DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.” On the other hand, there have been a number of recent studies that have investigated the role of DHEA supplementation in patients with adrenal insufficiency. In this condition, DHEA(-S) levels appear to be reduced in parallel to the reduction in cortisol, and replacement therapy with DHEA appears to give additional benefits over and above that seen with cortisol replacement (Arlt et al., 1999; Hunt et al., 2000). It is also of interest to note the recent literature regarding the importance of the cortisol/DHEA ratio in major depression, where an emerging literature suggests that it is a high cortisol/DHEA ratio that may be the most important indicator of excessive physiological effects of cortisol on the brain (Goodyer et al., 2001; Young et al., 2002). In other words, either low DHEA or high cortisol could contribute to the excess cortisol effect on the brain.” Hydrocortisone may reduce elevated DHEA in chronic fatigue patients. On the other hand, low DHEA in adrenal insufficiency may improve with DHEA supplementation.
Allostasis differs from homeostasis Vis-a` -Vis its emphasis on dynamic rather than static biological set-points, considerations of the brain’s role in feedback regulation, and view of health as a whole-body adaptation to contexts (Schulkin, 2003b). These insights have encouraged new ways of conceptualizing complex, multi-systemic biological activities where, as Heraclitus wrote, ‘‘the only constant is change’’. The allostatic load model expands the theory of allostasis by applying it to the cause and effects of chronic stress… Allostatic load (AL) represents the ‘wear and tear’ the body experiences when repeated allostatic responses are activated during stressful situations (McEwen and Stellar, 1993). Real or interpreted threats to homeostasis initiate the sympathetic– adrenal–medullary (SAM) axis release of catecholamines and the hypothalamic–pituitary–adrenal (HPA) axis secretion of glucocorti- coids that mobilize energy necessary for fight-or-flight responses (Sapolsky et al., 2000)… While adaptive acutely, chronic over-activation of SAM- and HPA-axis products induce a ‘domino effect’ on interconnected biological systems that overcompensate and eventually collapse themselves, leaving the organism susceptible to stress-related diseases (Korte et al., 2005; Lupien et al., 2006; McEwen, 1998b)… A key feature of allostasis, AL, and ultimately allostatic overload is that multiple mediators of adaptation are involved and interconnected in a non-linear network… At first, prolonged secretion of the stress hormones epinephrine, norepinephrine, and cortisol (antagonized by dehydroepiandosterone) can falter in their ability to protect the distressed individual and instead begin to damage the brain and body (McEwen, 2006a)… Over time, subsidiary biological systems compensate for the over and/or under production of primary mediators and in turn shift their own operating ranges to maintain abated chemical, tissue, and organ functions. This prodromal stage is referred to as the secondary outcomes, whereby metabolic (e.g., insulin, glucose, total cholesterol, high density lipoprotein cholesterol, triglycerides, visceral fat depositing), cardiovascular (e.g., systolic and diastolic blood pressure), and immune (e.g., fibrinogen, c-reactive protein (CRP)) parameters reach sub-clinical levels. The final stage of AL progression is allostatic overload, whereby the culmination of physiological dysregulations leads to disordered, diseased, and deceased endpoints referred to as tertiary outcomes.
When the SAM- and HPA-axes are repeatedly activated during stressful situations — at work and/or at home — they exert a pathophysiological strain on the individual. This maladaptive process is referred to as allostatic load (McEwen and Stellar, 1993). Because burnout remains an ill understood condition that is often treated like depression, evidence-based approaches and technologies that disentangle them are needed. We believe that the development of AL algorithms might be extremely beneficial for healthcare providers that are not currently equipped to prevent, detect, or even accurately diagnose burnout. As chronic stress at work contributes to both depression and burnout, it follows that measuring AL along with stress hormone dynamics might help differentiate these and other diseases. In addition to being an integral product of stress responses and a key mediator leading to AL, cortisol follows a normal diurnal rhythm necessary for proper functioning. A normal circadian profile consists of an acute increase during the first hour after awakening (Federenko et al., 2004; Pruessner et al., 1997), followed by gradual decreases throughout the day. The awakening cortisol response (ACR) is used as a robust marker of HPA-axis integrity and is very sensitive to psychological stress (Schulz et al., 1998). In a recent meta-analysis of 62 articles, it was found that the magnitude of the ACR is positively associated with job stress and general life stress, but negatively associated with fatigue, burnout, and exhaustion (Chida and Steptoe, 2009). Indeed, hypocortisolism is a phenomenon that occurs in approximately 20—25% of patients suffering from stress-related diseases like chronic fatigue syndrome, fibromyalgia, PTSD, burnout, and atypical depression to name a few (for a review, see Fries et al., 2005).
Studies of the hypothalamo-pituitary adrenal (HPA) axis in chronic fatigue syndrome show a mild hypocortisolism of central origin, in contrast to the hypercortisolism of major depression…In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.
Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.
The hypothalamo-pituitary-adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.
Endocrinologists were not included in the multidisciplinary working groups that prepared two recent reports on chronic fatigue syndrome, despite its unequalled clinical overlap with Addison's disease, which is a classic endocrine disorder. The failure to include at least one endocrinologist in those panels may explain why in their extensive reports there is not a single word about the 42 clinical features that chronic fatigue syndrome shares with Addison's disease, including all the signs and symptoms listed in the case definition of this syndrome.
Studies have demonstrated clomid also has a positive effect on bone mineral density and BMI. Its low side effect profile makes it a good choice long-term management of hypogonadism in men.
Clomid may be the best alternative to exogenous testosterone for treating symptomatic hypogonadism in men who want to preserve their fertility. Exogenous testosterone impairs spermatogenesis because it naturally feeds back on the HPG axis, suppressing LH and FSH. In some men this leads to testicular atrophy.
Exogenous T supplementation decreases sperm production. Studies of hormonal contraception indicate that most men have a return of normal sperm production within 1 year after discontinuation. Clomiphene citrate is a safe and effective therapy for men who desire to maintain future potential fertility. Although less frequently used in the general population, hCG therapy with or without T supplementation represents an alternative treatment
Inducing Endogenous Testosterone & Preserving Spermatogenesis - Clomid is a safe and effective way to raise serum testosterone and improve libido, energy, enjoyment in life, mood, and sports performance. It does not work as well if FSH & LH are already elevated (e.g. primary testis failure).
Restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects
Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) decrease with aging and are important androgen and estrogen precursors in older adults. Declines in DHEAS with aging may contribute to physiological changes that are sex hormone dependent… DHEA replacement therapy for 1 yr improved hip BMD in older adults and spine BMD in older women.
Hormone Precursor - DHEA decreases with age and replacement may help mitigate the effects of age-related physical decline through its role as a precursor to androgens and estrogens. “[T]he present study demonstrates that 25 mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.”
DHEA has been studied for its affects on stress adaptation. “Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously.”
Low-dose GHR [growth hormone replacement] improves body composition and QoL [quality of life] as early as 1 month after commencement and the beneficial effects continue at 3 months. Most importantly, these changes occur in the absence of side-effects. We therefore suggest the use of low-dose GH therapy, maintaining IGF-I between the median and upper end of the age-related reference range, for the treatment of AGHD [Adult Growth Hormone Deficiency].
Growth Hormone Deficiency - Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age.
Progesterone is administered along with estrogen for women undergoing peri-menopause. It may help contribute to the relief of menopausal and may enhance well-being, energy, and libido. Progesterone is given with estrogen to women who have not undergone hysterectomy to balance the effects of estrogen on the uterine endometrium and reduce the risk of unopposed endometrial stimulation. In a study of 50,000 postmenopausal women followed for an 5.8 year study period it was discovered that bioidentical progesterone decreased the risk of breast cancer (RR= 9; P <.001) while synthetic progestin use increased the risk of breast cancer (RR = 1.4).
Bioidentical or natural hormones. These are a class of hormones including estradiol, progesterone, and testosterone that are pharmaceutically indistinguishable from the same hormones naturally produced by the human body (as opposed to equine estrogens, which are the source of conjugated estrogens and are not a natural hormone combination for humans). Bioidentical or natural hormones have been used for decades in Europe and since the 1990s in the United States. Until recently, no distinction has been made between bioidentical and synthetic hormones, thus leaving a deficit in the public and physicians’ knowledge and understanding of hormones in general. With the lack of distinction between types of hormones, we have been left with treatment recommendations based solely on the information obtained from studies on synthetic hormones. This has led to recommendations of continued, but shorter-term, use of synthetic hormone replacement combinations. The widely accepted ‘gold standard’ information on estrogen and progestogens in menopausal women stems overwhelmingly from the Women’s Health Initiative (WHI). This large-scale (>16,000 women) placebo-controlled study that started in 1991 evaluated the long-term effects of conjugated equine estrogens alone or in conjunction with medroxyprogesterone acetate (MPA) versus placebo… A major criticism has been that the women in the study were, on average, more than 10 years post-menopause, averaging 63 years of age at the initiation of therapy, which is usually considered old for women to start on hormone replacement, and had preexisting conditions that negatively affected outcome… Large-scale studies have been conducted in Europe, where bioidentical HRT is the main type of hormone therapy in menopausal women. The most significant study is the E3N or Epic cohort study that followed 80,000 postmenopausal women on various types of hormones including bioidentical hormones for more than 8 years, with 56,666 having used some form of HRT and 23,723 having never used any form of HRT. The results demonstrated there was no significant increased risk of breast cancer in those who used estrogen-only therapy (98.7% used bioidentical estradiol and only 1.3% used conjugated equine estrogen), but the use of a synthetic progestin increased the risk to 1.69 times that of control subjects.
This article presents an up-to-date review of the literature on hormone augmentation in the elderly to help primary care physicians better evaluate and utilize hormone replacement and optimization strategies to benefit their patients. The scientific literature suggests that hormone supplementation with estrogen, progesterone, testosterone, growth hormone, and thyroid hormone has the potential to improve quality of life and to prevent, or reverse, the many symptoms and conditions associated with aging, including fatigue, depression, weight gain,frailty, osteoporosis, loss of libido, and heart disease. Possible long-term side effects are also considered.
