Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS 201–995 before transsphenoidal surgery

✓ The purpose of this study was to determine whether the long-acting somatostatin analog SMS 201–995 (octreotide) shrinks growth hormone (GH)-secreting adenomas and improves the results of subsequent transsphenoidal surgery. Ten previously untreated active acromegalic patients (nine women and one man) with invasive tumors were treated with SMS 201–995 (100 µg subcutaneously every 8 hours) for 6 weeks prior to transsphenoidal surgery. The clinical activity, mean GH secretion, insulin-like growth factor (IGF)-I concentration, and tumor volume were measured under basal conditions and on Days 14, 28, and 42 of treatment. The SMS 201–995 improved the symptoms of acromegaly in all patients. Mean levels of both GH and IGF-I (± standard deviation) were significantly decreased by Day 14 (from 92.9 ± 30.5 to 44.9 ± 20.3 µg/liter and from 10.6 ± 7.4 to 5.9 ± 2.6 U/ml, respectively), after which there were only slight further decreases. Six (60%) of the 10 patients experienced tumor shrinkage ranging from 9% to 78% (mean 30%). When it occurred, tumor shrinkage was significant by Day 14 (7.9 ± 6.3 to 6.5 ± 5.1 cu cm) and no further shrinkage was achieved by longer administration. Transsphenoidal surgery reduced postoperative GH levels to less than 2 µg/liter and IGF-I to less than 1.5 U/ml in six patients (60%). This percentage of cure is higher than expected from the literature and the authors' previous experience. However, an investigation of the influence of this drug on several parameters, such as reduction of tumor size or GH and IGF-I concentrations, has failed to prove any relationship. Only pretreatment size of the tumor was of predictive value with respect to the surgical outcome.

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Differential effects of octreotide treatment and transsphenoidal surgery on growth hormone—binding protein levels in patients with acromegaly

Journal of Neurosurgery ◽

10.3171/jns.1999.90.4.0647 ◽

1999 ◽

Vol 90 (4) ◽

pp. 647-650 ◽

Cited By ~ 1

Author(s):

Irma Hernandez ◽

Daniela Soderlund ◽

Ana Laura Espinosa-de-los-Monteros ◽

Raquel Ochoa ◽

Arturo Zarate ◽

...

Keyword(s):

Growth Hormone ◽

Transsphenoidal Surgery ◽

Binding Protein ◽

Hormone Binding ◽

Content Type ◽

Growth Hormone Binding Protein ◽

Igf I ◽

Octreotide Treatment ◽

Hormone Binding Protein ◽

Fine Print

Object. The high-affinity growth hormone—binding protein (GHBP) represents the extracellular portion of the growth hormone (GH) receptor, and its serum levels are a reflection of the tissue receptor status. Levels of GHBP are decreased in patients with active acromegaly, probably because of downregulation of GH receptors. However, there are no studies of patients with acromegaly in which the effects of medical (that is, administration of somatostatin analogs) and surgical therapy on GHBP levels have been compared. That is the task the authors set out to accomplish in this study.Methods. The authors studied seven patients in whom acromegaly had been recently diagnosed. They examined these patients at baseline, 2 months after octreotide treatment (subcutaneous administration of 100 µg octreotide three times per day), and 1 month after transsphenoidal surgery. Growth hormone—binding activity was measured, as well as the following biochemical markers of the somatotropic axis: GH suppression induced by oral administration of glucose, insulin-like growth factor-I (IGF-I), and insulin-like growth factor—binding protein-3 (IGFBP3). Although octreotide treatment induced a decrease in the levels of GH, IGF-I, and IGFBP3, as well as an increase in the level of GHBP, these biochemical markers did not reach normal levels. On the other hand, after transsphenoidal surgery, GHBP levels became normal, particularly in those patients in whom serum GH could be suppressed to an undetectable level after glucose loading.Conclusions. The authors conclude that persistently low GHBP levels in patients with acromegaly are normalized by successful pituitary surgery and correlate well with disease activity.

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Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients

Acta Endocrinologica ◽

10.1530/eje.0.1500489 ◽

2004 ◽

pp. 489-495 ◽

Cited By ~ 57

Author(s):

SW van Thiel ◽

JA Romijn ◽

NR Biermasz ◽

BE Ballieux ◽

M Frolich ◽

...

Keyword(s):

Growth Hormone ◽

Binding Affinity ◽

Receptor Subtype ◽

Somatostatin Analogue ◽

Deconvolution Analysis ◽

Octreotide Lar ◽

Gh Secretion ◽

Igf I ◽

Long Acting ◽

Lanreotide Autogel

OBJECTIVE: Recently a new depot preparation of the long-acting somatostatin analogue, lanreotide Autogel was introduced for the treatment of acromegaly. Like octreotide long-acting repeatable (LAR), it has high binding affinity for the somatostatin receptor subtype SSTR 2 and less binding affinity for SSTR 5. We hypothesized that the ability to suppress growth hormone (GH) secretion in patients with acromegaly would be similar for these depot preparations. PATIENTS AND STUDY DESIGN: Seven patients (mean age+/-S.E.M. 48.4+/-7 years) on long-term octreotide LAR treatment at a monthly injection interval for a mean of 2.8 years were enrolled in the study. They underwent a GH secretory profile study with 10 min sampling for 24 h, 28 days after an injection. At 2, 4 and 6 weeks after the next injection fasting GH profiles (every 30 min for 3.5 h) and serum IGF-I measurements were measured. These investigations were repeated 12 months later, when the patients were on an individually titrated stable dose of lanreotide Autogel. RESULTS: Secretory characteristics and total 24 h GH secretion, estimated by deconvolution analysis of the 10 min 24 h plasma GH concentrations, did not show differences between these two long-acting somatostatin analogues. Both drugs were equally effective in GH and IGF-I suppression as measured at 2, 4 and also at 6 weeks following an injection. CONCLUSION: The efficacy of lanreotide Autogel and octreotide LAR was equal, notwithstanding that these drugs are administered in a different way and have different pharmacokinetics.

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The pathogenesis of acromegaly

Journal of Neurosurgery ◽

10.3171/jns.1985.63.1.0035 ◽

1985 ◽

Vol 63 (1) ◽

pp. 35-38 ◽

Cited By ~ 29

Author(s):

Edward R. Laws ◽

Bernd W. Scheithauer ◽

Sandra Carpenter ◽

Raymond V. Randall ◽

Charles F. Abboud

Keyword(s):

Growth Hormone ◽

Success Rate ◽

Pituitary Adenomas ◽

Pituitary Hormone ◽

Content Type ◽

Gh Secretion ◽

Fine Print

✓ A series of 75 patients with acromegaly and immunocytochemically characterized pituitary adenomas has been analyzed. Tumors secreting growth hormone (GH) only were found in 21% of cases. The remainder had tumors immunoreactive for more than one pituitary hormone: GH and prolactin in 31%; GH, prolactin, and glycoprotein in 40%; and GH and glycoprotein in 8%. Microadenomas were surgically treated in 17 patients with a success rate of 82%. Overall, normalization of basal GH secretion (to ≤ 5 ng/ml) was achieved in 54% of cases. The implications of these findings for the pathogenesis and neurosurgical management of acromegaly are discussed.

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The effect of somatostatin analogue on chiasmal dysfunction from pituitary macroadenomas

Journal of Neurosurgery ◽

10.3171/jns.1989.71.5.0687 ◽

1989 ◽

Vol 71 (5) ◽

pp. 687-690 ◽

Cited By ~ 37

Author(s):

André Warnet ◽

José Timsit ◽

Philippe Chanson ◽

Pierre-Jean Guillausseau ◽

Françoise Zamfirescu ◽

...

Keyword(s):

Tumor Volume ◽

Visual Fields ◽

Somatostatin Analogue ◽

Tumor Shrinkage ◽

Content Type ◽

Gh Secretion ◽

Visual Improvement ◽

Long Acting ◽

Pituitary Macroadenomas

✓ The long-acting somatostatin analogue SMS 201-995 has been shown to be efficient in the treatment of somatotropic and thyrotropic adenomas. In some cases, it can suppress adenoma secretion and lead to tumor shrinkage. Pituitary macroadenomas are often associated with a vision-threatening chiasmal syndrome. In this series, SMS 201-995 was administered subcutaneously to eight patients with pituitary macroadenomas of various types responsible for severe long-lasting visual defects. An obvious improvement of both visual fields and acuity occurred in six patients, in two of these during the first 4 to 6 hours of treatment; in two patients, gonadotropic adenomas were unresponsive. Maximal improvement (normalization of visual fields in three cases) occurred within 6 to 45 days and was sustained during the 1- to 12-month follow-up period. This effect seems independent of the type of adenoma since the adenomas secreting growth hormone (GH) and thyroidstimulating hormone and silent corticotropic-secreting adenomas responded as well as did two of the non-functioning adenomas. In one acromegalic patient visual improvement was obtained while the abnormal GH secretion remained unaltered. In all cases but one, no tumor shrinkage could be demonstrated. These data demonstrate that SMS 201-995 can rapidly improve the chiasmal syndrome due to pituitary macroadenoma, and suggest that this effect might be independent of a reduction in tumor volume.

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Changing patterns of insulin-like growth factor—I and glucose-suppressed growth hormone levels after pituitary surgery in patients with acromegaly

Journal of Neurosurgery ◽

10.3171/jns.2002.97.2.0287 ◽

2002 ◽

Vol 97 (2) ◽

pp. 287-292 ◽

Cited By ~ 49

Author(s):

Ana Laura Espinosa-de-los-Monteros ◽

Moisés Mercado ◽

Ernesto Sosa ◽

Oscar Lizama ◽

Gerardo Guinto ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Magnetic Resonance Images ◽

Insulin Like Growth Factor ◽

Content Type ◽

Postoperative Course ◽

Igf I ◽

Active Disease ◽

Age And Sex ◽

Fine Print

Object. According to a recent consensus statement on the treatment of acromegaly, its biochemical cure is defined as the normalization of age- and sex-adjusted insulin-like growth factor (IGF)—I levels and the suppression of growth hormone (GH) by glucose to lower than 1 ng/ml. The present study was prompted by the clinical observation that many cases of acromegaly can be considered cured according to one criterion but not others at different moments in a patient's postoperative course. Methods. Fifty-three patients with acromegaly (30 women and 23 men) harboring nine microadenomas and 44 macroadenomas were evaluated after surgery by assessing age- and sex-adjusted IGF-I levels as well as glucose-suppressed GH levels. Fifty of these patients were studied more than once during follow up. Acromegaly was categorized as cured if the patient's IGF-I level was normal and their glucose-suppressed GH level was lower than 1 ng/ml; the disease was considered to be active if the patient's IGF-I level was high and the GH nadir was higher than 1 ng/ml following administration of glucose. Discordant categories of the disease were found in patients with high IGF-I levels and a GH nadir lower than 1 ng/ml after glucose administration and in those with normal IGF-I levels and a GH nadir higher than 1 ng/ml after glucose intake. At the first postoperative biochemical evaluation (1–3 months), 34% of patients harboring macroadenomas were classified as having been cured of acromegaly, 39% as having the active disease, and 27% as having the discordant form of the disease. When last evaluated (≥ 12 months postoperatively), the percentage of patients with the discordant form dropped to 14% and the proportion of cases cured and active was 44% and 41%, respectively. Of the nine patients with microadenomas, 44.4% were cured of acromegaly, 33.2% had the active disease, and 22% had the discordant variety on first evaluation. Twelve months or longer after transsphenoidal surgery, 55.5% of cases were cured, 11.1% were active, and 33% were discordant. In most cases, the discordant variety developed because of a persistently elevated level of IGF-I, followed by an incompletely suppressed GH level. Nineteen patients (38%) modified their biochemical category. In 15 of these patients this change in category was due to a change in IGF-I levels, becoming normal in 12 patients and rising to above normal range in three. A tumor remnant was demonstrated on magnetic resonance images in only four of these 19 patients. Conclusions. The authors conclude that the discordance rate between the biochemical markers that define cure in acromegaly is higher than previously reported, and the biochemical status assigned to a patient early in the postoperative course is very likely to change later, particularly when initially discordant.

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Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice

Journal of Neurosurgery ◽

10.3171/jns.2001.94.3.0487 ◽

2001 ◽

Vol 94 (3) ◽

pp. 487-492 ◽

Cited By ~ 90

Author(s):

Ian E. McCutcheon ◽

Allan Flyvbjerg ◽

Holly Hill ◽

Jessica Li ◽

William F. Bennett ◽

...

Keyword(s):

Growth Hormone ◽

Receptor Antagonist ◽

Tumor Volume ◽

Vehicle Group ◽

Content Type ◽

Gh Receptor ◽

Igf I ◽

The Mean ◽

Fine Print

Object. The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were performed to evaluate the efficacy of GH receptor blockade in vivo. Methods. Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 ± 18.8 mm3 in the vehicle group and 291.1 ± 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 ± 18.9 mm3 compared with 350.1 ± 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 ± 12.9 µg/L compared with 257 ± 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)—3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 ± 0.01 g compared with 0.057 ± 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-II levels were highly variable (0–38.2 ng/g tissue) and did not differ significantly between treatment groups. Conclusions. In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.

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Transsphenoidal surgery and adjuvant gamma knife treatment for growth hormone—secreting pituitary adenoma

Journal of Neurosurgery ◽

10.3171/jns.2001.95.2.0285 ◽

2001 ◽

Vol 95 (2) ◽

pp. 285-291 ◽

Cited By ~ 66

Author(s):

Hidetoshi Ikeda ◽

Hidefumi Jokura ◽

Takashi Yoshimoto

Keyword(s):

Growth Hormone ◽

Pituitary Adenoma ◽

Mr Imaging ◽

Transsphenoidal Surgery ◽

Residual Tumor ◽

Cure Rate ◽

Content Type ◽

Transsphenoidal Microsurgery ◽

Biochemical Cure ◽

Fine Print

Object. The results of combined transsphenoidal surgery and adjuvant gamma knife surgery (GKS) for growth hormone (GH)—secreting adenoma were investigated using biochemical cure criteria for surgery and biological cure criteria for adjuvant GKS. Methods. Ninety patients (42 male and 48 female patients), ranging from 11 to 75 years of age, underwent transsphenoidal surgery for GH-secreting pituitary adenoma. Preoperative and postoperative GH and insulin-like growth factor-I levels were measured, as was the postoperative GH level after the oral glucose tolerance test. Tumor size, cavernous sinus (CS) invasion, and residual tumor were evaluated using magnetic resonance (MR) imaging. Transsphenoidal microsurgery was performed, followed by adjuvant GKS when there was persistent biochemical evidence of GH hypersecretion with residual tumor detectable in the CS on MR imaging. Patients in whom GKS was contraindicated were treated with conventional radiotherapy or by medical means. Conclusions. The overall surgical cure rate was 57% based on recently accepted biochemical cure criteria. Patients with no CS invasion achieved a 100% cure rate, whereas patients with CS invasion achieved an 82% cure rate (14 of 17 patients) after adjuvant GKS. The combination of transsphenoidal microsurgery and adjuvant GKS is the optimal therapy for patients with GH-secreting adenoma.

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Transsphenoidal microsurgical removal of growth hormone-secreting pituitary adenomas

Journal of Neurosurgery ◽

10.3171/jns.1982.56.5.0634 ◽

1982 ◽

Vol 56 (5) ◽

pp. 634-641 ◽

Cited By ~ 77

Author(s):

David S. Baskin ◽

James E. Boggan ◽

Charles B. Wilson

Keyword(s):

Growth Hormone ◽

Pituitary Adenomas ◽

Partial Remission ◽

Transsphenoidal Surgery ◽

Content Type ◽

Group A ◽

Group B ◽

Suprasellar Extension ◽

Fine Print

✓ A series of 137 patients with growth hormone (GH)-secreting pituitary adenomas were treated by transsphenoidal surgery during a 10-year period. Group A comprised patients for whom this surgery was the first therapeutic intervention, and Group B included those who underwent the surgery after previous therapeutic intervention. The results were analyzed considering preoperative and postoperative endocrinological, neurological, ophthalmological, and neuroradiological data. Remission was defined as clinical response and a normal postoperative GH level, and partial remission as clinical response and postoperative reduction of the GH level by more than 50%. Any other result was considered failure. The mean follow-up period was 37.1 months; follow-up review was achieved in all the patients. Among the 102 patients in Group A, remission was achieved in 80 (78%) patients with transsphenoidal surgery alone, and in an additional 16 (16%) after postoperative irradiation (combined response rate, 94%). All failures and patients with partial remission had preoperative GH levels of more than 50 ng/ml and suprasellar extension of the tumor. There were no deaths; 8% of patients had minor surgical morbidity; 5% had new hypopituitarism postoperatively. Of patients subsequently irradiated, 71% developed hypopituitarism. Among the 35 patients in Group B, remission was achieved in 26 (74%), partial remission was obtained in two (6%), and seven (20%) were considered treatment failures. There were no deaths, and the morbidity rate was 14%; 66% of patients had hypopituitarism postoperatively. Of the eight patients who had received prior irradiation only, seven (88%) went into remission. All failures and partial responders had preoperative GH levels greater than 40 ng/ml; 56% had suprasellar extension. These results confirm the efficacy of the transsphenoidal approach for the treatment of GH-secreting pituitary adenomas.

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Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

Hormone Research in Paediatrics ◽

10.1159/000516407 ◽

2021 ◽

pp. 1-24

Author(s):

Jan M. Wit ◽

Sjoerd D. Joustra ◽

Monique Losekoot ◽

Hermine A. van Duyvenvoorde ◽

Christiaan de Bruin

Keyword(s):

Growth Hormone ◽

Differential Diagnosis ◽

Growth Hormone Secretion ◽

Normal Growth ◽

Stimulation Test ◽

Healthy Children ◽

Genetic Causes ◽

Gh Secretion ◽

Igf I

The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.

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Pituitary adenoma producing growth hormone and adrenocorticotropin: a histological, immunocytochemical, electron microscopic, and in situ hybridization study

Journal of Neurosurgery ◽

10.3171/jns.1998.88.6.1111 ◽

1998 ◽

Vol 88 (6) ◽

pp. 1111-1115 ◽

Cited By ~ 27

Author(s):

Kalman Kovacs ◽

Eva Horvath ◽

Lucia Stefaneanu ◽

Juan Bilbao ◽

William Singer ◽

...

Keyword(s):

Growth Hormone ◽

In Situ Hybridization ◽

Pituitary Adenoma ◽

Immunoelectron Microscopy ◽

Secretory Granules ◽

Cell Types ◽

Content Type ◽

Separate Cell ◽

Fine Print

✓ The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells—one somatotroph and one corticotroph—transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.

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