DHEA-S levels in hypopituitaric patients with severe GH deficiency are strongly reduced across lifespan. Comparison with IGF-I levels before and during rhGH replacement

Abstract

Both IGF-I and DHEA-S undergo an age-related decrease and their decrease could be involved in age-related changes in body composition, structure functions and metabolism. On the other hand, it is well known that mean IGF-I levels are clearly reduced in hypopituitaric patients with GH deficiency (GHD) while data about dehydroepiandrosterone sulfate (DHEA-S) levels in hypopituitarism are scanty. We evaluated DHEA-S and IGF-I levels and their relationship in 90 patients with panhypopituitarism (HYPOPIT) with severe GHD [49 women and 41 men; age, mean+/-SE: 47.9+/-1.49 yr, range: 20-80 yr, BMI: 26.4+/-0.6 kg/m2; 21 with childhood-onset (CO) and 69 with adult-onset (AO) HYPOPIT]. DHEA-S and IGF-I levels were also evaluated in 24 HYPOPIT with GHD after 3-month recombinant human GH (rhGH) replacement. Data in HYPOPIT were compared with those in a large group of healthy controls (NS, 233 women and 103 men, aged 20-80 yr; all subjects were within +/-15% of their ideal body weight). In NS both DHEA-S levels and IGF-I were gender-independent while showed a strong, inverse correlation with age (r=-0.6; p<0.001 and r=-0.56; p<0.0001, respectively). Nevertheless, no relationship was found between DHEA-S and IGF-I levels in NS. In HYPOPIT, age-adjusted mean DHEA-S and IGF-I levels were clearly lower than those in NS (2.3+/-0.4 vs 16.0+/-0.7 microg/l, p<0.005; 71.1 +/- 4.5 vs 170+/-4.7 microg/l, p<0.005). IGF-I levels in CO-HYPOPIT were lower (p<0.01) than those in AO-HYPOPIT (49.6+/-4.8 vs 77.0+/-5.4 microg/l), while DHEA-S levels were similar in both subgroups (2.6+/-0.7 vs 2.3+/-0.4 microg/l). In HYPOPIT both DHEA-S and IGF-I were independent of age and gender while there was a trend toward a positive association between each other (r=0.45; p<0.003). Analyzing individual levels in HYPOPIT with respect to age-adjusted normal ranges, IGF-I levels were below normal in 84, 62 and 0% between 20-40, 40-60 and 60-80 yr, respectively. On the other hand, DHEA-S levels were below normal in 84, 86 and 67% between 20-40, 40-60 and 60-80, respectively. In HYPOPIT rhGH treatment strikingly increased IGF-I levels (150+/-3.2 vs 85.3+/-4.1 microg/l, p<0.005) while did not modify DHEA-S levels (1.7+/-0.2 vs 1.6+/-0.2 microg/l). In conclusion, our results demonstrate that DHEA-S and IGF-I are negatively and independently associated to age in physiological conditions but not in hypopituitaric patients in whom both are strikingly reduced. Both DHEA-S and IGF-I levels in HYPOPIT show some overlap with those in normal subjects; thus the assay of these parameters is not diagnostic for hypopituitarism. DHEA-S reduction in HYPOPIT does not depend on IGF-I as indicated also by evidence that GH replacement restores IGF-I but does not modify DHEA-S levels.

The effect of growth hormone replacement therapy on adrenal androgen secretion in adult onset hypopituitarism

“…In the present study, the dose of hGH required to obtain a similar response in IGF‐I tended to be lower in ACTH‐sufficient patients than in ACTH‐deficient patients, although the groups also differed in the percentage of patients on oestrogen replacement therapy. Previous studies have shown a positive correlation between DHEAS and IGF‐I levels (Morales et al ., 1994), also described in hypopituitary patients (Aimaretti et al ., 2000). In our study, DHEAS was significantly different between the two groups; it seems possible that the higher DHEAS levels in the ACTH‐sufficient patients may have had a favourable effect on IGF‐I generation.…”

“…Information regarding serum adrenal androgen levels in GH‐deficient individuals has been conflicting and limited to a small number of reports mainly derived from studies performed in children (Cohen et al ., 1981; Ilondo et al ., 1982b; Lew et al ., 1988; Juul et al ., 1998). There are few studies available showing decreased adrenal androgen levels in adult panhypopituitary patients (Young et al ., 1997; Aimaretti et al ., 2000; Miller et al ., 2001). The present study demonstrates that even adult patients with partial hypopituitarism who are ACTH‐sufficient, have decreased serum DHEAS levels despite maintaining normal basal and stress‐stimulated cortisol levels.…”

“…Although we cannot exclude the possibility that the increase in DHEAS levels following GH treatment may merely be a consequence of a direct effect of GH/IGF‐I on the enzymatic activity of the adrenal cortex, this is less likely as it fails to explain the dissociation between cortisol and adrenal androgen secretion and the preferential DHEAS increase at the time of adrenarche (Ibanez et al ., 2000; l’Allemand and Biason‐Lauber, 2000). This view is reinforced further by the absence of an increment in serum DHEAS during GH replacement therapy, despite an adequate increment in IGF‐I levels, in 69 adults with panhypopituitarism and ACTH‐deficiency (Aimaretti et al ., 2000).…”

Diagnosis and Treatment of Hypopituitarism: An Update

“…One study found low DHEA-S levels in all 35 patients with hypopituitarism, implying that a DHEA-S concentration above 53.5 ug/dl (1.4 umol/l) makes the diagnosis of corticotropin deficiency extremely unlikely [17]. However, in the second study, some overlap of DHEA-S concentration in corticotropin deficient patients and those in normal subjects was found [18]. Partial corticotropin deficiency in some patients might explain these discrepant results.…”

RET, a targetable driver of pancreatic adenocarcinoma

“…In addition to the oncogenic activity of RET , several RET polymorphisms have been described in patients with PDA, most of them resulted in enhanced activation of downstream RET signaling . Genetic studies revealed higher allelic frequency of certain single nucleotide polymorphisms (SNPs) in cancer compared to normal controls . These SNPs are associated with increased sensitivity of RET to its ligand GDNF, and increased MAPK pathway activation .…”