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Non-functioning pituitary adenomas (NFPAs) comprise silent tumors of different pituitary lineages that tend to escape early detection and present as invasive macroadenomas with symptoms of mass effect. Incomplete surgical resection is common and may be followed by significant rates of subsequent remnant progression. Pituitary tumors are defined as refractory when resistance to optimal standard therapies including surgery, radiotherapy, and medical treatment is documented. In the absence of approved medications for the treatment of NFPAs, the last criterion to classify these tumors as refractory is ill defined. Silent corticotroph and null cell adenomas have been reported, albeit not in all studies, to be larger and recur more often compared with silent gonadotroph tumors. Nevertheless, it is currently unknown if certain NFPA subtypes are more often refractory using well defined criteria. The response rate to temozolomide is lower in NFPA compared to that seen in functioning tumors. Refractory NFPAs present a significant diagnostic and therapeutic challenge and are associated with increased morbidity and mortality rates., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gonadotroph cell adenoma is the most common clinically nonfunctioning pituitary adenoma; and is pathologically defined by immunopositivity for SF-1, GATA2 and ER-α. Most tumors also stain for follicle stimulating hormone and luteinizing hormone β-subunits, but are usually hormonally silent and discovered incidentally or due to local mass effects. Complete transsphenoidal resection should be attempted when surgery is indicated. Post-surgical treatment can include radiation of the tumor remnant and medical treatment. Among medical treatments, dopamine agonists show the best evidence for preventing the need for recurrent surgery or radiation, and should be considered in patients with relatively bulky remnants or who have high risk features associated with tumor progression. Temozolomide is indicated for aggressive adenomas and carcinomas. Less well-established treatments include somatostatin receptor ligands, peptide receptor radionucleotide therapy and immunomodulatory agents., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment., Methods: This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records., Results: Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%., Conclusions: Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-functioning pituitary adenomas (NFPA) usually present with symptoms of mass effect. Thus, the first-line treatment generally consists of transsphenoidal surgery. Since these tumors are usually large and invasive, post-surgical tumor remnants are common. Active surveillance is the follow-up strategy adopted by most pituitary centers, although the prevalence of residual tumor growth may reach 50% in 5-10 years, often leading to repeat surgery, radiation therapy, or both. NFPA remain the only pituitary tumor type for which no medical therapy has been approved. In this debate, we consider the evidence in favor and against using cabergoline to treat progressing NFPA.

Thyrotropin (TSH)-secreting pituitary tumors are the rarest functioning pituitary tumors. Nonetheless, they are not infrequently plurihormonal, as they may express/secrete hormones made by other pituitary cells derived from the Pit-1 lineage such as growth hormone (GH), prolactin (PRL), and α-subunit (αSU). However, adrenocorticotropin (ACTH) or gonadotropin secretion by such a tumor is exceptional. Although double pituitary tumors are rare, they often combine ACTH and GH secretion. A 41-year-old presented almost 2 years after delivering her 10th child; she had thyrotoxicosis (goiter and palpitations) masquerading as autoimmune postpartum thyroiditis. She was still breastfeeding and amenorrheic. She proved to have TSH, GH, PRL, and ACTH hypersecretion. Imaging revealed an invasive pituitary macrotumor. She had stigmata neither of Cushing's disease nor of acromegaly. Prior to surgery, hormonal control was achieved for close to 1 year by combined octreotide and cabergoline treatment with significant shrinking of the tumor. Following surgery, pathology revealed a collision tumor; the dominant lesion was positive for GH, βTSH, βFSH, and αSU and expressed both Pit-1 and SF-1.The smaller lesion was a corticotroph tumor. We report an unusual plurihormonal tumor co-expressing Pit-1 and SF-1 along with hormones made by cells of both lineages. Its simultaneous occurrence adjacent to a corticotroph tumor raises questions regarding the pathogenesis of these tumors. We propose the possibility of a stem cell tumor with multiple lineage differentiation. We hypothesize that pregnancy might have played a permissive role in tumorigenesis.

In contrast to the clear indication for surgical treatment in symptomatic patients with clinically nonfunctioning pituitary adenomas (NFPA), there are no randomized controlled studies comparing therapeutic strategies such as watchful waiting, irradiation or medical therapy for the management of NFPA after surgery. Further, no medical therapy is currently approved for the treatment of NFPA. In this review, we summarize accumulating data on medications currently approved for secreting pituitary adenomas, used off-label in patients with NFPA. Perspectives on overall treatment optimization and potential future therapies are also detailed., (© 2017 European Society of Endocrinology.)

Purpose: Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing's disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center., Methods: Retrospective review of data extracted from clinical files., Results: Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment., Conclusions: We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.

Objective: Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants., Design: The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up., Methods: Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment., Results: Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001.Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P<0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P=0.002). Outcome measures were not related to NFPA D2R abundance., Conclusions: Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection., (© 2016 European Society of Endocrinology.)

Transsphenoidal surgery is the treatment of choice for large non-functioning pituitary adenomas (NFPA) and symptomatic patients. The therapeutic strategies for the management of NFPA after surgery, i.e., watchful waiting, irradiation, or medical therapy have not been compared by randomized controlled trials. Slow re-growth is common, but the natural history of untreated tumors is variable. Conservative follow-up is associated with progression rates of over 40 %. Radiation is highly effective in preventing residual tumor growth, but has serious long-term side effects. Finally, no medications are currently approved for the treatment of NFPA. In this review, we present our view of the optimal management of these tumors, which includes risk stratification for the identification of high-risk patients suitable for active intervention, leaving low-risk patients for careful monitoring.

Objective: KISS1 is a metastasis suppressor gene involved in cancer biology. Given the high expression levels of KISS1 and KISS1R in the hypothalamus and the pituitary respectively, we hypothesized that this system could possibly affect tumor invasiveness and clinical behavior of pituitary tumors., Methods: Expression levels of KISS1 and KISS1R mRNA were evaluated by RT-PCR. Clinical information pertaining tumor characteristics was extracted from patients' charts., Results: Tumors from 39 patients (21 females, mean age 47.5 years) were examined. KISS1R was expressed in 26 (67%) of samples (94% of NFPA, 42% of GH-, 67% of ACTH-, and 25% of PRL-secreting adenomas) and was found more often in female patients (81 vs. 50% males, p < 0.05); and in NFPA (94 vs. 45.5% in secreting tumors; p = 0.003). Patients expressing KISS1R were older at presentation (50.5 ± 1.4 vs. 38.1 ± 1.3 years; p = 0.008). In the multivariate analysis, factors significantly associated with KISS1R expression included female gender (OR 13.8, 95 % CI 1.22-155.9; p = 0.03) and having a NFPA (OR 24.7, 95% CI 1.50-406.4; p = 0.02). Tumor size, invasiveness and age at presentation were not independently associated with KISS1R expression. Pituitary tumors and normal pituitary were negative for KISS1 mRNA expression., Conclusions: The majority of human NFPA expressed KISS1R with lower rates of expression in other types of pituitary tumors. KISS1R expression did not impart a clinical beneficial tumor phenotype, as it was not associated with tumor size or invasiveness. Additional studies are required to elucidate the role of KISS1 receptor in pituitary gland physiology and pathology.

Objectives: Patients with acromegaly usually harbor macroadenomas measuring between 10 and 30 mm in maximal diameter. Giant (adenoma size ≥40 mm) GH-secreting pituitary tumors are rarely encountered and the aim of this study is to analyze different methods for managing them., Design and Methods: We have identified 34 patients (15 men and 19 females) with giant adenomas among 762 subjects (4.5%) with acromegaly in our records, and characterized their clinical characteristics and response to treatment., Results: Mean age at diagnosis was 34.9±12.5 years (range, 16-67 years). Mean adenoma size was 49.4±9.4 mm (range, 40-80 mm); 30 adenomas showed cavernous sinus invasion and 32 had suprasellar extension. Twenty-nine (85%) patients had visual field defects. Mean baseline IGF1 was 3.4±1.8×ULN. All patients except one underwent pituitary surgery (one to three procedures), but none achieved hormonal remission following first surgery. Among the 28 subjects with visual disturbances, 14 recovered post-operatively and 13 improved. Treatment with somatostatin analogs was given to all patients after surgical failure. Six achieved remission, nine others were partially controlled (IGF1<1.5×ULN; 3/9 when combined with cabergoline), and 17 did not respond (two were lost). Nine patients were treated with pegvisomant, alone (n=4) or in combination with somatostatin analogs (n=5); five are in remission and two are partially controlled. Pasireotide-LAR achieved hormonal remission in one of the six patients. Currently, after a mean follow-up period of 8.9 years, 17 patients are in biochemical remission, eight are partially controlled, and seven are uncontrolled (two were lost to follow-up)., Conclusions: Giant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission., (© 2015 European Society of Endocrinology.)

Non-functioning pituitary tumours are mostly of gonadotroph cell origin and are devoid of humoral hypersecretory syndromes. They are usually large at the time of diagnosis, commonly presenting with headaches, visual field defects and hypopituitarism. Trans-sphenoidal surgery remains the treatment of choice for rapid decompression of neighbouring structures, often bringing to normalisation or improvement of visual and pituitary function. The management of patients with postoperative residual tumours is still a matter of debate and may include observation alone, the use of dopamine agonists or radiation therapy. There are no controlled or comparative studies of the available therapeutic options; therefore, recommendations are not evidence based. Patients need long-term follow-up for the detection and treatment of hypopituitarism, visual dysfunction and tumour growth that may develop over time.

Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas but is seldom curative. Tumour progression rates are high in patients with postoperative remnants. Therefore, long-term monitoring is necessary to detect tumour growth, which may be asymptomatic or manifest with visual field defects and/or pituitary dysfunction. In view of the generally slow-growing nature of these tumours, yearly magnetic resonance imaging, neuro-ophthalmologic and pituitary function evaluation are appropriate during the first 3-5 years after surgery. If there is no evidence for tumour progression during this period, testing intervals may be extended thereafter.

Objective: There is no consensus as to the optimal postoperative treatment of patients with clinically nonfunctioning pituitary adenomas (NFPA) in whom total tumour removal has not been achieved. In this study we assessed whether dopamine agonist (DA) treatment can prevent postoperative remnant enlargement in NFPA., Design and Methods: Thirty-three patients (25 men/8 women; mean age, 61.7 +/- 11.2 years; mean follow-up, 40.6 +/- 4.8 months) were treated with DA, and their outcome was compared to that of 47 untreated patients (33 men/14 women; mean age, 59 +/- 2 years; mean follow-up, 42.9 +/- 4.2 months)., Results: Tumour mass decreased or remained stable in 18/20 patients in whom DA treatment was initiated upon detection of residual tumour on postoperative MRI (group I). In 13 subjects (group II), DA therapy was started when tumour remnant growth became evident during the course of routine follow-up. Tumour growth stabilized or decreased in 8/13 (61.5%) of these patients. In contrast, tumour size remained stable in only 38.3% (18/47) of the untreated subjects (P < 0.0001 for comparisons among the three groups) and increased in the remaining 29 patients. Tumour enlargement free mean survival time was 103.7 +/- 8.8 months (CI 86.3-121) for group I, 43.9 +/- 9.6 months (CI 25.2-62.8) for group II and 36.7 +/- 3.8 (CI 29.2-44.2) for the control group (P = 0.0017). Treatment vs. control hazard ratio for tumour enlargement was 0.135 for group I (P = 0.007, 95% CI 0.032-0.577) and 0.892 for group II (P = 0.817; 95% CI 0.34-2.34)., Conclusions: Dopamine agonist therapy is associated with a decreased prevalence of residual tumour enlargement in patients with nonfunctioning pituitary adenomas, particularly when treatment is instituted before tumour remnant growth is detected.

Background: Postoperative management of clinically nonfunctioning pituitary adenomas (NFPA) presents difficult challenges. There are no good serum markers for presence or growth of the tumour, medical treatment is not effective and radiotherapy carries the risk of significant side-effects., Objective: The purpose of this study was to investigate the natural history and biological behaviour of surgically treated NFPA, with a special effort to identify characteristics indicative of a more aggressive course that could assist in the clinical decision-making process., Study Design: Patients operated on at our institution for NFPA undergo uniform routine clinical follow-up at the endocrine clinic. Magnetic resonance imaging (MRI) studies are performed 3, 6 and 12 months after transsphenoidal surgery and yearly thereafter for the first 5 years. Subsequently, imaging is performed once every 2 years or as clinically indicated. From 1992 onwards, no patient received immediate postoperative radiation therapy., Patients: One hundred and twenty-two patients (78M/45F) operated on at our institution since 1989 and with a minimal follow-up of 1 year comprised the study group., Measurements: Tumour size and characteristics were determined by MRI using a modification of Hardy's and Wilson's classifications. Maximal tumour height was also recorded and the information was routinely stored in a computerized database., Results: Mean (+/- SD) follow-up was 51 +/- 31 months. Fourteen patients received postoperative radiation therapy. Subsequent tumour growth was observed in five of them, reduction in tumour size in four and no size changes in five. One hundred and eight patients did not receive postoperative radiation. Tumour enlargement occurred in 41 of 78 and in six of 30 patients with and without residual tumour after operation (P = 0.0024). The presence of cavernous sinus invasion before surgery [P = 0.02, odds ratio (OR) 2.72; confidence interval (CI) 1.1-6.43] and the extent of suprasellar extension in the postoperative tumour remnant (P = 0.0054 for presence of stage A, OR 4.4; 95% CI 1.5-12.5; and P = 0.012 for presence of stages B or C, OR 16.2; CI 1.8-144) were strong independent predictors of tumour enlargement., Conclusion: Our data may ease the selection of patients in whom radiation therapy is likely to be necessary for tumour control, and confirms that close postoperative follow-up is an adequate primary approach in low-risk patients.

Objective: To explore the hypothesis that most of the pituitary abnormalities compatible with the diagnosis of microadenoma, and detected in about 10% of the normal adult population, represent asymptomatic gonadotropinomas., Design: Patients diagnosed with pituitary microincidentalomas at the Institute of Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta-subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min after the intravenous injection of 400 microgram TRH., Patients: Twenty-two patients with pituitary incidentaloma and 16 normal volunteers were tested., Results: In 16 of the 22 patients, an abnormal beta-subunit response was detected after the TRH challenge. Three patients had an abnormal increase in both beta-FSH and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH responses were demonstrated in five and eight patients respectively. Six patients had normal basal and stimulated gonadotropin subunit values, raising the possibility that their lesions were not pituitary microadenomas. There was a significant overall difference between the response to TRH of the patient and control groups. In the gonadotropin positive group, comprising 16 patients, serum beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after TRH stimulation, whereas no changes were detected in the control group after TRH injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/-2.3 ng/ml; P=0.24)., Conclusion: In about 73% of patients with pituitary incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta-subunits. This observation raises the possibility that non-functioning pituitary micro- and macroadenomas, which share a similar response to TRH, originate in a common ancestor cell type, probably a pituitary gonadotrope.

In most patients with growth hormone (GH) secreting pituitary adenomas and clinically nonfunctioning pituitary tumors (NFPT) the intravenous injection of thyrotropin releasing hormone (TRH) augments the secretion of GH and subunits of gonadotropin hormones respectively. Similar hormone responses to TRH have been detected in rat pituitary cell lines and in primary human pituitary tumor cultures in vitro. Nevertheless the TRH effect on tumor hormonal secretion has not been well characterized. In the present study we examined TRH-induced hormone secretion in GH secreting tumors and in NFPT in vitro. Cultured cells secreted betaLH and betaFSH (NFPT) or GH (GH secreting adenomas) up to 14 days in culture. In NFPT TRH (10(-8) mol/l) elicited peak betaLH and betaFSH secretion at 60 to 90 min, with no further increase at 24 h. TRH-stimulated GH secretion peaked at 90-120 min, and decreased after 3 h, but a secondary rise occurred after 24 h of incubation. Chronic daily exposure to TRH followed by an acute TRH challenge resulted in a further increase of GH secretion after one hour. In contrast, acute TRH administration following chronic exposure did not elicit increased P-subunits secretion in NFPT. Coadministration of cycloheximide did not change TRH induced beta-subunits secretion in NFPT. However, when it was administered 24 h prior to TRH, it blocked both basal and TRH induced beta-subunits levels in NFPT. Cycloheximide had no effect on basal or stimulated GH secretion when administered concomitantly or 24 h before TRH. Incubation of cultured GH secreting tumors with cycloheximide during 5 days blocked both basal and TRH stimulated GH secretion, thus indicating dependency on protein synthesis during the chronic, secondary phase. Since the acute secretion was not affected by coadministration of cycloheximide, these early increases in hormone levels apparently reflect the release of stored hormone. In summary, GH secreting adenomas and NFPT differ significantly in their hormonal response to continuous exposure to TRH. The mechanisms underlying the sustained effect of TRH on GH secretion in vitro remain to be investigated. If endogenous TRH exerts a similar continuous effect it may contribute to the disregulated GH secretion in acromegaly.

Objective: Clinically nonfunctioning pituitary adenomas (NFA) are mostly of gonadotroph origin. However, increased levels of circulating hormones or subunits in patients with NFA usually do not cause clinical symptoms, nor are they used as biological tumour markers. In this study we assessed the value of measuring beta subunits of gonadotrophin hormones in the post-operative follow-up of patients bearing these tumours., Design: Patients harbouring NFA were studied before and three months after transphenoidal pituitary surgery. beta-LH and beta-FSH levels were measured before and following TRH administration on the two occasions. Hormone levels were analyzed in relation to imaging studies performed before and after surgery., Patients: Twenty four patients operated at the Tel Aviv-Sourasky Medical Centre for NFA., Results: Pathological beta-FSH and beta-LH levels were detected in 79% and 60% of patients respectively. beta-LH levels decreased after surgery but there were no significant changes in beta-FSH levels. There was a tendency for tumours with high basal beta-LH levels to be larger and to have a poor surgical outcome. Normalization of beta-LH levels post-operatively was usually associated with a decrease in tumour mass or complete removal of the tumour. Persistent pathological responses of beta-LH to TRH after surgery were common in patients with residual tumours on imaging. Nevertheless there were exceptions to this pattern, rendering post-operative beta-LH levels insufficiently reliable as a marker for the presence of residual tumour., Conclusion: Although there appears to be a relationship between beta-LH levels, tumour size and surgical outcome, this association is presently insufficient to allow the routine use of either basal or TRH induced beta-LH responses in the post-surgical follow-up of clinically nonfunctioning pituitary adenomas.

It is now recognized that most clinically nonfunctioning pituitary tumors express gonadotropin hormones or their subunits in vitro, and sometimes in vivo. Many of these tumors are diagnosed by sensitive imaging techniques while patients are still asymptomatic. We outline an overview of the diagnosis and clinical management of these tumors.

Pre- and postoperative anterior pituitary function was assessed in 26 subjects with nonfunctioning macroadenoma (NFMA) and in 15 acromegalic subjects with macroadenomas. Preoperatively, NFMA patients had a higher prevalence of secondary hypogonadism (78% vs. 40%; P < 0.05), hypothyroidism (23% vs. 0%; P = 0.06), and hypoadrenalism (43% vs. 7%; P = 0.02) compared to individuals with GH-secreting macroadenoma (GHMA). Patients with NFMA also had a higher prevalence of more severe pituitary failure compared with acromegalic patients; 56% of the patients in this group had more than one pituitary hormone axis impaired compared to only 8% in the acromegalic group. These differences could not be accounted for by tumor grade and/or stage. Transsphenoidal pituitary surgery led to a significant improvement in anterior pituitary function in the NFMA group. Nevertheless, the prevalence of pituitary deficiency postoperatively was still significantly greater in NFMA patients than in the acromegalic group (68% vs. 17%, respectively; P < 0.04). The results suggest that anterior pituitary function is better preserved in GHMA than in NFMA and that this difference is independent of tumor size. The mechanism underlying the lower rate of hypopituitarism in acromegalics with macroadenomas remains to be elucidated.

The expression of three somatostatin receptor subtypes, SSTR3, SSTR4, and SSTR5, was evaluated in 33 pituitary tumor specimens. SSTR3 expression was studied by reverse transcription coupled to polymerase chain reaction, whereas SSTR4 and SSTR5 expression was determined by ribonuclease protection assay. SSTR3 was expressed in 6 of 7 GH-secreting tumors, all 8 clinically nonfunctioning tumors, all 3 prolactinomas, and 1 of 2 ACTH-secreting tumors tested. Eight nonfunctioning adenomas had undetectable messenger ribonucleic acid levels of SSTR4, and only 1 of them expressed SSTR5. SSTR4 expression was also undetectable in 11 GH-secreting tumors, 3 prolactinomas, and 1 ACTH-secreting tumor tested. In contrast, SSTR5 was highly expressed in 10 of 11 GH-secreting adenomas and 1 prolactinoma. Two prolactinomas and 1 ACTH-secreting tumor had low levels of expression of SSTR5. The widespread pituitary adenoma expression of SSTR3, regardless of hormonal secretory type, suggests that SSTR3 might be involved in a somatostatin action(s) other than GH or TSH regulation. SSTR5 is expressed predominantly in mammosomatotroph-derived tumors, suggesting that this receptor subtype may be an important determinant of GH secretion in acromegaly.

The expression of two somatostatin receptor subtypes, SSTR1 and SSTR2, was studied in 27 pituitary tumors and 1 chronic lymphocytic leukemia pituitary infiltrate. Solution hybridization techniques were used for RNA analysis. SSTR1 and SSTR2 were, respectively, expressed in 3 of 7 and 9 of 10 GH-secreting tumors, 1 of 9 and 5 of 9 nonfunctioning tumors, 4 of 5 and 0 of 5 of prolactinomas, and 1 of 3 and 0 of 3 ACTH-secreting tumors. The chronic lymphocytic leukemia infiltrate expressed the SSTR2 subtype. No correlation was detected among tumor size, level of hormonal hypersecretion, and somatostatin receptor expression status. Two acromegalic patients who responded to octreotide therapy exclusively expressed the SSTR2 subtype in their tumors. The results indicate that two SSTR subtypes are heterogeneously expressed in different pituitary adenoma cell types.