The results of our study show that patients with either active or medically controlled acromegaly exhibit significant overhydration compared to a reference healthy population, consistent with the systemic effects mediated by GH and IGF-I. In contrast, patients with cured disease show a significantly longer Biavector than those with active disease, suggesting reduced fluid retention; however, their Biavector remains distinct from that of the Italian reference population.

The sodium and water-retaining effect of the somatotropic axis has been recognized for decades, first identified in rats and later confirmed in human beings [9, 29]. As of today, however, the pathophysiological mechanism has not been fully elucidated yet and several direct and indirect pathways have been proposed, since both GH and IGF-I have specific receptors at the renal level [10]. Specifically, increased sodium reabsorption appears to depend on hyperactivation of the epithelial sodium channel (ENaC) in the collecting duct, resulting in an increase of TBW and ECF [30]. Conversely, an action at the level of the proximal convoluted tubule has been apparently ruled out [30, 31].

In our study, we observed a significant negative correlation between IGF-I and both Rz and Rz/H. Considering that a reduction of these BIVA variables generally indicates an increase in TBW [26, 27], our data confirm that somatotropic hypersecretion may be directly involved in the pathophysiology of fluid overload. Moreover, among the proposed indirect mechanisms of action, involvement of the renin-angiotensin-aldosterone system, inhibition of atrial natriuretic peptide, as well as interaction mediated by AVP or insulin have been suggested [10].

Studies concerning the hydration status in patients with acromegaly are mostly outdated and have certainly confirmed a trend towards TBW and ECF overload [9, 10, 29]. Although isotope dilution remains the gold standard for assessing water distribution in the body [14, 15], science is actively seeking alternatives to reduce sanitary costs and patients’ exposure to radiation. In this regard, BIVA analysis employs a small, portable device and represents a considerably less expensive alternative. Several studies in the past have compared the accuracy of BIA with other methods for assessing body composition, such as dual-energy X-ray absorptiometry (DXA), finding a very high degree of correlation [32, 33]. Of note, this finding has also been recently confirmed in the acromegalic population [22] and such patients were shown to have increased TBW and ECF compared to controls [21, 23].

If the sodium and water-retaining action of the somatotropic axis is mediated primarily by GH and IGF-I, it is reasonable to expect that patients with either medically controlled or cured disease would have a lower tendency towards fluid accumulation compared to those with active disease. In our study, however, no difference in terms of hydration status between patients with active and controlled disease was observed and both groups presented a significant fluid overload compared to a reference healthy Italian population. In contrast, only patients with cured disease showed a reduced hydration status compared to patients with active disease, although no difference was observed with medically controlled patients.

In this regard, it is important to note that patients in the latter group were significantly older than those in the other groups. Older individuals often have more comorbidities and are at greater risk of altered hydration status. Specifically, these patients may experience a decrease in maximal renal water excretion, decreased eGFR, and increased secretion of AVP, while also exhibiting reduced thirst perception and impaired urine concentration ability [34]. However, no significant differences in renal function or u-Osm were observed in our cohort of medically controlled patients compared to the other groups. Therefore, it is possible that the older age in the medically controlled disease group may have both attenuated and exacerbated the impact of GH/IGF-I reduction on water balance in this group [34, 35]. Nonetheless, when comparing individuals of the same age, subjects with cured disease exhibited a longer Biavector compared to those with active disease, indicating a reduced fluid status. Additionally, the number of patients on diuretic therapy (loop and thiazide diuretics) was low and not significantly different across the three groups.

In the study by Lopes et al. [22], similarly, no significant differences in body composition were identified between patients with either active or medically controlled disease. In that study, however, a multifrequency BIA was used and the aim was to assess specifically the quantity of lean or fat mass, while BIVA analysis was not performed.

Regarding the BIVA analysis, it is worth noting that we compared our population data with the normal reference ellipses first proposed by Piccoli et al. in 1995 [19]. While a more recent study redefined these ellipses based on a larger sample, showing a general leftward shift in the mean vectors on the RXc graph [36], it focused on a population aged 18–65 years. In contrast, nearly half of the subjects in our cohort (n = 27) were over 65, which aligns more closely with the broader age range (15–85 years) of Piccoli’s original reference population [19].

Moreover, nearly all patients with medically controlled disease in our cohort were treated with somatostatin receptor ligands, which are generally considered the first-line medical treatment for acromegaly [37]. Although not previously reported in the context of acromegaly, studies conducted initially in rabbits [38, 39] and subsequently in humans [40] have shown that treatment with octreotide is capable of stimulating water and sodium reabsorption predominantly through an action at the level of the small intestine. Indeed, these drugs are also used for the treatment of refractory secretory diarrhea and dumping syndrome [41]. In this regard, therefore, a potential confounding effect of the same medical therapy on the hydration status cannot be completely ruled out.

Finally, patients with cured disease were less affected by diabetes mellitus compared to the other subjects, and as a consequence, they had significantly lower blood glucose levels. This finding seems to confirm that biochemical control of the disease has a positive metabolic impact, potentially leading to the remission of pre-existing diabetes mellitus [42, 43]. Furthermore, diabetes mellitus itself may lead to volume overload, and its resolution or better management, especially through the use of SGLT-2i, has been shown to improve BIVA parameters [18]. In any case, it is relevant to note that in our cohort diabetes mellitus was well-controlled in almost all patients and only 5 individuals were treated with SGLT-2i, thus minimizing the impact of this comorbidity on the results obtained.

Our study presents some strengths and limitations. One strength is the sample size, significantly larger than previous studies [22, 23]. Additionally, unlike other studies, we performed BIVA, which, as previously mentioned, allows for the accurate assessment of hydration status even in unhealthy individuals, based directly on bioimpedance parameters. Finally, we included a subgroup of subjects with cured disease in the absence of medical therapy, and our cohort was quite homogeneous in terms of both sex distribution and disease activity. The major limitation of the study concerns its cross-sectional design, in which patients were evaluated at a single point in their disease history. Additionally, information on water and salt intake was collected through direct inquiry, which may render it less reliable. It is important to note, however, that current evidence does not clearly associate variations in BIVA parameters with differing levels of routine fluid or salt intake. This contrasts with the acute consumption of beverages or food, which can significantly influence bioimpedance results [44, 45]. Finally, in patients with cured acromegaly, the somatotropic axis was not reassessed to exclude potential GHD, which could otherwise contribute to a reduction in body water content [46]. However, only 2 patients among them presented concomitant anterior panhypopituitarism, and only one individual had IGF-I values below the age-normal limit, making it unlikely that this significantly affected our results.