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Freda, P. U., S. L. Wardlaw, J. N. Bruce, K. D. Post and R. S. Goland (1995). “Differential diagnosis in cushing syndrome. Use of corticotropin-releasing hormone.” Medicine (Baltimore) 74(2): 74-82.

Testing with ovine corticotropin-releasing hormone (CRH) has facilitated the differential diagnosis of Cushing syndrome, which is often not straightforward. We provide our experience between January 1989 and August 1993 with 30 patients with Cushing syndrome and describe 4 cases in detail to illustrate how CRH testing can be successfully applied to some of the difficulties encountered in the evaluation. CRH testing proved to be particularly useful in distinguishing cases of Cushing syndrome of adrenal etiology from those of Cushing disease with low or undetectable adrenocorticotropin (ACTH) levels. CRH testing during petrosal sinus sampling was also found to help distinguish the ectopic ACTH syndrome from pituitary-dependent Cushing syndrome. Our cases illustrate the need for careful biochemical evaluation before proceeding to imaging studies. Using CRH testing to evaluate cases of Cushing syndrome in which standard testing was inconclusive can provide useful information and lead to a more rapid determination of etiology and definitive therapy than previously possible.

Freda, P. U., C. I. Andreadis, A. G. Khandji, M. Khoury, J. N. Bruce, T. P. Jacobs and S. L. Wardlaw (2000). “Long-term treatment of prolactin-secreting macroadenomas with pergolide.” J Clin Endocrinol Metab 85(1): 8-13. Freda, P. U., C. M. Reyes, A. T. Nuruzzaman, R. E. Sundeen and J. N. Bruce (2003). “Basal and glucose-suppressed GH levels less than 1 microg/L in newly diagnosed acromegaly.” Pituitary 6(4): 175-180.

The development of highly sensitive and specific GH assays has necessitated a critical re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. Use of these assays has revealed that GH levels after oral glucose in healthy subjects and postoperative patients with active acromegaly can be significantly less than previously recognized with older GH assays. In order to assess GH criteria for newly diagnosed acromegaly with a modern assay we have evaluated GH levels in 25 patients referred to our Neuroendocrine Unit for evaluation of untreated acromegaly. All patients underwent measurement of basal GH and IGF-I levels and 15 of these patients also underwent oral glucose tolerance testing for GH suppression (OGTT). Basal GH levels were < 1.0 microg/L at diagnosis in 5 of these 25 patients. Nadir GH levels were less than 1 microg/L also in 5 of 15 patients, and as low as 0.42 microg/L. All patients had elevated IGF-I levels preoperatively and pathological confirmation of a GH secreting pituitary tumor at the time of transsphenoidal surgery. The clinical presentations of these patients was variable. Most patients presented with classical manifestations of acromegaly, but 3 of the 5 patients with low nadir GH values had only very subtle signs of acromegaly. Although most newly diagnosed patients have classically elevated GH levels and obvious clinical features of acromegaly, early recognition of disease may uncover patients with milder biochemical and clinical abnormalities. The diagnosis should not be discounted in patients who have elevated IGF-I levels, but have basal or nadir GH levels less than 1 microg/L. Conventional GH criteria for the diagnosis of acromegaly cannot be applied to the use of modern sensitive and specific GH assays.

Freda, P. U., W. K. Chung, N. Matsuoka, J. E. Walsh, M. N. Kanibir, G. Kleinman, Y. Wang, J. N. Bruce and K. D. Post (2007). “Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission.” Pituitary.

Although the molecular mechanisms underlying GH secreting pituitary tumor formation are not well understood, mutations in the alpha-subunit of the stimulatory G gene, GNAS, have been identified in up to 40%. As these mutations could play a role in tumor growth, we screened 60 GH secreting tumors for GNAS mutations and assessed whether mutation status correlated with their clinical and pathological characteristics. Tumor specimens obtained at surgery were snap frozen. Tumor DNA was extracted, and PCR was used to amplify regions containing 2 sites of recurrent activating somatic mutations in codons 201 and 227 in GNAS. Amplicons were bi-directionally sequenced and analyzed. GNAS mutations were present in 24/60 (40%) of tumors; these were arg201cys(n = 15), arg201ser(n = 2), arg201his(n = 2), gln227leu(n = 4), gln227arg(n = 1). Preoperative IGF-I levels (age-adjusted) were higher (p = 0.01), but GH levels were slightly higher (p = 0.18) in mutation positive vs. negative groups. Mutation positive tumors were somewhat smaller than negative tumors (p = 0.07). The proportion of tumors >2 cm was somewhat less among positive (8.3%) vs. negative tumors (25%) (p = 0.10). Neither mib proliferation index, the proportion of invasive tumors nor surgical remission rates differed in the groups. IGF-I normalization rate with somatostatin analog therapy was similar in positive (3 of 6) vs. negative (3 of 7) patients. GH secreting tumors harboring GNAS mutations had higher preoperative IGF-I levels, somewhat higher preoperative GH levels and tended to be smaller than tumors without mutations. Presence of a GNAS mutation did not predict a difference in a proliferation marker, surgical remission or response to somatostatin analog therapy.

Ausiello, J. C., J. N. Bruce and P. U. Freda (2008). “Postoperative assessment of the patient after transsphenoidal pituitary surgery.” Pituitary 11(4): 391-401.

While most transsphenoidal pituitary surgery is accomplished without complication, monitoring is required postoperatively for a set of disorders that are specific to this surgery. Postoperative assessments are tailored to the early and later postoperative periods. In the early period, which spans the first few weeks after surgery, both monitoring of anterior and posterior pituitary function and managing neurosurgical issues are the focus of care. Potential disruption of pituitary-adrenal function is covered with perioperative glucocorticoids. Various strategies exist for ensuring the integrity of this axis, but typically this is done by measuring a morning cortisol on the 2nd or 3rd postoperative days. Patients with levels <10 mug/l should continue therapy with reassessment in the later postoperative period. Monitoring for water imbalances, which are due to deficiency or excess of ADH (DI or SIADH, respectively), is accomplished by continuous accounting of fluid intake, urine output and specific gravities coupled with daily serum electrolyte measurements. DI is characterized by excess volumes of inappropriately dilute urine, which can lead to hypernatremia. Most patients maintain adequate fluid intake and euvolemia, but desmopressin therapy is required for some. SIADH, which peaks in incidence on 7th postoperative day, presents with hyponatremia that can be severe and symptomatic. Management consists of fluid restriction. Neurosurgical monitoring is primarily for disturbances in vision or neurological function, and although uncommon, for CSF leak and infections such as meningitis. In the later postoperative period, the adrenal, thyroid and gonadal axes are assessed. New persistent hypopituitarism is rare when transsphenoidal surgery is performed by an experienced surgeon. Various strategies are available for assessing each axis and for providing replacement therapy in patients with deficiencies. Long term monitoring with assessments of visual, neurological and pituitary function coupled with pituitary imaging is necessary for all patients who have undergone surgery, irrespective of the hormone status of their tumors.

D’Ambrosio, A. L., O. N. Syed, B. T. Grobelny, P. U. Freda, S. Wardlaw and J. N. Bruce (2009). “Simultaneous above and below approach to giant pituitary adenomas: surgical strategies and long-term follow-up.” Pituitary 12(3): 217-225.

INTRODUCTION: Giant pituitary adenomas of excessive size, fibrous consistency or unfavorable geometric configuration may be unresectable through conventional operative approaches. We present our select case series for operative resection and long-term follow-up for these unusual tumors, employing both a staged procedure and a combined transsphenoidal-transcranial above and below approach. METHOD: A retrospective chart review was performed on patients operated via the staged, and combined approaches by the senior author (J.N.B.). Preoperative characteristics and postoperative outcomes were reviewed. A detailed description of the operative technique and perioperative management is provided. RESULTS: Between 1993 and 1996, two patients harboring giant pituitary adenomas underwent an intentionally staged resection, and between 1997 and 2006, nine patients harboring giant pituitary adenomas underwent surgery via a single-stage above and below approach. Nine patients (82%) presented with non-secreting adenomas and two patients (18%) presented with prolactinomas refractory to medical management. Gross total resection was achieved in six patients (55%), near total resection in 1 (9%), and subtotal removal in 4 (36%). Seven patients (64%) experienced visual improvement postoperatively and no major complications occurred. Long-term follow-up averaged 51.6 months. Panhypopituitarism was observed in four patients, partial hypopituitarism in four, persistent DI in two, and persistent SIADH in one. CONCLUSIONS: The addition of a transcranial component to the transsphenoidal approach offers additional visualization of critical neurovascular structures during giant pituitary adenoma resection. Complications rates are similar to other series in which complex pituitary adenomas are resected by other means. The above and below approach is both safe and effective and the immediate and long-term advantages of a single-stage approach justify its utility in this select group of patients.

Reid, T. J., K. D. Post, J. N. Bruce, M. Nabi Kanibir, C. M. Reyes-Vidal and P. U. Freda (2010). “Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed.” Clin Endocrinol (Oxf) 72(2): 203-208.

BACKGROUND: Traditionally, acromegaly evaded diagnosis until in its clinically obvious later stages when treatment is more difficult. Over the last 25 years diagnostic tests have improved, but whether clinical disease detection also improved was unknown, so we tested if disease severity at diagnosis had changed from 1981 to 2006. METHODS: Data on 324 consecutive acromegaly patients presenting from 1981 to 2006 at two New York City hospitals were collected by retrospective review (n = 324) and by interview (n = 200). The main complaint, acromegaly associated comorbidities, signs, symptoms, healthcare providers visited, preoperative GH and IGF-I levels and pituitary tumour size at diagnosis were compared in patients presenting in the earlier vs. later halves of the time period. RESULTS: Times from symptom onset to diagnosis were 5.9 year (early) vs. 5.2 year (late; P = NS). At diagnosis, 96% of early and late groups had facial feature changes and/or hand/foot enlargement. Comorbidities included hypertension 37% (early) vs. 36% (late), carpal tunnel syndrome (24%vs. 24%), sleep apnoea (13%vs. 29%; P < 0.01), osteoarthritis (25%vs. 23%) and diabetes mellitus (18%vs. 15%); each patient had 1.2 (early) vs. 1.3 (late; P = 0.53) comorbidities. Groups were similar in signs, symptoms, tumour size, GH and IGF-I. CONCLUSIONS: Clinical, biochemical and tumour size characteristics at diagnosis of acromegaly patients were unchanged from 1981 to 2006. Most patients still have marked manifestations of acromegaly at diagnosis, suggesting that acromegaly remains clinically under-recognized. Healthcare professionals should more commonly consider acromegaly, which can lead to earlier diagnosis and better treatment outcome.

Freda, P. U. and J. N. Bruce (2010). “Surgery: Risks of pituitary surgery in the elderly.” Nat Rev Endocrinol 6(11): 606-608.


Freda P, Bruce J: Tumors of the pituitary gland. In: Rowland LP, Pedley TA (eds) Merritt’s Neurology. Lippincott Williams and Wilkins, Philadelphia, pp 419-425

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