Preoperative Normalization of Cortisol Levels in Cushing's Disease After Medical Treatment: Consequences for Somatostatin and Dopamine Receptor Subtype Expression and In Vitro Response to Somatostatin Analogs and Dopamine Agonists

Pas, Rob van der; Feelders, Richard A; Gatto, Federico; Bruin, Christiaan de; Pereira, Alberto M.; Koetsveld, Peter M. van; Sprij-Mooij, Diana; Waaijers, A. M.; Dogan, Fadime; Schulz, Stefan; Kros, Johan M.; Lamberts, S. W. J.; Hofland, Leo J.

doi:10.1210/jc.2013-1987

Cited by 44 publications

(36 citation statements)

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“…The studies are described in the text (Lamberts et al 1989a,b, Biller et al 2008. After eucortisolemia restoration, SSTR2 expression recovers, becoming similarly abundant to SSTR5, thus improving treatment responsiveness (Feelders et al 2010a, van der Pas et al 2013. The SSTR2 mRNA expression, however, did not correlate with protein levels.…”

Section: Somatostatin Receptor Ligandsmentioning

confidence: 98%

Treatment of Cushing's disease: a mechanistic update

Cuevas‐Ramos¹,

Fleseriu²

2014

Journal of Endocrinology

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Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.

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Section: Somatostatin Receptor Ligandsmentioning

confidence: 98%

Treatment of Cushing's disease: a mechanistic update

Cuevas‐Ramos¹,

Fleseriu²

2014

Journal of Endocrinology

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“…Briefly, to perform β-arrestin, GRK-2, and SSTR mRNA evaluation, we isolated poly A + mRNA from adenoma tissues using Dynabeads Oligo (dT) 25 (Dynal AS, Oslo, Norway). cDNA was synthesized using the poly A + mRNA, which was eluted from the beads in H 2 O twice for 2 min at 65°C, using Oligo (dT)12 -18 Primer (Invitrogen).…”

Section: Quantitative Pcrmentioning

confidence: 99%

“…Immunostaining and subsequent immunoreactivity score (IRS) evaluation were performed as previously described (10,25). Briefly, formalin-fixed paraffinembedded tissues were cut, deparaffinized, and rehydrated.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly

Gatto

Biermasz

Feelders

et al. 2016

European Journal of Endocrinology

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Objective: The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst 2 ) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function. Design: To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands. Methods: β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients. Results: β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = -0.69, P = 0.0011 and ρ = -0.67, P = 0.0016). Conclusions: Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.

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“…Somatotroph and lactotroph adenomas frequently have SSTR1, SSTR5 and SSTR2 expression (Hofland et al 2004, Thodou et al 2006, Taboada et al 2007, Fusco et al 2008, Cuny et al 2012, Ibáñez-Costa et al 2016; and corticotroph adenomas typically express SSTR5 (Arnaldi & Boscaro 2010, Feelders et al 2010, Colao et al 2012, Golor et al 2012, Lu et al 2013, Ibáñez-Costa et al 2016. Classic SSAs aimed to SSTR2 are not effective although corticotroph tumours express high levels of SSTR5 followed by SSTR2 (Hofland et al 2005, Batista et al 2006, de Bruin et al 2009b, Tateno et al 2009, Lupp et al 2012, van der Pas et al 2013, Ibáñez-Costa et al 2016, probably, at least partly, because high levels of glucocorticoids decrease SSTR2 levels (de Bruin et al 2009a). Several studies focused on the role of SSA on gonadotrophderived tumours, particularly on non-functioning pituitary adenomas, tumours with gonadotroph origin but without hormone hypersecretion.…”

Section: Somatostatin Analogues and Pituitary Adenomasmentioning

confidence: 99%

AIP and the somatostatin system in pituitary tumours

Ibáñez‐Costa

Korbonits

2017

Journal of Endocrinology

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Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

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Preoperative Normalization of Cortisol Levels in Cushing's Disease After Medical Treatment: Consequences for Somatostatin and Dopamine Receptor Subtype Expression and In Vitro Response to Somatostatin Analogs and Dopamine Agonists

Cited by 44 publications

References 50 publications

Treatment of Cushing's disease: a mechanistic update

Treatment of Cushing's disease: a mechanistic update

Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly

AIP and the somatostatin system in pituitary tumours

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