David S. Klein, M.D.
The Importance of Hormone Balance
Introduction:
The command and control of the many organs, organ systems and tissues in the living organism is accomplished through the nervous and endocrine systems. Just as with the familiar telephone system, part of it is 'wired' and part is 'wire-less.' The Nervous System controls through discrete nerves to small areas of the body, extremities or regions, and this is analogous to the 'hard-wired' telephone system. Through the use of chemicals called 'hormones,' the body is able to communicate, each cell to every other cell, tissue to tissue, through the Endocrine System, and this is analogous to the 'wireless' telephone system.
The effect of imbalance in the nervous system is far better recognized, but increasing attention is being paid to the effect of imbalance of the endocrine system. Disorders of Thyroid, Adrenal, Gonadal and other endocrine centers result in systemic complaints, inability to heal, and failure to achieve optimal function.
A brief overview of some of the areas of concern are mentioned, below.
Testosterone is present in significant amount in both males and females. This hormone is necessary for maintenance of cellular function, immune function, and in anabolic activities that include the healing process. Levels of testosterone decrease with age, and as these levels decrease, the body's ability to heal decreases. The incidence of auto-immune disorders increases with decreases in testosterone. Dementia, osteoporosis, decreased libido, depression are all associated with low levels of circulating testosterone.Circulating testosterone is present in several forms, as free hormone (not bound to any protein) or (bound relatively) weakly to albumin. Most of the circulating testosterone, however, is bound to sex hormone binding globulin (SHBG), and is biologically inactive. Free testosterone and albumin-bound testosterone together comprise what is called "bioavailable" testosterone, and it is this quantity of testosterone that is responsible for peripheral androgenic effects.Testosterone is converted further to other important hormones in the peripheral circulation and in the peripheral tissues. Dihydrotestosterone (DHT) is produced by reduction through the action of 5-alpha Reductase. Testosterone is metabolized to Estradiol (E2) by means of esterification of testosterone involving the enzyme aromatase. It can be expected that in certain disease states, the production of Estradiol and DHT may be accelerated, such as in liver failure and in (male) obesity. Elevated levels of E2 will result in increased levels of SHBG, thereby reducing available testosterone by binding more and more circulating testosterone, and E2 can down regulate the hypothalamic-pituitary-gonadal axis, resulting in decreased gonadotropin secretion and decreased circulating Testosterone levels.Testosterone levels can be adjusted by increasing production, and by decreasing degradation to estradiol. Blocking aromatase and 5-alpha reductase will increase circulating testosterone levels while simulataneously decreasing estradiol levels. Transdermal testosterone is easily absorbed, and if progesterone & chrysin is added to the testosterone gel, levels of testosterone can be obtained while minimizing the transcutaneous conversion to estradiol.
Estrogen Accelerates Wound Healing
This study, originally undertaken by two universities simultaneously, was reported initially by Gillian S. Ashcroft, Joanne Dodsworth, Egon van Boxtel, Roy W. Tarnuzzer, Michael A. Horan, Gregory S. Schultz & Mark W.J. Ferguson from the University of Florida in 1997. The research was conducted at the Immunology and Development Division, School of Biological Sciences, Stopford Building University Manchester, Oxford Road, Manchester, Geriatric Medicine Department, University Hospital of South Manchester, Withington, Manchester M202LR, UK. At the same time, the Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida was conducting a similar study. Results include:
"The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically- macroscopically, and with reduced levels of transforming growth factor —beta1(TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by systemic administration of hormone replacement therapy (HRT)." "Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels."Transdermal estrogen has been used safely by women for decades for its cardioprotective effects, osteoprotective effects, and recently for decreasing wrinkling and improving skin tone in older women. This new potential use provides increased knowledge of the function of the skin and its ability to repair and heal.
Estrogen Replacement Reduces Tooth Loss
In addition to ameliorating osteoporosis, ERT/HRT may provide benefit for another condition that involves the skeletal system: tooth loss. Approximately 32% of US women aged 65 have no teeth. Although the prevention of periodontal disease is the most important factor in maintaining teeth, it has been hypothesized that some tooth loss may occur as a result of resorption of the alveolar bone. This sign of impending osteoporosis should be looked at seriously by all women. If you are losing teeth, get a bone scan as soon as possible. There is some evidence that bone mineral density (BMD) of most postmenopausal women is directly correlated with the number of teeth. Once the BMD drops below normal, the bones supporting the teeth lose calcium as bone resorption occurs and the spine begins to lose calcium as well due to a deficiency of essential hormones like DHEA/Progesterone which regulate bone metabolism.
Brittle Bones, The Final Straw
Bone mass normally begins to decline with aging as a result of an imbalance in bone remodeling; that is, bone resorption occurs at a faster rate than bone formation. The decline in a woman's bone mineral density (BMD) begins at about age 18 and progresses steadily. Osteoporosis and Osteopenia (brittle bones) are both conditions which occur with aging of both men and women. In summary, ERT/HRT is first-line therapy for osteoporosis for most women, and treatment should begin as soon as possible after the menopause. It is estimated that 10% of the total bone mass is lost each year without protection by hormones.
Long-Term Benefits of Complete Hormone Replacement Therapy
Preventive efforts, which might include combinations of hormones e.g., progesterone-estrogen-testosterone-DHEA or Complete Hormone Replacement Therapy (CRT) can forestall a number of serious conditions and can preserve and improve the quality of life for all women. The potential for realizing the benefits of CRT goes beyond symptom relief, particularly for a number of conditions that have long-term health implications, including osteoporosis, cardiovascular disease (CVD), Alzheimer's disease, tooth loss, aging and cancer. Women should be counseled about the benefits of continuing HRT/ERT or CRT< so they can make an informed decision about whether to reap or forgo the other benefits of replacement therapy. Replacement therapy in the form of estrogen alone (estrogen replacement therapy; ERT) or estrogen combined with a progestin, is an individual choice. Because estrogen replacement is useful for treating the more immediate and bothersome menopausal symptoms, most women have their initial experience with estrogen to alleviate those symptoms. However, it is important to know that testosterone and DHEA, COMPLETE the Hormone package. In addition to ERT, Androgen Replacement Therapy (ART), (including testosterone/DHEA for women) offers both short and long-term benefits to the majority of menopausal women.
Estrogen plus Testosterone
Estrogens are the sex hormones produced primarily by a female's ovaries that stimulate the growth of a girl's sex organs, as well as her breasts and pubic hair, known as secondary sex characteristics. Estrogens also regulate the functioning of the menstrual cycle. There are three major estrogens acting on the female body. Estrone is formed from Androstenedione and becomes estriol and estradiol. Hormone replacement therapy for women is changing. As new information emerges that women and men share all the hormones but at different levels, replacement therapy is changing. Women without a uterus have only been given estrogen replacement (ERT) and while a true estrogen can ameliorate the sleep disorders and hot flashes that accompany menopause, it does not provide the other important hormones, DHEA, Testosterone, and Progesterone.
Bi-est, a topical compounded cream combines the two most critical human estrogens. Estriol, and Estradiol. The appropriate transdermal cream, will contain containing estriol, estradiol, DHEA, progesterone and testosterone in customized amounts that reflect the individual needs of the patient.
In order to are determined by serum (blood) study, saliva testing, or combination of both, the dosage is chosen to replace that which is missing, and not administer hormoneintelligently select the appropriate dosage, hormonal testing is performed. Whether hormone levels s that are not necessary. Basically, replacement of a missing piece is the intention, but too much of a good thing can become a bad thing, indeed. These hormones are chemically identical to those secreted by the adrenal glands, testicles or ovaries. Because the dosage ratios are not 'fixed,' adjustment can be guided by sequential, periodic hormone levels. Application is best performed in the morning, after shower. The volar aspect of the forarms, that is, the inner thinner skin, permits easy application.Often, patients are advised to put these medications on the inner aspect of the thigh or on the tummy. This is a particularly bad idea. Contact with a spouse or significant other will permit trans-application to the bed-partner. For this reason, morning application avoids transfer to the bedsheets and/or bed partner(s).
Androgen Replacement for Women
Although the postmenopausal ovary remains an important source of testosterone production, there is nevertheless a decline in total circulating androgen levels with age. A role for androgen replacement in addition to estrogens in some postmenopausal, particularly ovariectomized, women is increasingly gaining acceptance. Scientific studies of hormone delivery or the pharmacokinetics of two existing testosterone preparations, an oral testosterone and subcutaneous testosterone implants, revealed some interesting findings.Oral testosterone produced inappropriate high levels at all doses, with wide variations between subjects, confirming that oral testosterone is unpredictably absorbed and unlikely to be satisfactory for use in women. Subcutaneous testosterone implants produce non physiological levels for at least 1-2 months. The transdermal cream delivery system maintained relatively stable testosterone levels within narrow ranges with little variation. The study concluded that such transdermal systems may be of value for androgen therapy in postmenopausal women. Transdermal systems provide a highly controllable way of delivering testosterone in combination with estrogen noninvasively and reliably, and achieve mean physiological levels not possible with existing methods.
Estrogen May Protect Against Alzheimer's
Alzheimer's Disease is a neurodegenerative process of the brain that causes a slow, progressive loss of mental function. AD currently affects approximately 5 million Americans. It is the leading cause of lost independence and institutionalization. In terms of both prevalence and incidence, AD is a major health issue for women. Women comprise 72% of the population over the age of 85 years, and roughly half of this group has AD. Not only do women constitute a greater proportion of this older population, but AD is expressed earlier in women than in men. This may be related to the estrogen loss that occurs with menopause. Although estrogen has no current FDA indication for this type of therapy, the scientific evidence is exciting. Estrogen is recommended for postmenopausal women.
The best evidence that relates estrogen deficiency to Alzheimer's Disease (AD) comes from several recent epidemiologic studies. The 5 independent studies in the RR scale in Figure 3 consistently demonstrate a 40% to 60% reduction in the risk of AD in women who have taken ERT. In addition to these epidemiologic studies, there are some older studies that examine the effects of estrogen administration in an elderly population of women. However, these patients were not necessarily diagnosed with AD. The estrogen-treated women demonstrated a significant improvement in memory and a significant delay in progression of cognitive loss.There is growing evidence of estrogen's beneficial effect on central nervous system (CNS) function. Estrogen Replacement Therapy (ERT) delays the onset and progression of Alzheimer's Disease (AD). For example, in studies of postmenopausal women taking an examination, those taking estrogen performed better than those without. When estrogen replacement therapy (ERT) was given to the other group, their test performance improved as well.
The effect of Melatonin:
NOTE: Melatonin is very useful for sleep disorders, but it has primary analgesic effects, as well. That is, two bangs for your buck.
Ulugol A, Dokmeci D, Guray G, et al. Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the l-arginine-NO pathway and opioid system. Life Sci. 2006 Feb 28;78(14):1592-7.
The present study was undertaken to determine the effects of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) melatonin on mechanical allodynia and thermal hyperalgesia in mice with partial tight ligation of the sciatic nerve, and how the nitric oxide (NO) precursor l-arginine and the opiate antagonist naloxone influence this effect. A plantar analgesic meter was used to assess thermal hyperalgesia, and nerve injury-induced mechanical hyperalgesia was assessed with von Frey filaments. 1-5 weeks following the surgery, marked mechanical allodynia and thermal hyperalgesia developed in neuropathic mice. Intracerebroventricular and intraperitoneal melatonin, with its higher doses, produced a blockade of thermal hyperalgesia, but not mechanical allodynia. Administration of both l-arginine and naloxone, at doses which produced no effect on their own, partially reversed antihyperalgesic effect of melatonin. These results suggest that although it has different effects on neuropathic pain-related behaviors, melatonin may have clinical utility in neuropathic pain therapy in the future. It is also concluded that l-arginine-NO pathway and opioidergic system are involved in the antihyperalgesic effect of melatonin in nerve-injured mice.
Song GH, Leng PH, Gwee KA, et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005 Oct;54(10):1402-7. Epub 2005 May 24.
BACKGROUND AND AIMS: Melatonin, a sleep promoting agent, is involved in the regulation of gastrointestinal motility and sensation. We aimed to determine if melatonin was effective in improving bowel symptoms and sleep disturbances in irritable bowel syndrome (IBS) patients with sleep disturbance.
METHODS: Forty IBS patients (aged 20-64 years; 24 female) with sleep disturbances were randomly assigned to receive either melatonin 3 mg (n = 20) or matching placebo (n = 20) at bedtime for two weeks. Immediately before and after the treatment, subjects completed bowel, sleep, and psychological questionnaires, and underwent rectal manometry and overnight polysomnography.
RESULTS: Compared with placebo, melatonin taken for two weeks significantly decreased mean abdominal pain score (2.35 v 0.70; p<0.001) and increased mean rectal pain threshold (8.9 v -1.2 mm Hg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not significantly differ after treatment in both groups. Data from sleep questionnaires and polysomnography showed that the two week course of melatonin did not influence sleep parameters, including total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stages 1-4, rapid eye movement (REM) sleep, and REM onset latency.
CONCLUSIONS: Administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles.
Li SR, Wang T, Wang R, et al. Melatonin enhances antinociceptive effects of delta-, but not mu-opioid agonist in mice. Brain Res. May 10;1043(1-2):132-8, 2005.
This present study examines the effect of melatonin on antinociceptive action induced by opioid agonists in mice using the tail-flick test. When injected either by intraperitoneal (i.p.) (1, 5, 25 mg/kg) or by intracerebroventricular (i.c.v.) (0.25, 0.5, 1 mg/kg) routes, melatonin significantly enhanced the delta-opioid agonist deltorphin I induced antinociception, but not mu-opioid agonist endomorphin-1. Further investigation showed that i.c.v. luzindole (0.5 mg/kg) (an antagonist of melatonin receptor) significantly antagonized the enhanced antinociceptive effect of i.c.v. melatonin. These results demonstrated that melatonin can specifically enhance the antinociception induced by specific opioid receptor agonist (i.e., delta opioid agonist) acting on melatonin receptor and that melatonin may have augmentation effect on analgesia with delta-, but not mu-opioid agonists in mice.
Shavali S, Ho B, Govitrapong P, Sawlom S, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 2005 Jan 30;64(6):471-9.
The occurrence of systematic diurnal variations in pain thresholds has been demonstrated in human. Salivary melatonin levels change following acute pain when other factors that could explain the change have been removed or controlled. Melatonin-induced analgesia is blocked by naloxone or pinealectomy. By using selective radioligands [3H]-DAMGO, [3H]-DPDPE, [3-U69593, and 3H]-nociceptin, we have shown that the bovine pinealocytes contain delta and mu, but not kappa or ORL1 opioid receptor subtypes. In the present study, by using melatonin receptor agonists (6-chloromelatonin or 2-iodo-N-butanoyl-5-methoxytryptamine) or melatonin receptor antagonist (2-phenylmelatonin), we have shown that these agents do not compete with opioid receptor subtypes. However, we observed a time-dependent release of beta-endorphin an endogenous opioid peptide, by melatonin from mouse pituitary cells in culture. Hence, it is suggested that melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by binding to its own receptors and increasing the release of beta-endorphin.
Almay BG, von Knorring L, Wetterberg L: Melatonin in serum and urine in patients with idiopathic pain syndromes. Psychiatry Res. 1987 Nov;22(3):179-91.
In 16 healthy volunteers, 16 patients with neurogenic pain syndromes, 37 patients with idiopathic pain syndromes, and 30 depressed patients, melatonin in serum was determined at 2 a.m. when the peak concentration was expected. In a somewhat larger series comprising 53 healthy volunteers, 14 patients with neurogenic pain syndromes, and 35 patients with idiopathic pain syndromes, melatonin was measured in urine collected during the night in a standardized manner. Chronic pain patients (with neurogenic or idiopathic pain disorders) and depressed patients had significantly lower melatonin in serum at 2 a.m. than healthy volunteers. Chronic pain patients also had significantly lower melatonin in urine than healthy volunteers, even when age, sex, and body weight were taken into account. The low melatonin concentrations were related to increased depressive symptomatology, especially sadness, bodily discomfort, inner tension, concentration difficulties, and pain. As low concentrations of melatonin in serum and urine also are found in patients with depressive disorders, the results are in line with the suggestion that the chronic idiopathic pain syndrome may be a variant of depressive disease, or the two syndromes may share a common pathogenic mechanism.
David S. Klein, MD, FACA, FACPM, FACMIMS
Director, Pain Center of Orlando
www.suffernomore.com