Adrenal cysts less than 10 cm can be safely observed.

BACKGROUND: Adrenal cysts are rare and appropriate management is unclear due to a lack of data on their natural history. Understanding adrenal cyst growth patterns would assist in clinical management. METHODS: This single-institution study included all adult patients diagnosed with simple adrenal cysts between 2004 and 2021. Baseline characteristics and outcomes of those who underwent resection (ADX) or observation (OBS) were compared using the chi-squared test, student's t-test, and Wilcoxon rank-sum test. Growth curves and sensitivity analysis were plotted for all patients who had follow-up imaging. RESULTS: We identified 77 patients with imaging-confirmed adrenal cysts. The majority were female (75.3%) and more than half were white (55.8%). One-third of patients underwent ADX, and the remaining were observed. ADX patients were younger (median age [IQR]: 55.5 y [45.0-68.2 y] vs. 44.2 y [38.7-55.0 y], p = 0.01) and more likely to be Hispanic (12% vs. 0%, p = 0.05). ADX patients presented with larger cysts (5.6 vs. 2.6 cm, p = 0.002). The median time from diagnosis to last follow-up was 1.1 y for ADX and 4.1 y for OBS. Average growth for OBS was 0.3 cm/y, while average growth for ADX was 3.9 cm/y. In ADX patients, cysts >10 cm grew significantly faster than cysts <10 cm (median growth rate 13.2 cm/y vs. 0.3 cm/y, p < 0.05). There was no adrenal malignancy diagnosis, hyperfunctionality, or observation-related complications (e.g., rupture). CONCLUSION: While size >4-6 cm has guided surgical referral for solid adrenal masses, this study demonstrates a size threshold of 10 cm, below which asymptomatic, simple adrenal cysts can safely be observed.

The 5-factor modified frailty index predicts health burden following surgery for pituitary adenomas.

PURPOSE: Frailty is known to influence cost-related surgical outcomes in neurosurgery, but quantifying frailty is often challenging. Therefore, we investigated the predictive value of the 5-factor modified frailty index (mFI-5) on total hospital charges, LOS, and 90-day readmission for patients undergoing pituitary surgery. METHODS: The medical records of all patients undergoing endoscopic endonasal resection of pituitary adenomas at an academic medical center between January 2017 and December 2018 were retrospectively reviewed. Bivariate statistical analyses were conducted using Fisher's exact test, chi-square test, and independent samples t-test. Linear and logistic regression models were used for multivariate analysis. RESULTS: Our cohort (n = 234) had a mean age of 53.8 years (standard deviation 14.6 years). Sex distributions were equal, and most patients were Caucasian (59%). On multivariate linear regression, with each one-point increase in mFI-5, total LOS increased by 0.64 days in the overall cohort (p < 0.001), 1.08 days in the Cushing disease cohort (p = 0.045), and 0.59 days in non-functioning tumors cohort (p = 0.004). Total charges increased by $3954 in the whole cohort (p < 0.001), $10,652 in the Cushing disease cohort (p = 0.033), and $2902 in the non-functioning tumors cohort (p = 0.007) with each one-point increase in mFI-5. Greater mFI-5 scores were associated with greater odds of 90-day readmission in both overall and Cushing disease cohorts, but these associations did not reach statistical significance. CONCLUSION: A patient's mFI-5 score is significantly associated with increased length of stay and hospital charges for patients undergoing pituitary surgery. The mFI-5 may hold peri-operative value in patient counseling for pituitary adenoma surgery.

THE EFFECT OF RALOXIFENE ON SERUM PROLACTIN LEVEL IN PATIENTS WITH PROLACTINOMA.

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.

TSH-STAINING PITUITARY ADENOMAS: RARE, SILENT, AND PLURIHOROMONAL.

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.

Surgical outcomes in patients with Cushing's disease: the Cleveland clinic experience.

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.

EVALUATION AND MANAGEMENT OF ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTS: DISEASE STATE REVIEW.

OBJECTIVE: The definition of normal adrenal function in critically ill patients remains controversial, despite a large body of literature. We review the clinical presentation, diagnosis, and treatment of adrenal insufficiency in critically ill patients and discuss the authors' personal approach to patient management. METHODS: Extensive literature review, guidelines from professional societies, and personal experience. RESULTS: A decrease in cortisol breakdown rather than an increase in cortisol production has been suggested as the main contributor to elevated cortisol levels in critically ill patients. The concept of relative adrenal insufficiency has multiple pathophysiologic flaws and is not supported by current evidence. Patients with septic shock who are pressor dependent or refractory to fluid resuscitation may receive a short course of hydrocortisone regardless of their serum cortisol levels or their response to a cosyntropin stimulation test (CST). Patients without septic shock who are suspected to have adrenal insufficiency should have their random cortisol levels measured. In patients with low and near-normal cortisol-binding proteins, a serum cortisol of <10 or 15 µg/dL, respectively, may trigger need for glucocorticoid treatment. Assays of free cortisol levels offer an advantage over total cortisol levels in patients with low binding proteins. Most critically ill patients have a normal random free cortisol level of >1.8 µg/dL, although further studies are needed to define a normal range in critically ill patients based on both severity and duration of illness. A CST may be used to further evaluate adrenal function in patients without septic shock who have borderline random serum or free cortisol levels. CONCLUSION: Evaluation of adrenal function in critically ill patients is complex. Recent findings of decreased cortisol breakdown in critically ill patients as the main contributor to elevated cortisol levels calls for better-designed studies to explore the optimal evaluation and treatment of adrenal insufficiency in critically ill patients. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CBG = corticosteroid-binding globulin; CORTICUS = Corticosteroid Therapy of Septic Shock; CRH = corticotropin-releasing hormone; CST = cosyntropin stimulation test; GC = glucocorticoid; GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; IL = interleukin; RAI = relative adrenal insufficiency.

Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.

CONTEXT: Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic-pituitary-adrenal (HPA) axes using weight-based dosing for the GST. OBJECTIVE: To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5 mg in patients >90 kg) with weight-based dosing (WB: 0.03 mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3 ng/ml and ≥18 µg/dL, respectively. DESIGN: 28 Patients with hypothalamic-pituitary disease and 1-2 (n = 14) or ≥3 (n = 14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order. RESULTS: Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92 % sensitivity, 100 % specificity) and 2.0 ng/mL (96 % sensitivity and 100 % specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r = -0.32, P = 0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8 µg/dL (92 % sensitivity, 100 % specificity) and 11.2 µg/dL (92 % sensitivity and 100 % specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST. CONCLUSION: The GST correctly classified GHD using GH cut-points of 1 ng/ml for FD-GST and 2 ng/ml for WB-GST, hence using 3 ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9 µg/dL for FD-GST and 11 µg/dL for WB-GST.

Osilodrostat, a potent oral 11ß-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease.

PURPOSE: In a 10-week proof-of-concept study (LINC 1), the potent oral 11ß-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease. METHODS: Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50% decrease from baseline) at weeks 10 and 22. RESULTS: Overall response rate was 89.5% (n/N = 17/19) at 10 weeks and 78.9% (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels. CONCLUSIONS: Osilodrostat treatment reduced UFC in all patients; 78.9% (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: DIAGNOSIS OF RECURRENCE IN CUSHING DISEASE.

Recurrence of hypercortisolemia after initial treatment of Cushing disease (CD) is more common than previously thought, with a third of patients suffering a recurrence over their lifetime. Awareness of this high rate and delayed timeline (sometimes decades) of potential recurrence is critical and patients with CD should be monitored at regular intervals throughout their lives. In this manuscript, we review the complex evaluation needed for defining CD remission versus persistent disease after surgery, and focus on challenges in diagnosing early recurrent hypercortisolemia. Late night salivary cortisol appears to be an earlier predictor of recurrence when compared with urinary free cortisol (UFC) excretion. We also review the criteria suggested to define recurrence of hypercortisolemia in patients treated with medical therapy. Further research is needed to determine the optimal way to evaluate a patient with CD recurrence as well as the riskbenefit ratio of treatment in early, mild recurrent disease. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CD = Cushing disease CDDT = coupled dexamethasone desmopressin test CR = circadian rhythm CRH = corticotropin-releasing hormone GC = glucocorticoid GCR = global clinical response HPA = hypothalamic-pituitary-adrenal LDDST = low-dose dexamethasone suppression test LNSC = late-night salivary cortisol ODST = overnight dexamethasone suppression test TSS = trans-sphenoidal surgery.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: CLINICAL RELEVANCE OF MACROPROLACTIN IN THE ABSENCE OR PRESENCE OF TRUE HYPERPROLACTINEMIA.

OBJECTIVE: To review the current literature regarding the prevalence of macroprolactin (macroPRL) in hyperprolactinemic patients and determine recommendations for testing. METHODS: An electronic United States National Library of Medicine PubMed search (through October, 2014) was conducted for search term "macroprolactin." Only English-language articles were considered. RESULTS: MacroPRL is an under-recognized cause of elevated prolactin (PRL) and is present in approximately 4% to 40% of hyperprolactinemic patients depending on the referral population. Clinical findings which could be due to hyperprolactinemia are the impetus for testing for PRL. Because of this there is significant overlap in the clinical presentation of patients with true hyperprolactinemia and those with macroPRL, differentiation cannot always be made on the basis of symptoms. A lack of recognition of the presence of macroPRL can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment. CONCLUSION: Until there is a commercially available PRL assay that is not subject to interference by macroPRL, clinicians should consider the possibility of macroPRL, especially if the clinical presentation, imaging findings, and/or response to therapy reveal inconsistencies.

Genetics of primary aldosteronism.

OBJECTIVE: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases. METHODS: Case presentation, discussion of literature, table, and bullet point conclusions. RESULTS: Primary aldosteronism (PA) is the most common form of secondary hypertension. Early detection, surveillance, and treatment of PA may mitigate future cardiovascular risk. The genetics of PA are rapidly evolving, and the consideration for genetic causes of PA are growing. Three inheritable forms of PA are now recognized: familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism), familial hyperaldosteronism type II, and familial hyperaldosteronism type III. The recent discovery of familial hyperaldosteornism type III spurred a flurry of international and collaborative research that is identifying more genetic and molecular causes of PA that relate to mutations in membrane electrolyte transport channels of zona glomerulosa cells. CONCLUSION: This article reviews the various genetic forms of PA, including a focus on the molecular mechanisms involved, diagnosis, and treatment.

PITUITARY MRI FINDINGS IN PATIENTS WITH PITUITARY AND ECTOPIC ACTH-DEPENDENT CUSHING SYNDROME: DOES A 6-MM PITUITARY TUMOR SIZE CUT-OFF VALUE EXCLUDE ECTOPIC ACTH SYNDROME?

OBJECTIVE: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS). METHODS: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS. RESULTS: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3-14) and 8 mm (2-31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN) Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.

Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study.

BACKGROUND: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. AIM: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. METHODOLOGY: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. RESULTS: The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). CONCLUSIONS: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Absence of immunostaining for growth hormone in a subset of patients with acromegaly.

The presence of growth hormone (GH) immunostaining in patients who lack the biochemical and clinical features of acromegaly has been described. In contrast, there is little information on the absence of GH immunostaining in patients with acromegaly. We describe five patients with acromegaly with no intratumoral immunostaining for GH. We reviewed all patients undergoing surgery for acromegaly. Out of 136 patients treated surgically in a 10 year period, five (3.7%) were found to have no GH immunostaining on repetitive testing at pathological examination. Their pathology slides were re-examined by an experienced neuropathologist, along with twenty nonfunctional pituitary tumors and ten GH-positive adenomas as negative and positive controls, respectively. All patients had clinical features consistent with acromegaly and elevated baseline insulin-like growth factor-1 (IGF-1) and GH. All patients had no immunostaining for GH on multiple inspections. Of twenty patients with nonfunctional tumors, two had ≤25% staining for GH in a scattered and non-coherent pattern and the rest were negative. In all ten positive control patients >25% of the tumor cells stained diffusely for GH. All five patients achieved biochemical remission at 1.4-8 years post-op using a combination of primary surgery alone (n = 1), repeat surgery (n = 1), radiotherapy (n = 3) and/or medical therapy (n = 2). GH immunostaining of an adenoma may not be sufficient to confirm the diagnosis of acromegaly. All patients in our small series achieved remission by multimodality therapies. Further studies are needed to evaluate the significance of our observation and whether this subset of patients follows a distinct long term clinical course.

Is a stable or decreasing prolactin level in a patient with prolactinoma a surrogate marker for lack of tumor growth?

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.

AACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease.

OBJECTIVE: To review available medical therapies for patients with Cushing disease and to provide a roadmap for their use in clinical practice. METHODS: PubMed searches were performed to identify all of the available published data on medical management of Cushing disease. RESULTS: Medical therapy is usually not the first-line treatment for patients with Cushing disease but may be used to improve clinical manifestations of Cushing disease in patients who are not suitable candidates for surgery, following unsuccessful surgery or recurrence, or as a "bridge therapy" in those who have undergone radiotherapy. Medical therapy may also be used in preoperative preparation of patients with severe disease. Current available medical options for patients with Cushing disease include centrally acting agents, steroidogenesis inhibitors, and a glucocorticoid receptor antagonists. At present, there are no head-to-head studies comparing the efficacy, tolerability, and safety of different U.S. Food and Drug Administration (FDA)- and non-FDA-approved drugs in patients with Cushing disease. With the initiation of new studies and the completion of ongoing clinical trials, the number of FDA-approved drugs for medical treatment of Cushing disease is expected to increase. CONCLUSION: Medical therapy has an important adjunctive role in the management of patients with Cushing disease. The decision to initiate medical treatment depends on many factors, including patient characteristics and preference. Long-term studies are needed to better define the clinical efficacy, safety, and tolerability of medical treatment of Cushing disease, including the role of combination therapies.

Significant hypercortisolism during fractionated radiotherapy in a patient with a large corticotroph adenoma: a case report and literature review.

OBJECTIVE: We describe a patient with a large, invasive corticotroph adenoma who developed severe hypercortisolism shortly after starting fractionated radiotherapy. METHODS: We reviewed the patient's clinical course, along with relevant literature for similar reported cases. RESULTS: A 29-year-old man was referred for radiotherapy for a residual and recurrent, invasive corticotroph adenoma. Prior to radiotherapy, he had a normal urine free cortisol (UFC) level of 44.7 µg/24 hours, with minimal symptoms. Within 2 weeks of radiotherapy, he developed hypertension, ankle edema, and hypokalemia (potassium level, 2.8 mEq/L), with a markedly elevated UFC level of 9,203 µg/24 hours. His UFC gradually decreased and normalized by the end of radiotherapy. One month later, the patient became adrenal insufficient, with a nondetectable 24-hour UFC. His adrenal function slowly recovered in 3 months. We are aware of only one previous case report of clinically significant hypercortisolism following radiotherapy in Cushing disease. CONCLUSION: Radiotherapy may result in acute severe hypercortisolism in patients with a large corticotroph adenoma. This uncommon, but clinically significant, acute adverse effect of radiotherapy suggests that clinical observation and biochemical monitoring during or soon after radiotherapy may be indicated.

The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study.

BACKGROUND: Current evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown. METHODS: This multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997-2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma. RESULTS: Of the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting. Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively. Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P = .06. On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% ≥40, stage III and cortisol secretion were associated with worse disease-free survival. CONCLUSION: Mixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.

Predictors of the effects of 4 years of growth hormone replacement on bone mineral density in patients with adult-onset growth hormone deficiency - a KIMS database analysis.

OBJECTIVE: Growth hormone (GH) replacement may increase bone mineral density (BMD) in GH-deficient (GHD) adults. The goal of this study was to identify predictors of BMD response to GH replacement in GH naïve adults. DESIGN AND MEASUREMENTS: This was a retrospective analysis of data extracted from KIMS (Pfizer International Metabolic Database), an international pharmacoepidemiological survey of adult GHD patients from 31 countries. PATIENTS: A total of 231 GH naive adults were identified (115 women and 116 men) who had BMD measured on the same densitometer in the lumbar spine (LS) and/or femoral neck (FN) both at baseline and after 4 years of GH replacement. RESULTS: After 4 years, there was a median (10th, 90th percentile) 4·6% (-5·2%, 12·2%) increase in LS BMD over baseline (P = 0·0001). There was a positive correlation between per cent change in LS BMD and age at the onset of pituitary disease (r = 0·25, P = 0·001). There was no change in FN BMD over baseline [0·0% (-7·3%, 8·5%)]. On multivariate analysis, older age at the onset of pituitary disease predicted a greater increase in LS BMD on GH replacement (r = 0·55, P < 0·0001). CONCLUSIONS: In a population of GH naïve adults, GH replacement led to a significant increase in LS BMD over baseline, but no change in FN BMD. The potential for greater BMD improvement on GH replacement therapy in adults with disease of later onset should be considered when making treatment decisions in this patient population.

Is chronic nipple piercing associated with hyperprolactinemia?

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.