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Endo-depression; definition and suggestion's background.


Endo-Depression is the group of depressive disorders that appear in endocrine diseases or in hormone dependent syndromes occurring after the damage/excision of an endocrine gland or the neuroendocrine connections among glands, due to iatrogenic, pharmaceutical or surgical interventions, trauma, environmental causes, ageing, and other more rare causes.

The reason that Endo-Depression term is suggested to be added to the medical terminology is that all the diseases/ syndromes covered at this point by the psychiatric specialty, are not psychiatric disorders in their basis, and would be better and more successfully handled by endocrinologists or endocrine surgeons.

Terminology, Prevention, Diagnosis and Treatment

The medical specialties were first founded as a way for better study, diagnosis and treatment. However, middle ground diseases were always thought as found under a constant claim among various specialties. Some diseases, like depression, are met in millions of people, who do not exactly present the same clinical findings. So, even the study of one disease became a dividable concept.

Prevention is perhaps the most difficult part for any disease. Because we should have a good knowledge of predisposing factors in order to prevent a disease successfully. Also, diagnosis needs the knowledge and experience of all possible causes. Finally, treatment should be causative and not symptomatic, if we wish to treat the patient radically.

For all the above reasons, sometimes, terminology should become the triggering factor that will lead to better prevention, diagnosis and treatment for cases that do not exactly belong to the large coffin of the "mother disease".


Brain-Gut Syndromes

Brain-Gut Syndromes or Functional Gastrointestinal Syndromes are a group of diseases that have a common pathophysiological basis, which is the imbalance of brain-gut axis. More common among them is the Irritable Bowel Syndrome, which is treated successfully with antidepressive drugs. Other syndromes like these are the inflammatory bowel diseases, peptic ulcer, functional dyspepsia, gastrooesophageal reflux, the chronic abdominal pain in childhood, and the chronic chest pain in adults, which is related to visceral pain. Brain and gut communicate via the autonomous neural system and the gastrointestinal hormones secreted by the neuroendocrine cells of the diffuse neuroendocrine system of the gastrointestinal tract. The detection of the neuropeptides of the CRH family (Corticotrophin Releasing Hormone) and selective receptors in the gastrointestinal tract has made clear the role of HPA (Hypothalamus-Pituitary-Adrenals) axis in brain-gut syndromes. The cross talk of HPA axis and Brain-gut axis and the neuroendocrine mapping of the gastrointestinal tract enhances the perspectives for novel molecular therapeutic interventions targeting the brain-gut axis. Thus, the treatment of depression found in brain--gut syndromes may be treated in the future by CRH products, and not by antidepressive drugs.

Eating disorders and Depression

Both depression and eating disorders are multidimensional and heterogeneous disorders. If we examine the nature of their relationship under the endocrine aspect, we find clinical descriptive and biological studies of extreme interest. Recent studies confirm the prominence of depressive symptoms in eating disorders, such as the similarity of the concurrent endocrine disorders. Interestingly, clinical studies declare for starvationinduced endocrine changes that they mimic the symptoms considered diagnostic for depression. (1) Disorders of the hypothalamus--pituitary axis, with target organs the adrenals, the gonadals, the thyroid and the epiphysis, are common in eating disorders. Newly discovered hormones and peptides as leptin, ghrelin and adiponectin are the molecular protagonists in eating disorders, while melatonin is almost having its role currently. (2) Although a neuroendocrine basis between eating disorders and depression is not yet absolutely clear, it is expected that pharmaceutical industry's research will complete the analysis and interpretation of the ongoing high volume of relevant data.

Osteoporosis and Depression

Cizza et al3 investigated the role of depression as a causative factor for the development of osteoporosis. The question that would be of bigger interest is "if osteoporosis is considered a causative factor for the development of depression". Mezuk et al (4) reviewed epidemiological studies and confirmed that osteoporosis and depression are statistically related in a positive way. In the study of Ilias et al (5) there is a study that examines the osteoporosis in men. According to their study, a potential mechanism of bone loss in depression involves concurrent activation of the hypothalamic-pituitary-adrenal and sympathoadrenal axes, suppression of the gonadal and somatotrophic axes, high interleukin-6 and low leptin levels. After controlling depression, antidepressant medication use was associated with decreased BMD(bone mineral density) in women but not in men, according to Mezuk et al. (6) The question is, if we treat osteoporosis successfully, would depression symptoms decrease, and how close are we to the multi-drug that would control the neuro-hormonal link between the two medical entities?

Obesity and Depression

Who is the specialist that would treat effectively obese with or without diabetes suffering from depression? Brain is the centre of eating behaviour and eating disorders. Research data in animals and observations in the obese lead to the result that no other factor than the cognitive is the crucial component in obesity etiology. Obese people may be thought as powerful members of society, since according to Darwin, they seem to survive through years and become more and more, but on the other hand, obese individuals may represent the phenotype of a sick society (counteraction between humans and environment). Obesity should not be labelled as a common disease, but is seeming to be an allostatic condition (7) that helps survival in difficult environments, and is very difficult to change, if the environment remains the same. On the other hand, the hormonesprotagonists obesity do not depend on cognition. (2) Also, even if a bariatric surgical operation is done, hormonal results prevail. (2)

The endocrine concept for depression in obesity is that the fat tissue is such a huge organ in obese that creates problems with the psychic sphere due to over-production of hormones and other biochemical factors (leptin, tumor necrosis factor alpha, resistin, adiponectin, interleukin-6, free fatty acids and other substances that influence the condition of insulinoresistance, one of the main factors responsible for Diabetes Mellitus Type 2. What all obese patients in the world are waiting for is the endocrine treatment to their problem. When the endocrine treatment for obesity is found, then depression of obesity will be treated, too. At the moment, we know that people with bipolar disorder are at risk of obesity and metabolic syndrome, showing that the retrograde pathophysiologic route between phychiatric disorders and obesity is present. (8)

PTSD Syndrome and Depression

Ducrocq et al (9) examined the comorbidity and the etiologic connection between PTSD syndrome and depression. According to their study, physical and psychic traumata (or traumas) can provoke in different ways the appearance of depressive symptoms. Post-traumatic depression, reactional depression, major depressive disorder and post-traumatic stress disorder represent different clinical and nosographic disorders despite of their occasionally common symptomatic core. (9) The clinical features of depressive episodes comorbid or associated with PTSD have some characteristics making it possible to individualize various clinical forms as a function of traumatic event type: asthenic, characterial or with somatic symptoms. According to the majority of authors, the co-occurrence of post-traumatic stress disorder and major depressive disorder is high although differential diagnosis is sometimes difficult. (9) The American national study of comorbidity in which Kessler concludes that for 78% of the subjects who present a comorbidity PTSD/MDD (comorbidity raised for 48% of the 5,877 subjects included) concludes that the mood disorder is secondary to PTSD. (10) On the other hand, PTSD is considered an endocrine syndrome, as hypocortisolemia and HPA axis function alterations are found and contribute in the diagnosis and treatment approaches. (11) The link between PTSD Syndrome, endocrine imbalance and depression might be the future multi-drug, that would provide the potential to treat both endocrine and psychic disorders.

Post Operative Depression a) Post-Prostatectomy Depression

Prostate cancer is a hormone dependent disease and its prognosis is directly related with the androgen levels in blood. About the 95% of androgens comes from the testes and the 5% is produced by the adrenals. The GhRH--As (Gonadotropin hormonereleasing hormone analogs), used for the treatment of advanced prostate cancer, as complimentary therapy or monotherapy, cause a pharmaceutical orchiectomy by prohibiting the androgen secretion from the testes. Nonsteroidal antiandrogens (NSAAs) cause inhibition of the androgens secreted by the adrenals by blockade of their receptors. Common complications of radical prostatectomy are urine incontinence and sexual dysfunction. The atrophy of pinus and the resulting sexual impotence as well as the urine incontinence cause serious problems to the patients'quality of life and well being, with a 10% depression postoperatively as it was found in men operated for prostate cancer 32 months -mean-time-before the investigation. (12) The role of a surgeon in prostate cancer is very important as the prostatectomy. The new surgical approach with the autonomic nerve preservation leads to improved quality of life in the operated patients. Robotic surgery seems to help in the improvement of this technique. (13) Also, a new technique, the male sling, treats the patient from the urine incontinence and improves his quality of life. (14) Apparently, the depression that occurs in prostate cancer sufferers is mostly dependent on the work done by surgeons and endocrinologists/oncologists and not on antidepressive drugs.

b) Post--Mastectomy Depression

Breast cancer is the first to cancers that have been studied for their psychosocial dimensions. One out of 8 women suffers from breast cancer and depression is expected to happen because breast is related to sexuality and self-confidence. Post-mastectomy depression is frequently diagnosed early. Older studies refer that psychologic problems like depression and anxiety disorders were developed in 10-56% of operated women during the first 2-year post mastectomy. (15) In operated women after 2 years, the quality of life is better and equal with women who did not have a mastectomy. (16) The role of surgery became very important when minimal operations improved the aesthetic result after the suggestion of Umberto Veronesi and the National Anticancer Centre of WHO in Milan in 1968; this led to the broad acceptance of minimal operations (segmentectomy) for breast cancer surgery, and the oncologic results remained equally radical. (17) Thus, a new era began in the issue depression and breast cancer, with protagonist contributions of the surgeons and not of psychiatrists. One important improvement was the use of silicone for the aesthetic surgical rehabilitation in very short time after the operation, so operated women did not feel the loss of the breast in their somatic image. (18) Once again, surgeons and endocrinologists/oncologists (for hormonal therapies following mastectomy), are contributing much more in the prevention -or failure of prevention- of the postoperative depression in comparison to psychiatrists who act with a symptomatic approach only.

c) Post--Adrenalectomy Depression

The effects of adrenalectomy in the psychic sphere of patients has been studied since adrenalectomies were more in number. However, the current progress in the study of neuropeptides, receptors and molecular connections between the brain and peripheral organs has given us the chance to collect knowledge about the post-adrenalectomy depression. After an adrenalectomy, protagonistic hormonal change is the decrease of glucocorticoids. However, because the patient receives replacement hormonal therapy, all postoperative effects tend to be diminished. In cases that the replacement is not adequate in comparison to patients'needs, then depression may be developed as well as panic attacks. It has been found that in the 3 first months after the operation for Cushing's syndrome, the total psychopathology (atypical depression and other symptoms) remains in a percentage of 53% of patients, in 6 months symptoms are decreasing to 36% and in the end of the first year to 24,1%.19 The recovery of HPA axis is confirmed with the use of stimulation tests with the use of ACTH (Adrenocorticotropic Hormone). It has been observed that the psychological improvement is related adversely with the basic morning cortisol secretion, but there is not correlation of the cortisol level that is produced with ACTH stimulation in 60 minutes. In the postoperative period in patients with Cushing's syndrome, depressive disorder is the predominant disorder among the observed psychiatric problems. Important to be highlighted is the fact that suicide idealism and panic crises are increased in the number postoperatively. The fact that depression exists in both pre- and postoperative periods, while cortisol has been corrected, may be caused by the inhibition of CRH production by the chronic cortisol appearance in the blood circulation. The mild increase of panic disorder after the correction of cortisol is related to the reduced chemical connection of glucocorticoids in the central sympathetic system. With time, an improvement in depressive symptoms are occurring, but the panic crises as well as the suicide idealism is to be taken seriously during the postoperative follow up. (19)

According to Dr Santibanez et al (20), adrenalectomy decreases Corticotropin-Releasing Hormone (CRH) gene expression and increases noradrenaline and dopamine extracellular levels in the rat lateral bed nucleus of the stria terminalis (BNST). They suggest that the BNST and the central nucleus of the amygdala form part of an adrenal steroid-sensitive extrahypothalamic circuit that has been involved in fear and anxiety responses and in clinical syndromes such as melancholic depression, posttraumatic stress disorders, and addiction. According to these findings, it may be explained why some patients who undergo adrenalectomy present a psychological imbalance during the postoperative period, and why this period may last for more than one year. Especially in the patients who stop the replacement therapy one year after the operation and their needs have not yet been covered by the endogenous cortisol produced from the remnant adrenal gland, problems may be constant and won't be helped much by anti-depressive drugs. According to Alkatib et al (21), women with primary or secondary adrenal insufficiency report a decreased health-related quality of life (HRQOL) despite traditional adrenal replacement therapy. In their review, they studied 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta-analysis showed a small improvement in HRQOL in women treated with Dehydroepiandrosterone (DHEA) compared with placebo. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant. They concluded that DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. However,the evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.

d) Post--ovariectomy depression

In 1989, a team from Italy studied the influence of ovariectomy, estradiol and progesterone on the behavior of mice in an experimental model of depression. (22) They used the tail suspension test as an animal model of depression. Their findings indicated that ovarian sex hormones, while having no "antidepressant" effect on the behavior of intact adult female mice, have such an effect in ovariectomized mice, and enable the animal to cope in a "normal" way with adverse environmental situations. (22)

Since then, much progress has been done, with the replacement hormonal therapies for women who have undergone an ovariectomy. Data with important implications regarding the prevention of depression in postmenopausal women undergoing estrogen therapy, are given by Nakagawasai et al (23), who found that with the administration of 17beta-estradiol to ovariectomized mice, on postoperative day 11, significant results were produced in the anxiety and depressive symptoms.

LaPlant et al24 performed microarray analysis in nucleus accumbens (NAc), a key brain reward region implicated in depression, in ovariectomized and gonadally intact female mice after chronic unpredictable stress and measured stressinduced depression-like behavior. They found that stress regulation of genes in NAc of gonadally intact female mice is blunted in ovariectomized mice. Their results suggested a hormonal mechanism of NFkappaB -a pro-survival transcription factor involved in cellular responses to stress which is highly upregulated in NAc ovariectomized mice- regulation that contributes to stress-induced depressive behaviors in female subjects and might represent a mechanism for gender differences in prevalence rates of these disorders in humans.

Walf et al (25) used an animal model to investigate the long term versus the short term effects of replacement therapy with estradiol, in female rats (ovariectomized). They found that estradiol-replacement reduced anxiety and depression behavior and improved cognitive performance of aged female rats; however, delay in estradiol treatment influenced whether there were favorable effects of estradiol in some tasks. This study shows that not only depressive disorders but also cognitive defects may be related to post-ovariectomy effects. Michelsen et al (26) explored mental distress and somatic complaints in 503 women after RRSO(salpingo-oophorectomy) compared to controls from the general population. The operation was recommended for the protection against ovarian cancer in BRCA mutation carriers and in women at risk for hereditary breast ovarian cancer. The mean age of cases and controls was 54.6 years at survey, and the mean time since surgery was 5.3 years. Compared to controls, the RRSO group had more palpitations, constipation, pain and stiffness, osteoporosis and musculoskeletal disease even after adjustments for demographic factors including use of hormonal replacement therapy. The RRSO group had lower levels of depression and total mental distress compared to controls. In multivariate linear regression analyses, RRSO was associated with lower levels of depression and total mental distress. In contrast to the general feeling for the low estradiol period in womens' life, it was found that more somatic morbidity such as osteoporosis, palpitations, constipation, musculoskeletal disease and pain and stiffness was produced among women who had undergone RRSO compared to controls, but lower levels of mental distress. This might indicate that mental and mood problems derive via most complex mechanisms that are not controlled only by the hormones of ovaries. Finally, DeRogatis et al (27) suggested that a transdermal testosterone patch (TTP) treatment produced statistically significant improvements in a satisfying sexual activity (SSA), sexual desire, and personal distress in surgically menopausal women suffering from hypoactive sexual desire disorder (HSDD). In conclusion, although the classical results connected directly depression and ovariectomy, current research shows that complex mechanisms cause depression to ovariectomized women and as well as cognitive defects, and that treatment will be more complex than we expected. However, at the moment general surgeons would help women--more than antidepressive drugs- if they reduced the number of useless ovariectomies for minimal ovarian problems, in emergency laparotomies for acute abdominal pain; especially the bilateral ovariectomy!

e) Post--thyroidectomy depression

After total thyroidectomy, hypothyroidism is treated with replacement therapy. However, if the dose is low for the patients' needs or the patient is not conformed with the daily treatment scheme, hypo-thyroidism may occur. Hypothyroidism in depressive patients is a negative prognostic parameter and requires therapy. Psychiatric symptoms associated with hypothyroidism are usually reversible under levothyroxine within 4-8 weeks. The standard for hypothyroidism is mono-levothyroxine therapy.

Dr Miccoli et al (28) investigated the impact of thyroidectomy in quality of life among patients with thyroid diseases. Their results indicated that patients showed a significant improvement of mental health and a reduction of psychiatric symptoms, even long after the thyroidectomy. Nevertheless, patients continued to have a poorer quality of life compared to the Italian normative sample, used as control group. Mental health improved significantly after surgery but social functioning remained markedly impaired.

In a depression animal model induced by thyroidectomy, Masalova and Sapronov29 tested the results of an SSRI (selective serotonin re-uptake inhibitor), citalopram, in young male rats with thyroid hormone disbalance. Thyroidectomy increased the level of depressed behavior and enhanced the expression of emotional behavior. The replacement treatment of thyroidectomized rats with triiodothyronine (T3) produced antidepressant and anxiolytic effects. The chronic administration of citalopram also produced an antidepressant action, the drug effect being more pronounced in the case of a combined treatment with citalopram and T3 (synergism).

Depression during pregnancy and Post-Partum Depression

Depression is the most common psychiatric disease among women, two or three times more common than in men. Postpartum depression (PPD) is the most common medical complication of childbearing. Clinical risk factors, diagnostic criteria and screening tools have been developed and are used by obstetrician-gynecologists for the examination and follow up of patients. The postpartum period is considered the time of greatest risk for women to develop major depression and postpartum depression affects approximately 7-14% of women. (30) Although conventional pharmacologic and psychotherapeutic antidepressant treatments are effective for PPD, a natural alternative may be preferred by postpartum women, especially those who breastfeed their infants. In their review, Moses-Kolko EL et al (31), they concluded that estradiol treatment for PPD requires confirmation of efficacy in a randomized clinical trial before routine clinical use as monotherapy. Additional data regarding maternal tolerability of cyclic progestins, long-term safety of estradiol treatment, estradiol passage into breast milk and infants, and interdisciplinary collaboration among psychiatrists and gynecologists is also needed before estradiol is used in women who decline or fail to respond to first-line antidepressant treatments, or as an augmentation of conventional antidepressant treatment.

Depression of the elderly

Endocrine glands tend to become atrophic in ageing. This physiological result is more intense for some people, especially in people who have been treated with hormonal therapies, related to the hypothalamus and the pituitary function (like the Gonadotropin hormone-releasing hormone analogs), or had a brain operation/trauma in the past.

The endocrine causes of depression in ageing are numerous, and are related not only with the physiological atrophy of endocrine glands, but also come from the accumulation of operative, traumatic, pharmaceutical, and psychosocial causes of depression, all them endocrine-dependent. Even psychosocial causes of depression are related with alterations in the function of HPA-axis, and cause catastrophic endocrine results, including depression. (32)

One of the recognized endocrine syndromes of elderly that cause depression, that is treated nowadays with hormones and not with psychiatric medications, is the Testosterone Deficiency Syndrome (33) associated with the loss of libido, erectile dysfunction, depression, decreased cognitive ability, lethargy, osteoporosis, and loss of muscle mass and strength. This constellation of symptoms is known collectively as andropause or Late Onset Hypogonadism (LOH) or Androgen Decline in the Aging Male (A.D.A.M.). Although menopause has been known and studied earlier than andropause, suggested hormonal drugs in the problem of depression are not applied in broad application due to their side effects (carcinogenesis). On the other hand, men tend to be more interested in the sexual life improvement, which is of course related to mood improvement and their problem is mostly solved with hormonal supplements and not with psychiatric drugs. (34)

Conflict of interest: None declared.


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(33.) Jacob Rajfer. Decreased Testosterone in the Aging Male. Rev Urol. 2003; 5 (Suppl 1): S1-S2.

(34.) Mayo Clinic Staff. Testosterone therapy: Can it help older men feel young again? Online article in "Men'sHealth" section, at http://www.Mayo Clinic. Com. Link (accessed at August 2,2009)

Corresponding author: Irene Christodoulou, MD, MSc

8 Heronias Str, Sikies, 56626,

Thessaloniki, Greece

Tel. +302310613736


Irene Christodoulou

Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece & Medical School, Democritus University of Thrace, Alexandroupolis, Greece
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Title Annotation:original article
Author:Christodoulou, Irene
Publication:International Journal of Health Science
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2009
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