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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

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Abstract

Discordant GH and IGF-1 levels after adenomectomy are well recognized in acromegalics. The aim of this study was to evaluate the clinical features and natural course of postoperative acromegaly associated with discordant GH and IGF-1 levels over a postoperative period. A total of 69 acromegalics underwent surgery with at least 1 year of follow-up and received 75-g oral glucose tolerance tests (OGTTs) at 3 months postoperatively. The patients were categorized into four groups according to the postoperative nadir GH levels and IGF-1 levels: controlled group (normal GH and normal IGF-1), high-IGF-1 group (normal GH and high IGF-1), high-GH group (high GH and normal IGF-1), and uncontrolled group (high GH and high IGF-1). The incidence of discordant GH and IGF-1 levels was 27.5 %: high-IGF-1 group = 10.1 % (n = 7) and high-GH group = 17.4 % (n = 12). All patients in the high-IGF-1 group exhibited a decline in the IGF-1 level after surgery, with normalization observed in 71.4 % of the patients without additional treatment (median 23 months). These subjects had preoperatively high IGF-1 levels despite not demonstrating higher GH levels than the patients in the controlled group. On the other hand, four patients in the high-GH group exhibited an elevated nadir GH level higher than 1.0 μg/L on repeated OGTTs after 3 months, and one patient experienced a recurrence of acromegaly. Patients in the high-IGF-1 group require no additional treatments, and their IGF-1 levels are likely to normalize within a few years. However, patients in the high-GH group should be carefully followed due to the possibility of recurrence.

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Acknowledgments

This work was supported in part by Research Grants from the Ministry of Health, Labour and Welfare of Japan and the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Yasuyuki Kinoshita, Atsushi Tominaga, Satoshi Usui & Kaoru Kurisu

  2. Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Kazunori Arita

  3. Department of Neurosurgery, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530, Japan

    Tetsuhiko Sakoguchi

  4. Department of Clinical Oncology and Neuro-oncology Program, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Kazuhiko Sugiyama

Authors
  1. Yasuyuki Kinoshita
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  2. Atsushi Tominaga
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  3. Satoshi Usui
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  4. Kazunori Arita
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  5. Tetsuhiko Sakoguchi
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  6. Kazuhiko Sugiyama
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  7. Kaoru Kurisu
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Correspondence to Yasuyuki Kinoshita.

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Comments

Michael Buchfelder, Erlangen, Germany

Acromegaly is usually diagnosed with a pathological secretion of both, growth hormone (GH) and IGF-1. Since IGF-1 secretion is effected by GH, both parameters can be used for diagnosis and follow-up of the disease and one would suppose concordancy. In recent years, what is considered “normal” and “pathological” has been defined and redefined, due to the development of more sophisticated and specific assays. The reference values derive from the normal population, those in which acromegaly was excluded. However, due to the age dependency of normal levels and the assay variability, many problems have been encountered. One of these, a discordance of both hormonal parameters was addressed in the present study by Yasuyuki et al. It must be very irritating for us, that in 27.5 % of their patients 3 months after surgery, one parameter was abnormal and the other one normal. Moreover, they found a different prognostic value of GH and IGF-1 levels. The persistent decline of IGF-1 in the subsequent period might partially be explained by the late effects of preoperative medical treatments and the much longer half life of IGF-1 as compared to GH. Another point might be the arbitrary cutoff levels used. The article challenges the notion in guidelines in which normalization is equated with age-related normal IGF-1 levels and normal suppression of GH during the provocative test of glucose suppression but do not specify at which time after surgery the levels are measured.

Ludwig Benes, Arnsberg, Germany

This well written paper upon a large group of acromegaly patients with discordance in the GH and IGF-1values three month after adenomectomy. Although the problem of discordance of GH- and IGF-1 values is well published, the authors constructively address this problem with their work and give a reasonable management proposal to the reader. The study design is well elaborated. The absolute number of patients is high. The subdivision into 4 groups seems reasonable but actually makes the subgroups very small to allow a clear down-to-earth conclusion. Especially, when having in mind that the the GH-value e.g. is very variable to physical exercise and may raise nearly 100 times as recently published in young hockey players. The decision to treat acromegaly patients postoperatively should not only be decided on the laboratory parameters alone. They should consider the result of the GH- IGF-1 values, the clinical condition and the MRI. The knowledge of all these parameters allows us to decide upon an additional treatment of acromegaly patients immediately after adenomectomy with a resonable follow-up period.

Rudolf Fahlbusch, Hannover, Germany

Yasuyuki et al report on a well known result after adenomectomy in 69 operated acromegalic patients: the discordance of GH and IGF-1 levels.

Both parameters can be used for defining the operative result and for follow up. A burden are the continuously changing “normalization criteria” by the International Acromegaly Study Group”, including arbitrary cut off levels for GH and IGF-1, which depend on development of more sophisticated and sensitive assays .In many centers follow-up is in the hands of endocrinologists. However pituitary surgeons should be able to evaluate and also to manage the next steps for follow up by themselves too, especially if re-operation maybe considered. [1] An optimal way is the solution process in an interdisciplinary conference.

For early evaluation of the surgical result the authors defined two significance groups :the one with normal GH values and elevated IGF-1 levels(10.1%) belonging to the longer half life time IGF-1 can normalize within 3 months and even later. In case there is no longer a tumor remnant in MRI and active symptoms of acromegaly had disappeared observation is justified. In case of florid acromegaly endocrinologists however would be in favour with additional medical treatment by dopaminagonists, also somatostatin analoga.

In the other group (17,4%) with still elevated GH-levels, but normalized IGF-1 levels additional treatment, such as re-operation, medical treatment, even radiotherapy would be indicated by us.

Within postoperative follow up our first evaluation of GH and other pituitary hormones is performed one week after surgery. After 3 months we normally can come to a definite evaluation of all data, including IGF-1 .We are not surprised that the authors, without documenting their evaluation times precisely, observe hormonal improvements in rare cases even later. That is why personalized decisions are demanded.

Reference

[1] P Nomikos,M Buchfelder,R Fahlbusch- The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical”cure” Europ J Endocrinol 152(2005) 379-387.

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Discordant GH and IGF-1 in acromegaly

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Kinoshita, Y., Tominaga, A., Usui, S. et al. 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, 313–319 (2016). https://doi.org/10.1007/s10143-015-0692-5

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