Management policy for postoperative acromegaly patients with normal IGF-1 and high GH levels on oral glucose tests

doi:10.21203/rs.3.rs-4855161/v1

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Management policy for postoperative acromegaly patients with normal IGF-1 and high GH levels on oral glucose tests

https://doi.org/10.21203/rs.3.rs-4855161/v1

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Purpose

Acromegaly patients occasionally achieve either the remission criterion of IGF-1 or GH level postoperatively; however, whether additional treatment modalities should be administered in patients with unclear clinical courses remains unclear. This study aimed to clarify the clinical courses and features of postoperative patients with normal IGF-1 and high GH levels and support their management.

Methods

In total, 110 acromegaly patients underwent initial surgery and a 75-gram oral glucose tolerance test (OGTT) 3 months postoperatively. Patients with normal IGF-1 and high GH levels on OGTT (high-GH group) were categorized into three subtypes based on their clinical courses thereafter: late-remission type (nadir GH level on OGTT of < 0.4 µg/L later), recurrence type (elevated IGF-1 and GH levels later), and persistent type (normal IGF-1 levels and constantly high nadir GH levels on OGTTs).

Results

The proportion of patients in the high-GH group was 23.6%, and they were distributed as follows: late-remission type (n = 10), recurrence type (n = 5), and persistent type (n = 8). There were significantly more females (P = 0.0178) than males in the late-remission type, and patients in the persistent type had significantly larger tumors (P = 0.0110) and higher preoperative GH levels (P = 0.0018) than those who achieved complete remission 3 months postoperatively.

Conclusion

Careful monitoring without additional medications is recommended at first in acromegaly patients with normal IGF-1 and high GH levels because of the low recurrence rate, especially in female patients and patients with high preoperative GH levels.

acromegaly

growth hormone

insulin-like growth factor-1

discordance

discrepancy

In 2010, the Acromegaly Consensus Group revisited the guidelines on remission criteria for acromegaly defined in 2000 and defined the postoperative remission of acromegaly as achieving a normal IGF-1 level adjusted for age and sex and a random GH level of < 1.0 µg/L or a nadir GH level of < 0.4 µg/L on the 75-gram oral glucose loading test (OGTT) [1, 2]. Moreover, 30% patients have been reported to achieve either remission criterion of IGF-1 or GH level [1, 3]. However, treatments for patients with discordant IGF-1 and GH levels have not been established because of their unclear clinical courses in long-term postoperative periods.

We previously reported that 27.5% of postoperative acromegaly patients had discordant IGF-1 and GH levels and that high IGF-1 levels in patients with normal GH levels were likely to normalize a few years after surgery [4]. In contrast, the detailed clinical courses of patients with normal IGF-1 and high GH levels could not be clarified because of the small number of patients and short follow-up durations in our previous study [4]. Furthermore, the mechanism underlying normal IGF-1 and high GH levels remains unclear because patients with normal IGF-1 and high GH levels do not always have any clear pharmacological, physiological, or pathological mechanism [5]. In the present study, we focused on acromegaly patients with normal IGF-1 and high nadir GH levels on OGTT performed 3 months postoperatively and retrospectively examined their clinical courses after OGTT and features. Moreover, we proposed a management policy for postoperative acromegaly patients with normal IGF-1 and high GH levels.

This retrospective cohort study was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval no: E-2020-2022-02).

In total, 110 patients initially underwent surgery for GH-producing pituitary neuroendocrine tumor at Hiroshima University Hospital between October 1, 2005 and December 31, 2022 and OGTTs preoperatively and 3 months postoperatively as per standard procedures after overnight fasting. Normal GH secretion was defined as a nadir GH level of < 0.4 µg/L on OGTT [1]. IGF-1 level was evaluated as the standard deviation (SD) score based on a reference range established for the Japanese population that was dependent on both age and sex [6], and a high IGF-1 level was defined as an IGF-1 SD score of ≥ 2.0.

The median ages of 55 males and 55 females were 41.0 and 56.0 years, respectively. The females included 35 patients aged > 50 years old (63.6%). Twenty-three patients had diabetes, which was not well controlled in three cases despite treatment (HbA1c > 8.0%). No patient was administered oral estrogens and had untreated hypothyroidism, liver dysfunction, renal dysfunction, or poor nutrition, which could influence the serum IGF-1 level.

Postoperative endocrinological examinations were performed 3 months after surgery to determine whether the patients met the acromegaly remission criteria. The 110 patients were categorized into four groups according to their IGF-1 SD score and nadir GH level on OGTT performed 3 months postoperatively: 1) remission group: normal IGF-1 level and nadir GH level of < 0.4 µg/L, 2) high-IGF-1 group: high IGF-1 level and nadir GH level of < 0.4 µg/L, 3) high-GH group: normal IGF-1 level and nadir GH level of ≥ 0.4 µg/L, and 4) nonremission group: high IGF-1 level and nadir GH level of ≥ 0.4 µg/L. The median postoperative follow-up period was 71 months (interquartile range: 33.0–116.5 months).

Furthermore, the patients in the high-GH group were divided into three subtypes according to their clinical courses after OGTT performed 3 months postoperatively: late-remission type: nadir GH level of < 0.4 µg/L on OGTT performed after 3 months postoperatively, recurrence type: elevated IGF-1 and nadir GH levels on repeated OGTTs due to tumor recurrence or residual tumor regrowth, and persistent type: normal IGF-1 levels and constantly nadir GH levels of > 0.4 µg/L on repeated OGTTs.

Additional postoperative treatments were conducted after provocative tests that were performed 3 months postoperatively, except in patients with active acromegaly caused by residual tumors (included in the nonremission group). Even patients who were not categorized into the remission group were monitored for IGF-1 and GH levels without medications because of the presence of a normal IGF-1 level or a nadir GH level of < 0.4 µg/L on the OGTT. In addition, we measured random IGF-1 and GH levels on OGTTs every 6–12 months.

Assays

Serum GH levels were assayed using an immunoenzymometric assay (E-test TOSHO II HGH, TOSHO Co, Tokyo, Japan) with a recombinant 22-kDa GH calibrator (International Reference Preparation 98/574), and serum IGF-1 levels were assayed using an immunoradiometric assay (Somatomedin C・II SIEMENS, Siemens Healthcare Diagnostics Inc, NY, USA).

Statistical analysis

All statistical analyses were performed using JMP® Pro software (v. 16.0; SAS Institute, Cary, NC). Data are presented as medians and compared using the Mann–Whitney U, Fisher’s exact, or chi-square test. Differences were considered significant at a P-value of < 0.05.

Patients with discordant IGF-1 and GH levels 3 months postoperatively

The number of patients in the four groups is shown in Table 1. The number of patients in the high-GH group was 26 (23.6%), including 4 patients with a residual tumor on magnetic resonance imaging (MRI) after surgery; nevertheless, they achieved normal IGF-1 levels. Conversely, the number of patients in the high-IGF-1 group was 9 (8.2%). Approximately, one-third of patients had discordant IGF-1 and GH levels 3 months after surgery.

Table 1

Number of patients categorized by IGF-1 and nadir GH levels on OGTT 3 months postoperatively
	IGF-1 SD score < 2.0	IGF-1 SD score ≥ 2.0
Nadir GH < 0.4 µg/L	Remission group	High-IGF-1 group
Nadir GH < 0.4 µg/L	58 (52.7%)	9 (8.2%)
Nadir GH ≥ 0.4 µg/L	High-GH group	Nonremission group
Nadir GH ≥ 0.4 µg/L	26 (23.6%)	17 (15.5%)
Data are expressed as no. (%). SD standard deviation

Nadir GH levels on OGTT in the high-GH group

Figure 1 shows nadir GH levels on OGTT 3 months postoperatively in the high-GH group. The nadir GH levels ranged from 0.4 to 1.0 µg/L on OGTT in 20 (76.9%) patients, including 10 patients in the late-remission type and 5 patients in the persistent type.

Changes in nadir GH levels on OGTT in the high-GH group

Changes in nadir GH levels in the high-GH group are illustrated in Fig. 2. Three patients were lost after OGTT performed 3 months postoperatively in the high-GH group. Thus, the remaining 23 patients were divided into three subtypes: late-remission type (n = 10) (Fig. 2A), recurrence type (n = 5) (Fig. 2B), and persistent type (n = 8) (Fig. 2C). Seven patients in the late-remission type had nadir GH levels of < 0.4 µg/L within 24 months postoperatively (Fig. 2A). In the recurrence type, four patients had elevated nadir GH levels due to the presence of a residual tumor, and one patient had tumor recurrence 24 months postoperatively (Fig. 2B). In the persistent type, all eight patients had normal IGF-1 levels and constantly high GH levels on repeated OGTTs after 3 months (Fig. 2C).

Features of patients in the high-GH group

The features of patients in the late-remission and persistent types were examined and compared with those of patients in the remission group (Table 2). There were significantly more females (P = 0.0178) than males in the late-remission type. In contrast, patients in the persistent type had significantly larger tumors (P = 0.0110) with higher Knosp grades [7] (P = 0.0334) than those in the remission group. Furthermore, preoperative endocrinological findings revealed that baseline GH (P = 0.0018) and nadir GH (P = 0.0046) levels on OGTT were higher in the persistent type than in the remission group.

Table 2

Comparison of the clinicopathologic characteristics between patients in the remission group and in the late-remission type or in the persistent type
	Remission group	High-GH group
	Remission group	Late-remission type	P value	Persistent type	P value
n	58	10		8
Age (years)	49.5	59.0	0.0889	45.0	0.8058
Sex (female), n	22 (37.9%)	8 (80.0%)	0.0178	5 (62.5%)	0.2561
Female of > 50 years old, n	17 (77.3%)	6	> 0.9999	2	0.1358
BMI	23.6	23.0	0.7233	24.8	0.3154
Preop endocrinological findings
OGTT
Base GH (µg/L)	10.1	6.6	0.8562	37.8	0.0018
Nadir GH (µg/L)	7.9	8.0	0.8152	27.7	0.0046
IGF-1 (µg/L)	655.4	606.0	0.4079	682.8	0.6642
IGF-1 SD score	6.5	6.2	0.8278	6.7	0.4024
TRH responder, n	44/53 (83.0%)	8/8 (100%)	0.5911	5/7 (71.4%)	0.6017
LHRH responder, n	10/53 (18.9%)	2/8 (25.0%)	0.6500	2/7 (28.6%)	0.6187
MRI findings
Tumor size (mm)	14.0	18.0	0.1717	23.5	0.0110
Knosp grade [7] 0–2, n	54 (93.1%)	9 (90.0%)	0.5604	5 (62.5%)	0.0334
MIB-1	1.0	1.0	0.6273	1.5	0.7814
Postop endocrinological findings
OGTT
Base GH (µg/L)	0.7	1.7	0.0055	2.5	0.0005
Nadir GH (µg/L)	0.2	0.5	< 0.0001	0.9	< 0.0001
IGF-1 (µg/L)	171.2	143.5	0.0908	189.2	0.5793
IGF-1 SD score	0.4	0.3	0.7488	0.2	0.7833
Data are expressed as no. (%) and medians. BMI body mass index; OGTT 75-gram oral glucose tolerance test; Preop preoperative; Posto postoperative; SD standard deviation

Illustrative case (Persistent type)

A 48-year-old man was referred to our department with acromegalic features. Random GH and IGF-1 levels were 20.7 µg/L and 995 µg/L (SD score: 8.5), respectively. MRI revealed a pituitary tumor on coronal gadolinium-enhanced T1-weighted imaging (Fig. 3A). Total tumor removal was confirmed through intraoperative findings and postoperative coronal gadolinium-enhanced T1-weighted imaging (Fig. 3B). Although the IGF-1 level declined to the normal range 3 months postoperatively (IGF-1: 223 µg/L; SD score: 1.1), the nadir GH level on OGTT was 1.3 µg/L. Thereafter, nadir GH levels on repeated OGTTs remained in the 0.4–1.0 µg/L range for 7 years without medications (Fig. 4).

Some acromegaly patients achieve a normal criterion of either IGF-1 level or nadir GH level of < 0.4 µg/L on OGTT after surgery [8–10]. In the present study, we demonstrated that the proportion of acromegaly patients with normal IGF-1 and high nadir GH levels on OGTT 3 months postoperatively was 23.6%; these patients were categorized into three subtypes based on their clinical courses after OGTT was performed 3 months postoperatively.

The simplest reason for the high postoperative GH levels on OGTT was the presence of residual tumor cells after surgery. In this study, some patients with visible residual tumors on MRI achieved normal IGF-1 levels, possibly due to the low GH secretion character of the tumor. It is reasonable that some patients with invisible remnant tumor cells temporarily achieve normal IGF-1 levels. These patients have a potential risk of IGF-1 and GH level elevation due to tumor recurrence during long-term follow-up.

In this study, patients without recurrence in the high-GH group were divided into two subtypes: late-remission and persistent types. Patients in the late-remission type were mostly females. Sex differences play an important role in the GH axis. Healthy females secrete more GH than males despite comparable IGF-1 levels [11], and female patients with GH deficiency require a higher dose of GH preparation than males to attain appropriate serum IGF-1 levels [12]. Furthermore, female acromegaly patients exhibit higher GH levels than males despite comparable IGF-1 levels [13–15]. The main mechanism underlying sex differences was identified to be the direct and indirect influence of estrogen on the GH axis [15–18]; moreover, sex differences were reported to continue in postmenopausal periods [8, 13]. Based on these facts, female acromegaly patients are likely to have high GH levels in proportion to normal IGF-1 levels after surgery, and high GH levels in female patients with normal IGF-1 levels may slowly decline after surgery compared with those in male patients. Female patients with normal IGF-1 and high GH levels should be carefully assessed to determine whether additional treatment modalities are needed.

Patients in the persistent type maintained normal IGF-1 and constantly high nadir GH levels on OGTTs repeated in long-term postoperative periods. This might be caused by the current remission criteria for acromegaly. The remission criteria for acromegaly have been strictly revised to enhance precision [1, 2]. Per the former criterion of a nadir GH level of < 1.0 µg/L on OGTT, more than half of the patients in the persistent type met the remission criteria for acromegaly. It is reasonable that the proportion of patients with normal IGF-1 levels and high GH levels depends on the GH remission criteria [8]. In practice, patients with the persistent type may have a potential risk of tumor recurrence similar to patients with the recurrence type because they had large and invasive tumors in the present study. However, patients with persistent type may be an independent unique group because the current remission criteria are not suitable for all individual acromegaly patients. Patients with the persistent type (who might have a failed original homeostasis of the GH–IGF-1 axis due to their disease) could stray from the current remission criteria for acromegaly. In some patients with high preoperative GH levels, the nadir GH levels on postoperative OGTT may not achieve the current normal criterion of < 0.4 µg/L without tumor recurrence in long-term postoperative periods. These patients should be identified and carefully monitored without additional treatment modalities until obvious acromegaly recurrence is confirmed.

Limitations

First, the number of patients was small and the follow-up durations were too short to examine the outcomes of acromegaly; therefore, further studies in more number of patients and for longer periods are needed. Second, OGTTs were conducted 3 months postoperatively. The timing of postoperative examinations may have affected the study’s results. Despite these limitations, this study reveals important information on the clinical course and features of patients with normal IGF-1 and high GH levels, providing clues for improved long-term acromegaly management.

Postoperative acromegaly patients with normal IGF-1 level and high nadir GH level of ≥ 0.4 µg/L on OGTT have a possibility of remission and should be carefully monitored without additional treatment modalities until obvious acromegaly recurrence is confirmed. Female patients are likely to achieve complete remission criteria after 3 months postoperatively. Patients with high preoperative GH levels may have constantly high nadir GH levels on repeated OGTTs without recurrence in long-term postoperative periods.

Funding:

This study was partially supported by JSPS KAKENHI (grant number: JP23K066970A).

Conflicts of interest/Competing interests:

The authors declare no conflict of interest in association with the present study.

Ethics approval:

This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (E-2020-2022-02).

Disclosure statement: The contents of this manuscript have not been published in full elsewhere in any form.

Author Contribution

YK: Conception and design. YK, FY, ATa, ATo, and SO: Acquisition of data. YK: Analysis and interpretation. YK: Drafting the article. FY, ATo, and NH: Critically revising the article. NH: Study supervision. All authors reviewed the manuscript.

Acknowledgement

The authors would like to thank Enago for the English language review.

Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S (2010) A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95(7):3141–3148. https://doi.org/10.1210/jc.2009-2670
Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S (2000) Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 85(2):526–529. https://doi.org/10.1210/jcem.85.2.6363
Kanakis GA, Chrisoulidou A, Bargiota A, Efstathiadou ZA, Papanastasiou L, Theodoropoulou A, Tigas SK, Vassiliadi DA, Tsagarakis S, Alevizaki M (2016) The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis. Clin Endocrinol (Oxf) 5(5):681–688. https://doi.org/10.1111/cen.13129
Kinoshita Y, Tominaga A, Usui S, Arita K, Sakoguchi T, Sugiyama K, Kurisu K (2016) Clinical features and natural course of acromegaly in patients with discordance in the nadir GH level on the oral glucose test and the IGF-1 value at 3 months after adenomectomy. Neurosurg Rev 39(2):313–318. https://doi.org/10.1007/s10143-015-0692-5
Peixe C, Sánchez-García M, Grossman AB, Korbonits M, Marques P (2022) Biochemical discrepancies in the evaluation of the somatotroph axis: elevated GH or IGF-1 levels do not always diagnose acromegaly. Growth Horm IGF Res 64:101467. https://doi.org/10.1016/j.ghir.2022.101467
Isojima T, Shimatsu A, Yokoya S, Chihara K, Tanaka T, Hizuka N, Teramoto A, Tatsumi KI, Tachibana K, Katsumata N, Horikawa R (2012) Standardized centile curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a normal Japanese population using the LMS method. Endocr J 59(9):771–780. https://doi.org/10.1507/endocrj.ej12-0110
Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary-adenomas with invasion of the cavernous sinus space - a magnetic-resonance-imaging classification compared with surgical findings. Neurosurg 33(4):610–618. https://doi.org/10.1227/00006123-199310000-00008
Campana C, Cocchiara F, Corica G, Nista F, Arvigo M, Amarù J, Rossi DC, Zona G, Ferone D, Gatto F (2021) Discordant GH and IGF-1 results in treated acromegaly: impact of GH cutoffs and mean values assessment. J Clin Endocrinol Metab 106(3):789–801. https://doi.org/10.1210/clinem/dgaa859
Elias PC, Lugao HB, Pereira MC, Machado HR, Castro M, Moreira AC (2010) Discordant nadir GH after oral glucose and IGF-I levels on treated acromegaly: refining the biochemical markers of mild disease activity. Horm Metab Res 42(1):50–55. https://doi.org/10.1055/s-0029-1239522
Alexopoulou O, Bex M, Abs R, T'Sjoen G, Velkeniers B, Maiter D (2008) Divergence between growth hormone and insulin-like growth factor-I concentrations in the follow-up of acromegaly. J Clin Endocrinol Metab 93(4):1324–1330. https://doi.org/10.1210/jc.2007-2104
van den Berg G, Veldhuis JD, Frölich M, Roelfsema F (1996) An amplitude-specific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. J Clin Endocrinol Metab 81(7):2460–2467. https://doi.org/10.1210/jcem.81.7.8675561
Span JP, Pieters GF, Sweep CG, Hermus AR, Smals AG (2000) Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement. J Clin Endocrinol Metab 85(3):1121–1125. https://doi.org/10.1210/jcem.85.3.6463
Dal J, Rosendal C, Karmisholt J, Feldt-Rasmussen U, Andersen MS, Klose M, Feltoft C, Heck A, Nielsen EH, Jørgensen JOL (2023) Sex difference in patients with controlled acromegaly-a multicentre survey. Clin Endocrinol (Oxf) 98(1):74–81. https://doi.org/10.1111/cen.14750
Dal J, Skov BG, Andersen M, Feldt-Rasmussen U, Feltoft CL, Karmisholt J, Nielsen EH, Dekkers OM, Jørgensen JOL (2021) Sex differences in acromegaly at diagnosis: a nationwide cohort study and meta-analysis of the literature. Clin Endocrinol (Oxf) 94(4):625–635. https://doi.org/10.1111/cen.14392
Parkinson C, Ryder WD, Trainer PJ (2001) The relationship between serum GH and serum IGF-I in acromegaly is gender-specific. J Clin Endocrinol Metab 86(11):5240–5244. https://doi.org/10.1210/jcem.86.11.8006
Birzniece V, Ho KKY (2017) Sex steroids and the GH axis: implications for the management of hypopituitarism. Best Pract Res Clin Endocrinol Metab 31(1):59–69. https://doi.org/10.1016/j.beem.2017.03.003
Birzniece V, Sutanto S, Ho KK (2012) Gender difference in the neuroendocrine regulation of growth hormone axis by selective estrogen receptor modulators. J Clin Endocrinol Metab 97(4):E521–527. https://doi.org/10.1210/jc.2011-3347
Meinhardt UJ, Ho KK (2006) Modulation of growth hormone action by sex steroids. Clin Endocrinol (Oxf) 65(4):413–422. https://doi.org/10.1111/j.1365-2265.2006.02676.x

No competing interests reported.

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You are reading this latest preprint version

Management policy for postoperative acromegaly patients with normal IGF-1 and high GH levels on oral glucose tests

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Assays

Statistical analysis

Results

Patients with discordant IGF-1 and GH levels 3 months postoperatively

Nadir GH levels on OGTT in the high-GH group

Changes in nadir GH levels on OGTT in the high-GH group

Features of patients in the high-GH group

Illustrative case (Persistent type)

Discussion

Limitations

Conclusions

Declarations

Funding:

Author Contribution

Acknowledgement

References

Additional Declarations

Status:

Version 1