NeuroEndocrine Theory of Aging

Controlling the Global Downstream Impact of Stress Hormones Dr. Chris D. Mele,s DrMele,[email protected] Facebook.com/DrMele,s Prior to Metabolic Syndrome The Neuroendocrine Theory of Aging is a fascina,ng explana,on for why we develop many of the diseases of our ,me, from depression to obesity to diabetes and many more, along, of course, with aging itself. Russian scien,st Vladimir Dilman, M.D., Ph.D., D.M.Sc first proposed The Neuroendocrine Theory of Aging in 1954 in a Master's Thesis. Ward Dean, M.D. began communica,ng with Dilman, and in 1992 they co-­‐authored a book The Neuroendocrine Theory of Aging and Degenera3ve D
isease.
Dr. Ward Dean deserves the credit for helping to bring Dilman's theory before the American public. Waking Up-­‐-­‐-­‐-­‐Astonished at Reality An ExplanaFon for Why We Age
The main line of thought behind The Neuroendocrine Theory of Aging is that as we age, receptors in our body begin to ignore the effects of hormones and other messenger substances. Normally, when the body is overproducing a hormone or other substance there are mechanisms established to shut off the overproduc,on. However, when receptors become desensi,zed to those signaling substances that tell them to stop overproducing, more and more of those signaling substances are needed in order for the receptors to understand the message. Insulin Resistance www.redbookmag.com www.nuTers.com ATribute: Dr. Ward and Dr. Dilman It's the same concept as an elderly person who is hard of hearing. When they were younger they could hear a whisper. But now, people may have to talk really loud or even shout for that elderly person to hear them. In the same way, when your receptors become desensi,zed, your hormones and signaling substances must increase their "volume" more and more for the cells to understand the direc,ons they are being given. At some point, the cells may become completely deaf to the message the hormones and signaling substances are sending. www.precisionnutri,on.com www.ion.ac.uk When our ancestors encountered danger, it was oYen short-­‐lived. Cor,sol levels rose to help them deal with the danger and then returned to normal aYer it was over. However, when we are exposed to chronic stress such as the emo,onal demands of work deadlines, financial challenges, raising kids, and countless other stressors, our cor,sol levels tend to rise, and to remain elevated longer than normal. These types of stressors are “the saber-­‐tooth ,gers” of our ,me. Chronic Acute When Pregnenolone & DHEA Go South Pregnenolone Progesterone DHEA Cor,sol Andosteronedione Testosterone Estradiol Pregnenolone 25 mg Micronized hTp://www.drlam.com/ar,cles/adrenal_fa,gue_and_hormone.asp A Global Look at Adrenal Glands The Body’s Race Car Adrenal Cortex-­‐ Cor,sol and Cor,sone Adrenal Medulla-­‐ Epinephrine (adrenaline) Norepinephrine Cortex Medulla zona glomerulosa mineralocor,coids (aldosterone) zona fasiculata glucocor,coids (cor,sol) zona re,cularis sex steroids (androgens) catecholamines (epinephrine and norepinephrine) Creating a Healthier Ecology
Addressing the:
When
Where
How
Why
Removing
Obstacles:
Poor Diet
Apnea
Stress
Adrenal
Dysfunction
Obesity
GI Health
Estrogen-ism
….
Hypothesis Enzyme InducFon DriO-­‐Effect Tracking Your PaFent On the Timeline Promotion
Desk
Marriage
Job
Injured
Back
Metabolic
Syndrome/
Snoring
Progressive Cellular Aging
Poor
Childhood
Diet
Predict
His
Future
Part of Life’s Journey Going...Going…Gone? Very ConservaFve EsFmates Low Testosterone Prevalence Prevalence of
Hypogonadism
(13.8 Million Men in the US) 50%
40%
30%
20%
10%
0%
Patient Age Range
Not All Men are Created Equal RelaFve to Testosterone Young Adult
Male Serum
Testosterone Range
The Same is the Case for Women Conditions in which low
testosterone is prevalent
Prevalence of Low T in Other Conditions
Chronic opioid use for pain 74%
Obesity 52%
Diabetes 50%
AIDS (HIV 30%)
Hypertension 42%
Hyperlipidemia 40%
ED 19%
Low Testosterone Prevalence
Daniel HW. J Pain. 2002: 3:377-­‐384 Mulligan T, et al., Int J Clin Pract. 2006; 60: 762-­‐769 Grinspoon S, et al., Ann Intern Med. 1998; 129:18-­‐26 Dobs AS. Bailliere Clini Endocrin Metabol. 1998 Simple Metabolism ConsideraFons •  5-­‐alpha-­‐reductase, an enzyme found in mul,ple ,ssues but especially high in the prostate gland, testosterone can be converted into dihydrotestosterone (DHT). •  Aromatase, an enzyme in skin, fat, bone and brain cells, transforms testosterone into estrogen. Nelson LR, et al. Jour of Amer Acad Derm 2001 Sep; 45(3): 116-24.
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5
6
2
4
3
7
Cholesterol Vitamin D Pregnenolone DHEA Progesterone 5 –Beta-­‐Reductase 5 -­‐alpha reductase Modified from Rhein Labs Diagram Compensatory Mechanism It has been shown in studies of obese pa,ents—both male and female—that 5-­‐alpha reductase levels rise in response to the development of insulin resistance and that the rise in the 5-­‐alpha reductase levels are associated with inac,va,on of cor,sol levels in the liver. It's believed that this rise in 5-­‐alpha reductase is a compensatory mechanism to protect against corFsol levels rising too high. Although this increase in 5-­‐alpha reductase protects against corFsol, it leaves the body wide open for the other negaFve effects of the DHT produced. Balding and Prostate (NeSID Theory Applied) •  A link between increased stress and increased prostate disease? Specifically via induc,on of 5-­‐alpha reductase. •  A link between life stressors and hair loss, either transient or permanent. Specifically via induc,on of 5-­‐ alpha reductase. www.hairomega.com COMT and Estrogenic Cancers DopamineàNorepinephrineàEpinephrine Brain COMT Catechol-­‐O-­‐methyltransferase plays an important role in the inacFvaFon of catecholamine neurotransmiZers (dopamine, epinephrine, and norepinephrine) in the brain. The type of genotype of the COMT gene that a person possesses dictates how well he or she can adapt to stress. In a study of 321 healthy college volunteers, male subjects with the COMT Met-­‐
present genotype were significantly more resilient to stress than the subjects with the Val/Val genotype. Increasing ac,vity of COMT may also unfavorably influence metabolism of estrone, one of three major endogenous estrogens found in humans along with estradiol and estriol. Estrone is converted in fat ,ssue from estradiol and adrenal androstenedione. Estrone has a higher affinity for an estrogen receptor found in breast cancer cells, the estrogen receptor alpha. Estrone can be pro-­‐carcinogenic in women and also is linked to hypertension, leg cramps, and breast tenderness. In men, estrone is linked to erecFle dysfuncFon. Limited effect of testosterone treatment for erecFle dysfuncFon caused by high-­‐estrogen levels in rats
“Further, the erec,le func,on was significantly decreased. In the ES+TE group, neither smooth muscle func,on nor erec,le func,on was significantly improved.” “In conclusion, a high-­‐estrogen milieu affected erec,le func,on in rats, and testosterone treatment did not improve the ED caused by high-­‐estrogen levels.” Int J Impot Res. 2013 Nov-­‐Dec;25(6):201-­‐5 Sex steroid hormone metabolism in relaFon to risk of aggressive prostate cancer •  “Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone raFo (OR 4th quar,le vs. 1st = 0.27; 95% CI, 0.12-­‐0.59, Ptrend = 0.003) and posiFvely associated with 2:16α-­‐
hydroxyestrone raFo (OR 4th quar,le vs. 1st = 2.44; 95% CI, 1.34-­‐4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk.” CONCLUSIONS:
•  Our findings suggest that sex steroid hormones, specifically the estrogen-­‐
androgen balance, may be important in the development of aggressive prostate cancer. Sex steroid hormone metabolism in rela,on to risk of aggressive prostate cancer. Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2374-­‐82. Different Strokes for Different Folks Everyone has a different tolerance for stress. What is stressful for one person may not bother someone else. Researchers are now discovering that the acFvity of an enzyme called catechol-­‐O-­‐methyltransferase, which is encoded by the COMT gene, may explain why some people are more resilient to stress than others. The COMT gene directs the body to produce two versions of catechol-­‐O-­‐
methyltransferase. One version—membrane-­‐bound catechol-­‐O-­‐methyltransferase (MB-­‐COMT)—
is a longer form and is primarily produced in the brain's nerve cells. A shorter version of catechol-­‐O-­‐methyltransferase—soluble catechol-­‐O-­‐
methyltransferase (S-­‐COMT)—is produced in the liver, kidneys, and blood and plays a role in regula,ng levels of some hormones. BRAIN COMT •  Catechol-­‐O-­‐methyltransferase is parFcularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates informa,on from other parts of the brain. •  This region is involved with personality, planning, inhibiFon of behaviors, abstract thinking, emoFon, and working (short-­‐term) memory. •  The prefrontal cortex requires signaling by neurotransmiTers such as dopamine and norepinephrine. Catechol-­‐O-­‐methyltransferase helps maintain appropriate levels of these neurotransmiZers in this part of the brain. COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk • 
Catechol-­‐O-­‐methyltransferase (COMT) catalyzes the O-­‐methyla,on of catechol estrogens (CEs), using S-­‐adenosylmethionine (SAM) as a methyl donor. • 
Several studies have indicated that the val108met COMT polymorphism, which results in a 3–4-­‐fold decrease in ac,vity, is associated with increased breast cancer risk. • 
Folate, whose intake levels have also been associated with breast cancer risk, and other micronutrients in the folate metabolic pathway influence levels of SAM and S-­‐adenosylhomocysteine (SAH), a COMT inhibitor generated by the demethyla,on of SAM. • 
“An increasing number of COMTL alleles was significantly associated with increased breast cancer risk in women with below median levels of folate (Ptrend = 0.05) or above median levels of homocysteine (Ptrend = 0.02).” • 
“These findings are consistent with a role for certain folate pathway micronutrients in mediaFng the associaFon between COMT genotype and breast cancer risk.” Carcinogenesis (2001) 22 (10):1661-1665. COMT and Estrogen Detox •  Several of the enzymes that catalyze CE detoxifica,on are polymorphic, including COMT. •  A val to met coding polymorphism in the COMT gene is present in up to 75% of Caucasians. Thompson,P.A. and Ambrosone,C. (2000) Molecular epidemiology of gene,c polymorphisms in estrogen metabolizing enzymes in human breast cancer. J. Natl Cancer Inst. Monogr., 27, 125–134. Weinshilboum,R.M. and Raymond,F.A. (1977) Inheritance of low erythrocyte catechol-­‐O-­‐methyltransferase ac,vity in man. Am. J. Hum. Genet., 29, 125–135. Estrogen, Aromatase and COMT • 
This muta,on results in a 3–4-­‐fold decrease in enzyme ac,vity, although the mechanism responsible for the reduced ac,vity is unknown. • 
The low ac,vity COMT allele, COMTL, has been found to be associated with breast cancer risk in four of five published peer-­‐reviewed studies. Weinshilboum,R.M. and Raymond,F.A. (1977) Inheritance of low erythrocyte catechol-­‐O-­‐methyltransferase ac,vity in man. Am. J. Hum. Genet., 29, 125–
135. Lavigne,J.A., Helzlsouer,K.J., Huang,H.Y., Strickland,P.T., Bell,D.A., Selmin,O., Watson,M.A., Hoffman,S., Comstock,G.W. and Yager,J.D. (1997) An associa,on between the allele coding for a low ac,vity variant of catechol-­‐O-­‐methyltransferase and the risk for breast cancer. Cancer Res., 57, 5493–5497. Millikan,R.C., PiTman,G.S., Tse,C.K., Duell,E., Newman,B., Savitz,D., Moorman,P.G., Boissy,R.J. and Bell,D.A. (1998) Catechol-­‐O-­‐methyltransferase and breast cancer risk. Carcinogenesis, 19, 1943–1947. Thompson,P.A., Shields,P.G., Freudenheim,J.L. et al. (1998) Gene,c polymorphisms in catechol-­‐O-­‐methyltransferase, menopausal status, and breast cancer risk. Cancer Res., 58, 2107–2110. Huang,C.S., Chern,H.D., Chang,K.J., Cheng,C.W., Hsu,S.M. and Shen,C.Y. (1999) Breast cancer risk associated with genotype polymorphism of the estrogen-­‐
metabolizing genes CYP17, CYP1A1, and COMT: a mul,genic study on cancer suscep,bility. Cancer Res., 59, 4870–4875. Yim,D.-­‐S., Park,S.K., Yoo,K.-­‐Y. et al. (2001) Rela,onship between the val158met polymorphism of catechol O-­‐methyl transferase and breast cancer.Pharmacogene,cs, 11, 1–8. Role of the folate metabolic pathway and COMT in breast cancer risk (B12, vitamin 12; COMT, catechol-­‐O-­‐methyltransferase; PLP, pyridoxal 5ʹ′-­‐
phosphate; SAH, S-­‐adenosylhomocysteine; SAM, S-­‐adenosylmethionine). DHT or Estrogen? A study
published in 1993 showed that men treated with
DHT (which cannot convert to estrogen) actually showed
a reduction in the size of their prostate with no sign of
prostate cancer.
“Estrogenic stimulation through estrogen receptor alpha
in a milieu of decreasing androgens [testosterone]
contributes significantly to the genesis of benign prostatic
hyperplasia, prostate dysplasia, and prostate cancer.”
de Lignieres B. Ann Med 1993 Jun; 25: 235-41.
Steiner MS, World J Urol 2003 May; 21(1): 31-6.
17beta-E2 and (25OHD) in Relation to All-Cause
mortality in Older Men
(the MINOS study)
CONCLUSIONS: •  In older men, increased 17beta-­‐E(2) level predicted mortality aYer 3 years of follow-­‐up. Thus, high 17beta-­‐E(2) level may reflect presence of risk factors precipita,ng development of diseases. •  Low 25OHD level predicted mortality more weakly, mainly for the first 3 years of the follow-­‐up, and was strongly influenced by the confounding variables. Thus, low 25OHD level may reflect poor current health status and unhealthy lifestyle. Clin Endocrinol (Oxf). 2009 Oct;71(4):594-­‐602. Epub 2009 Jan 22. 2/16 OH Estrone (Urinary Metabolites) •  16-­‐alpha-­‐hydroxyestrone is a breakdown product of estrogen metabolism that has been implicated in cancer. •  2-­‐hydroxyesterone is believed to be much less harmful, and in fact, a ra,o ,l,ng toward 2-­‐hydroxyesterone is thought to be beneficial. Vote for 2! 16 The Trojan Protector
The Sprouting Up of a Protector
•  Studies have demonstrated that I3C increases the ra,o of 2-­‐
hydroxyesterone to 16-­‐alpha-­‐hydroxyesterone, thereby causing a decrease in “bad” estrogen and an increase in “good” estrogen. •  In a 2002 Study, the associa,on of prostate cancer risk with estrogen metabolism, the authors stated that “results of this case-­‐control study suggest that the estrogen metabolic pathway favoring 2-­‐hydroxyla,on over 16-­‐alpha-­‐hydroxyla,on may reduce risk of clinically evident prostate cancer.” Muti P, et al. Cancer Causes Control 2002 Dec; 13(10): 947-55.
Broccoli-­‐Derived ProtecFon • 
Prostate cancer cell culture models • 
DIM and I3C at 1-­‐5 µM inhibited androgen and estrogen-­‐
mediated pathways and induced xenobio,c metabolism pathway. • 
An inhibitory effect of DIM and I3C on cell growth involves inhibi,on of insulin-­‐like growth factor-­‐1 receptor expression. “Based on our results, a model for cancer protecFve effects of DIM and I3C was proposed.” Mol Carcinog. 2011 Apr 22.
Treatment Considera,ons: Probio,cs, DIM or I3C, Progesterone Case Study on Estrogen
70 year old man, 10 mg per day transdermal testosterone.
Suffered breast tenderness and growth and surge of estradiol.
• 
• 
• 
• 
Resveratrol (Trans form) 300 mg per day PO
Quercetin 1000 mg BID
Chrysin (added in Lipoderm base to testosterone)
Split dosing ½ of Testosterone AM and ½ mid-afternoon
Optional Rx Approach:
Arimidex 0.5 mg per week and possible 2 mg/week if estradiol really high
**Recently I have been combining 0.1 mg in topical base for daily use
• 
• 
"Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone
levels". J. Clin. Endocrinol. Metab. 89 (3): 1174–80, 2004
ChemMedChem. 2007 Dec;2(12):1750-62.
Zinc–Essen,al for Sexual Health
(Zinc 30 to 60 mg QD with Food –Remember Copper)
•  There have been mul,ple studies on the effec,veness of zinc in trea,ng male infer,lity due to low testosterone levels. •  In a study of 37 infer,le men with decreased testosterone levels and associated low sperm counts. The men were given 60 mg of zinc daily for 45 to 50 days. •  In 22 pa,ents, testosterone levels significantly increased and mean sperm count rose from 8 to 20 million. Tikkiwal M, et al. Ind J Phys Pharm 1987 Jan-­‐Mar; 31(1):30-­‐34. Takihara H, et al. Urology 1987 Jun; 29(6): 638-­‐641. NeTer A, et al. Arch Androl 1981; 7(11): 69-­‐73. Pubertal Arrest Due to Zn Deficiency: The Effect of Zinc SupplementaFon
•  Hypogonadism is a major manifesta,on of zinc (Zn) deficiency in both humans and animals. The mechanism of hypogonadism caused by Zn deficiency has not been clarified. •  We present a 19 year-­‐old boy with short stature, pubertal arrest, iron deficiency anemia and Zn deficiency. Based on the dynamic tests, the hypogonadism seems to be due to hypothalamic dysfunc,on. •  The growth retarda,on was associated with low IGF-­‐I and normal growth hormone (GH) secre,on, indica,ng GH receptor or post receptor defect. Growth accelera,on and tes,cular development was observed aYer Zn supplementa,on. Zn deficiency, although very rare, should be considered in pa,ents with poor growth and hypogonadism associated with skin changes and anemia. Hormones (Athens). 2007 Jan-­‐Mar;6(1):71-­‐4. Zinc Therapy and Level of Sex Hormones BACKGROUND: •  It is demonstrated that the zinc level is significantly lower in the hemodialysis pa,ents. OBJECTIVE: •  In this clinical trial, we inves,gate the effect of zinc supplement therapy on the serum levels of sexual hormones in hemodialysis male pa,ents. PATIENTS AND METHODS: •  The pa,ents received zinc supplement (zinc sulfate, 250 mg/day) for 6 weeks, and sex hormones and zinc plasma level were checked again. RESULTS: •  Serum level of FSH and prolac,n did not have any significant changes before and aYer interven,on, but serum level of testosterone, LH, and zinc increased significantly. Ren Fail. 2010 May;32(4):417-­‐9. Testosterone Free Approach 1. 
2. 
3. 
4. 
5. 
Improve Lean Body Mass Lower SHBG (Ge~ng more Free T) Decrease Aromatase (TàE Conversion) Decrease 5 alpha-­‐Reductase (TàDHT) Test and Op,mize: DHEA, Pregnenolone Total T >18% Free T > 25% SHBG < WNL Estradiol < WNL Select Overview Modulator
Saw Palmetto
5 Alpha Reductase
Inhibition
Aromatase
Inhibition
SHBG
Lowering
320 mg QD to BID
(85-95% Fatty Acids)
Astaxanthin
4 mg QD to BID
Black Cohosh
40 to 80 mg QD to
BID
standardized to 2.5%
triterpene glycosides
Quercitin
1000 mg QD to BID
Chrysin (w/
500 to 1000 mg QD
to BID
Bioperine)
Green Tea Extract
(98% polyphenols,
80% catechins, 50%
EGCG (leaves)
500 -1000 mg QD to
BID
Boron
10 mg QD
Nettles
500 to 1000 mg BID
(0.8% sterols)
Vitamin D Vitamin D and Testosterone •  The male reproduc,ve tract is a target ,ssue for vitamin D. •  200 Healthy overweight nondiabe,c men undergoing a weight reduc,on program. •  Par,cipants received either 83 micrograms (3,332 IU) vitamin D daily for 1 year (n=31) or placebo (n=23).
Vitamin D Impact—on Low T
With Vitamin D use it was noted: Significant increase in total testosterone levels Ø  (from 10.7±3.9 nmol/l to 13.4±4.7 nmol/l; p<0.001) Increase of bioac,ve testosterone Ø  (from 5.21±1.87 nmol/l to 6.25±2.01 nmol/l; p=0.001) Increase of free testosterone levels Ø  (from 0.222±0.080 nmol/l to 0.267±0.087 nmol/l; p=0.001) By contrast, there was no significant change in any testosterone measure in the placebo group.
E. Zittermann Hormone and Metabolic Research, Dec 10, 2010
AssociaFon of Vitamin D Status with Serum Androgen Levels in Men
•  Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG. CONCLUSION: •  Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal varia,on. Clin Endocrinol (Oxf). 2010 Aug;73(2):243-8.
Low Protein Can Increase SHBG “…diets low in protein in elderly men [40-to-70 years old]
may lead to elevated SHBG levels and decreased
testosterone availability.”
Longcope C, et al. J Clin Endocrinol Metab 2000 Jan; 85(1): 293-­‐96. (picture) www.examiner.com/ar,cle/low-­‐carb-­‐paleo-­‐diet-­‐advocates-­‐rip-­‐high-­‐protein-­‐diet-­‐study-­‐as-­‐misleading Soy Keep Estrogen and SHBG in Check •  Aging Men oYen experience an increase in SHBG and estrogen via ac,vity of the aromatase enzyme, both of which can lead to a decrease in testosterone levels. •  A study of 97 men, 49-­‐to-­‐72 years of age showed that men who had high levels of soy intake had lower levels of estradiol when compared to men with lower levels of soy intake. •  They postulated that this beneficial inverse rela,onship could be due to inhibi,on of the aromatase enzyme by soy and soy-­‐
based food products. Nagata C, et al.. Nutr Cancer 2000; 36(1): 14-­‐18. Something Fishy •  Essen,al faTy acids EPA and DHA impact on SHBG levels in men 43-­‐to-­‐88 years of age. •  AYer controlling for other variables, the researchers came to the conclusion that both EPA and DHA decreased levels of SHBG in middle-­‐aged and elderly men. Nagata C, et al. Nutr Cancer 2000; 38(2): 163-67.
Each Man Needs a
Different Dosing,
The Key is Nudging not Shoving.
Treat the Adrenals First.
Final Medley Random Clinical Tidbits Aggression: The Testosterone-­‐Serotonin link The relevance of central neurotransmission to aggressive and impulsive behavior has become more evident due to extensive research in humans and animals. Among other findings, there are abundant data rela,ng low serotonin ac,vity-­‐-­‐as measured by low cerebrospinal fluid 5-­‐hydroxyindolace,c acid, and a blunted response of prolac,n to fenfluramine-­‐-­‐to impulsive behavior. Many studies on testosterone ac,vity show a rela,on between high plasma levels and a tendency towards aggression. It is hypothesized that the interac,on between low serotonin and high testosterone levels in the central nervous system has a significant effect on the neural mechanisms involved in the expression of aggressive behavior. It seems that testosterone modulates serotonin receptor acFvity in a way that directly affects aggression, fear and anxiety. Our survey reviews the main findings on serotonin, testosterone and the possible interac,on between them with regard to these behavioral phenomena. Be'er Yaakov Mental Health Center, Magen Prison, Ramleh, Israel. Isr Med Assoc J. 2003.
NeuroEndocrine Link yet AGAIN!! Low serotonin ac,vity is associated with hyper-­‐responsiveness to aversive s,muli and therefore results in a greater likelihood of an intensely nega,ve emo,onal reac,on and, thus, a greater chance of aggressive behavior. It is speculated that the hypothalamus and amygdala, which are prominently associated with both testosterone and serotonin, play a key role in aggressive responses to situa,ons in which efforts at dominance are frustrated. In comparison to nonaggressive animals, aggressive animals were found to have lower serotonin levels in the hypothalamus and the amygdala. Testosterone ac,on in both of these brain structures was shown to increase aggression in various animal species. Bernhardt PC. Influences of serotonin and testosterone in aggression and dominance: convergence with social psychology. Curr Direc Psychol Sci 1997;6:44±8. IMS (Irritable Male Syndrome) Irritable Male Syndrome (IMS) refers to: Feelings of withdrawal, sadness, anxiety, frustra,on, being unenthusias,c or uninterested. Stress can also contribute to IMS. In a recent study, 46 percent of the men surveyed stated they felt oYen or almost always stressed and 40 percent claim they are rarely sexually sa,sfied, 55 percent stated they had a strong fear of failure and 62 percent expressed a desire to "get away from it all." Mood swings related to stress can include anger, tenseness, sarcasm, hos,lity, unloving, defensiveness, dissa,sfac,on, impa,ence, argumenta,ve and demanding. IMS—Depression and Beyond More than six million men are diagnosed with depression each year. (Na,onal Ins,tutes of Mental Health) Males tend to "act-­‐out" their depression symptoms; including: self-­‐
destruc,veness, drug use, gambling, womanizing and workaholism. Symptoms of depression and IMS overlap: sadness, feelings of hopelessness, pessimism, feelings of guilt, worthlessness, helplessness, loss of interest or pleasure in hobbies and ac,vi,es, decreased energy, fa,gue, being "slowed down," difficulty concentra,ng, remembering, making decisions, difficulty sleeping, early-­‐morning awakening, or oversleeping, appe,te and/or weight changes, thoughts of death or suicide; suicide aTempts, restlessness and irritability. DHEAS Concentrations Increased after Melatonin Therapy
Moreover, a tendency towards a higher DHEAS/cortisol ratio was
found after 6 months of treatment.
Neuroendocrinology Letters 2002 Apr; 23 Suppl 1: 17-9
REST-­‐ora3on-­‐ Restoring the Body and Mind •  “DHEA administraFon induced a significant (P < 0.05) increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with the placebo condiFon.” •  “Spectral analysis of five selected EEG bands revealed significantly (P < 0.05) enhanced EEG acFvity in the sigma frequency range during REM sleep in the first 2-­‐h sleep period aOer DHEA administraFon.” American Journal of Physiology, Endocrinology and Metabolism 1995; 31: E107-­‐E113 Dehydroepiandrosterone combined with Exercise Improves Physical FuncFon •  Par,cipants received 50 mg/d DHEA or placebo for 6 months; all received calcium and cholecalciferol. Women par,cipated in 90-­‐minute twice-­‐weekly exercise regimens. CONCLUSION: •  DHEA supplementa,on improved lower extremity strength and func,on in older, frail women involved in a gentle exercise program of chair aerobics or yoga. J Am Geriatr Soc. 2010 Sep;58(9):1707-­‐14 DHEA, Important Source of Sex Steroids in Men and Women •  DHEA secre,on decreases from the age of 30 years and is already decreased, on average, by 60% at ,me of menopause. •  “Since there is no other significant source of sex steroids aYer menopause, one can reasonably believe that low DHEA is involved, in associa,on with the aging process, in a series of medical problems classically associated with post-­‐
menopause”. Progress in Brain Research: 97-­‐148. 2010 DHEA Restora,on— Beyond the Adrenals for Men •  In men, the contribu,on of adrenal DHEA to the total androgen pool has been measured at 40% in 65-­‐75-­‐year-­‐old men. •  Comparable decrease in serum DHEA levels observed in both sexes has less consequence in men who conFnue to receive a pracFcally constant supply of tesFcular sex steroids during their whole life. Progress in Brain Research: 97-­‐148. 2010 DHEA-­‐ Medical Literature Dosing Commentary Clinical trials suggest that 50 mg of oral DHEA, but not <30 mg, can increase serum androgen levels to within the physiologic range for young adults with primary and secondary adrenal insufficiency, possibly improve sexual func,on, improve mood and self-­‐esteem (depression) and decrease fa,gue. Commentary: Side Effects? Cameron DR, et al., Treat Endocrinol. 2005;4(2):95-­‐114
. Low Serum DHEA Sulfate Predicts All-Cause and ++
+Cardiovascular Mortality+++
MAIN OUTCOME MEASURES: •  Associa,on between low DHEA-­‐S and CVD death remained aYer adjustment for C-­‐reac,ve protein and circula,ng estradiol and testosterone levels. CONCLUSIONS: •  Low serum levels of DHEA(-­‐S) predict death from all causes, CVD, and ischemic heart disease in older men. J Clin Endocrinol Metab. 2010 Sep;95(9):4406-­‐14. Topical DHEA—Beyond Atropy? •  A recent randomized, placebo-­‐controlled study has shown that all the signs and symptoms of vaginal atrophy, a classical problem recognized to be due to the hormone deficiency of menopause, can be rapidly improved or corrected by local administraFon of DHEA without systemic exposure to estrogens. Progress in Brain Research: 97-­‐148. 2010 “NeSID” Theory (A Term I’ve Coined) NeuroEndocrine Stress Induced Dysregula3on Induc,on of 5 alpha reductase by stress –  CorFsol Metabolism •  (Increased Cor,sol catabolismàaccelerates TàDHT) –  Testosterone to DHT Metabolism •  (Robust T to DHT conversion induces Cor,sol Catabolism) Induc,on of COMT by stress –  Enhanced NeurotransmiZer Catecholamine Metabolism •  (Increasing COMT may nega,vely impact Estrone Metabolism –  Estrone Metabolism •  (Robust Estrone Metabolism can increase NT metabolism) How Mitochondria Affect Hormones The mitochondria give birth to all hormones. Steroid hormone biosynthesis begins in the mitochondria because the conversion of cholesterol to pregnenolone — the precursor to all steroid hormones — occurs through the acFvity of the cytochrome P450 side-­‐chain cleavage enzyme located on the inner mitochondrial membrane. The electron transport chain of mitochondria is involved in testosterone producFon in the Leydig cells and manipulaFon of this pathway has been shown to increase producFon of testosterone. Ramalho-­‐Santos J and Amaral S. Mol Cell Endocrinol. 2013 Oct 15;379(1-­‐2):74-­‐84. Strushkevich N, et al. Proc Natl Acad Sci USA. 2011 Jun 21;108(25):10139-­‐43. Le B, et al. Andrology. 2014 May 12. VITAMIN D DIHYDROTESTOSTERONE (DHT) It is Time To Unravel Our Pa,ents’ Chemistry!!!
DrMele,[email protected]