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...

/pdf/acromegaly-an-endocrine-society-clinical-practice-guideline-21g8xh5e8c.pdf

Acromegaly: An Endocrine Society Clinical Practice Guideline

Objective: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). Participants: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. Process: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. Conclusions: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develo...

/pdf/clinical-practice-guidelines-for-multiple-endocrine-iebfm32j0y.pdf

Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.

/pdf/systemic-complications-of-acromegaly-epidemiology-48hlt1tw8j.pdf

Systemic complications of acromegaly: epidemiology, pathogenesis, and management.

Background: Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population ex...

/pdf/management-guidelines-for-children-with-thyroid-nodules-and-1aqe86ijrc.pdf

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of "stress" diabetes during fasting and inflammatory illness, and perhaps for the "Dawn" phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant-probably related to increased adiposity, reduced LBM, and impaired physical performance-which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment.

Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects.

The effects of a very prolonged treatment with octreotide (OC)-long-acting repeatable (LAR) were retrospectively evaluated in 110 patients with acromegaly, showing a GH/IGF-I decrease of at least 20% vs. baseline after a short-term (6-month) OC-LAR challenge. OC-LAR was given (20 mg, im, every 28 d for 3 injections, then individually tailored) as adjuvant treatment (AT) in 59. The other 51 [primary treatment (PT)] were naive or previously treated by pharmacotherapy. IGF-I normalized in 83 patients [75%; from 770 +/- 26 (mean +/- SE) to 276 +/- 15 micro g/liter; P < 0.0001; median follow-up, 30 months; range, 18-54 months). A progressive increase in the rate of IGF-I normalization was observed. GH fell to less than 2.5 micro g/liter in 72% and to less than 1 micro g/liter in 27% (from 20.7 +/- 2.4 to 2.2 +/- 0.2 micro g/liter; P < 0.0001). PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Patients attaining safe GH and normal IGF-I had GH levels below 5 micro g/liter after 3 months and IGF-I levels below 550 micro g/liter after 6 months. No tachyphylaxis was observed. The up-titration to 30 mg improved IGF-I suppression. Elderly patients had greater sensitivity. Tumor shrank in 46% of assessable patients, in 77% of PT patients, and in 91% of naive patients. The powerful suppression of GH/IGF-I levels without tachyphylaxis, the finding of progressive increase in the rate of IGF-I normalization and of superimposable effects in PT and AT patients, and the predictive value of short-term results support the role of PT of acromegaly with OC-LAR in at least some patients.

/pdf/four-year-treatment-with-octreotide-long-acting-repeatable-3f7xaainll.pdf

Four-Year Treatment with Octreotide-Long-Acting Repeatable in 110 Acromegalic Patients: Predictive Value of Short-Term Results?

Objective and design Eighteen active acromegalics entered a prospective open study with cabergoline (CAB), a dopaminergic drug much more potent than bromocriptine (Br). Methods CAB was administered for 6 months at doses ranging between 0.5 mg twice weekly and 0.5 mg/day. Clinical-anamnestic characteristics of the patients were: (i) sensitivity to dopamine agonist drugs (10 patients); (ii) resistance to somatostatin analogs (SAs) (8 patients): (iii) intolerance to SA (3 patients). In 2 patients marked hyperprolactinemia was present. Results Basal GH was 6.6 microg/l (2.2-50) (median (range)), and on treatment it was 3.5 microg/l (1.2-34) (P=0.013). The corresponding IGF-I values were 720 microg/l (410-1438) and 375 microg/l (167-1260) respectively (P=0.00001). Individual GH levels decreased below 2 microg/l in 5 patients, and between 2 and 5 microg/l in another 5 patients. IGF-I levels were suppressed below 50% of baseline in 8 patients and normal age-adjusted IGF-I values were reached in 5 patients (27% of the series). The retrospective comparison with previous chronic treatment with Br in the 10 suitable patients showed a greater effectiveness of CAB (IGF-I decrease on CAB treatment, 46.8%, on Br treatment, 31%, P=0.02). Adenoma shrank in the 3 patients whose pituitary imaging was repeated during CAB. Conclusions These results envisage that CAB may represent a worthy therapeutic tool in acromegalic patients, inducing a degree of IGF-I and GH suppression comparable to SAs, administered by the oral route and much less expensive.

/pdf/cabergoline-in-acromegaly-a-renewed-role-for-dopamine-1tqe0dtoj2.pdf

Cabergoline in acromegaly: a renewed role for dopamine agonist treatment?

Background: At present long-acting somatostatin analogs represent the first-line medical treatment of acromegaly. These drugs produce stable suppression of GH in most sensitive patients and IGF-I normalization in many; they also increase the compliance of acromegalic patients. The recent availability of octreotide (OC)-LAR, a somatostatin analog to be administered at 28-day intervals, has prompted us to compare, in the same group of patients, its effects and those of another somatostatin analog already available, lanreotide-SR (LSR, to be administered at 14-day intervals). Patients: Twelve somatostatin analog-sensitive acromegalic patients with active disease were enrolled in a prospective open sequential study after giving their informed consent. After chronic treatment with LSR (6‐24 months), the patients were changed to treatment with OC-LAR, without wash-out. LSR had been administered at individually tailored dosages (30 mg i.m. at 7‐21-day intervals, median 10 days ‐ every 7 days in seven patients, 10 days in two patients, 14 days in two patients and 21 days in one patient) according to GH and IGF-I responses. Disease stability was obtained, as shown by maximal GH/IGF-I suppression without any significant hormonal change between the last two control measurements. OC-LAR was administered i.m. at 28-day intervals six times at the dosage of 20 mg for the first three times and 10 or 30 mg for the last three times (according to individual GH/IGF-I responses). GH (mean of three, hourly samples) and IGF-I concentrations were evaluated on the same day as each administration of the drug, before its injection. Results: GH and IGF-I values were significantly decreased by LSR treatment. GH decreased from 41.6 6 14.6 mg/l (mean 6 S.E.) to 7.2 6 1.5 mg/l (P < 0.02), whereas IGF-I values declined from 959 6 95 mg/l to 460 6 61 mg/l (P < 0.00001), expressed as absolute values, and from 287 6 30% to 137 6 19% expressed as percentage of the upper limit of normal range (%ULNR). At the end of the last cycle, OC-LAR treatment achieved a significant further suppression both in GH (to 5.1 6 1.1 mg/l, P < 0.05 compared with LSR) and in IGF-I concentrations (to 374 6 60 mg/l, P < 0.05 compared with LSR, and to 112 6 19% as %ULNR). LSR decreased GH concentrations to less than 2.5 mg/l in one patient and normalized IGF-I concentrations in four patients. OC-LAR decreased GH concentrations to less than 2.5 mg/l in four patients and normalized or near-normalized IGF-I concentrations (i.e. to < 110%ULNR) in eight patients. Conclusions: These preliminary results show that the once-monthly OC-LAR administration schedule proved more efficacious than LSR given every 7‐21 days, in a greater number of acromegalic patients.

/pdf/a-comparison-between-octreotide-lar-and-lanreotide-sr-in-the-1b21fj7fl7.pdf

A comparison between octreotide-LAR and lanreotide-SR in the chronic treatment of acromegaly.

Background: IGF-I suppression in acromegaly obtained by tamoxifen, a selective estrogen receptor modulator (SERM), prompted us to evaluate the effects of the administration of a newer SERM, raloxifene (RAL), devoid of estrogenic activity at uterine level, on GH/IGF-I levels in patients with this disease. Patients: Thirteen post-menopausal acromegalic women (aged 55 – 84 years) with active acromegaly entered a prospective open pilot study of RAL treatment at 60 mg/day. Nine of the patients, who were resistant to somatostatin analog and dopamine agonist treatment, were not undertaking therapy; the other four, who were partially sensitive to medical treatment, maintained treatment at the maximally effective dosages throughout the study. Results: IGF-I levels fell significantly from 444 (median, interquartile 393 – 590)mg/l to 300 (216 – 608) mg/l ðP ¼ 0:0192Þ after 1 month of RAL administration and this fall remained stable up to the final evaluation at 5^1 months from the start of RAL treatment (260 (187 – 410) mg/l). An IGF-I decrease greater than 30% of basal values was observed in 10 patients (mainly in patients with IGF-I levels lower than 600mg/l) and normal values were reached in seven (54%). GH levels did not change (basal 6 (4.1 – 8) mg/l, final 5.5 (3.2 – 7.4) mg/l). The clinical picture improved in patients sensitive to RAL. RAL withdrawal was followed by the return of IGF-I levels to pretreatment values within 8 weeks in all patients. Conclusions: RAL decreases IGF-I levels in most acromegalic women with mild or intermediate disease (i.e. with values lower than 600mg/l) and normalizes it in many. A prospective randomized study in patients resistant or partially sensitive to other medical treatments is warranted.

/pdf/raloxifene-lowers-igf-i-levels-in-acromegalic-women-1euohf2b1i.pdf

Raloxifene lowers IGF-I levels in acromegalic women.

In some acromegalic patients medical treatment does not succeed in normalizing GH/IGF-I values. Data showing IGF-I suppression in acromegaly by estrogen and by tamoxifen use prompted us to reevaluate the effects of estro-progestins (EP) supplementation on GH/IGF-I levels in acromegalic women resistant or only par-tially sensitive to medical treatment. Eight active acromegalic women (30–52 yr, 4 with regular menses) entered a prospective open pilot study. Three of them, resistant to medical treatment, were off therapy; the remaining five, partially sensitive, maintained it at the maximally effective dosages throughout the study. Patients were treated with a triphasic pill (ethynil-estradiol 30–40–30 μg/day and desogestrel 50–70–100 mg/day) for 13±7 months. IGF-I levels fell from 512 (median, interquartile 436–657) μg/l to 282 (244–526) μg/l (p=0.0414); the decrease was observed in 6 patients (75%), and normal values were reached in 4 (50%). GH levels did not change [basal 7.6 (6.2–8.6) μg/l, final 7.6 (6.5–8.3) μg/l]. Effectiveness of treatment was not dependent on concomitant anti-GH treatment or gonadal status. In all patients IGF-I levels re-increased after EP withdrawal. This pilot study shows a marked IGF-I lowering effect of pill in acromegalic women, and warrants a prospective randomized study in patients resistant or partially sensitive to other medical treatments.

Estroprogestinic pill normalizes IGF-I levels in acromegalic women.

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