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Effective Combined Medical Treatment With Octreotide Long Acting Release (Sandostatin LAR) and Cabergoline for an Extremely Rare Pituitary Somatotroph Adenoma Producing Growth Hormone-Releasing Hormone
Abstract
Combined medical treatment with long acting octreotide and cabergoline is now used with active patients with acromegaly and can reduce serum growth hormone (GH) and insulin-like growth factor-1 levels. In this article, we analyzed again the molecular aspects of the previously reported rare GH-releasing hormone (GHRH)-producing somatotroph adenoma, and introduce the effects of the combined medical treatment using octreotide LAR and cabergoline for GHRH-producing somatotroph adenoma. The present GHRH-producing somatotroph adenoma had a high Ki-67 staining index, weak, and cytoplasmic-dominant immunostaining of somatostatin receptor 2A, and no gsp mutation. This adenoma was predicted to be resistant to the medical therapy using octreotide LAR. In this extremely rare GHRH-producing pituitary somatotroph adenoma, octreotide LAR alone cannot reduce random GH and insulin-like growth factor-1 levels sufficiently, but combined medical therapy with octreotide LAR and cabergoline can reduce them into the normal range. We show that combined medical treatment with octreotide LAR and cabergoline was effective for a somatotroph adenoma that had a high proliferative potential, weak and cytoplasmic-dominant immunostaining of somatostatin receptor 2A, and no gsp mutation, and has active GH production and secretion regulated by locally generated GHRH from adenoma cell.
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We have investigated the possibility that local production of GHRH within the adenohypophysis could be an aetiological factor in the development of human pituitary somatotroph and other tumours. We examined 51 human pituitary adenomas for GHRH transcripts using in situ hybridization histochemistry. GHRH transcripts were identified in 13 of 17 somatotroph adenomas, 4 of 10 corticotrophs, 1 of 6 lactotrophs and 1 of 18 endocrinologically inactive adenomas. In 11 GHRH-expressing somatotroph adenomas, SRIH transcripts were also identified. In all cases except one (a corticotroph adenoma) the average number of GHRH transcripts exceeded that found in the arcuate nucleus of simultaneously hybridized rat brain sections. In some pituitary adenomas, GHRH transcripts were clearly localized to a discrete subpopulation of cells and in these, the amount of GHRH mRNA per cell was comparable to that found in the GHRH-expressing cells of the rat arcuate nucleus. Although we have not directly demonstrated an association between the two, the identification of localized, high level GHRH gene expression in somatotroph adenomas suggests that GHRH may have a role in pituitary adenoma formation.
Pituitary cells synthesize various neuropeptides that influence pituitary hormone secretion. GH-releasing factor (GRF) may also be produced by normal or pituitary tumor cells. We examined GRF gene expression in pituitary tumors. Standard techniques for the analysis of GRF gene expression did not appear to be suitable. Highly sensitive reverse transcription coupled to polymerase chain reaction was used. Specimens of pituitary adenoma were obtained by transsphenoidal adenomectomy from six patients with acromegaly and three patients with no clinical evidence of pituitary hormone overproduction; non-functioning adenoma. Pituitary glands were collected at autopsy from three patients who died from nonendocrine disorders. A specific GRF gene transcript was detected in five out of six GH-producing pituitary adenomas, whereas this was not found in three separate specimens of nonfunctioning pituitary adenoma or anterior and posterior pituitary tissue. The data suggest that GRF is synthesized as an intrinsic product in human GH-producing pituitary adenoma.
Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.
Neuropeptides such as vasoactive intestinal peptide, LHRH, or TRH have been found in rat pituitary tissue and could act via paracrine or autocrine actions in this tissue. In this study we investigated whether normal human pituitary tissue and GH-secreting human pituitary adenomas could release somatostatin (SRIH) and GHRH. Fragments from three human pituitaries and dispersed cells from six GH-secreting adenomas (four adenomas were studied for GHRH release and five for SRIH release) were perifused using a Krebs-Ringer culture medium, and the perifusion medium was collected every 2 min (1 mL/fraction for 5 h). GH, GHRH, and SRIH were measured by RIA under basal conditions and in the presence of 10(-6) mol/L TRH or SRIH. Both normal pituitaries and GH-secreting pituitary adenomas released SRIH and GHRH. SRIH release commenced 90-180 min after initiation of the perifusion, at which time GH secretion had decreased significantly. TRH stimulated SRIH release from normal pituitary tissue and inhibited SRIH release from adenoma tissue. GHRH was present at the start of the perifusion, but rapidly disappeared. However, SRIH stimulated GHRH release from normal pituitary tissue, but not from adenoma tissue. Significant amounts of GHRH and SRIH were released during the experiments, suggesting their local synthesis. These results indicate that pituitary cells can release hypothalamic peptides. The liberation of these neuropeptides is regulated, and moreover, their regulation differs between normal and adenomatous pituitaries.
The case of a 52-year-old woman with acromegaly, diabetes insipidus, and visual impairment caused by a metastatic growth hormone—releasing hormone (GRH)—produced pancreatic tumor is reported. Serum growth hormone (GH) and somatomedin C levels were elevated to 14 ng/ml (normal < 5 ng/ml), and 3.20 U/ml (normal < 1.88 U/ml), respectively. Paradoxical increases were observed in GH levels after glucose tolerance and thyrotropin—releasing hormone-stimulation tests. Biopsy of a pituitary tumor observed on computerized tomography scans and magnetic resonance studies revealed a metastatic cancer. When circulating GRH levels were measured, a marked increase in plasma GRH (1145 pg/ml; normal < 4—1 pg/ml) was observed. The patient died of cachexia due to metastases.
Postmortem examination revealed that a primary tumor, a malignant endocrine lesion, was present in the pancreas, with metastatic tumors in the pituitary, lung, liver, and adrenal glands. Synthesis and production of GRH by the tumor was demonstrated by Northern blotting and immunohistochemical analysis. The pituitary gland showed hyperplastic, but not adenomatous changes. The authors stress the importance of both exploration for an ectopic source of GRH and the search for a GH-producing pituitary adenoma when unusual signs and symptoms are seen in patients with acromegaly.
Yang I, Park S, Ryu M, Woo J, Kim S, Kim J, Kim Y, Choi Y. Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients. Eur J Endocrinol 1996;134: 720–6. ISSN 0804–4643
A subset of human growth hormone (GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the α-subunit of the stimulatory GTP-binding protein (G s α). This study was undertaken to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical characteristics of these patients to endocrine testing. Direct polymerase chain reaction sequencing revealed the gsp oncogene mutation in 9 out of 21 tumors (43%) at amino acid 201 of the G s α protein. A single nucleotide mutation in the tumors carrying the gsp oncogene was observed, which replaced an arginine (CGT) in the normal protein with cysteine (TGT) in eight tumors and serine (AGT) in one tumor. The patients with the gsp oncogene mutation (group 1) were older (54 ± 10 vs 41 ±11 years, p = 0.0085) than those without the mutation (group 2). Sex, tumor size and grade, basal GH and prolactin levels, the GH response to oral glucose loading, the GH fluctuation and the paradoxical response to thyrotropin-releasing hormone or gonadotropin-releasing hormone did not differ between the groups. The gsp oncogene was found mostly in somatotroph adenomas. The octreotide-induced GH suppression was significantly higher in group 1 than in group 2 (95 ± 5% vs 81 ± 17%, p = 0.0335). The GH response to bromocriptine did not differ between the groups. These results suggest that the G s α mutations of GH-secreting tumor are observed in Korean acromegalic patients with similar frequency to those of western countries. The patients with gsp oncogene are likely to be older than those without the oncogene, and show excellent response of GH suppression to octreotide.
Inmyung Yang, Division of Endocrinology, Department of Internal Medicine, Kyunghee University School of Medicine, 1 Hoiki-dong, Dongdaemoon-ku, Seoul 130-702, Korea
In more than one third of growth hormone (GH)-secreting pituitary adenomas, a point mutation in the gene for the alpha-chain of the G stimulatory protein (gsp oncogene) causes the constitutive activation of the membrane adenylyl cyclase (AC) resulting in uncontrolled cyclic adenosine monophosphate (cAMP) elevation and GH hypersecretion. Tumors expressing gsp are characterized by high membrane AC activity, elevated intracellular cAMP content, and high rates of GH release in culture medium. The AC activity is not further stimulated by GH-releasing hormone (GHRH) and other specific and non-specific agents, while it is lowered by somatostatin, as the G inhibitory protein (Gi) is normally working. Acromegalic patients bearing adenomas with the gsp mutation do not present with any obvious clinical or epidemiological distinctive features. However, they have smaller tumors in relation to their circulating GH levels, suggesting that the gsp oncogene maintains a high rate of secretory activity in vivo. Most of these patients show paradoxical GH increases to thyrotropin-releasing hormone (TRH), but none to gonadotropin-releasing hormone (GnRH) or an oral glucose tolerance test (OGTT). As with the in vitro data, these patients are not very sensitive to GHRH administration, but are sensitive to the inhibitory action of somatostatin. In our experience, only three of six patients with non-gsp-mutated tumors had lowered serum GH levels during the administration of octreotide (100 micrograms thrice daily for 4 years), while all of six patients with gsp-mutated tumors had serum GH levels suppressed by octreotide treatment. Such a good GH suppressibility by somatostatin makes patients with gsp-mutated tumors the best candidates for medical treatment with somatostatin analogs.
The characteristic features of a 48-year-old male presenting with isolated acromegaly caused by a GRH-producing pancreatic endocrine tumor bearing no relation to MEN1 was reported. The clinical features, laboratory findings, and sellar enlargement were improved after removal of the pancreatic tumor. The resected pancreatic tumor showed positive GRH immunoreactivity and contained abundant GRH mRNA. This tumor is extremely rare and to date only 10 cases have been reported. In the management of acromegaly, the measurement of GRH is recommended and the search for an ectopic source will prevent unnecessary and potentially ineffective pituitary surgery.
An acromegalic patient with a pituitary somatotroph adenoma associated with an extremely elevated plasma GHRH concentration is presented. The preoperatively high concentration of plasma GHRH returned to the normal level after successful removal of the adenoma. GHRH production and GHRH gene expression were confirmed in the adenoma by studies including immunohistochemistry and in situ hybridization. Expression of GHRH receptor messenger ribonucleic acid was verified by in situ hybridization. Immunohistochemical double staining for GH and GHRH revealed their colocalization in single adenoma cells. These findings confirmed the autocrine or paracrine regulation of GH production by endogenous GHRH from the adenoma cells. GHRH synthesis in the pituitary gland has recently been demonstrated, however, there have been no previous reports of a GHRH-producing pituitary somatotroph adenoma associated with an elevated plasma GHRH concentration. The existence of this GHRH-producing adenoma suggests a possible role of locally generated GHRH in the progression of somatotroph adenomas, i.e. the monoclonally established somatotroph adenomas develop further under the influence of locally produced GHRH. The demonstration of GHRH production by this somatotroph adenoma is of importance in clarifying the autocrine or paracrine regulation of GH production and the progression of human somatotroph adenomas.
Growth hormone-releasing hormone (GHRH) is a well-known hypothalamic hormone that stimulates the synthesis and release of growth hormone (GH) as well as the proliferation of GH-producing cells in the anterior pituitary gland. Recent reports have shown GHRH synthesis in pituitary somatotroph adenomas, but GHRH immunoreactivity has not been shown in previous studies. To confirm the role of locally generated GHRH for the progression of somatotroph adenomas, we investigated the expression of GHRH in 25 pituitary somatotroph adenomas immunohistochemically, through the use of both conventional avidin-biotin-complex (ABC) method and novel catalyzed signal amplified (CSA) system. In addition, we investigated the expression of GHRH mRNA and GHRH receptor mRNA with in situ hybridization (ISH) using the CSA system. The weak immunopositivity of GHRH was observed in only 2 adenomas (8.0%) of 25 somatotroph adenomas using the ABC method. In contrast, 15 adenomas (60.0%) of 25 somatotroph adenomas were immunopositive for GHRH, as shown by CSA system. Very few of nonsomatotroph adenomas were immunopositive for GHRH using the CSA system. The expression of GHRH mRNA was confirmed, using the CSA-ISH system in 13 adenomas (72.2%) of 18 somatotroph adenomas. In 11 adenomas (61.1%) of 18 somatotrophic adenomas, the expression of GHRH receptor mRNA was demonstrated using the CSA-ISH system. This is a first report that clarified histopathologically GHRH production in pituitary somatotrophic adenomas. The demonstration of GHRH and its receptor expression is meaningful in clarifying the autocrine or paracrine regulation of GHRH in GH production and progression of pituitary somatotroph adenomas.
Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH-IGF-I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long-acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking.
Prospective open trial.
In 19 acromegalic patients with active disease (34-82 years old, seven males, 12 females) resistant to chronic (9-12 months) depot SA (octreotide-LAR, 30 mg/28 days in 13 patients, lanreotide, 60 mg/28 days intramuscularly in six patients) cabergoline was added (combined treatment). In these patients, SA treatment had partially relieved GH and IGF-I hypersecretion but no patient had achieved 'safe' GH and normal IGF-I-values. Eight patients had PRL levels greater than 15 micro g/l (range 16-60 micro g/l; 1 micro g = 21.2 mIU). Immunohistochemistry (IHC) was positive for PRL in four out of eight operated patients.
The addition of cabergoline, using the minimal effective and the maximal tolerated dose (range 1-3.5 mg/week), decreased GH from 6.6 +/- 0.9 to 4.6 +/- 0.6 micro g/l (P = 0.018), and IGF-I from 552 +/- 44 to 428 +/- 54 micro g/l (P = 0.019) after 6 months (median, range 3-18 Months). Combined treatment decreased GH to < 2.5 micro g/l in four patients (21%) and normalized IGF-I for age in eight patients (42%). It obtained a decline of both GH and IGF-I (-49 +/- 7%, and -47 +/- 5%, respectively) in nine patients (47%), and a partial improvement in six (32%) patients (GH decreased by 43 +/- 8% in four, and IGF-I by 35-38% in two patients). No change was observed in two patients, and worsening in two other patients. Results were not dependent on PRL status (serum levels or IHC). Combined treatment was well tolerated.
The addition of cabergoline to depot SA-resistant acromegalic patients is effective, not dependent on PRL values and normalizes IGF-I levels in 42% of patients. The association of long-acting DA and SA deserves a more relevant role in the therapeutical algorithm of acromegaly.
The excess mortality and morbidity associated with acromegaly are secondary to prolonged elevation of GH and IGF-I. Vigorous control of these biochemical parameters results in improved morbidity and mortality. Somatostatin analogues (SAs) allow adequate control of GH and IGF-I in approximately 65% of subjects, leaving a significant cohort uncontrolled. Dopamine agonists (DAs), a cheap alternative to SAs, allow control of GH and IGF-I in less than 20% of patients with acromegaly.
To assess the effectiveness of adding DA therapy to SA in the biochemical control of acromegaly.
One hundred and twenty cases from the Sheffield Acromegaly Register were reviewed; 24 (20%) did not require medical treatment following pituitary surgery alone; 16 (13%) had safe GH levels following surgery and radiotherapy; and 58 (48%) required medical treatment despite having had surgery, radiotherapy or both. The remaining 22 (18%) received only medical treatment.
In nine subjects a DA (three bromocriptine, six cabergoline) was added to an SA to control active disease. GH day curves and IGF-I levels were compared before and after the addition of a DA to existing SA treatment. All were on stable maximum-dose treatment with an SA, with inadequate biochemical control prior to addition of DA therapy. Mean duration of treatment on a DA before biochemical assessments were made was 10.3 months. Six subjects had previously been treated with either transsphenoidal surgery, radiotherapy or both. In three subjects SA was the primary therapy.
All subjects exhibited a fall in median GH and IGF-I levels. Introduction of a DA resulted in a 36.1% reduction in median GH levels (8.3 vs 5.3 mIU/l; P = 0.008) on a GH day curve and a 35.2% reduction in IGF-I levels (387.2 vs 251.0 microg/l; P = 0.018). Only four subjects had elevated prolactin levels prior to the addition of a DA (>368 mIU/l).
Addition of DAs to SAs is of benefit in the biochemical control of acromegaly and should be considered in those inadequately controlled. Furthermore, the beneficial effects of DAs occur even when pre-treatment prolactin levels are within the normal range.