Growth Hormone Overproduction Research Articles

Therapie der Akromegalie – Daten aus dem Deutschen Akromegalie Register

Acromegaly is a rare disease in which chronic growth hormone overproduction (usually from an anterior pituitary adenoma) leads to various systemic complications. The management of acromegaly and the comorbidities of the disease is complex and requires a multidisciplinary approach. Early diagnosis is extremely important, as then the chances of a complete cure are significantly higher. The operation is the therapy of first choice and should be performed at a specialized center with an experienced neurosurgeon. With good patient information and guidance, the drug therapy of acromegaly patients in specialized practices and clinics can usually lead to biochemical control and thereby normalization of mortality risk. As with numerous rare diseases, care in specialized centers and recording and evaluation in registry studies can contribute to better patient care and the optimization of therapy and diagnostic guidelines. We assume that with the help of the German Acromegaly Registry, which currently includes more than 2500 patients with acromegaly, we will be able to present a realistic picture of the care situation in Germany in the coming years.

Marked reduction of proteinuria after removal of a growth hormone-producing pituitary adenoma in a patient with focal segmental glomerulosclerosis: a case report and literature review.

Focal segmental glomerulosclerosis is a rare complication of acromegaly. A 74-year-old man was found to have acromegaly features such as enlargement of the forehead, nose, and hands. Laboratory tests showed a urine protein/creatinine ratio of 3.16g/gCr and serum creatinine of 1.34mg/dL. The levels of growth hormone and insulin-like growth factor I were markedly elevated, and the growth hormone level was not suppressed after 75g oral glucose loading. Magnetic resonance imaging revealed a pituitary tumor with a diameter of 1.2cm. Renal biopsy confirmed the diagnosis of focal segmental glomerulosclerosis. Transsphenoidal resection of the pituitary tumor led to remission of acromegaly and reduction in proteinuria highlighting the causal link between growth hormone overproduction and proteinuria. Treatment of acromegaly may be effective for acromegaly-associated focal segmental glomerulosclerosis.

Circulating Plasma MicroRNA in Patients With Active Acromegaly.

Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms. To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults. A cross-sectional case-control study was conducted at a tertiary medical center. We enrolled 12 consecutive patients with acromegaly along with 12 age- and sex-matched controls in the discovery phase of the study and then extended this cohort to 47 patients with acromegaly and 28 healthy controls for the validation study. Plasma miRNAs were quantified by next-generation sequencing (NGS) in the discovery phase. Levels of selected miRNAs were validated on extended cohorts using reverse transcription quantitative polymerase chain reaction (RT-qPCR), compared between groups, and correlated with clinical parameters. Based on NGS data, we selected 3 plasma miRNAs downregulated in patients with acromegaly compared to healthy controls: miR-4446-3p -1.317 (P = 0.001), miR-215-5p -3.040 (P = 0.005), and miR-342-5p -1.875 (P = 0.013) without multiplicity correction for all 3 miRNAs. These results were confirmed by RT-qPCR in the validation phase for 2 miRNAs out of 3: miR-4446-3p (P < 0.001, Padjusted < 0.001), area under the receiver-operator curve (AUC) 0.862 (95% CI 0.723-0.936; P < 0.001) and miR-215-5p (P < 0.001, Padjusted < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) to differentiate patients with acromegaly from healthy controls. In a 2-phase experiment using 2 different techniques we found and validated the downregulation of plasma miR-4446-3p and miR-215-5p in patients with acromegaly compared to healthy subjects, which makes them promising biomarkers for further research.

Acromegaly: current therapies benefits and burdens

Acromegaly, caused by growth hormone overproduction, is associated with comorbidities causing significant clinical dysfunction and high mortality risk. Outcomes are hampered by late diagnosis and poor treatment tolerance and adherence. The goal of this paper is to present a scoping review of the benefits and characterize potential burdens of current treatments that may limit achieving disease control or treatment continuity. Current treatments include transsphenoidal surgery, often followed by the use of synthetic somatostatin analogues or growth hormone receptor antagonists. Radiotherapy is considered an adjunct to treatment for nonresponsive patients or recurrent tumors. Despite therapeutic benefits the burdens to the patient equate to an estimated one quarter of patients discontinuing treatment or that are lost to follow up with up to 88% of these cases having uncontrolled disease. Although disease outcomes are improved with early disease identification and prompt treatment, attention to long term treatment adherence is critical to outcomes. The most cost effective and efficacious strategies involve a significant understanding of the individual patient’s disease and treatment burdens, the patient’s knowledge regarding their disease and the full utilization of all health care team resources. Provider awareness of factors impacting follow-up, the application of precision medicine and implementation of a team approach that actively involves the patients, nurses, and physicians in treatment decisions, location convenient disease monitoring with coordination of treatment for co-morbidities and home drug administration are key factors in facilitating long term treatment adherence.

The possible role of mRNA expression changes of GH/IGF-1/insulin axis components in subcutaneous adipose tissue in metabolic disturbances of patients with acromegaly.

We explored the effect of chronically elevated circulating levels of growth hormone (GH)/insulin-like-growth-factor-1 (IGF-1) on mRNA expression of GH/IGF-1/insulin axis components and p85alpha subunit of phosphoinositide-3-kinase (p85alpha) in subcutaneous adipose tissue (SCAT) of patients with active acromegaly and compared these findings with healthy control subjects in order to find its possible relationships with insulin resistance and body composition changes. Acromegaly group had significantly decreased percentage of truncal and whole body fat and increased homeostasis model assessment-insulin resistance (HOMA-IR). In SCAT, patients with acromegaly had significantly increased IGF-1 and IGF-binding protein-3 (IGFBP-3) expression that both positively correlated with serum GH. P85alpha expression in SCAT did not differ from control group. IGF-1 and IGFBP-3 expression in SCAT were not independently associated with percentage of truncal and whole body fat or with HOMA-IR while IGFBP-3 expression in SCAT was an independent predictor of insulin receptor as well as of p85alpha expression in SCAT. Our data suggest that GH overproduction in acromegaly group increases IGF-1 and IGFBP-3 expression in SCAT while it does not affect SCAT p85alpha expression. Increased IGF-1 or IGFBP-3 in SCAT of acromegaly group do not appear to contribute to systemic differences in insulin sensitivity but may have local regulatory effects in SCAT of patients with acromegaly.

Rosiglitazone as an option for patients with acromegaly: a case series

IntroductionIn the patient with acromegaly, pituitary surgery is the therapeutic standard. Despite undergoing surgery, a significant number of patients with acromegaly continue to have uncontrolled growth hormone secretion. These patients require other treatments such as external irradiation and/or drug therapy.Case presentationWe present the clinical and laboratory responses to six months of treatment with rosiglitazone in four cases. In all four cases, the patients had persistent growth hormone overproduction despite previous surgical treatment and other conventional therapy. Case 1 is a 57-year-old Caucasian woman, case 2 is a 51-year-old Hispanic man, case 3 is a 32-year-old Hispanic woman, and case 4 is a 36-year-old Hispanic man. In three of these patients, basal and nadir growth hormone and insulin-like growth factor 1 levels were significantly decreased (P < 0.05 and P < 0.01, respectively).ConclusionRosiglitazone could be a treatment option in select patients with acromegaly.

Growth hormone overproduction in a patient with multiple endocrine neoplasia type I

Abstract. Hermans MMH, Lips CJM, Bravenboer B (Catharina Hospital Eindhoven, Eindhoven, and University Hospital Utrecht, Utrecht, the Netherlands). Growth hormone overproduction in a patient with multiple endocrine neoplasia type I (Case Report). J Intern Med 2000; 248: 527–532. In a 69-year-old woman with a complicated history of multiple endocrine neoplasia type I (MEN 1), growth hormone overproduction was found without clinical features of acromegaly. Zollinger-Ellison syndrome was diagnosed at the age of 36 years. Total gastrectomy and partial pancreatectomy were performed. Two years later hypercalcaemia occurred, hyperparathyroidism was suspected and three hyperplastic parathyroid glands were removed. In 1994 the plasma gastrin level was elevated and a computertomography of the abdomen revealed a 1.5-cm large pancreatic tumour. Screening of the pituitary functions was unremarkable and a magnetic resonance scan of the pituitary gland showed no abnormalities. In 1995 type II diabetes mellitus was diagnosed. In 1997 basal plasma growth hormone levels were raised and plasma IGF-I levels were alternately high and normal. The patient had no clinical signs of acromegaly, but glucose tolerance testing resulted in a paradoxical rise in growth hormone concentration compatible with the diagnosis of growth hormone overproduction. Magnetic resonance imaging of the pituitary gland revealed a microadenoma.

Somatostatin analog treatment is associated with an increased sleep latency in patients with long-term biochemical remission of acromegaly

Background Somatostatin analogs induce alterations in sleep in healthy adults. Presently, it is unknown whether somatostatin analog treatment affects sleep parameters in patients with acromegaly. Design Case-control study. Patients and measurements We assessed sleepiness and sleep patterns in 62 adult patients (32 men, age 61 years (33–88 years) controlled by surgery alone or postoperative radiotherapy (69%), and/or somatostatin analogs (31%). We used two validated sleep questionnaires (Epworth sleepiness score and Münchener chronotype questionnaire). Patient outcomes were compared to controls. Results Sleep duration and timing of sleep were not different in patients compared to controls. However, sleepiness score was increased in all patients compared to controls: 6 (1–20) vs. 4 (0–14), P = 0.014 (median (range)), reflecting increased daytime sleepiness. Snoring was reported in 68% of both patients and controls ( P = 0.996), observed apnoea’s and restless legs in 23% and 37% of patients compared to 12% and 21% of controls ( P = 0.062 and P = 0.031, resp.). In addition, sleep latency was increased in patients treated by somatostatin analogs compared to patients cured by surgery and/ or radiotherapy (52 ± 48 min vs. 26 ± 40 min, P = 0.005), resulting in a delayed sleep onset (24:08 ± 1:26 h vs. 23:25 ± 0:43 h, P = 0.053). Sleep duration was unaffected. Conclusions Daytime sleepiness is increased in a homogeneous cohort of patients in long-term remission from acromegaly. In addition, somatostatin analog treatment increases sleep latency and delays sleep onset in patients with long-term biochemical control of growth hormone overproduction without altering total sleep duration.

Changes in tissue cellularity are associated with growth enhancement in genetically modified arctic char (Salvelinus alpinus L.) carrying recombinant growth hormone gene.

Biochemical and histological analyses were used to study the number and size of cells (cellularity) in tissues of fast-growing, genetically modified Arctic char (Salvelinus alpinus L.), overexpressing sockeye salmon (Oncorhynchus nerka) growth hormone gene (OnGH1). DNA contents of muscle, heart, and liver were compared in transformed, sibling (age control) and 1 year older (size control) char. Total white muscle cross-sectional area, white muscle fiber number, and total nuclei number within the muscle tissue were determined from one complete half-section of each fish. The analyzed tissues responded differently to growth hormone overproduction. In muscle tissue of OnGH1-transformed char, the enhanced growth was clearly associated with proliferation of muscle cells (hyperplasia), whereas in heart tissue both cell proliferation and increase in cell size (hypertrophy) were enhanced. The relative DNA concentration in the liver of transformed char was significantly greater than that of control fish, suggesting reduction in size of hepatic cells.

Systemic over-secretion of growth hormone in transgenic mice results in a specific pattern of skeletal modeling and adaptation.

The effects of growth hormone (GH) over-secretion on bone modeling and remodeling in transgenic mice were investigated using systematic and hierarchical methods. The results showed that continual systemic stimulation of GH over-secretion in mice resulted in an initial increase in bone mass, but its bone quality was not comparable with that of the littermate controls. Further continual over-stimulation of GH resulted in an increase in bone resorption leading to thinner cortices with inferior tissue mechanical properties. Three biological mechanisms following GH over-production are formulated to explain the observed results: GH over-secretion stimulated the production of inferior bone matrices, i.e., woven bone and cartilage, in addition to the production of normal lamellar bone; the increased bone formation stimulated by GH was followed by an exaggerated bone resorption process, resulting in cortical tissue with inferior mechanical properties; and a cortical shift occurred following GH over-stimulation that appeared to be caused by the combined effects of GH over-secretion and a variation in mechanical stimuli in the metallothionein-1 growth hormone regulating hormone transgenic mice. An "Optimal Strain Environment" model is proposed to help explain the observed results. From the results of the present and previous studies, we believe that the primary goal of bone adaptation to a biological perturbation, at least in mice, is to ensure proper mechanical function by maintaining structural integrity. In the process of maintaining a targeted whole bone structural integrity, the mechanical integrity of tissue may be sacrificed.

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice.

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

Actions and interactions of growth hormone and insulin-like growth factor-II: body and organ growth of transgenic mice.

To characterize long-term actions and interactions of growth hormone (GH) and insulin-like growth factor-II (IGF-II) on postnatal body and organ growth, hemizygous phosphoenolpyruvate carboxykinase (PEPCK)-human IGF-II transgenic mice were crossed with hemizygous PEPCK-bovine GH transgenic mice. The latter are characterized by two-fold increased serum levels of IGF-I and exhibit markedly increased body, skeletal and organ growth. Four different genetic groups were obtained: mice harbouring the IGF-II transgene (I), the bGH transgene (B), or both transgenes (IB), and non-transgenic controls (C). These groups of mice have previously been studied for circulating IGF-I levels (Wolf et al., 1995a), whereas the present study deals with body and organ growth. Growth curves (week 3 to 12) were estimated by regression with linear and quadratic components of age on body weight and exhibited significantly (p < 0.001) greater linear coefficients in B and IB than in I and C mice. The linear coefficients of male I and C mice were significantly (p < 0.001) greater than those of their female counterparts, whereas this sex-related difference was absent in the bGH transgenic groups. The weights of internal organs as well as the weights of abdominal fat, skin and carcass were recorded from 3.5- to 8-month-old mice. In addition, organ weight-to-body weight-ratios (relative organ weights) were calculated. Except for the weight of abdominal fat, absolute organ weights were as a rule significantly greater in B and IB than in I and C mice. IGF-II overproduction as a tendency increased the weights of kidneys, adrenal glands, pancreas and uterus both in the absence and presence of the bGH transgene. Analysis of relative organ weights demonstrated significant (p < 0.05) effects of elevated IGF-II on the relative growth of kidneys (males and females) and adrenal glands (females), confirming our previous report on organ growth of PEPCK-IGF-II transgenic mice. In females, IGF-II and GH overproduction were additive in stimulating the growth of spleen and uterus, providing evidence for tissue-specific postnatal growth promoting effects by IGF-II in the presence of elevated IGF-I.

Effects of growth hormone overproduction on grip strength of transgenic mice

Growth hormone (GH) is used by athletes like bodybuilders to increase muscle strength and weight gain. On the other hand, chronic hypersecretion of GH in active acromegaly may result in outwardly hypertrophied but functionally weaker muscles. As a model for studying long-term effects of GH on muscle strength, we analysed transgenic mice (TM) carrying rat phosphoenolpyruvate carboxykinase-bovine GH (PEPCKbGH) fusion genes, which are expressed in liver and kidney but not in skeletal muscle. Circulating GH levels in TM ranged between 0.5 and 3 micrograms/ml, resulting in increased (p < 0.001) body weight (wt) as well as increased (p < 0.01) weights of forelimb and hindlimb muscles. However, muscle weight/body wt ratios of TM were 16-20% smaller than in controls (p < 0.05). Forelimb grip strength of hemizygous TM (16 males, 132 +/- 45 days old, body wt = 56.8 +/- 8.3 g; 32 females, 146 +/- 38 days old, body wt = 54.9 +/- 6.1 g) and non-transgenic controls (28 males, 127 +/- 47 days old, body wt = 40.5 +/- 2.9 g; 33 females, 126 +/- 47 days old, body wt = 32.1 +/- 3.6 g) was determined using an automated grip strength meter. Data were computed by analysis of variance, taking into account effects of group, sex and age. Least-squares means estimated for the grip strength (N) of male TM (1.91) and controls (1.92) were significantly (p < 0.05) greater than those of female TM (1.78) and controls (1.61). A significant difference between groups was only seen in females (p < 0.01). Least-squares means estimated for grip strength/body wt ratios (N/10 g) of male (0.34) and female TM (0.33) were 29% and 35% lower than those of male (0.48) and female controls (0.51), respectively (p < 0.001). In summary, long-term elevated GH levels in TM increased muscle weight less efficiently than body weight, and muscle strength did not increase proportionally with muscle weight.

Early postoperative basal serum GH level and the GH response to TRH in relation to the long‐term outcome of surgical treatment for acromegaly: a report on 39 patients

During a 10-year period 39 patients with acromegaly, aged 23-73 years, underwent selective adenomectomy via a trans-sphenoidal or transfrontal (one case) approach. Six to 12 months after the operation, the serum level of growth hormone (GH) was reduced to less than 5 micrograms l-1 in 28 patients (74%) in at least two of three random samples and/or suppressed to less than 3 micrograms l-1 during an oral glucose load, thus fulfilling the commonly used criteria for a successful operation. In 10 patients these criteria for adequate GH reduction were not fulfilled, but their median S-GH level was reduced from 38 to 11 micrograms l-1 (P less than 0.01) after the operation. Surgery was successful in 11 of 13 (85%) patients with a microadenoma (less than 10 mm in diameter), in 10 of 14 (71%) patients with an adenoma of diameter greater than 10 mm but still enclosed in the sella, and in seven of 11 (64%) patients with locally invasive tumours. Impaired pituitary function was observed in 23% of the patients after surgery, independent of tumour size. In one patient the postoperative period was complicated by a lethal intracranial infection. During follow-up for 1-10 years, four patients relapsed, after 1, 1.5, 6 and 9 years, respectively. Patients for whom surgery appeared to have been ineffective at the evaluation 6-12 months postoperatively, or who later relapsed were identified by early (within 7 d) postoperative serum GH with a sensitivity of 90%. The accuracy for identification of a satisfactory outcome of surgery was 85%, and the predictive value was 90%. The corresponding values for the GH response to TRH measured 6-12 months postoperatively were 47, 40 and 54%, respectively. It is concluded that the basal level of serum GH measured 1-7 d postoperatively has higher sensitivity and specificity than the GH response to TRH 6-12 months postoperatively for evaluation of the effect of surgery on GH overproduction, and that it has a higher predictive power with regard to the long-term outcome of surgery for acromegaly.

Acromegaly and thymic hyperplasia: a case report

Growth hormone overproduction is characterized by increased size of visceral organs as well as growth of bone and soft tissues. We describe a case of a 23-year-old female acromegalic patient, who had been previously unsuccessfully operated upon by transsphenoidal pituitary surgery and then irradiated. In November 1987 a routine X-ray chest examination revealed a mediastinal mass, subsequently confirmed by CT scan. The patient underwent surgical removal of the mass: macroscopical aspect, histological sections and immunocytochemistry showed typical thymic structures without any evidence of neurosecretory activity. No GH-positive cells were found and only small amounts of immunoreactive GHRH like material (9.2 ng/g wet wg) were detected in the tumor extract. Before surgery plasma GHRH levels were not elevated (26 pg/ml); serum GH and IGF-I levels were 27.4 +/- 4.9 micrograms/l and 191 nmol/l, respectively, and remained unchanged after surgery. These data ruled out a GHRH and/or GH ectopic production, confirming the primitive pituitary origin of acromegaly in this patient. It is likely that thymic hyperplasia may be explained by longstanding overproduction of GH and the young age of the patient.

Medroxy-progesterone acetate administration to ovariohysterectomized, oestradiol-primed beagle bitches. Effect on secretion of growth hormone, prolactin and cortisol.

Growth hormone (GH), prolactin (Prl) and cortisol secretion was studied in 5 ovariohysterectomized dogs before and after oestradiol implantation and medroxyprogesterone acetate (MPA) administration. MPA was given at regular intervals during a period of 10 months in a total of 12 injections. Short-term effects of oestradiol were restricted to significantly enhanced Prl responses to thyrotropin-releasing hormone (TRH). MPA treatment after oestradiol implantation resulted in significantly elevated basal GH levels in all dogs, with a continuing increase in one dog. Only in the latter dog was a significant decrease in basal Prl levels seen. MPA administration did not significantly change Prl responses to TRH. The GH responses to clonidine were significantly reduced at 9 and 16 weeks of oestradiol and MPA treatment. In the one dog which exhibited the greatest rise in basal GH levels, GH responses were completely abolished at 9, 16 and 43 weeks of oestradiol and MPA treatment. TRH never evoked significant GH responses. Both basal and lysine-vasopressin (LVP)-stimulated cortisol levels were significantly suppressed during combined oestradiol-MPA treatment. These findings denote that in the dog. Oestradiol rapidly induces an enhanced Prl response to TRH. The oestradiol-MPA induced GH overproduction is associated with a reduced responsiveness of GH to clonidine and is not accompanied by GH responsiveness to TRH. Oestradiol-MPA treatment suppresses both basal and LVP-stimulated cortisol secretion.

Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly.

Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 +/- 1.9 mM, mean +/- SEM) were accompanied by fasting hyperinsulinaemia (144 +/- 21 microU/ml, mean +/- SEM) and drastic elevation of plasma growth hormone (GH) levels (112.6 +/- 45 ng/ml, mean +/- SEM). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.

CRITICAL STUDY OF THE GROWTH HORMONE RESPONSE TO DYNAMIC TESTS AND THE INSULIN GROWTH FACTOR ASSAY IN ACROMEGALY AFTER MICROSURGERY

SUMMARYEighteen acromegalic patients were studied 8 months to 5 years after transsphenoidal selective adenomectomy in order to evaluate the most reliable criteria for assessing the efficacy of treatment. Dynamic growth hormone (GH) studies were performed after administration of oral glucose (OGTT), thyrotro‐phin‐releasing‐hormone (TRH) or l‐dopa, and after insulin‐induced hypogly‐caemia. Insulin‐like growth factor (IGF) was measured by means of a competitive protein‐binding assay which detects all somatomedins, particularly those which are GH‐dependent.Of the 18 subjects reported in our study, five showed clinical symptoms of persistent acromegaly. After oral glucose, seven patients had minimum plasma GH levels above 5 ng/ml, five had GH levels between 5 and 2 ng/ml (three of whom maintained a positive GH response to TRH), and six had minimum plasma GH values below 2 ng/ml. Only the latter six patients had normal IGF levels; however, one was still responsive to TRH and three did not increase their GH plasma levels after insulin or l‐dopa administration.Thus, our data suggest that the criteria used to assess the cure of acromegaly should be more rigorous than those generally applied. When plasma GH levels remain above 2 ng/ml after OGTT, it is doubtful that the cure is complete. A positive GH response to TRH after neurosurgery indicates incomplete removal of the adenoma. The lack of a GH response following insulin‐induced hypoglycaemia and l‐dopa administration suggests that the initial somatotroph dysfunction persists. Finally, high plasma IGF levels point to residual GH overproduction. The definition of cure in acromegaly should involve stricter biochemical criteria than those currently in use.