support ahealthy response to stress.

1. Behavioral techniques to lowerstress and manage high cortisollevels• Exercise: 30-45 minutes of

both anaerobic (resistancetraining) and aerobic (jogging,cycling) every other day.

• Meditation/relaxation:15-30 minutes daily.

2. Supplements to reduce highcortisol levels secondary tostress• Vitamin C: 1000-3000 mg/day.• Fish oil (omega-3 tatty acids):

1 -4 gm/day.• Phosphatidylserine:

300-800 mg/day.• Rhodiola rosea:

100-200 mg/day,standardized extract.

• Ginseng:100-300 mg/day,standardized extract.

• Ginkgo biloba:100-200 mg/day,standardized extract.

• DHEA: 25-50 mg/day (anyhormone supplementationshould be monitored by yourphysician). •

THE CORTISOL-OBESITYCONNECTION

Emerging studies suggest a linkbetween central obesity—markedby abdominal fat and a high waist-to-hip ratio—and elevated cortisollevels.

One such study examined 59healthy premenopausal women, 30of whom demonstrated central fatdistribution as determined by a highwaist-to-hip ratio, and 29 of whomdid not.̂ ^ All 59 women participatedin three sessions of psychosocialchallenges on four consecutive daysto gauge and measure their reactionto stress. Women with higher waist-to-hip ratios experienced the labo-ratory challenges as morethreatening, performed more poorlyon them, and reported more chron-ic stress. These women also secretedmore cortisol than women with low-er waist-to-hip ratios. The investiga-tors noted that central fatdistribution is related to greater psy-chological vulnerability to stress andcortisol reactivity. Furthermore,stress-induced cortisol secretionmay contribute to centrai fat.

In a study published in 2004,researchers examined the relation-ship between stress levels, cortisol,and abdominal obesity in 22 obesewomen, 11 of whom had a binge-eating disorder''^ The researchersfound a positive correlationbetween high stress and cortisollevels and central obesity, noting,"hyperactive HPA axis due to stressraises cortisol, which may con-tribute to binge eating and abdom-inal obesity."

Clearly, there is an intimate rela-tionship between stress, cortisol lev-els, and overall health. Modulatingcortisol levels may thus offer sup-port for healthy weight manage-ment and prevent negative healthoutcomes associated with centralobesity, such as type II diabetes.

December 2005 LIFE EXTENSION 47

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