https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

Objective: The aim was to formulate clinical practice guidelines for acromegaly. Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. Conclusions: Using an evidence-based approach, this acromegaly guideline addresses impor...

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Acromegaly: An Endocrine Society Clinical Practice Guideline

It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)

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Growth hormone and bone.

Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Conclusions: Treatment of Cushing's syndrome is essential to reduce mortality and associ...

/pdf/treatment-of-cushing-s-syndrome-an-endocrine-society-1caxu7uhbn.pdf

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

GH and IGF-I are important regulators of bone homeostasis and are central to the achievement of normal longitudinal bone growth and bone mass. Although GH may act directly on skeletal cells, most of its effects are mediated by IGF-I, which is present in the systemic circulation and is synthesized by peripheral tissues. The availability of IGF-I is regulated by IGF binding proteins. IGF-I enhances the differentiated function of the osteoblast and bone formation. Adult GH deficiency causes low bone turnover osteoporosis with high risk of vertebral and nonvertebral fractures, and the low bone mass can be partially reversed by GH replacement. Acromegaly is characterized by high bone turnover, which can lead to bone loss and vertebral fractures, particularly in patients with coexistent hypogonadism. GH and IGF-I secretion are decreased in aging individuals, and abnormalities in the GH/IGF-I axis play a role in the pathogenesis of the osteoporosis of anorexia nervosa and after glucocorticoid exposure.

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Growth Hormone, Insulin-Like Growth Factors, and the Skeleton

Background Irradiation of the pituitary is widely considered the most appropriate treatment for patients with Cushing's disease in whom transsphenoidal microsurgery has been unsuccessful. However, there is little information about the long-term efficacy of this treatment. Methods We used external pituitary radiation to treat 30 adult patients with persistent or recurrent Cushing's disease after unsuccessful transsphenoidal surgery. The mean (±SD) dose of radiation was 50±1 Gy. Pituitary and adrenal function was assessed every six months after radiation therapy. Remission was defined as the regression of symptoms and signs of Cushing's syndrome, normal urinary cortisol excretion, and a low plasma cortisol concentration in the morning after the administration of 1 mg of dexamethasone at midnight. Results Twenty-five patients (83 percent) had remissions during a median follow-up of 42 months (range, 18 to 114). The remissions began 6 to 60 months after radiation therapy, but in most cases (22 patients) remis...

https://www.nejm.org/doi/pdf/10.1056/NEJM199701163360303

The Long-Term Outcome of Pituitary Irradiation after Unsuccessful Transsphenoidal Surgery in Cushing's Disease

Summary
objective  To develop a disease-specific questionnaire suitable to measure health-related quality of life (HRQOL) in acromegaly (ACROQOL).

design, patients and measurements  For the development of the ACROQOL questionnaire different sources of information were used: First, a literature search was performed to identify relevant papers describing the impact of acromegaly in HRQOL. Second, 10 endocrinologists identified the main domains of impact on HRQOL in patients with acromegaly. Third, 10 in-depth, semistructured interviews were conducted in acromegalic patients to identify domains and items related to the self-perceived impact of acromegaly in patients’ life. Qualitative analyses of the information were performed identifying domains and items to be included in the questionnaire. Those items considered ambiguous, complicated to read, double-barrelled, with jargon terms, too long, or negatively worded were excluded. Each remaining item was subsequently rated by the same panel of endocrinologists and experts in HRQOL evaluation, and assessed according to clarity of wording, frequency of occurrence and importance among patients with acromegaly. Analysis of internal consistency of the questionnaire was evaluated with a Cronbach's Alpha. A preliminary questionnaire was administered to 72 patients with acromegaly. Rasch analysis (dichotomous logistic response model) of the answers given by these patients allowed parameter estimates and model data fit indices to be computed and misfitting items deleted. Frequency of occurrence and degree of agreement with the statements were selected as response choices in a 5-point Likert type scale.

results  The following domains related to HRQOL in acromegaly were identified: physical and psychological functions, social, daily activities, symptoms, cognition, general health perception, sleep, sexual function, pain, energy and body image. An initial set of 204 expressions were identified from the initial transcripts of the patient interviews. After elimination of ambiguous or unclear expressions, 142 items remained drafted in question form. From the quantitative analysis of the item rank position within each of the three areas of clarity, frequency and importance, the 38-item questionnaire was produced, with satisfactory internal consistency (Cronbach's Alpha 0·94). Rasch analysis produced a further reduction to the final 22-item questionnaire (Cronbach's Alpha 0·91) containing two scales that evaluate physical (eight questions) and psychological aspects related to appearance and personal relations (seven items each). The evaluation of the item parameters confirmed the construct validity of the new instrument. The substantial reliability of the questionnaire suggested the sample was well targeted by the questionnaire. The initial Spanish version was translated into English and presented to five English-speaking Australian patients with acromegaly to assess and correct for comprehension, clarity, cultural relevance and suitable wording.

conclusions  We present the ACROQOL questionnaire, developed and preliminarily validated to specifically assess HRQOL in patients with acromegaly.

Acromegaly Quality of Life Questionnaire (ACROQOL) a new health-related quality of life questionnaire for patients with acromegaly: development and psychometric properties

Transsphenoidal microsurgery is the standard treatment for patients with Cushing's disease. However, there is general lack of agreement regarding the definition of cure. We studied 58 patients with corrected hypercortisolism after transsphenoidal surgery for Cushing's disease. Plasma and urinary cortisol levels were measured after surgery. After the postsurgical hypocortisolism stage (or periodically in patients without hypocortisolism), urinary free cortisol, plasma cortisol at 0800 h and 2300 h, morning cortisol after 1 mg dexamethasone, and cortisol response to insulin-induced hypoglycemia were performed. Patients were classified in 3 groups: group I, patients with transient hypocortisolism and normal hypothalamus-pituitary-adrenal axis afterwards; group II, patients with transient hypocortisolism and abnormalities in the circadian rhythm or the stress response afterwards; and group III, patients without postoperative hypocortisolism. Thirty-three patients were included in group I, 8 in group II, and 17 in group III. Groups I and II were similar in postsurgical plasma cortisol (46.9 +/- 30.3 vs. 60.7 +/- 38.6 nM) and mean follow-up (69.8 vs. 68.8 months) but were significantly different in their recurrence rate (3.4% vs. 50%, P < 0.001). Patients in group III had normal postsurgical plasma and urinary cortisol but persistent abnormalities in circadian rhythm and stress response. After a mean follow-up of 39.1 months, their recurrence rate was similar to that of group II (64.7% vs. 50%). The complete normalization of the adrenocortical function, which is always preceded by postsurgical hypocortisolism, is associated with a very low recurrence risk and should be considered, in our opinion, the main criterion of surgical cure in Cushing's disease.

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The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease.

A series of 35 patients with non-functioning pituitary adenomas undergoing transsphenoidal surgery is presented. In most cases, the presenting symptoms were related to the mass effect of the tumor. There was no operative mortality. Before surgery, visual field defects were documented in 21 patients (60%). After surgery, excluding 3 patients with preoperative blindness, 28% regained normal vision and 67% showed variable improvement. Preoperatively, 24 patients (69%) had abnormal pituitary function, 24 (69%) had hypogonadism, 7 (20%) adrenal insufficiency, 8 (23%) hypothyroidism and 2 (6%) panhypopituitarism. After pituitary surgery, all but one patient with normal preoperative function retained it. Of the patients with hypopituitarism, 11 (46%) had variable improvement and 13 (54%) had persistent deficits. After surgery, 4 patients (57%) with adrenal insufficiency recovered normal adrenal function, 7 patients (29%) with hypogonadism recovered gonadal function and 1 patient (13%) with hypothyroidism recovered thyroid function. Prior to surgery, the presence of a normal or slightly elevated PRL and a rise in TSH after TRH and in LH after GnRH stimulation were of value in predicting possible recovery of pituitary function after surgery. These observations suggest the presence of viable pituitary tissue in these cases and point out that, in some instances, the mechanism of hypopituitarism may be compression of the portal circulation, rather than destruction of the normal pituitary gland.

Recovery of visual and endocrine function following transsphenoidal surgery of large nonfunctioning pituitary adenomas

OBJECTIVE While inferior petrosal sinus (IPS) sampling correctly diagnoses pituitary-dependent Cushing's syndrome if a significant ratio of plasma ACTH between the IPS and the peripheral blood is demonstrated, little has been said about the significance of a negative ratio in Cushing's disease (e.g. a false-negative result). This study evaluates the results of IPS sampling in patients with Cushing's disease, and compares them with both imaging findings and transsphenoidal examination.

DESIGN The results of IPS sampling were retrospectively compared with both imaging findings and transsphenoidal examination. IPS samples were obtained before and 2, 5 and 10 minutes after intravenous administration of 100 μg of CRH.

PATIENTS Thirty-two patients with Cushing's disease were evaluated. All subsequently underwent transsphenoidal examination of the pituitary gland.

MEASUREMENTS The ratio of the ACTH concentrations at the IPS and in the peripheral blood (IPS : P ratio), and the ratio of the ACTH concentrations between the IPSs (interpetrosal ratio) were calculated. Radiographic evaluation of the pituitary gland was performed with magnetic resonance imaging (MRI, 29 cases) or computed tomography imaging (CT, 3 cases).

RESULTS Transsphenoidal examination of the pituitary gland revealed a microadenoma in 27 cases. Radiological imaging showed a signal compatible with a microadenoma in 22 cases (68.8%), and correctly located the tumour at the side found at surgery in 14 of the 22 cases with positive transsphenoidal findings (MRI 13 cases, CT 1 case, overall 63.6%). Successful bilateral catheterization was accomplished in 30 patients (93.8%). Samples before and after CRH stimulation were drawn in 24 cases. No major complications were observed with the technique. IPS catheterization correctly predicted Cushing's disease (by means of a significant IPS : P ACTH ratio) in 27 of the 30 patients (90%) with basal sampling, and in 23 of the 24 cases with samples drawn before and after CRH administration (95.8%). Taking into account the 12 patients with a lateral microadenoma shown at transsphenoidal examination, IP sinus ACTH ratio was in agreement with the side recorded by the neurosurgeon in 8/12 cases (66.7%). MRi correctly located the tumour in 8/12 patients (66.7%). One patient showed no significant IPS : P ACTH ratio in any set of samples. His MRI showed no sign of a microadenoma. Two years later, another pituitary MRI evaluation showed a midline hypodense signal. The transsphenoidal examination revealed a microadenoma and the post-operative plasma cortisol and urinary free cortisol fell to 293 nmol/l and 100 nmol/24 h, respectively.

CONCLUSIONS Only when a significant IPS : P ACTH ratio is present can Cushing's disease be established by IPS sampling. The absence of a significant IPS : P ACTH ratio does not necessarily imply ectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralization by IPS sampling do not remove the need for a thorough transsphenoidal examination of the contents of the sella turcica.

Tomás Lucas

Papers

The Long-Term Outcome of Pituitary Irradiation after Unsuccessful Transsphenoidal Surgery in Cushing's Disease

Acromegaly Quality of Life Questionnaire (ACROQOL) a new health-related quality of life questionnaire for patients with acromegaly: development and psychometric properties

The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease.

Recovery of visual and endocrine function following transsphenoidal surgery of large nonfunctioning pituitary adenomas

Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results