Psychopathology in Endocrine Disorders: Why So Persistent after the Cure?
Authors: Luis Gonçalves Sobrinho
Journal: Psychotherapy and Psychosomatics (2004)

The study by Sonino et al. [1]in this issue of Psychotherapy and Psychosomatics provides important, provocative data. The most striking observation is the high prevalence of positive diagnoses of psychiatric disorders (62% by DSM-IV criteria) or of subclinical psychological syndromes (66% by DCPR criteria) in an unselected population of 146 patients with cured, or acceptably compensated, endocrine disorders of different kinds. The observations gain further consistence by the reported agreement between the above observer-rated diagnoses and the self-assessment scales of distress, well-being and quality of life (PSI and MOS).One would feel more confident if the study had included a control population instead of comparing the observed data with prevalences reported in the literature. This comment holds true despite the appalling high number of positive diagnoses.The population studied suffers primarily from three types of medical conditions – hyperprolactinemia (52 patients), thyroid disorders (39 patients, of which 22 were hypothyroid) and Cushing's disease (15 patients). Also included were patients with acromegaly (n = 10), hypopituitarism (n = 5), cortisol-secreting adrenal adenoma (n = 3), 2 patients with non-secreting pituitary adenomas, 4 with hyperaldosteronism, 2 with Addison's disease, 1 with adrenogenital syndrome, 1 with nonfunctioning adrenal adenoma, 8 with hirsutism, 2 with diabetes insipidus, 1 with pheochromocytoma, 1 with nonsecreting adrenal adenoma and 1 with hyperparathyroidism, a blend that increases the noise and dilutes the information contained in the data. Still, it is noteworthy that the three main conditions and the miscellaneous group of the remaining 41 patients have a similar percentage of psychiatric and psychological diagnoses.How can we explain such findings?Before jumping to the logical conclusion that endocrine disorders in general have the common property of being associated with psychopathology even after the correction of the hormonal variables, we will have to consider that: (1) the high prevalence of psychopathology in the heterogeneous group cannot be construed as meaning that all the conditions involved contribute to such prevalence; (2) there is no control group of patients with other chronic disorders, observed by the same raters with the same instruments, and (3) even if some endocrine diseases are strongly associated with psychopathology, this does not mean that the mechanisms involved are similar.The present series is heavily weighted by pituitary disorders (84/146 patients).There are intimate, and complex, relations between pituitary disorders and psychopathology. Pathological hyperprolactinemia (with or without morphological evidence of prolactinoma) is associated with disturbed affect that improves only partially upon normalization of the serum prolactin concentrations [2], affects predominantly women brought up under conditions of paternal deprivation [2, 3, 4, 5, 6, 7], and its clinical onset is preceded by life events [2, 3, 8]. The nature of the relations between prolactin and psychological variables, in health and disease, has been discussed in detail elsewhere [2, 9, 10].Major depression has long been recognized as a component of Cushing's syndrome, and the recovery from depression after surgical or medical treatment [11]underscores the importance of hypercortisolism in its genesis. Some of the authors of the present paper [1]probed further into this matter and made the seminal contribution of demonstrating that life events frequently precede the clinical onset of Cushing's disease, but not of Cushing's syndrome due to adrenal or ectopic tumors [12], and that persistence of depression has predictive value for recurrent disease [13].The above observations on pathological hyperprolactinemia and Cushing's disease inevitably lead to the hypothesis that the early organization of personality and interactions with the environment must be causally related to the pathogenesis of these conditions. This hypothesis implies that the pituitary disease, even when it is an adenoma, may be considered a symptom of a specific vulnerability, and provides a possible explanation for the persistence of disease after the correction of the endocrine abnormalities. As most, if not all, pituitary adenomas are monoclonal, it is likely that hypothalamic stimuli, acting upon the pituitary, promote the growth of pre-existing, hitherto silent adenomas, found to be present in 11% of the population in a meta-analysis of studies encompassing 12,000 autopsies [14].It is unclear whether prolactin and ACTH-producing adenomas result from the same hypothalamic stimulus, in which case the type of tumor depends on pituitary factors, or from hypothalamic stimuli specific to each type of tumor. The second possibility is favored by the finding that the environmental stimuli that drive prolactin or cortisol secretion are different and that the responses of these hormones to some stimuli correlate negatively [10, 15].On the other hand, both prolactin and cortisol act upon the brain and may cause psychological symptoms, either directly or indirectly, by changing behavior and conditioning the relations with the environment. In the case of Cushing's syndrome it has been reported that several aspects of impaired cognitive performance showed little change 1 year after successful surgery, suggesting that prolonged hypercortisolism may have long-lasting deleterious effects on brain function [16].The only other important group of diseases in the report by Sonino et al. [1]– thyroid disorders – is heterogeneous. Most diseases of thyroid function are autoimmune in nonendemic areas. There is a large body of evidence that emotional factors affect the immune system and, in the case of Graves' disease, there is a large convergence of reports associating the onset of the symptoms with life events [17, 18, 19]. There are no corresponding data for hypothyroidism for the simple reason that its very slow evolution precludes the definition of a 'clinical onset', something that also applies to acromegaly. Like prolactin and cortisol, thyroid hormones affect brain function and behavior.Of course, there is no reason to believe that the mechanisms involved in the transduction between environment, coping strategies and emotions on one side and 'organic disease' on the other are the same in autoimmune thyroid disorders and in pituitary disorders.A different type of explanation for the findings by Sonino et al. [1]relates to the intrinsic imperfections of endocrine replacement therapy [20]. Replacing hormones with short half-lives and pulsatile patterns of secretion by a single or a few daily administrations of growth hormone or corticosteroids is obviously nonphysiological, even if this therapy has a high degree of efficacy. Thyroxin has a long half-life and its concentrations can be easily maintained. However, thyroxin is primarily a prohormone and the rate of intracellular conversion to tri-iodothyronine depends on desiodinases that are regulated differently in different tissues. Combined administration of thyroxine and tri-iodothyronine has been advocated for hypothyroid patients that remained unwell after appropriate treatment with thyroxin [21], but the results are suboptimal and the appropriate proportions can only be guessed. Tri-iodothyronine is not easily absorbed by some tissues (e.g. the brain) that rely on its intracellular production from thyroxin [22]. The regulation of androgen and estrogen effects also depends primarily on local (intracellular) mechanisms and is much more complex than that of thyroid hormones [20, 23].Is correction of gross hormonal deviations enough to restore full normality or would fine tuning be essential for optimal performance? Although major dysfunctions can be easily overcome, an incoming flux of 'error messages' from several tissues to the brain may result in vague complaints not easily traceable to any specific origin. The absence of markers of biological effect and the impossibility of major improvements in the current treatment protocols leave this question open.Suboptimal replacement therapy can only explain the persistence of symptoms in hypothyroid patients and some others, since most of the patients in the study by Sonino et al. [1], including those with hyperprolactinemia, are not supposed to have been on replacement therapy.Looking at the paper by Sonino et al. [1]from a more general point of view, it appears that one major driving force of the authors was to emphasize two distinct, though related, points. The first one is directly pertinent to patient care and can be stated as follows: cure of a disease, as evaluated by the physician, may be very different from cure of the dis-ease as felt by the patient or as evaluated by comparing the outcome with desirable standards of well-being. The removal of an adrenal adenoma through a lumbar route is rated as a success by the surgeon, but the resulting neuralgia feels more like a failure to the patient.The provider should pay attention to the satisfaction of the client. Applied to medicine, this principle overwrites the Hippocratic practice of authoritarianism, however benign and paternalistic, by doctors who know best, even when it comes to expectations and values. Transposing business culture to medical practice became a necessity in a society in which information flows easily and health is touted as a commodity. The shift from a doctor-patient culture to a provider-consumer one has some very particular consequences. Publications on quality-of-life assessment in endocrine journals only attracted attention after growth hormone became widely available and the purpose of the therapy was expanded beyond improving the final height of a few, carefully selected, patients to the amelioration of symptoms, however subtle, of demonstrated or presumed growth hormone deficiency.The second point is more conceptual and addresses the formulation that the hormonal system is only a component (albeit important) of the bio-psychosocial equilibrium of each individual [24]. The conventional treatments of endocrine disorders are oblivious to the maladjustments between the coping capabilities of the individual and the external (and internal) demands that may have provoked the disorder in the first place, and they also ignore the long-term consequences of a disruption that may have driven the whole system to a new, less satisfactory, state of equilibrium. The report that endocrine disorders in general, even when adequately compensated, are associated with a high number of psychiatric diagnoses or of sub-clinical psychological syndromes and poor quality of life strongly supports this view.