Search

Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs)., Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures., Results: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience., Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs., (© Endocrine Society 2020.)

Background: To examine the clinical and hormonal profiles, comorbidities, treatment patterns, surgical pathology and clinical outcomes of patients diagnosed with acromegaly at the Cleveland Clinic over a 15-year period., Methods: A retrospective chart review of patients with acromegaly who underwent surgical resection between 2003 and 2018., Results: A total of 136 patients (62 men; mean age 48.1 years) with biochemical evidence of acromegaly were analyzed. Median insulin-like growth factor 1 (IGF-1) level at diagnosis was 769.0 ng/mL and most patients had a macroadenoma (82.2%). Immunoreactivity to growth hormone (GH) was noted in 124 adenomas, with co-staining in 89 adenomas. Complete visible tumor resection during initial surgery was achieved in 87 patients (64.0%). In this cohort, complete response to surgery alone was observed in 61 patients (70.1%), while 31 out of 65 patients (47.7%) who received additional post-surgical medications and/or radiation therapy achieved complete response. At most recent follow-up, 92 patients achieved eventual complete response by documented normalization of IGF-1 levels. Higher IGF-1 level at diagnosis ( P  = 0.024) and cavernous sinus invasion ( P  = 0.028) were predictors for failure to respond to surgery., Conclusion: In this study, the majority of tumors were macroadenoma, plurihormonal, and treated effectively with surgery alone or surgery with adjuvant medical or radiation therapy. More studies are needed to identify additional molecular biomarkers, tumor characteristics and imaging findings to individualize treatment and better predict treatment outcomes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Objective: To evaluate the effect of raloxifene on prolactin (PRL) levels in addition to dopamine agonist (DA) therapy in patients with prolactinoma. Methods: We conducted a retrospective chart review of 14 patients with prolactinoma on stable dose of DA for 6 months who received raloxifene 60 mg daily, as PRL could not be normalized despite being on fairly high doses of DA. Patients were informed that raloxifene is not approved by the Food and Drug Administration for prolactinoma treatment. PRL level was measured at 1 to 6 months after starting raloxifene and at 1 to 3 months following its discontinuation. Raloxifene was stopped in 8 out of 14 patients after 2 (1 to 6) months of treatment as the absolute change in PRL level was felt to be small. Results: The median age and female/male sex ratios were 50 years (range 18 to 63 years), 6/8 respectively. The baseline DA dose was 3 mg/week (0.5 to 7 mg/week) for cabergoline and 15 mg/day for bromocriptine. Ten patients had an absolute and percentage decrease in PRL of 8.3 ng/mL (1.5 to 54.2 ng/mL) and 25.9% (8 to 55%) from baseline, respectively, after 1 to 6 months on raloxifene treatment. Among 10 patients with a decrease in PRL level, 2 (20%) achieved PRL normalization. Two patients had no change in PRL and two patients had an increase in PRL level by 22.8 ng/mL and 8.8 ng/mL (47% and 23.6%), respectively. Conclusion: Raloxifene was associated with a 25.9% (8 to 55%) decrease in PRL level in 10/14 (71%) patients with prolactinoma who were on stable doses of DA including 2 patients (14%) who achieved normoprolactinemia. Abbreviations: CV = coefficient of variation; DA = dopamine agonist; FSH = follicule-stimulating hormone; LH = luteinizing hormone; PRL = prolactin; PTTG = pituitary tumor transforming gene.

Objective: To characterize a single referral center experience with thyroid-stimulating hormone (TSH)-staining adenomas., Methods: A retrospective chart review was conducted on histopathologic-proven TSH-staining adenomas resected between 2000-2015 at a single center. Tumors were classified as functional (hormonally active) or silent (hormonally inactive). Categorical variables were summarized using counts (n) and percentages; continuous variables were summarized using medians and ranges., Results: From the 1,065 pituitary adenomas operated, 32 (3.0%) showed diffuse staining for TSH. Median (range) age of patients was 49 years (20 to 77 years), and 21 (66%) were male. Tumor diameter was 20 mm (2 to 37 mm), with 7 (22%) microadenomas and 25 (78%) macroadenomas. Functional tumors (n = 5, 16%) had median diameter of 10 mm (5 to 21 mm) (2 microadenomas). At diagnosis, median (range) TSH was 4.3 μU/mL (1.2 to 6.9 μU/mL), and free thyroxine (FT4) was 2.4 ng/dL (2.1 to 3.4 ng/dL). Three tumors stained for TSH alone, and 2 tumors costained with growth hormone (GH). No cavernous sinus invasion was seen, and 3 (60%) were considered cured after surgery. Silent tumors (n = 27, 84%) had median diameter of 20 mm (2 to 37 mm), with 5 (19%) microadenomas and 22 (81%) macroadenomas. Median (range) TSH was 1.2 μU/mL (0.48 to 4.6 μU/mL), and FT4 was 1.2 ng/dL (0.6 to 1.6). Only 2 (7.4%) tumors stained for TSH alone; the rest were plurihormonal, with GH being the most common. Cavernous sinus invasion was seen in 7 (27%) of the tumors, and 17 (63%) were considered surgically cured., Conclusion: In our series, 22% of TSH-staining adenomas were microadenomas, and 84% were silent. Most TSH-staining adenomas were plurihormonal, particularly costaining with GH., Abbreviations: αSU = alpha-subunit; ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FT4 = free thyroxine; GH = growth hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; PRL = prolactin; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Purpose: The appropriate cosyntropin dose during cosyntropin stimulation tests remains uncertain. We conducted a prospective, randomized pilot study to compare 1 μg IV low dose cosyntropin test, 25 μg IM medium dose cosyntropin test, and 250 μg IM standard dose cosyntropin test to evaluate secondary adrenal insufficiency. Insulin tolerance test was used as the gold standard., Method: The study included patients with hypothalamic/pituitary disease (n  = 10) with at least one pituitary axis deficiency other than ACTH deficiency and controls (n  = 12). All tests were done in random order. Sensitivity and specificity were calculated for total cortisol and serum free cortisol cut-off levels during cosyntropin stimulation tests., Results: The median (range) age and F/M sex ratios for patients and controls were 54 years (23-62), 2/8, and 33 years (21-51), 6/6, respectively. The best total cortisol cut-off during low dose cosyntropin test, medium dose cosyntropin test, 30 min and 60 min standard dose cosyntropin test were 14.6 μg/dL (100% sensitivity & specificity), 18.7 μg/dL (100% sensitivity, 88% specificity), 16.1 (100% sensitivity & specificity), and 19.5 μg/dL (100% sensitivity & specificity), respectively. There was no difference in the ROC curve for cortisol values between the cosyntropin stimulation tests (p  > 0.41). Using a cortisol cut-off of 18 μg/dL during cosyntropin stimulation tests, only cortisol level at 30 min during standard dose cosyntropin test provided discrimination similar to insulin tolerance test. The best peak free cortisol cut-off levels were 1 μg/dL for insulin tolerance test, 0.9 μg/dL for low dose cosyntropin test, 0.9 μg/dL for medium dose cosyntropin test, and 0.9 μg/dL and 1.3 μg/dL for 30 min and 60 min standard dose cosyntropin test, respectively., Conclusion: All cosyntropin stimulation tests had excellent correlations with insulin tolerance test, when appropriate cut-offs were used. This pilot study does not suggest an advantage in using 25 μg cosyntropin dose during the cosyntropin stimulation test. A serum free cortisol cut-off of 0.9 μg/dL may be used as pass criterion during low dose cosyntropin test, standard dose cosyntropin test cosyntropin test, and 30 min standard dose cosyntropin test.

Context: Transsphenoidal surgery (TSS) to resect a pituitary adenoma is considered first-line treatment for patients with Cushing's disease (CD). Early, post-operative remission rates >80% are expected for patients with a microadenoma (≤ 10 mm) visible on magnetic resonance (MR) imaging., Objective: To report surgical outcomes and predictors of remission in a specialist center for patients with CD., Patients and Methods: Clinical data was obtained from a prospective CD database in addition to review of all electronic medical, laboratory and surgical patient records. Patients who underwent their first TSS by one neurosurgeon between 2004 and 2013, and had a minimum 1 year follow up, were evaluated., Results: One hundred and one consecutive patients with CD (73F, 28M) underwent TSS. Median (range) age and follow-up were 47 (15-87) and 4.33 (1-9.8) years, respectively. At surgery, 74 (73.2%) patients had a microadenoma, 27 a macroadenoma; six of the latter patients had a planned, subtotal resection to control neurological signs due to mass effect. Initial remission rates were: microadenoma, 89% (66/74); macroadenoma, 63% (17/27); and 81% (17/21) in those macroadenomas where complete surgical removal was anticipated. Initial non-remission occurred in 18 patients, ten macro- and eight microadenoma; six of 18 had residual disease on most recent follow up. Six (2 macro, 4 micro) of the 83 patients with initial remission have had late (>12 months) recurrence of hypercortisolism that required either repeat TSS or adjunctive therapy, three of whom have persistent hypercortisolism. Macroadenoma (p = 0.003) and tumor invasion beyond the pituitary and sella (p < 0.001) were associated with failure to obtain remission with the initial TSS and greater likelihood of late recurrence. Patients in whom no lesion was seen on neuroimaging had rates of initial remission (21/25 or 84%) and a similar late recurrence rate of 4% (1/25) in comparison with those with MR-visible microadenomas (3/49, or 6%)., Conclusions: A team-based approach, in a specialized pituitary center, can lead to initial and durable, long-term remission in patients with CD. The presence of a macroadenoma and tumor extension beyond the pituitary and sella were predictive of initial non-remission as well as risk of late recurrence.

Lymphocytic infundibulo-neurohypophysitis is an uncommon inflammatory disorder postulated to be autoimmune in origin. Because of the location of inflammation, it selectively affects the posterior lobe of the pituitary (neurohypophysis) and pituitary stalk (infundibulum). The most common presentation is central diabetes insipidus. Although the definitive diagnosis is established histologically by a pituitary biopsy, radiological imaging can be valuable in diagnosing this condition. In this paper, we provide an overview of the pathophysiology, investigations, management, and outcomes of lymphocytic infundibulo-neurohypophysitis.

We review the etiology, investigations, management and outcomes of pituitary tumor apoplexy. Pituitary tumor apoplexy is a clinical syndrome which typically includes the acute onset of headache and/or visual disturbance, cranial nerve palsy and partial or complete endocrine dysfunction. It is associated with either infarction or hemorrhage of a pre-existing pituitary adenoma and is associated with significant morbidity and potential fatality. Not all patients will present with classic signs and symptoms, therefore it is pertinent to appreciate the clinical spectrum in which this condition can present., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The use of intra-articular (IA) glucocorticoids for reducing pain and inflammation in patients with osteoarthritis, rheumatoid arthritis, and other inflammatory arthropathies is widespread among primary care physicians, specialists, and non-specialists in the United States. Injectable glucocorticoids have anti-inflammatory and analgesic properties which can be effective in improving clinical parameters such as pain, range of motion, and quality of life. After injection into the IA space, glucocorticoids may be systemically absorbed; the degree of absorption can depend on the size of the joint injected, the injectable glucocorticoid preparation used, the dosage, and the frequency of the injection. The adverse effects of intra-articular glucocorticoid injections (IAGC) can often be overlooked by both the patient and physicians who administer them, in particular the potential deleterious effect on the hypothalamic-pituitary-adrenal (HPA)-axis which can result in adrenal suppression and/or iatrogenic Cushing syndrome. In this paper we provide an overview on the often under-recognized effects of IAGC on HPA-axis function.

Ectopic pituitary adenomas are defined by the presence of adenomatous pituitary tissue outside the sella and distinctly separate from the pituitary gland. Ectopic ACTH-secreting pituitary adenomas (EAPAs) are a rare cause of Cushing's syndrome. Detecting these radiologically can prove difficult, in part, due to their typically small size and unpredictable anatomical location. In ACTH-dependent Cushing's syndrome, if, despite comprehensive testing, the source of excess ACTH remains occult (including negative work up for ectopic ACTH syndrome) thought should be given to the possibility of the patient harboring an EAPA. In most cases, ectopic ACTH pituitary adenomas within the sphenoid sinus will manifest with symptoms of hormonal excess, have an obvious sphenoid sinus mass on pre-operative imaging and will demonstrate resolution of hypercortisolism after surgical excision if located and removed. Twenty cases of EAPAs have been reported in the literature to date. This paper will review the current literature on all previously reported EAPAs within the sphenoid sinus in addition to the current case.

The optimal interval for follow-up imaging of patients with prolactinomas is unclear. We wish to determine the likelihood of tumor enlargement in patients with prolactinomas who have a stable or reduced prolactin (PRL) level over time, whether or not they are treated with a dopamine agonist (DA). We identified 80 patients with prolactinomas (34 men, 46 women) who had at least two paired sets of serum PRL levels and pituitary MRIs, 3 or more months apart. Patients with hyperprolactinemia due to drug or stalk effects were excluded. The median (range) age was 45 (25-77) years. Sixty-three patients (78.8%) were treated with DA. PRL levels (ng/mL) at the initial and latest sets were 114 (0.3-15,732) and 16 (0.3-1,204), respectively. In patients with identifiable tumors, the maximum tumor diameters (mm) at the initial and latest MRI studies were 12.5 (2-60) and 12.5 (2-39) respectively, with an interval of 2.9 (0.3-9.7) years. Sixty percent of patients (n = 48) had a macroadenoma. Forty-two (52.5%) patients had either disappearance of the tumor (n = 22) or reduction (n = 20) in tumor size. In the remainder, tumor size was stable in 35 but increased in 3 patients. One of these patients, observed off therapy had a concomitant rise in PRL level. The other 2 had evidence of pituitary hemorrhage with no PRL increase. Tumor growth in prolactinoma patients with a stable or decreasing PRL level, regardless of size, is a rare event. Repetitive pituitary imaging in these patients may not be warranted.

Patients on continuous subcutaneous insulin infusion, or insulin pumps, are increasingly seen in hospitals. Inpatient providers need to have a working knowledge of insulin pumps to be able to decide, in conjunction with the patient whenever feasible, whether or not pump use is to be continued in the hospital, to assist patients in adjusting insulin doses via continuous subcutaneous insulin infusion, to transition patients to multiple daily subcutaneous insulin dosing as appropriate, and to prevent or manage problems that might arise from improper handling of the insulin pump. Clinical vignettes with key points and strategies for patient care are discussed in this article., (© 2013 Society of Hospital Medicine.)

Literature on hyperprolactinemia in the setting of a nipple piercing is limited to individuals with concomitant breast/chest wall infection. It is unclear if chronic nipple stimulation from a piercing alone can cause sustained elevations of serum prolactin. Nipple piercing is emerging as a more mainstream societal form of body art, and the answer to this clinical question would potentially alter patient management. Our aim was to assess serum prolactin levels in subjects with nipple piercing. Inclusion criteria were as follows: men and women ≥ 18 years old with nipple piercing(s) present > 6 months. Exclusion criteria included: women who are pregnant, lactating or < 6 months postpartum; subjects on medications known to increase prolactin levels; chest wall/breast infection at the time of phlebotomy or conditions known to be associated with hyperprolactinemia. Three men and eight women were enrolled. Median (range) ages for men and women were 33 (24-42) and 27 years (23-42), respectively. All except one subject had bilateral piercings. The median interval from nipple piercing to blood draw was 4.0 (2.0-12.0) years. None of the subjects had hyperprolactinemia. Median (range) prolactin levels for men and women were 5.6 ng/mL (3.8-7.4) and 8.0 ng/mL (2.8-10.9), respectively. Our results suggest that in the absence of any concomitant infection, chronic nipple piercing is not associated with hyperprolactinemia.

Objective: To report the utility of insulin-like growth factor-1 (IGF-1) as a single biomarker for establishing the diagnosis of acromegaly and to examine the clinical and biochemical profile of patients with an elevated IGF-1 in whom a diagnosis of acromegaly could not be confirmed by means of the oral glucose tolerance test (OGTT)., Methods: Between the years 1999 and 2010, we identified 101 patients who underwent pituitary surgery and had histologically proven somatotroph adenomas (Group 1, Gr 1). We selected 149 patients with non-growth hormone (GH) secreting pituitary macroadenomas (Gr 2, n = 97) and microadenomas (Gr 3, n = 52) to serve as control subjects. In addition, we identified 34 patients with elevated IGF-1values in whom acromegaly could not subsequently be proven by the OGTT (Gr 4)., Results: IGF-1 was elevated in all patients with acromegaly prior to therapy with a median (range) standard deviation score (SDS) of +9.52 (+2.34 to +9.2), compared to SDS -1.46 (-2.91 to +2.17) and -1.22 (-2.8 to +1.58) in Gr 2 and 3, respectively (P<0.001). IGF-1 SDS values were +3.28 (+2.05 to +6.1), and IGF-1 was less than twice the upper limit of normal in all patients in Gr 4. OGTT was performed in 51 of the 101 acromegalic patients. The nadir GH in these patients was 4.01 (0.2 to 46.7) in comparison with 0.2 (<0.05 to 0.6) in Gr 4 (P<0.001)., Conclusion: Elevated IGF-1 levels, alone, are sufficient to establish a diagnosis of acromegaly in the majority of clinically suspected cases. The OGTT may be useful to obtain corroborative evidence when there is modest elevation of IGF-1 with absent or equivocal clinical features.

Adrenocortical insufficiency may arise through primary failure of the adrenal glands or due to lack of ACTH stimulation as a result of pituitary or hypothalamic dysfunction. Prolonged administration of exogenous steroids will suppress the hypothalamic-pituitary-adrenal axis, and hence cortisol secretion. We review briefly the causes, investigation, and treatment of adrenal insufficiency, and highlight aspects of particular relevance to patients with adrenal tumors., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: Inferior petrosal sinus sampling (IPSS) distinguishes pituitary-dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization., Methods: Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology., Results: Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of ≥1·4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (≥1·4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0·041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio ≥1·8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland., Conclusion: Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD., (© 2012 Blackwell Publishing Ltd.)

To review the literature regarding the diagnosis and management of acromegaly during pregnancy. A systematic literature search was performed using MEDLINE including hand-searching reference lists from original articles. The diagnosis of acromegaly during pregnancy is made difficult due to the physiologic changes in pituitary GH secretion and IGF-1 production resulting from placental GH secretion and the inability of commercial assays to discriminate between pituitary and placental GH. Most patients with acromegaly during pregnancy do not have an increase in tumor size, metabolic complications are uncommon, and neonatal outcome is largely unaffected. IGF-1 levels tend to be stable in such patients possibly due to the high estrogen levels causing GH resistance. Dopamine agonists, somatostatin analogues, and a GH receptor antagonist have been reported to be safe during pregnancy. Patients with visual field defects should be considered for surgery, but in most cases this can be safely postponed until after delivery. Overall, pregnancy in acromegaly is uneventful and newborns unaffected. Dopamine agonists and somatostatin analogues have not been associated with major adverse effects to the fetus; however, more data are needed to validate their safety.

The increasing use of radiation treatment for head and neck cancers and other tumors, including pituitary adenomas, from the mid-20th Century onwards led to the recognition that pituitary function may be affected - often leading to some degree of pituitary insufficiency. Our knowledge is mostly based on observational or retrospective rather than randomized prospective studies. The various axes may be impacted at the hypothalamic or pituitary levels, or both. Some axes - the somatotropic and gonadotropic - appear to be especially vulnerable to radiation damage and may be affected quite early, whereas posterior pituitary function is rarely affected. Increased use of stereotactic radiosurgery, which focuses the radiation dose on the abnormal tissue, may be expected to reduce the impact on normal pituitary function, but such studies that are available are, as yet, relatively short term. Prospective studies of the effect of stereotactic radiosurgery on pituitary function would be valuable.

We describe four acromegalic patients with persisting typical symptoms - excessive sweating, lack of suppleness of hands, joint pains - despite the achievement of normal serum IGF-1 levels after pituitary surgery. In three patients there was a clear improvement in symptoms when lower IGF-1 levels within the normal range were achieved with pegvisomant treatment. In the fourth patient IGF-1 levels have fluctuated within the normal range with persistence of abnormal sweating, particularly at night. Two of three patients who had an oral glucose tolerance test when serum IGF-1 was in the normal range failed to suppress GH levels to less than 1 ng/ml. We conclude that, in the treated acromegalic patient, IGF-1 levels within the normal range need to be looked at critically to determine what is truly normal for that individual. Relief of symptoms seems a reasonable yardstick, in addition to population norms, by which to judge whether the prevailing IGF-1 level is appropriate; in some cases the aim should be an IGF-1 level in the lower half of the normal range, or perhaps even the lowest quartile.