Discordance Between GH and IGF-1 in Acromegaly: Insights and Recommendations

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Acromegaly, a rare disease driven by excess growth hormone secretion, often presents with discordant GH and IGF-1 levels post-treatment, challenging remission confirmation. Guidelines stress the importance of post-treatment biochemical marker evaluation, recommending specific thresholds for IGF-1 and GH levels. While these assessments are usually in agreement, cases of discordance highlight the need for careful monitoring and individualized management to ensure optimal outcomes in acromegaly patients.

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GH & IGF-1 Discordance in Acromegaly Rahim Zahedi MD

Introduction Acromegaly is a rare disease typically caused by an excess of growth hormone (GH) secretion from a pituitary adenoma The active disease is characterized by elevations of both GH and insulin-like growth factor-1 (IGF1) and the failure of GH suppression in oral glucose tolerance test(OGTT) Current evaluations estimate the incidence at about 3 4 per million persons per year ,with a prevalence of approximately 60 cases per million in the general population Transsphenoidal surgery is the treatment of choice, but remission is attained in only 50 70 % of cases

After treatment, confirming the remission by biochemical markers is crucial since the clinical parameters are neither sensitive nor specific New consensus guidelines recommend normal IGF1 level (adjusted for age and gender), GH random (GHr) of less than 1 mcg /l, and a GH nadir (GHn) of less than 0.4 mc g/l in OGTT While in most instances these assessments are concordant, cases with discordance (elevated IGF1 and normal GH, or elevated GH and normal IGF1) have been reported

1.1 We recommend measurement of IGF-1 levels in patients with typical clinical manifestations of acromegaly, especially those with acral and facial features. (1+++) 1.2 We suggest the measurement of IGF-1 in patients without the typical manifestations of acromegaly, but who have several of these associated conditions: sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis ,and hypertension. (2|++) 1.3 We recommend measuring serum IGF-1 to rule out acromegaly in a patient with a pituitary mass.

1.5 In patients with elevated or equivocal serum IGF-1 levels, we recommend confirmation of the diagnosis by finding lack of suppression of GH to1 mcg/L following documented hyperglycemia duringan oral glucose load.(1|+++) 4.6 Following surgery, we suggest measuring an IGF-1 level and a random GH at 12 weeks or later(2|+++) .We also suggest measuring a nadir GH level after a glucose load in a patient with a GH greater than 1 mcg/L.(2|+++) 3.1 We suggest a biochemical target goal of an age normalized serum IGF-1 value, which signifies control of acromegaly. (2|++) 3.2 We suggest using a random GH< 1.0 mcg/L as a therapeutic goal, as this correlates with control of acromegaly. (2|+) 3.3 We suggest maintaining the same GH and IGF-1 assay in the same patient throughout management.

Fifty-four consecutive patients (32 female, 22 male) with pathology that confirmed a GH secreting pituitary adenoma were identified. In all cases, the acromegaly diagnosis was also confirmed by biochemical assessment prior to resection. Median follow up for all patients was 22 months (range: 3 60 months) following surgery.

In this review, we have tried to discuss the rate of GH/ IGF1 discordance, the potential causes of such a discrepancy, confounding factors affecting the biochemical assays, and the impact of this discordance over mortality, morbidity and recurrence of the disease. The probable best approach for these patients has also been proposed

Discordance between GH and IGF1 in untreated patients with acromegaly Even in newly diagnosed patients with active acromegaly, noticeable elevated IGF1 levels with apparently normal plasma GH concentrations and vice versa have been occasionally described [28, 47 50] In Minuto et al. [51] study, as much as 30 % of patients had IGF1 values discordant with GH levels. However, this high rate of discordance is not confirmed by others, such as Machado et al. [52] and Mercado et al. [28] who showed the prevalence of such discordance to be 13.7 and 2.4 %

Using an ultrasensitive GH assay, Freda et al. [32] surprisingly found that up to 50 % of patients with active disease based on elevated IGF1 levels had GHn values less than 1.0 mcg/l after OGTT, while 39 % of the patients with apparent remission (normal IGF1) failed to adequately suppress GH In a recent study [62], 13.2 % of patients with normal IGF1 had supra normal GH values Thus, the variations in the definition of cut off values, the method of GH and IGF1 assays, and the lack of accurate information about the timing of GH and IGF1 assessment in different studies make it hard to draw a precise conclusion about the relative frequency of discordant GH/IGF1 patterns after surgery

Important factors affecting serum IGF1 and GH levels Liver produces about 85 % of serum IGF1, but other organs such as kidney, pituitary gland, gastrointestinal tract, muscles and cartilages are also involved [65]

Proposed causes of discordance Discordant values may originate from inaccurate assessment of GH status and lack of agreement between GHn and IGF1 when GH output is too high or too low Furthermore, OGTT may have very high false-negative rate in patients with relatively low GH output [36] the characteristics of GH pulsatility are also important. Patients with acromegaly have indeed a reduced proportion of pulsatile GH secretion and instead show persistently high GH values throughout the day due to more continuous secretion [16, 58] (Disturbed GH pulsatility) This information has led many authors to believe that there is a chronic neurosecretory abnormality in acromegaly that takes time to resolve [57], or even may never be normalized [80]

Proposed causes of discordance It has been speculated that normal GH with elevated IGF1 levels could be depicted by the production of low but continuous levels of GH (tonic secretion) during 24 h [20, 81] Overall, in comparison with normal control groups, the tonic levels of GH secretion have been demonstrated to be elevated in patients with acromegaly [15, 81] The elevated tonic level cannot explain the discordance by itself, but added with the intermittent mild pulsatile secretion it may become more plausible [20].

Proposed causes of discordance The discrepancy can normalize over time, but slightly supranormal GH levels in the presence of normalized IGF1 levels can be related to minimal persistent autonomous GH secretion that can be an early alarm of disease recurrence [39, 49, 57] On the other hand, it can be proposed that an enhanced tissue hypersensitivity to GH could account for fluctuating IGF1 level and some degree of clinical symptoms despite normal GH concentrations [30, 82] Also in some patients with late IGF1 normalization, the persistence of altered metabolic environment and probably the transient development of some degree of autonomy in target tissues can result in GH-independent IGF1 production [57]

Proposed causes of discordance There are several GH isoforms, with the 22-kDa type being the predominant circulating form [83, 84] The ratio between the differing forms of GH may be altered by the stimulation of GH secretory cells, and pituitary tumor may produce a predominant isoform of GH [85] Also, the non 22-kDa GH fraction including a variety of monomers and oligomers can be found in around 26 % of the patients with acromegaly, but, due to some practical and commercial issues the monoclonal antibodies of GH assays currently in use, only recognize 22KDa GH

Proposed causes of discordance The time of IGF1 assay after pituitary surgery for acromegaly is very important The slow decline in IGF1 concentration is probably related to the high sensitivity of the liver to serum GH after surgery due to the current lower GH concentration It might, therefore, be speculated that the transition from a relatively GH-resistant state toward normalized GH sensitivity is accompanied by IGF1 fluctuation until a normal GH responsiveness is established [37]

Proposed causes of discordance GH receptor (GHR) polymorphism also seems to be involved in the GH/IGF1 relationship postoperatively [59, 87] Indeed, d3-GHR carriers did show significantly lower GH levels compared to the subjects with the flfl-GHR haplotype, despite similar circulating IGF1 levels So, patients carrying d3-GHR allele may need lower GH concentrations to produce a given increase in serum IGF1 [59, 71]. Mercado et al. [88] demonstrated deletion of exon 3 to be a stronger predictor of persistently elevated IGF1 concentrations.

Proposed causes of discordance Gender, age, body composition, prior radiotherapy, and medical therapy are all known to alter the relationship between GH and IGF1 in acromegaly and consequently contribute to discordant values Thus, it has been suggested that OGTT should ideally be interpreted in relation to age, gender [24, 58, 91], and body mass index [11, 56].

. A total of 110 patients who had undergone transsphenoidal surgery for GH-secreting pituitary tumors were evaluated at least 6 months after surgery

IGF-I levels remained normal over the follow-up period in 14 subjects in group II. However, five subjects from group II developed an IGF-I level of 15% above their age-adjusted upper limit of normal along with continued abnormal GH suppression. New, persistent elevation of IGF-I level was considered to represent a biochemical recurrence. The rate of disease recurrence in group II was significantly higher than in group I (P = 0.003)

Utility of population based reference data? Ratio of Within to Between subject variances. Index of Individuality = CVI/ CVG Population Ref Intervals: - Index <0.6 = Limited in Value Index >1.4 = Applicable

Ideal test: small CVI high Index of Individuality making reference values useful in many clinical settings. But: Most tests have marked individuality (low II), which minimizes the usefulness of reference values in monitoring, diagnosis, and screening.