Jeffrey Dach MD Bio-Identical Hormone Blog

Ross Clark MD New Associate

Jeffrey Dach MD — Sat, 27 Feb 2010 12:27:00 GMT

Announcing Ross Clark MD, New Associate

We take pleasure in announcing our new associate, Ross N Clark, MD. Ross is well known and highly regarded thoughout the Hollywood and South Broward area as a thoughtful, caring, and compassionate doctor.

Ross was originally trained at the University of California Medical School in San Francisco with a surgical internship and residency at the Kaiser Hospitals. Following this, Dr Clark moved to New York for a 3 year ENT Head and Neck Surgery residency at Mt Sinai Hospital.

Dr Clark then moved to Florida and served for 25 years as Head and Neck Surgeon at Hollywood Memorial Hospital. After retirement from a successful ENT surgical practice, Dr. Clark opened an alternative medical practice in Aventura, Florida, offering intravenous chelation therapy.

Dr. Clark is board certified in Otolaryngology - Head and Neck Surgery, and Cosmetic Surgery. Dr Clark is a member of the American College of Surgeons, American Academy for Anti-Aging Medicine and the American College for Advancement in Medicine.

Dr. Clark specializes in the conversion from synthetic hormone replacement to bioidentical hormones, using the sophisticated testing and treatment protocols available at our TrueMedMD office. Call the office for an appointment with Dr. Clark.
954-983-1443

March 1, 2010
Jeffrey Dach MD
TrueMedMD
4700 Sheridan Suite T
Hollywood Fl 33021
954-983-1443
http://www.jeffreydach.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.truemedmd.com

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Low Testosterone From Pain Pills by Jeffrey Dach MD

Jeffrey Dach MD — Fri, 26 Feb 2010 17:36:00 GMT

Low Testosterone From Pain Pills by Jeffrey Dach MD

Joe has chronic fatigue, weakness, and erectile dysfunction. He was doing well until 10 years ago when he started pain pills after a car accident which left him with chronic back pain.

Left image: poppy field in Burma courtesy of wikimedia commons. Poppies are source for opium, a narcotic pain medication.

Chronic Pain Treated with Opioid Narcotics

After the car accident, Joe's family doctor prescribed oxycontin pain pills, hoping the chronic back pain would eventually get better. Unfortunately, Joe's back pain did not get better, and he still takes pain pills every day. Even though the pain pills are no longer effective, Joe finds it nearly impossible to get off them because of the severe withdrawal effects.

Low Testosterone Detected on Blood Tests

Joe's lab testing showed very low testosterone levels. This explained the fatigue, weakness and low libido. Joe was started on bioidentical testosterone as a topical gel, and 6 weeks later he reports that his fatigue and weakness is gone, and his wife is much happier with his renewed libido. Joe also noticed his chronic pain seemed to decrease in intensity, and he was now interested in pursuing the idea of tapering off the narcotic pain pills.(4)

Above Left image: Synthetic opiate hydrocodone (Vicodin Tablet) courtesy of wikimedia commons. Vicodin Tablet is chemically altered version of Opium Poppy.

Doctors Freely Prescribe Narcotic Pain Pills

When patients like Joe seek help from their doctor for a painful condition, they will be given narcotic pain tablets such as percocet, oxycodone, roxycodone and oxycontin. These pain pills are quite effective at relieving the painful condition. However, they come with severe adverse side effects.

Adverse Effects of Long Term Pain Pills (Opiates)

We all know that Pain Pills, such as opioid narcotics, are highly addictive and come with severe adverse effects. Opiate containing narcotic Pain Pills were never intended for long term use. They cause profound suppression of the endocrine system, and in men, profound inhibition of testosterone production. This type of low testosterone is quite common, and yet, may go unrecognized by the busy primary care doctor. (1)

Another adverse effect of long-term opioid use is opioid-induced hyperalgesia. This is a form of hypersensitivity to pain. The original painful condition becomes worse. Other adverse effects include impaired cognitive function, and suppression of the immune system with tendency to develop infection.(6)

Above image: OxyContin tablets crushed into powder for insufflation (snorting). Notice the tablets at the top with the coating removed. The tablets are distributed by AB Generics, hence the ABG stamp on the back. Image Courtesy of wikimedia commons. Oxycontin is chemically altered version of opium poppy.

Chronic Opioid Pain Pills Lose Effectiveness Long Term

Another problem with long term use of narcotic pain pills, is that they lose their effectiveness over time. The brain and nervous system develops a "tolerance" to the drug, and higher doses are required to achieve the same result.(7) The initial pain relief from opioid pain pills may not be sustained long term because of drug tolerance, opioid-induced hyperalgesia, and intermittent drug withdrawal effects. (7) In other words the pills lose their effectiveness, and yet continue to produce dependence and adverse effects.

Left image: Young drug addict injecting narcotic opiate drug into left arm. Heroin is chemically altered version of Opium Poppy. Courtesy of wikimedia commons.

Low Testosterone Goes Largely Unrecognized

Although quite common, Opioid-induced androgen deficiency and has gone largely unrecognized by the medical community(1). Low testosterone is caused by opioid drug inhibition of LH (Leutininizing Hormone), a pituitary hormone involved in testosterone production, as well direct inhibition of testosterone itself. Similarly, there is also inhibition of the entire endocrine system, and adrenal hormone suppression.

Symptoms of low testosterone include fatigue, depression, hot flashes, night sweats, diminished libido, erectile dysfunction, and diminished sexual arousal and satisfaction. Men may also develop osteoporosis, anemia, and diminished muscle mass. (2)(3)
Women who consume opioid-pain pills will stop having menstrual cycles and will notice greatly diminished libido (sex drive). (5)

Testosterone Treatment Effective and Recommended by Mainstream Medicine

Administration of topical testosterone, or injectable testosterone has been studied and found effective for men with low testosterone on pain pills. (4)

Left Image opium poppy courtesy of wikimedia commons. This plant is used to make opium, a natural source for narcotic pain medication. Courtesy of wikimedia commons.

Our Approach to Evaluation and Treatment

For men with a chronic pain condition who have been on long-term pain pills, our evaluation includes a complete blood testing panel looking for vitamin, mineral and nutritional deficiencies. We find these deficiencies quite commonly in this group.   In addition, evaluation includes a complete hormone panel looking at the entire endocrine system, and adrenal function. If extensive testing shows low hormone levels, then hormone supplementation is offered.

Opiate Detoxification Program is Essential

The reality is that hormone supplementation and nutritional supplementation for the long term opiate pain pill user is only a temporary bandaid. To fully restore health, the opiate addiction must be addressed and the patient must ultimately get off the pain pills. This may be difficult to do on their own because of severe drug withdrawal symptoms. Therefore, we provide the patient with a referral to any one of a number of doctors who specialize in narcotics detoxification, and urge the patient to strongly consider this option.

Above left image: 2D structure of synthetic opiate hydrocodone (Vicodin) courtesy of wikimedia commons.

Rick Sponaugle MD

One such specialist is Rick Sponaugle MD at the Florida Detox Center. Dr Sponaugle is board certified in anesthesiology and addiction medicine.

Dr Sponaugle's facility is, in actuality, an eight-story, medical hospital which offers a painless and rapid detox program, utilizing general anesthesia and sophisticated intra-operative monitoring of the brain and cardiovascular system.  Sophisticated monitoring is done with intra-operative trans-esophageal echocardiography for the ultimate in safety. This protocol prevents the usual body twitching and tremors associated with Oxycontin withdrawal. In addition, the center offers other programs for detox from alcohol and benzodiazepine addiction.

contact: Rick Sponaugle MD at the Florida Detox Center
Florida Detox & Wellness Institute phone 1-888-775-2770
1501 S. Pinellas Ave, Suite P, Tarpon Springs, FL 34689

Jeffrey Dach MD
4700 Sheridan Suite T
Hollywood Fl 33021
954-983-1443
http://www.jeffreydach.com/
http://www.drdach.com/
http://www.naturalmedicine101.com/
http://www.truemedmd.com/

Articles with related content

Low Testosterone Could Be Killing You by Jeffrey Dach MD

Links and References

(1) http://journals.lww.com/co-endocrinology/
Abstract/2006/06000/Opioid_induced_androgen_deficiency.6.aspx
Current Opinion in Endocrinology and Diabetes: June 2006 - Volume 13 - Issue 3 - p 262-266 . Opioid-induced androgen deficiency by Daniell, Harry W

Opioid-induced androgen deficiency has become one of the most common causes of testosterone deficiency among men in many communities. Its increase parallels the large increase in opioid use. This form of hypogonadotrophic hypogonadism is present in most men chronically consuming sustained-action opioids, including those receiving methadone for heroin addiction and those consuming opioids for control of either malignant or non-malignant chronic pain. A similar, but less well defined illness occurs in women. Opioid-induced androgen deficiency is not widely recognized. This review examines its pathophysiology, some of its signs and symptoms, and indicates some areas where current observations suggest additional investigations would be fruitful.

Recent findings: Recognition of opioid-induced androgen deficiency in men not receiving methadone for heroin addiction is a new observation, and in these men contributes to fatigue, depression, vasomotor phenomena, anemia, diminished libido, erectile dysfunction and osteoporosis. These signs and symptoms improved during testosterone replacement therapy in several small non-placebo-controlled trials.

Summary: A large majority of men consuming sustained-action opioids have symptomatic androgen deficiency which apparently responds to replacement therapy. Opioid-induced androgen deficiency is frequently overlooked, with its symptoms attributed to underlying disease states including malignant disease, chronic back disorders, HIV disease, and psychosocial illnesses contributing to opioid habituation.

(2) http://www.amjmed.com/article/S0002-9343(06)00614-0/fulltext
Volume 120, Issue 9, Page e21 (September 2007)

Opioid-induced Androgen Deficiency Discussion in Opioid Contracts Harry W. Daniell, MD

Strong inhibition of androgen production quickly follows the onset of sustained-action opioid use, whether the opioids are administered orally,2, 3, 4, 5 transdermally,4 or intrathecally.3, 5, 6, 7, 8 These low androgen levels result in classic symptoms of hypogonadism in a majority of opioid-consuming men, with most of them exhibiting various combinations of fatigue, depression, hot flashes, night sweats, diminished libido, erectile dysfunction, and diminished sexual arousal and satisfaction. Low androgen levels also contribute to physical changes, including osteoporosis, anemia, and diminished muscle mass. Similar changes occur in opioid-consuming premenopausal women, most of whom demonstrate amenorrhea or anovulatory menstrual cycles soon after beginning sustained-action opioid use.6, 8, 9, 10 Most premenopausal and postmenopausal women also demonstrate greatly diminished libido 6, 8, 10 at this time.

Signs and symptoms of hypogonadism typically improve in men with OPIAD during replacement testosterone therapy4 and in the few women who have received hormone replacement therapy for opioid-related symptoms of hormone deficiency.6, 10

In my private practice of general internal medicine, the discussion of OPIAD in our opioid contracts includes the potential usefulness of replacement hormonal therapy and potential complications of this therapy. We have found this information to be of help in establishing the patient-physician partnership described and recommended by Arnold et al,1 which clearly is required for optimal chronic use of opioids. As part of this information exchange, we obtain sex-hormone levels in all outpatients about to begin chronic sustained-action opioid therapy and again with the development of symptoms of hypogonadism.

(3) http://www.jpain.org/article/S1526-5900(02)00032-9/abstract?refuid=S0002-9343(06)00614-0&refissn=0002-9343

Hypogonadism in men consuming sustained-action oral opioids

Presented in part at the 16th Annual Meeting of the Society for Ambulatory Anesthesia, Palm Springs, CA, May 2-5, 2001. Harry W. Daniell Volume 3, Issue 5, Pages 377-384 (October 2002)

Naturally occurring opiates (endorphins) diminish testosterone levels by inhibiting both hypothalamic gonadotrophin releasing hormone production and testicular testosterone synthesis. Heroin addicts treated with a single daily dose of methadone and nonaddicts receiving continuous intrathecal opioids quickly develop low luteinizing hormone and total testosterone levels. A similar pattern was sought in men consuming commonly prescribed oral opioids. Free testosterone (FT), total testosterone (TT), estradiol (E2), dihydrotestosterone (DHT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in 54 community-dwelling outpatient men consuming oral sustained-action dosage forms of opioids several times daily for control of nonmalignant pain. Hormone levels were related to the opioid consumed, dosage and dosage form, nonopioid medication use, and several personal characteristics and were compared with the hormone analyses of 27 similar men consuming no opioids.

Hormone levels averaged much lower in opioid users than in control subjects in a dose-related pattern (P < .0001 for all comparisons). FT, TT, and E2 levels were subnormal in 56%, 74%, and 74%, respectively, of opioid consumers. Forty-eight men (89%) exhibited subnormal levels of either FT or E2. Either TT or E2 level was subnormal in all 28 men consuming the equivalent of 100 mg of methadone daily and in 19 of 26 (73%) consuming smaller opioid doses. Eighty-seven percent (39 of 45) of opioid-ingesting men who reported normal erectile function before opioid use reported severe erectile dysfunction or diminished libido after beginning their opioid therapy. Commonly prescribed opioids in sustained-action dosage forms usually produce subnormal sex hormone levels, which may contribute to a diminished quality of life for many patients with painful chronic illness.

(4) http://www.ncbi.nlm.nih.gov/pubmed/16516826
J Pain. 2006 Mar;7(3):200-10.

Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. Daniell HW, Lentz R, Mazer NA. Department of Family Practice, University of California Davis Medical School, Redding, California, USA.

We conducted a 24-week open-label pilot study of testosterone (T) patch therapy in 23 men with opioid-induced androgen deficiency (OPIAD). The T dosage was 5 mg/day for the first 12 weeks and 7.5 mg/day for the second 12 weeks. Seven subjects discontinued prematurely: 4 for noncompliance, 2 for skin irritation and 1 for hepatitis C treatment. In the "completers" population (n = 16), mean (SD) free T levels (normal range 52 to 280 pg/mL) were 28.5 (18.6) pg/mL at baseline, 72.8 (29.6) pg/mL on 5 mg/day (P < .001 vs. baseline), and 120.2 (69.5) pg/mL on 7.5 mg/day (P < .001 vs. baseline and P < .01 vs. 5 mg/day). Total T, dihydrotestosterone, and estradiol showed parallel changes. Sex hormone-binding globulin levels were elevated at baseline and decreased modestly with treatment (P < .05 vs. baseline at 5 mg/day; P < .01 vs. baseline at 7.5 mg/day). Luteinizing hormone levels were in the low-normal range at baseline and suppressed markedly with treatment (P < .001 vs. baseline at both doses). Androgen deficiency symptoms (ADSQ), sexual function (Watts SFQ), mood (PGW, depression (BDI-II), and hematocrit levels showed improvement during treatment, generally more so at the 7.5 mg/day dosage (P < .001 vs. baseline for most parameters). Pain scores (BPI-SF) decreased slightly on 7.5 mg/day (interference score: P < .05 vs. baseline and 5 mg/day); the use of opioids did not change appreciably. The testosterone patches were generally well tolerated.

PERSPECTIVE: Long-acting opioid preparations suppress the hypothalamic-pituitary-gonadal axis in men and produce a symptomatic state of opioid-induced androgen deficiency (OPIAD). Testosterone patch therapy at a dose of 7.5 mg/day normalizes hormone levels and appears to improve a number of quality of life parameters (eg, sexual function, well-being, mood) in men with OPIAD.

(5) http://www.ncbi.nlm.nih.gov/pubmed/17936076
J Pain. 2008 Jan;9(1):28-36. Epub 2007 Nov 1.

Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. Daniell HW. Department of Family Practice, University of California Davis Medical School, Redding, California, USA.

Hypogonadotrophic hypogonadism is characteristically induced in men by intrathecal, transdermal, or sustained-action opioids. Although women receiving intrathecal opioids have similar changes, often accompanied by amenorrhea, hypogonadotrophic hypogonadism has not been documented in women receiving sustained-action, transdermal, or oral opioids. Dehydroepiandrosterone sulfate deficiency, indicating adrenal inhibition, is present in most men and women chronically consuming sustained-action oral or transdermal opioids.

We recorded menstrual histories and measured gonadotrophin, androgen, and estradiol levels in 47 women ages 30 to 75 years who were consuming sustained-action oral or transdermal opioids for control of nonmalignant pain and in 68 non-opioid-consuming control subjects.

Testosterone, estradiol, and dehydroepiandrosterone sulfate values were 48% to 57% lower in opioid-consuming women with intact ovarian tissue than in control subjects (P < .01-.05). Luteinizing hormone and follicle-stimulating hormone values averaged 30% lower in premenopausal and 70% lower in postmenopausal opioid consumers (P < .001).

Among oophorectomized women not consuming estrogen, free testosterone levels were 39% lower in opioid consumers (P < .05), indicating impaired adrenal androgen production. Additional lowering of free testosterone levels was associated independently with oral estrogen replacement and low body mass index. Menses had often ceased soon after beginning sustained-action opioid therapy.

Our observations document hypogonadotrophic hypogonadism plus decreased adrenal androgen production in most women consuming sustained-action oral or transdermal opioids.

PERSPECTIVE: These observations demonstrate profound inhibition of ovarian sex hormone and adrenal androgen production among women chronically consuming sustained-action opioids. Related consequences include altered menstrual flow, probable reduced fertility, and possible contributions to opioid-associated depression, osteoporosis, and hyperalgesia. Measurements of bone density, estradiol, and free testosterone may guide appropriate therapy.

(6) http://www.ncbi.nlm.nih.gov/pubmed/17873598
Curr Opin Anaesthesiol. 2007 Oct;20(5):451-5.

An update on the role of opioids in the management of chronic pain of nonmalignant origin. Højsted J, Sjøgren P. Multidisciplinary Pain Center, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.

PURPOSE OF REVIEW: To summarize and reflect over primarily recent epidemiological and randomized controlled trials in opioid-treated chronic nonmalignant pain patients, focusing on effects, side effects, risks and long-term consequences of the treatment.

RECENT FINDINGS: In the western world opioids are increasingly being used for long-term treatment of chronic nonmalignant pain. While the long-term benefits of opioids regarding pain relief, functional capacity and health-related quality of life still remain to be proven, studies are emerging that describe serious long-term consequences such as addiction, opioid-induced hyperalgesia, cognitive disorders, and suppression of the immune and reproductive systems.

SUMMARY: Much more research is needed concerning long-time effects and consequences of opioid therapy in chronic nonmalignant pain patients; however, some clear warning signals have been sent out within recent years.

(7) http://www.ncbi.nlm.nih.gov/pubmed/18574357
Clin J Pain. 2008 Jul-Aug;24(6):469-78.

Efficacy of opioids for chronic pain: a review of the evidence. Ballantyne JC, Shin NS.Division of Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Opioid therapy for chronic pain has been popularized over the past few decades, and a concern has arisen that the analgesic efficacy of opioids is not always maintained over prolonged courses of treatment despite dose escalation and stable pain. Considering the potentially serious adverse effects of opioids, the idea that pain relief could diminish over time may have a significant impact on the decision to embark on this therapy, especially in vulnerable individuals. Possible loss of analgesic efficacy is especially concerning, considering that dependence may make it hard to withdraw opioid therapy even in the face of poor analgesia. This article first reviews the evidence on opioid efficacy when used for the treatment of chronic pain, and concludes that existing evidence suggests that analgesic efficacy, although initially good, is not always sustained during continuous and long-term opioid therapy (months to years). The theoretical basis for loss of analgesic efficacy over time is then examined. Mechanisms for loss of analgesic efficacy proposed are pharmacologic tolerance, opioid-induced hyperalgesia, subtle and intermittent withdrawal, and a number of psychologic factors including loss of the placebo component.

http://www.viamedica.pl/gazety/gazetaE/darmowy_pdf.phtml?indeks=33&indeks_art=263 Zbigniew Zylicz
Consultant in Palliative Medicine, Dove House Hospice, Hull, United Kingdom

Opioid-induced hypogonadism: the role of androgens in the well-being and pain thresholds in men and women with advanced disease

http://jcem.endojournals.org/cgi/content/full/85/6/2215
Endocrine Consequences of Long-Term Intrathecal Administration of Opioids

Roger Abs, Johan Verhelst, Jan Maeyaert, Jean-Pierre Van Buyten, Frank Opsomer, Hugo Adriaensen, Jan Verlooy, Tony Van Havenbergh, Mike Smet and Kristien Van Acker The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2215-2222

In conclusion, of all patients receiving intrathecal opioids, the large majority of men and all women developed hypogonadotropic hypogonadism, about 15% developed central hypocorticism, and about 15% developed GH deficiency. These findings suggest that further investigations are required to determine the need for systematic endocrine work-up in these patients and the necessity for substitutive therapy.

Jeffrey Dach MD
4700 Sheridan Suite T
Hollywood Fl 33021
954-983-1443
http://www.jeffreydach.com/
http://www.drdach.com/
http://www.naturalmedicine101.com/
http://www.truemedmd.com/

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BioIdentical Hormones Relieve Anxiety by Jeffrey Dach MD

Jeffrey Dach MD — Fri, 19 Feb 2010 21:58:00 GMT

BioIdentical Hormones
For Anxiety and Depression

by Jeffrey Dach MD

56 year old Susan suffered from anxiety and panic attacks, and had been prescribed Valium, Effexor and Wellbutrin by her primary care doctor. The drugs had adverse side effects and didn't seem to be helping, so she stopped taking them. After further discussion, she told me that symptoms started a few years ago when her monthly cycles stopped and with the onset of menopausal hot flashes. She noticed that the anxiety and panic attack seems to precede an episode of hot flashes.

Left Image: Anxiety, Fear and Panic courtesy of Wikimedia commons

Estrogen Deficiency Causes Anxiety

We sent Susan to the lab for a hormone panel, and sure enough, Susan's estrogen level was low. Susan's symptoms were caused by menopausal estrogen deficiency, a finding commonly seen in the post menopausal age group. Symptoms are promptly relieved with bioidentical estradiol applied as a topical cream twice a day. Additionally, Susan's tests revealed vitamin and mineral deficiencies which were, no doubt, aggravating the anxiety attacks.

Susan was started on her bioidentical hormone program which included estradiol and progesterone as a balanced topical cream. She was also started on vitamin B12 and Magnesium supplements. Six weeks later, Susan reported that her anxiety and panic attacks had improved and were almost gone. She also noticed better sleep and more clarity of mind, and her night sweats and hot flashes had resolved as well.

Anxiety is Associated with Hot Flashes

A study published in 2005 Menopause reported that anxiety is strongly associated with menopausal hot flashes, and usually precedes the hot flash episode. (13) Hot flashes are caused by estrogen deficiency, and are treated with bioidentical estradiol, which virtually eliminates them.(15)(16)(17)

above image: dont panic courtesy of wikimedia commons

The Benefits of Bioidentical Estrogen

My previous articles discuss the safety and the importance of bioidentical hormones.

Uzzi Reiss's new book Natural SuperWoman contains an excellent discussion of bioidentical hormones.  Chapter 4 covers anxiety, panic attacks and relief with bioidentical estrogen.(1) Numerous articles (see below) summarize the medical literature showing that low estrogen levels cause anxiety and depression in humans and animals. Estrogen treatment relieves anxiety and depression as well as virtually eliminates the hot flashes.

What is the Mechanism of Action Of Estrogen in Eliminating Anxiety and Depression?

Estrogen receptors have been found in the brain, and estrogen increases the expression of an enzyme in the brain called tryptophan hydroxylase-2 (TPH2). This enzyme converts tryptophan to serotonin, an important neurotransmitter responsible for an anti-anxiety and calming effect in the brain.  These estrogen receptors have been isolated to specific areas of the brain call the DRN, or the dorsal raphe nuclei (2)(3)(4)(5)(6).

Estrogen Effective for Perimenopausal Depression

A study published in the 2001 Archives of General Psychiatry evaluated bioidentical estrogen as treatment for peri-menopausal depression. They evaluated fifty women ages 40-55 years, suffering from a depressive disorder and irregular menstrual periods (FSH >25 IU/L). These women were treated with bioidentical estrogen or placebo over 12-weeks. Remission of depression was observed in 17 (68%) women treated with bioidentical estradiol compared with only 5 (20%) in the placebo group. The authors concluded, "Transdermal estradiol is an effective treatment of depression for perimenopausal women."(7)

Above left image: Brain Anatomy of DRN: The formatio reticularis of the medulla oblongata, shown by a transverse section passing through the middle of the olive of the midbrain showing (4) DRN Dorsal Raphe Nucleus courtesy of wikimedia commons  4. Raphe.

Estrogen Effective for Post-Partum Depression (after child birth)

Postpartum depression is seen in approximately 13% of women who have recently given birth, and often remains untreated. (10) Various treatments have been tried, including antidepressant drug therapy (SSRI's), bioidentical estrogen, individual psychotherapy, and group psychotherapy. (10)

A study published in the 2001 Journal of Clinical Psychiatry showed that bioidentical estrogen is effective for post-partum depression.(8) Twenty-three women suffering from postpartum depression were recruited from a psychiatric emergency unit. The women were treated over 8 weeks with bioidentical estradiol (sublingual form).  Baseline serum estradiol levels were very low with a mean of 80 pmol/L, or even lower suggesting ovarian failure. During the first week of estradiol treatment, depressive symptoms resolved rapidly, and serum estradiol levels increased to 340 pmol/L. By the second week of treatment, 83% of patients showed clinical recovery.

Left image: Harold Gilman (1876 - 1919). Mother and Child, 1918, oil on canvas. Auckland Art Gallery, courtesy of Wikimedia Commons.

A second earlier study published in 1996 Lancet showed that bioidentical estrogen is an effective treatment for post-partum depression. Sixty One women suffering from post partum depression were given transdermal estradiol (0.2 mg daily), and rapid improvement was reported during the first month of treatment.(9)

Many women with post-partum depression are treated with SSRI antidepressants which does not address the underlying estrogen deficiency and ovarian failure. In my opinion, bioidentical hormone treatment is a more effective and safer treatment alternative.    Bioidentical estrogen has none of the adverse effects associated with SSRI antidepressants which, after all, may end up in mother's milk, and may have adverse effects on the breast feeding baby.

Estradiol for Post Partum Psychosis

While post partum estrogen deficiency causes depression in 13% of patients, a smaller subset go on to develop full blown post partum psychosis. Bioidentical estrogen is also effective for this more severely effected group. A study done in Finland published in the 2001 Journal of Clinical Psychiatry evaluated 10 women suffering from post partum psychosis. All had low serum estradiol (mean of 50 pg/ml) indicating gonadal failure. All were treated with bioidentical estradiol, with serum estradiol levels rising to normal. Remarkably, estradiol treatment reversed psychiatric symptoms in all patients. (11)

Estradiol Improves Cognition for Alzheimer's Dementia

In a study published in 2001 Neurology, twenty postmenopausal women with Alzheimer's dementia were treated with bioidentical estradiol (0.10 mg per day, topical) and compared to placebo. Sophisticated neuropsychological tests showed improvement in attention, and in verbal, visual and semantic memory compared with subjects who received a placebo.(12)

Estradiol Reduces Anxiety in Mouse Model

Alicia A. Walf examined a mouse model in which Estradiol reduces anxiety- and depression-like behavior of aged female mice. Her findings were justpublished in   Neuroscience Research in Feb 2010. Matthew N. Hill investigated the mechanism of estradiol as an anxiolytic, and he implicated the enzyme, fatty acid amide hydrolase (FAAH), which degrades the endocannabinoid anandamide. FAAH is regulated by estrogen. Obviously, this is a fertile area for new research, as the exact mechanism has not yet been elucidated.

Left image : lab mice courtesy of wikimedia commons

Links to Associated Content:

The Importance of Bioidentical Hormones

The Safety Of Bio-Identical Hormones by Jeffrey Dach MD

The Battle for BioIdentical Hormones by Jeffrey Dach MD

Breast Cancer Prevention and Iodine Supplementation by Jeffrey Dach MD

Jeffrey Dach MD
4700 Sheridan Suite T
Hollywood Fl 33021
954-983-1443
http://www.jeffreydach.com/
http://www.drdach.com/
http://www.naturalmedicine101.com/
http://www.truemedmd.com/

Links and References

1) http://www.uzzireissmd.com/refs/04.html
Uzzi Reiss MD and Yfat Reiss Gendell- The Natural SuperWoman, references for Estrogen chapter.

Estrogen B Receptor in the Brain, 5 HTP and Anxiety

2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667128
Neuroscience. 2009 January 23; 158(2): 456–464.

Estrogen decreases 5-HT1B autoreceptor mRNA in selective subregion of rat dorsal raphe nucleus: inverse association between gene expression and anxiety behavior in the open field. by Ryoko Hiroiab and John F. Neumaierb a Department of Psychology, University of Washington, Seattle, WA 98195

We have recently shown that estrogen decreases anxiety and increases expression of tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme for serotonin synthesis.

The paradigm used in the present study, nevertheless, closely resembles menopausal women undergoing hormone replacement therapy and may have clinical significance, since anxiety disorders are associated with relatively low serum estrogen levels in several conditions, including menopause, and are often relieved by estrogen treatment (Best et al., 1992, Sichel et al., 1995, Arpels, 1996, Gregoire et al., 1996). Antidepressants targeting the serotonin system, collectively known as selective serotonin reuptake inhibitors (SSRIs), also successfully treat some symptoms of menopause, yet there is evidence that a lower response rate is augmented by estrogen treatment. These studies suggest a possible interaction of estrogen and serotonin in regulating anxiety and thus elucidating the exact mechanisms of the effects of estrogen on anxiety via the DRN serotonergic system may lead to further advancement in treating affective disorders.

3) http://endo.endojournals.org/cgi/content/full/endo;146/2/797
Endocrinology Vol. 146, No. 2 797-807, 2005 by The Endocrine Society

Novel Actions of Estrogen Receptor-ß on Anxiety-Related Behaviors by Trent D. Lund, Tomislav Rovis, Wilson C. J. Chung and Robert J. Handa

ESTROGENS ARE WELL-ESTABLISHED regulators of mood in humans and animals. Its effects, however, are varied, with both anxiolytic and anxiogenic actions, depending on factors such as age and stage of the reproductive cycle. In women, reduced estrogen levels, particularly at the menopause, are associated with depression, sleep disturbance, irritability, anxiety, panic disorders, and cognitive dysfunction (1, 2, 3). Estrogen replacement therapy in postmenopausal women is consistently reported to improve mood, feelings of general well being, and learning as well as increase general activity levels (3, 4). In contrast, an anxiogenic role for estrogens is suggested by the significantly higher level of depression reported in women compared with men (5, 6, 7), a sex difference that emerges at the time of puberty (5, 6, 7). Furthermore, research by Schmidt et al. (8) identified that women with severe premenstrual dysphoria developed anxiety and other mood symptoms when treated with estradiol in combination with leuprolide, an agonist analog of GnRH.

Similar effects of estradiol on anxiety and mood have been reported in rodents. For example, elevated levels of estradiol achieved during rodent proestrus, or after exogenous hormone injections to ovariectomized (OVX) females, exert anxiolytic actions in the elevated plus maze (9, 10); consistently, when endogenous estrogens are removed, via OVX, behavioral indices of anxiety increase (10, 11, 12, 13, 15).

DRN- Dorsal Raphe Nucleus in Midbrain E2 receptors regulate 5HT synthesis

(4) http://www.ncbi.nlm.nih.gov/pubmed/15820717?dopt=Abstract
Biol Psychiatry. 2005 Apr 15;57(8):938-42.

Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe. Gundlah C, Alves SE, Clark JA, Pai LY, Schaeffer JM, Rohrer SP. Synaptic Pharmaceutical Corporation, Paramus.

BACKGROUND: Distinct expression patterns of estrogen receptor (ER)-alpha and ER-beta are displayed in the murine central nervous system. ER-beta is the predominant form of the receptor expressed in the murine midbrain dorsal raphe nucleus (DRN). Tryptophan hydroxylase (TPH) is abundantly expressed in the serotonergic neurons of the DRN and is regulated by estrogen in both the monkey and the guinea pig.

METHODS: In this study we used immunocytochemistry to show that ER-beta and TPH are colocalized in the serotonergic cells of the murine DRN. We utilized the ER-alpha and ER-beta gene deletion mouse models and in situ hybridization to demonstrate that ER-beta is responsible for regulating TPH1 mRNA expression.

RESULTS: Estrogen increased TPH1 mRNA expression in the DRN of wild type and ER-alpha knockout mice (alpha-ERKO) but not ER-beta knockouts (beta-ERKO).

CONCLUSIONS: These data indicate that ER-beta is responsible for mediating estrogen regulated TPH1 expression in the murine DRN.

(5) http://www.ncbi.nlm.nih.gov/pubmed/19559077
Neuroscience. 2009 Oct 6;163(2):705-18. Epub 2009 Jun 23.

Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei.

Donner N, Handa RJ. Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80526, USA.

Dysfunctions of the brain 5-HT system are often associated with affective disorders, such as depression. The raphe nuclei target the limbic system and most forebrain areas and constitute the main source of 5-HT in the brain. All 5-HT neurons express tryptophan hydroxylase-2 (TPH2), the brain specific, rate-limiting enzyme for 5-HT synthesis. Estrogen receptor (ER) beta agonists have been shown to attenuate anxiety- and despair-like behaviors in rodent models. Therefore, we tested the hypothesis that ER beta may contribute to the regulation of gene expression in 5-HT neurons of the dorsal raphe nuclei (DRN) by examining the effects of systemic and local application of the selective ER beta agonist diarylpropionitrile (DPN) on tph2 mRNA expression.

Ovariectomized (OVX) female rats were injected s.c. with DPN or vehicle once daily for 8 days. In situ hybridization revealed that systemic DPN-treatment elevated basal tph2 mRNA expression in the caudal and mid-dorsal DRN. Behavioral testing of all animals in the open field (OF) and on the elevated plus maze (EPM) on days 6 and 7 of treatment confirmed the anxiolytic nature of ER beta activation.

Another cohort of female OVX rats was stereotaxically implanted bilaterally with hormone-containing wax pellets flanking the DRN. Pellets contained 17-beta-estradiol (E), DPN, or no hormone. Both DPN and E significantly enhanced tph2 mRNA expression in the mid-dorsal DRN. DPN also increased tph2 mRNA in the caudal DRN. DPN- and E-treated rats displayed a more active stress-coping behavior in the forced-swim test (FST). No behavioral differences were found in the OF or on the EPM.

These data indicate that ER beta acts at the level of the rat DRN to modulate tph2 mRNA expression and thereby influence 5-HT synthesis in DRN subregions. Our results also suggest that local activation of ER beta neurons in the DRN may be sufficient to decrease despair-like behavior, but not anxiolytic behaviors.

(6) http://www.albany.edu/~cafrye/papers/walfFrye06review.pdf
Neuropsychopharmacology (2006) 31, 1097–1111, 2006 Nature

Perspective - A Review and Update of Mechanisms of Estrogen in the Hippocampus and Amygdala for Anxiety and Depression Behavior by Alicia A Walf1 and Cheryl A Frye

Estrogen (E2) has many effects in the central nervous system, including effects on anxiety and depression behavior. This review will address effects of E2 on behaviors related to anxiety and depression in women and animal models and include recent findings from our laboratory related to this topic. E2’s antianxiety and antidepressant-like effects may depend upon many factors, including the regimen of
E2 utilized and interactions with the hypothalamic–pituitary–adrenal axis. Brain targets for E2’s effects on anxiety and depression include the hippocampus and amygdala.

Administration of E2, compared to vehicle, subcutaneously or to the hippocampus or amygdala of ovariectomized rats decreases anxiety and depressive behavior. Intracellular estrogen receptors (ERs) may be important for E2’s anxiolytic and antidepressant-like effects. Administration of an ER antagonist to the hippocampus, but not amygdala, increases anxiety and depression behavior of naturally receptive female rats. Studies utilizing ER knockout mice or selective ER modulators suggest that
ER-mediated effects of E2 on anxiety and depressive behavior may require ERb.

Estradiol Treats Depressive Disorder- Clinical Studies

Perimenopausal Mood Disorder and Depression

https://www.healthsystem.virginia.edu/
internet/neuroscience/BehavioralNeuroscience/soares-et-al.pdf

(7) http://www.ncbi.nlm.nih.gov/pubmed/11386980
Arch Gen Psychiatry. 2001 Jun;58(6):529-34.

Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. by Soares CN, Almeida OP, Joffe H, Cohen LS. Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts General Hospital, Harvard Medical School, 15 Parkman St, WACC 812, Boston, MA

BACKGROUND: Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women.

METHODS: Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores.

RESULTS: Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups.

CONCLUSION: Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.

Estrogen Treatment in Post Partum Depression in pts with low serum estrogen

(8) http://www.ncbi.nlm.nih.gov/pubmed/11411813
J Clin Psychiatry. 2001 May;62(5):332-6.

Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study.by Ahokas A, Kaukoranta J, Wahlbeck K, Aito M. Psychiatric Research Unit, Mehilainen Clinic, University of Helsinki, Finland.

BACKGROUND: The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol.

METHOD: Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS).

RESULTS: At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients.

CONCLUSION: This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.

(9) http://www.ncbi.nlm.nih.gov/pubmed/8598756
Lancet. 1996 Apr 6;347(9006):930-3.

Transdermal oestrogen for treatment of severe postnatal depression. by Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Mental Health Services, Salisbury Health Care, Salisbury, UK.

BACKGROUND
postnatal depression can have long-term adverse consequences for the mother, for the marital relationship, and for the infant's psychological development. Such depressions can be severe and resistant to both support and counselling and to therapy with antidepressant drugs. We investigated the antidepressant efficacy of oestrogen given transdermally.

METHODS: In a double-blind, placebo-controlled study, 61 women with major depression, which began within 3 months of childbirth and persisted for up to 18 months postnatally, were allocated randomly active treatment (n=34; 3 months of transdermal 17 beta-oestradiol 200 micrograms daily alone, then 3 months with added cyclical dydrogesterone 10mg daily for 12 days each month) or placebo (n=27; placebo patches and tablets according to the same regimen). The women were assessed monthly by self-ratings of depressive symptoms on the Edinburgh postnatal depression scale (EPDS) and by clinical psychiatric interview (schedule for affective disorders and schizophrenia [SADS]-change scale).

FINDINGS: On pretreatment assessments the women in both groups were severely depressed (mean EPDS score 21.8 [SD 3.0] active group, 21.3 [2.9] placebo group; SADS scores, 66.3 [11.4] and 64.3 [10.7]). During the first month of therapy the women receiving oestrogen improved rapidly, and to a significantly greater extent than controls (mean EPDS scores 13.3 [SD 5.7] vs 16.5 [5.3]. Patients receiving placebo also improved over time but, on average, their scores did not fall below the screening threshold for major depression for at least 4 months. The estimated overall treatment effect of oestrogen on the EPDS was 4.38 points (95% Cl 1.89-6.87). None of a range of other factors (age, psychiatric, obstetric and gynaecological history, severity and duration of current episode of depression, and concurrent antidepressant medication), influenced the response to oestrogen.

INTERPRETATION: This study has shown that transdermal oestrogen is an effective treatment for postnatal depression. Further studies are required to establish the minimum effective dose and shortest necessary duration of treatment as well as the mechanism of antidepressant action of oestrogen.

(10) http://www.jabfm.com/cgi/reprint/16/5/372.pdf

The Effectiveness of Various Postpartum Depression Treatments and the Impact of
Antidepressant Drugs on Nursing Infants Dwenda Gjerdingen, MD, MS (J Am Board Fam Pract 2003;16:372– 82.)

Background: Postpartum depression is seen in approximately 13% of women who have recently given birth; unfortunately, it often remains untreated. Important causes for undertreatment of this disorder are providers’ and patients’ lack of information about the effectiveness of various treatments, and their concerns about the impact of treatment on nursing infants. This article presents research-based evidence on the benefits of various treatments for postpartum depression and their potential risks to nursing infants.

There is evidence that postpartum depression improves with antidepressant
drug therapy, estrogen, individual psychotherapy, nurse home visits, and possibly group therapy.

Of the more frequently studied antidepressant drugs in breastfeeding women, paroxetine, sertraline, and nortriptyline have not been found to have adverse effects on infants. Fluoxetine, however, should be avoided in breastfeeding women. By administering effective treatment to women with postpartum depression,
we can positively impact the lives of mothers, their infants, and other family members. (J Am Board Fam Pract 2003;16:372– 82.)

72. Cizza G, Gold PW, Chrousos GP. High-dose transdermal estrogen, corticotropin-releasing hormone, and postnatal depression [letter]. J Clin Endocrinol Metab 1997;82:704.

73. Ahokas A, Kaukoranta J, Wahlbeck K, Aito M. Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic
17B-estradiol: a preliminary study. J Clin Psychiatry 2001;62:332– 6.

74. Ahokas AJ, Turtiainen S, Aito M. Sublingual oestrogen treatment of postnatal depression [letter]. Lancet 1998;351:109.

75. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet 1996; 347:930–3.

76. Ahokas A, Aito M. Role of estradiol in puerperal psychosis. Psychopharmacology (Berl) 1999;147: 108–10.

77. Ahokas A, Aito M, Turiainen S. Association between oestradiol and puerperal psychosis. Acta Psychiatr Scand 2000;101:167–70.

78. Granger ACP, Underwood MR. Review of the role Postpartum Depression Treatment 381 of progesterone in the management of postnatal mood disorders. J Psychosom Obstet Gynaecol 2001;22:49 –55.

Estradiol for Post Partum Psychosis

(11) http://www.ncbi.nlm.nih.gov/pubmed/10817099
J Clin Psychiatry. 2000 Mar;61(3):166-9. Positive treatment effect of estradiol in postpartum psychosis: a pilot study. Ahokas A, Aito M, Rimón R. Department of Psychiatry, Helsinki City Hospital, Finland.

BACKGROUND: Postpartum illnesses with psychiatric symptoms and serious adverse sequelae are highly prevalent during the childbearing years. Despite multiple medical contacts, these illnesses often remain unidentified and untreated. To study the association between estradiol and puerperal psychosis, we measured serum concentration of estradiol and performed an open-label trial of physiologic 17beta-estradiol in women with this disorder.

METHOD: Ten women with ICD-10 psychosis with postpartum onset consecutively recruited from a psychiatric duty unit were studied. Serum estradiol concentration was measured at baseline and weekly during sublingual 17beta-estradiol treatment for 6 weeks. The treatment effect was evaluated by a clinician-rated psychiatric symptom scale (the Brief Psychiatric Rating Scale [BPRS]).

RESULTS: The baseline serum estradiol levels (mean = 49.5 pmol/L; range, 13-90 pmol/L) were even lower than the threshold value of gonadal failure, and the patients exhibited high scores on the psychiatric symptom scale (mean BPRS total score = 78.3; range, 65-87). During the first week of 17beta-estradiol treatment, psychiatric symptoms diminished significantly (BPRS score decreased to a mean of 18.8, p < .001). Until the end of the second week of treatment, serum estradiol concentrations rose to near the values normally found during the follicular phase, and the patients became almost free of psychiatric symptoms.

CONCLUSION: The reversal of psychiatric symptoms in all patients by treating documented estradiol deficiency suggests that estradiol plays a role in the pathophysiology and may have a role in the treatment of this condition. There was a rebound of psychotic symptoms in the 1 patient who discontinued estradiol treatment. Given the small number of patients, this area deserves further study.

Estradiol for Alzheimers Disease - Improves Cognition

(12) http://www.neurology.org/cgi/content/abstract/57/4/605
Neurology 2001;57:605-612, 2001 American Academy of Neurology

High-dose estradiol improves cognition for women with AD Results of a randomized study by S. Asthana, MD;, L. D. Baker, PhD;, S. Craft, PhD;, F. Z. Stanczyk, PhD;, R. C. Veith, MD;, M. A. Raskind, MD; and S. R. Plymate, MD From Geriatric Research, Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System

Objective:— To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD.

Methods:— Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17ß-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest.

Results:— Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment.

Conclusions:— Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD.

Anxiety is Strongly Associated with HOT Flashes

(13) http://www.ncbi.nlm.nih.gov/pubmed/15879914

Menopause. 2005 May-Jun;12(3):258-66.

The role of anxiety and hormonal changes in menopausal hot flashes.
Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S, Ferdousi T. Department of Obstetrics/Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.

OBJECTIVE: To estimate the association of anxiety with menopausal hot flashes in the early transition to menopause.

DESIGN: A randomly identified, population-based cohort of midlife women followed up for 6 years to assess reproductive hormones and other physical, emotional, and behavioral factors. At enrollment, the women were premenopausal, aged 35 to 47 years, and had regular menstrual cycles in the normal range. Enrollment was stratified to obtain equal numbers of African American (n = 219) and white (n = 217) women.

RESULTS: At the 6-year endpoint, 32% of the women were in the early transition stage and 20% reached the late menopausal transition or were postmenopausal. Reports of hot flashes increased with the transition stages, which were determined by bleeding patterns. At endpoint, hot flashes were reported by 37% of the premenopausal women, 48% of those in the early transition, 63% of women in the late transition, and 79% of the postmenopausal women. Anxiety scores were significantly associated with the occurrence of hot flashes and were also significantly associated with the severity and frequency of hot flashes (each outcome at P < 0.001). Compared with women in the normal anxiety range, women with moderate anxiety were nearly three times more likely to report hot flashes and women with high anxiety were nearly five times more likely to report hot flashes. Anxiety remained strongly associated with hot flashes after adjusting for menopause stage, depressive symptoms, smoking, body mass index, estradiol, race, age, and time. In a predictive model, anxiety levels at the previous assessment period and the change in anxiety from the previous assessment period significantly predicted hot flashes (P < 0.001).

CONCLUSIONS: Anxiety is strongly associated with menopausal hot flashes after adjusting for other variables including menopause stage, smoking, and estradiol levels. Anxiety preceded hot flashes in this cohort. Additional studies are needed to examine the duration of menopausal hot flashes and to determine whether treatments that target anxiety effectively reduce menopausal hot flashes.

Estradiol Reduces Anxiety in Mice

(14) http://www.ncbi.nlm.nih.gov/pubmed/19804793

Estradiol reduces anxiety- and depression-like behavior of aged female mice by
Alicia A. Walf and Cheryl A. Frye Neuroscience Research, The University at Albany-SUNY, United States September 2009

Thus, an acute E2 regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice.

Estrogen Inhibits Anxiety Through EndoCannabinoid System

http://science.iowamedicalmarijuana.org/pdfs/psych/Hill%202007.pdf
Estrogen recruits the endocannabinoid system to modulate emotionality
Matthew N. Hill, Eda S. Karacabeyli, Boris B. Gorzalka in Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T1Z4

Estrogen administration elicits anxiolytic and antidepressant-like effects in female rats; however, the mechanism of this effect is unknown. Fatty acid amide hydrolase (FAAH), the enzyme which degrades the endocannabinoid anandamide, has been shown to be regulated by estrogen. Thus, we examined if the anxiolytic and antidepressant effects of estrogen implicated the endocannabinoid system. In the first experiment, ovariectomized female rats were administered a single injection of 17b-estradiol (10 mg) or oil, and 48 h later were given an injection of the cannabinoid CB1 receptor antagonist AM251 (1 mg/kg) or vehicle.

One hour after AM251 or vehicle administration, subjects were tested in either the open field test (OFT), elevated plus maze (EPM) or the forced swim test (FST). Estradiol treatment resulted in a significant increase in open arm entries in the EPM and time spent in the center quadrant of the OFT, which were reversed by co-treatment with AM251, suggesting that endocannabinoids are integral to the anxiolytic effects of estrogen.

In the second experiment, administration of the FAAH inhibitor URB597 (0.1 and 0.3 mg/kg) increased open arm entries in the EPM and time spent in the center quadrant in the OFT as well as significantly reduced immobility in the FST. Collectively, these data demonstrate that estrogen may elicit changes in emotional behavior through an endocannabinoid mechanism, and suggest that inhibition of FAAH represents a therapeutic target for anxiety and depression in women.

(15) http://www.ncbi.nlm.nih.gov/pubmed/15474758
Maturitas. 2004 Oct 15;49(2):140-7.

A short study in the treatment of hot flashes with buccal administration of 17-beta estradiol. Gass MS, Rebar RW, Cuffie-Jackson C, Cedars MI, Lobo RA, Shoupe D, Judd HL, Buyalos RP, Clisham PR.

OBJECTIVE: To assess the efficacy and safety of 17-beta estradiol buccal tablets in reducing hot flush frequency (HFF) in postmenopausal women. METHODS: Estradiol buccal tablets containing 0.05, 0.1, 0.2, or 0.4 mg or placebo were administered for 28 days to 99 postmenopausal women in a randomized, double-blind study; 19 premenopausal women were studied concurrently for comparison of laboratory data. Objective and subjective assessments of HFF were obtained along with measures of estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). RESULTS: Measurements of HFF revealed significant decreases from baseline in all estradiol groups (P < 0.01). In the 0.4 mg group, HFF decreased significantly compared to placebo (P < 0.01). All estradiol doses produced similar improvement in the vaginal maturation index. Mean serum estradiol levels increased as doses increased but were lower than in the premenopausal subjects. Mean serum FSH and LH levels decreased in all estradiol groups but not to the levels of the premenopausal subjects; the greatest decrease occurred at the two highest estradiol doses. CONCLUSION: A numerical dose-response relationship with hot flushes was seen in this pilot study comparing 0.05, 0.1, 0.2, and 0.4 mg buccal estradiol. Only 0.4 mg 17-beta estradiol significantly reduced the occurrence of hot flushes compared to placebo.

(16) http://www.ncbi.nlm.nih.gov/pubmed/11400216
Menopause as a Measure of Population Health - Physiology of hot flashes Robert R. Freedman 1 2 Am. J. Hum. Biol. 13:453-464, 2001

Hot flashes are the most common symptom of the climacteric, although prevalence estimates are lower in some rural and non-Western areas. The symptoms are characteristic of a heat-dissipation response and consist of sweating on the face, neck, and chest, as well as peripheral vasodilation. Although hot flashes clearly accompany the estrogen withdrawal at menopause, estrogen alone is not responsible since levels do not differ between symptomatic and asymptomatic women. Until recently it was thought that hot flashes were triggered by a sudden, downward resetting of the hypothalamic setpoint, since there was no evidence of increased core body temperature. Evidence obtained using a rapidly responding ingested telemetry pill indicates that the thermoneutral zone, within which sweating, peripheral vasodilation, and shivering do not occur, is virtually nonexistent in symptomatic women but normal (about 0.4°C) in asymptomatic women. The results suggest that small temperature elevations preceding hot flashes acting within a reduced thermoneutral zone constitute the triggering mechanism. Central sympathetic activation is also elevated in symptomatic women which, in animal studies, reduces the thermoneutral zone. Clonidine reduces central sympathetic activation, widens the thermoneutral zone, and ameliorates hot flashes. Estrogen virtually eliminates hot flashes but its mechanism of action is not known. . © 2001 Wiley-Liss, Inc.

(17) http://jcem.endojournals.org/cgi/content/abstract/61/4/627
Journal of Clinical Endocrinology & Metabolism Vol. 61, No. 4 627-632

Treatment of Hot Flashes with Transdermal Estradiol Administration*
KENNETH A. STEINGOLD, LARRY LAUFER, RYSZARD J. CHETKOWSKI, JOHN D. DEFAZIO, DENNIS W. MATT, DAVID R. MELDRUM and HOWARD L. JUDD Department of Obstetrics and Gynecology, University of California, Los Angeles, School of Medicine Los Angeles, California 90024

A randomized prospective double blind study was performed to assess the ability of a transdermal therapeutic system (TTS) delivering estradiol (E2) to suppress hot flashes (HFs) in symptomatic postmenopausal women. Patients were given placebo or E2 in four doses for a 20-day period, and serum gonadotropin and estrogen levels and the occurrences of HFs were measured.

Administration of placebo had no measurable effect on either estrogen or gonadotropin levels or the occurrence of HFs. A dose-response relationship was found between the rate of E2 administered and the circulating level of E2, with 25, 50, 100, and 200 µ/24 h dosages raising the mean E2 concentrations from mean baseline levels of 5-8 pg/ml to 18, 38, 73, and 100 pg/ml, respectively. Estrone levels also increased with TTS application, but to a lesser extent than did E2 levels. Doseresponse reductions of FSH and LH with increasing amounts of E2 administration occurred, but gonadotropin levels were not lowered in any of the patients into the ranges found in premenopausal women. TTS application significantly suppressed the occurrence of HFs at the 50 Mg/24 h dosage and higher. A significant negative correlation (r = 0.6045; P < 0.001) between E2 levels and the rates of occurrence of HFs was found during hormone administration. Based on this regression, 50% and100% reductions of HFs should occur at 61 and 122 pg/ml E2. These data indicate that the transdermal delivery of E2 with these systems significantly reduced the occurrence of HFs and allowed definition of the therapeutic range of hormone replacement in terms of lost ovarian function, as reflected by circulating E2 levels.

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