The patients of R2 showed similar metabolic parameter changes at 1 week after TSA compared with subjects of R1. Furthermore, no significant differences regarding these metabolic parameters were observed between patients R1 and R2 at 6 months after TSA (Table 2). During serial postoperative OGTTs for 12 months, both FFA levels at basal and 2 h did not differ between R1 and R2 (Fig. 1).
3.3 Glucose homeostasis changes after transsphenoidal adenomectomy
Glucose homeostasis changes were evaluated via OGTT, HOMA-%β, and HOMA-IR scoring. After TSA, most patients exhibited decreased HOMA-%β and HOMA-IR scores. Before TSA, no significant differences were observed in the HOMA-%β and HOMA-IR scores according to acromegaly biochemical status, that is whether the patient achieved remission or not (Table 1).
In R1, the median HOMA-%β score was significantly decreased [from 94.5 (70.7–151.7) to 64.2 (38.7–108.4)] at 1 week after TSA. Furthermore, this decrease in HOMA-%β was maintained throughout the rest of the study (Fig. 2A). Although there was no statistical significance due to the limited number of R2, similar changes of HOMA-%β were also shown in R2.
The patients of R1 and R2 showed abrupt reduction of their HOMA-IR scores at 1 week after TSA. The mean preoperative HOMA-IR score of R1 was 2.9 (2.0–5.4); this score decreased to 1.3 (0.8–1.9) at 1 week and then to 1.1 (0.7–1.5) at 6 months after TSA. This improvement in HOMA-IR score was maintained at least for 12 months after TSA, at which time the median score remained at 1.0 (0.7–1.5). Similar HOMA-IR changes were also observed in R2 (Fig. 2B).
During the OGTT, patients were classified as normal, IFG/IGT, or DM. Although only 15.0% reported previously diagnosed DM, half of the enrolled patients were categorized as DM through the preoperative OGTT. As shown in the changes of HOMA-IR and other metabolic parameters, the classifications of glucose homeostasis during OGTT improved abruptly after TSA and were maintained thereafter for at least 12 months. Regarding glucose homeostasis in the OGTT, similar patterns of change were observed between R1 and R2 (Fig. 3A and B). Among the 67 patients of R1 with DM in the preoperative OGTT, 30 (45.3%) exhibited improved glucose tolerance at 1 week after TSA.
3.4 Effects of each pituitary hormone on metabolic parameters
Hormones in the pituitary axes, including thyroid-stimulating hormone (TSH), gonadotropins, and adrenocorticotropic hormone (ACTH), were evaluated through CPFTs before and serially after TSA. Before TSA, patients with ACTH deficiency had significantly higher HOMA-%β and HOMA-IR scores compared with patients with intact ACTH secretory functions [187.6 (79.5–192.3) vs. 93.2 (63.7–137.7), 4.1 (2.7–6.1) vs. 2.2 (1.8–3.8), respectively]. However, no significant differences in HOMA scores were observed according to the classifications of the deficient pituitary axes after TSA (Fig. 4).
3.5 Body weight changes after transsphenoidal adenomectomy
In addition to the metabolic changes, some patients exhibited abrupt changes in body weight by 1 week after TSA. Specifically, 65 (34.8%) of the 187 enrolled patients presented body weight reduction of at least 1% compared with their preoperative body weight (Table 3). The median body weight decrease was 2.4% (1.6–4.0%) at 1 week after TSA; this decreased body weight was maintained throughout the duration of the study. Before TSA, patients with decreased body weight after TSA had significantly greater body weights, BMIs, fasting glucose level, and HOMA-IR scores. However, no significant differences in age, sex, remission rate, and incidence of preoperative comorbidities (including DM and hypertension) were observed in patients with decreased body weight after TSA. In patients with body weight reduction above 1% at a week after TSA, metabolic parameters including postoperative body weights, BMIs, and HOMA-IR became similar to those of the others at 6 months after TSA. Sixty-three of 65 patients (97%) with body weight reduction at a week after TSA maintained same body weight for up to 12 months. In contrast, only 17 of 122 patients (14%) without weight loss at a week after TSA experienced long-term reduction of body weight during 12 months after TSA.
In this study, we applied different cut-off nadir GH levels during OGTT and evaluated the changes in metabolic parameters in patients with normalized IGF-1 levels after TSA. We analyzed several metabolic parameters during the OGTT, including glucose, FFA, and insulin. The major findings of this study included: no significant difference in the change of any metabolic parameter was observed for nadir GH cut-offs between 0.4 and 1.0 ng/mL; metabolic parameters exhibited abrupt improvements by 1 week after TSA and these improvements were maintained for the duration of the study; and significant body weight reductions after TSA were mainly observed in obese patients with higher HOMA scores.
Metabolic syndrome is a leading cause of death in patients with acromegaly. Excess secretion of GH and IGF-1 has been shown to be associated with insulin resistance in patients with acromegaly.[7,8,17] Furthermore, patients with active acromegaly have been shown to have elevated serum triglyceride, low-density lipoprotein-cholesterol, apoB, and FFA levels. Even during medical treatment for acromegaly, somatostatin analogues and GH receptor antagonists influence glucose intolerance and lipid metabolism. However, few studies have evaluated the effects of surgical resection of the GH secreting pituitary adenoma on metabolic parameter changes. In 1992, M⊘ller et al evaluated metabolic parameters in 7 patients with acromegaly at 1 month prior to and again at 2 months after successful pituitary adenomectomy. They found that patients with active acromegaly exhibited increased serum levels of FFA and other lipid intermediates, reduced forearm uptake of glucose, and increased hepatic glucose production; moreover, these findings were reversed by surgical resection. Serri et al. analyzed 34 patients in remission who exhibited improved glucose tolerance after TSA. However, they failed to demonstrate the serial changes in metabolic parameters after surgical resection.
In this study, we evaluated the changes of metabolic parameters in 187 patients with acromegaly. To accurately evaluate the biochemical status of acromegaly, it is essential to determine the nadir GH level in the OGTT and the IGF-1 level. Previously, we demonstrated that recovery of biochemical activities developed early at a week after TSA and predicted long-term remission in patients with acromegaly (sensitivity 81.7% and specificity 95.1%). In this study, OGTTs were conducted before TSA and then again at 1 week after TSA. Follow-up OGTTs were then performed at 6 month intervals thereafter. Concerning the role of TSA on metabolic changes, we also reported that immediate postoperative changes of GH level during a week predicted the GH deficiency in surgically cured patients with acromegaly. In the current study, all patients exhibited immediate improvement of metabolic parameters by 1 week after TSA. Specifically, body weight, BMI, fasting glucose level, fasting insulin level, fasting FFA level, and postglucose suppressed FFA all exhibited significant changes immediately after TSA. Among these parameters, abrupt reduction of the fasting FFA level was slightly restored at 6 months after TSA and was maintained at these levels. GH and IGF-1 have opposite role in lipid metabolism.[22,23] Although GH excess itself has been shown to stimulate lipid utilization and produce FFA, IGF-1 reduces the circulating FFA in human. On the other hand, GH level decreases abruptly within a few hours and IGF-1 falls slowly during several weeks after TSA. Due to the difference of metabolic effect and time to fall between GH and IGF-1, changes of FFA might be slightly restored at 6 months after TSA. In serial OGTTs, both the fasting and glucose-suppressed FFAs were evaluated for 2 hours. Several studies suggested that glucose-suppressed FFAs present the superior markers to the fasting FFAs in determining the metabolic status. Furthermore, glucose-suppressed FFA presented close correlation with insulin resistance in metabolic syndrome. The patients of R1 and R2 showed identical values in glucose-suppressed FFA levels and maintained for 12 months after TSA (Fig. 1). Among the 187 enrolled patients, 143 patients had been followed up for more than 2 years after TSA. Their metabolic parameters at 2 years had persisted comparable to those at 6 months after TSA.
To minimize the complications associated with GH excess, many experts have consistently suggested lower GH and IGF-1 levels for defining biochemical remission of acromegaly.[11,12] However, excessive suppression of GH in patients with acromegaly is also associated with GH deficiency. In patients with acromegaly, both GH excess and deficiency induce insulin resistance and metabolic impairment. In this study, we compared various metabolic parameters according to 2 different nadir GH cut-offs during the OGTT, 0.4 ng/mL, and 1.0 ng/mL. Although only a limited number of patients exhibited a nadir GH level between 0.4 and 1.0 ng/mL (R2), no significant differences in the postoperative changes of metabolic parameters were observed between the 2 different cut-offs (R1 versus R2). Insulin resistance analysis revealed that the HOMA-IR score was slightly more improved in patients of R2 compared with subjects of R1 (Fig. 1B).
In patients with acromegaly, body weight is increased due to skeletal enlargement and water retention. Moreover, metabolic syndrome and glucose intolerance are more frequent in female patients with acromegaly. However, no significant differences were observed between male and female patients in the present study. Although body weight has been reported to be increased after TSA compared with values before TSA, most patients did not experience weight gain in the present study. Moreover, 65 of the 187 patients had lost more than 1% of their body weight by 1 week after TSA. Furthermore, most patients maintained their new body weights. Interestingly, more obese patients exhibited greater reductions in body weight after TSA. The discrepancy regarding body weight changes after TSA compared with the previous study might be due to race differences and/or the preoperative metabolic conditions of the 2 study populations. The patients in the present study were of a single Asian race. As shown in Table 1, the prevalence of past DM and hypertension were low compared with other studies. Furthermore, most of the enrolled patients had body weights and BMIs in the normal range. Although Reyes-Vidal et al. reported the increased body weight in surgically cured acromegalic patients whose body weight was 90.4 ± 3.4 kg, body weight of subjects was 68.0 (59.5–77.5) kg in this study. Since the majority of the enrolled patients were not obese before TSA, the postoperative changes of metabolic parameters could be influenced by GH itself, rather than other complicated organs involving insulin resistance such as adipose tissue and liver.
Hypopituitarism is an important risk factor for metabolic impairments and glucose intolerance. Although we found that patients with preoperative ACTH deficiencies had even unfavorable HOMA scores before TSA, no significant differences were observed regarding metabolic parameter changes with respect to the classification of the postoperative deficiency of each pituitary axis. Even GH deficiency did not have the significant difference on development of metabolic parameter changes. Since the secretory functions of each pituitary axis were evaluated relatively early (6 months after TSA), hypopituitarism might not have any effect on metabolic parameters.
The limitation of this study is the low number of R2, which were only 21 patients. However, logistic analysis including body weight, BMI, glucose, insulin, and FFA during OGTT also revealed that there was no difference between R1 and R2. Furthermore, degree of improvement in metabolic parameters before and after TSA was also comparable between R1 and R2. Although enough statistical power was not achieved due to the small number of R2, this study demonstrated the first possible evidence that no differences in metabolic parameters were observed between each cut-off of nadir GH during OGTT. Lastly, antihyperglycemic agents might influence the metabolic parameters during OGTT before and after TSA. However, only 4 of 136 (2.9%) patients in R1 and none in R2 received insulin therapy before TSA, and only 1 subject in R1 maintained the insulin at 6 months after TSA. Furthermore, most of patients taking oral antihyperglycemic agents before TSA experienced the reduction (3 of 16 in R1 and 2 of 3 diabetic patients in R2) or cessation (12 of 16 in R1 and 1 of 3 diabetic patients in R2) of medications at 6 months after TSA.
In conclusion, this is the first study to present clinical information regarding serial changes of metabolic parameters in patients with acromegaly who were cured by TSA. Our study is also the first to present this information according to different nadir GH cut-offs during the OGTT. Although most guidelines propose that relatively low GH levels should be used to define biochemical remission in patients with acromegaly, these data indicate that the different cut-offs are not associated with any significant differences, at least concerning the metabolic parameters investigated here. The cut-offs of nadir GH level 0.4 ng/mL during OGTT were not superior to 1.0 ng/mL in predicting better improvement of metabolic parameters in acromegalic patients. To determine the optimal biochemical targets for recovery from GH excess and for normalized metabolic parameters, future studies with large populations and long-term follow-up durations are required.
We appreciate Juyoon Park, RN, MPH, OCN, Hae Won Kim, RN, Eun Sook Kim, RN, Min Kyeong Jang, RN, Sung Ja Kang, RN, and Bok Soon Lee, RN, Pituitary Tumor Clinic, and Soo Yeon Choi, MPH, Department of Medical Recording, for their tremendous effort in performing the pituitary function tests and data acquisition for such a long follow-up duration.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
free fatty acid; gH-secreting pituitary adenoma; hOMA; insulin resistance; oral glucose tolerance test