CHAPTER 1
Pituitary Gland Therapies

1.1 CUSHING'S DISEASE

1.1.1 Pasireotide

1.1.1.1 Physiology

The Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis influences cortisol regulation through a complex balancing act between stimulatory and inhibitory factors. Corticotrophin-releasing hormone (CRH), produced in the paraventricular nucleus of the hypothalamus, is transmitted by the hypophyseal portal venous system to corticotroph cells in the anterior pituitary gland [1]. CRH subsequently binds to corticotrophin-releasing hormone type 1 receptor (CRH-R1) on the surface of corticotrophs. As a result, ACTH is released from secretory vesicles in corticotrophs. It should be noted that Arginine vasopressin (AVP) further potentiates the anterior pituitary effects of CRH by acting on its cognate Vasopressin subtype 1b receptor (V1b-R) present on corticotrophs. Additionally, CRH promotes the expression of the pro-opiomelanocortin (POMC) gene in the anterior pituitary gland, a process that also increases adrenocorticotropin hormone (ACTH) production as well [2] (see Section 3.1.1).

Subsequently, ACTH binds to the melanocortin-2 receptor (MCR-2) on cells present in the zona fasciculata of the adrenal cortex, leading to increased cortisol synthesis [3]. Adrenal-derived cortisol inhibits the secretion of POMC and ACTH by anterior pituitary corticotrophs through a negative feedback loop [4]. Additional negative feedback inhibition of CRH and AVP synthesis by cortisol occurs at the level of the hypothalamic paraventricular nucleus [5] (see Figure 1.1).

Normal and adenomatous corticotrophs express two subclasses of somatostatin receptors (SSR), namely somatostatin receptor subtype 2 (SSR2) and somatostatin receptor subtype 5 (SSR5). Somatostatin, a hypothalamic peptide, inhibits ACTH production through an inhibitory pathway regulated by circulating cortisol. Indeed, SSR2 receptors are easily downregulated by cortisol, compared to SSR5 (more resistant to negative feedback by cortisol). As a consequence, SSR2 receptor modulators (e.g. octreotide) are less effective in Cushing's disease compared to SSR5 modulators (e.g. pasireotide) [6].

Hypothalamic and pituitary processes: CRH is released under trophic stimulation by various factors, including catecholamines, angiotensin II, serotonin, stress, and cytokines [7]. On the contrary, GABA inhibits CRH release and ultimately ACTH production [8]. CRH from the hypothalamus stimulates anterior pituitary corticotrophs to release their preformed ACTH from secretory vesicles (fast response). Furthermore, CRH increases POMC gene expression by anterior pituitary corticotrophs (slow response).

FIGURE 1.1 Schematic representation of the HPA axis, highlighting critical stimulatory and inhibitory feedback loops.

Furthermore, AVP binds to V1b receptors on corticotrophs which further enhances the action of CRH at the level of the anterior pituitary gland [2]. Activation of dopamine D2 receptors (D2Rs) present on corticotroph cells by hypothalamic-derived dopamine inhibits ACTH synthesis and release (not shown) [9]. Adrenal cortex processes: The binding of ACTH to the MCR-2 receptors present on cells in the zona fasciculata promotes the synthesis of cortisol from cholesterol [3]. Feedback Loops Negative feedback inhibition of POMC and ACTH release is mediated by adrenal-derived cortisol [4]. Furthermore, cortisol inhibits the synthesis of CRH and AVP from paraventricular nuclei in the hypothalamus [5]. Cortisol-mediated inhibition of somatostatin receptor expression on corticotrophs affects SSR2 more than it does SSR5 [6]. + = shows stimulatory factors and feedback loops, and - = shows inhibitory factors and feedback loops.

1.1.1.2 Mechanism of Action

Pasireotide is a near pan-somatostatin receptor analog because it binds to four of the five isoforms of the somatostatin receptor family, namely (SSR1, SSR2, SSR3, and SSR5). Indeed, pasireotide binds to the SSR5 receptor subtype more avidly than the other SSR, thus its demonstrable efficacy in Cushing's disease. Corticotroph tumors in the anterior pituitary gland express more SSR5 receptors than other somatostatin receptor subtypes. Furthermore, cortisol's negative feedback inhibition of somatostatin receptor expression by corticotrophs tends to impact SSR2 receptors more than the SSR5 receptor subtype. Due to its affinity for SSR5 receptors, pasireotide is an ideal therapeutic option for Cushing's disease [10]. Also, see Figure 1.1.

1.1.1.3 Practice Guide

Pasireotide (Signifor) causes hyperglycemia, gastrointestinal discomfort, and cholelithiasis. The reported prevalence of hyperglycemia in clinical trials involving patients with Cushing's disease who received pasireotide ranged from 68.4% to 73% [11]. Therefore, it is reasonable to screen for diabetes before and during treatment with pasireotide [12]. Incretin mimetics, metformin, or insulin are preferred for treating pasireotide-mediated hyperglycemia [13]. The proposed mechanisms of pasireotide-mediated hyperglycemia are shown in Table 1.1.

Somatostatin inhibits both hepatic biliary secretions and contraction of the wall of the gallbladder in normal physiology. As a result, patients exposed to somatostatin analogs (SSAs) are predisposed to forming gallstones [16].

TABLE 1.1 Pathophysiological basis of pasireotide-mediated hyperglycemia.

Source: Adapted from refs. [11, 14, 15].

The typical dose range for immediate-release pasireotide is 0.3-0.9?mg (300-900?mcg) as a subcutaneous injection (thigh, upper arm, or abdomen) twice daily. A long-acting release (LAR) formulation is administered once a month (10-30?mg) intramuscularly as a depot injection by a health worker [13]. In practice, the LAR formulation is introduced after patients have demonstrated a response to immediate-release pasireotide.

Clinical Trial Evidence

SSR5 receptors are abundant in corticotroph tumors, as has been previously mentioned. The Pasireotide B2305 Study group trial investigated the efficacy of pasireotide, a SSA with a profound affinity for the SSR5 receptor, in reducing corticotroph tumor growth [17].

Key Message

Pasireotide led to a halving of median urinary-free cortisol levels in a cohort of patients with confirmed Cushing's disease (persistent, recurrent, or newly diagnosed).

The B2305 pasireotide study group evaluated the efficacy of pasireotide in Cushing's disease. In this pivotal phase 3 trial, 162 subjects with persistent, recurrent, or newly diagnosed Cushing's disease (not considered suitable candidates for transsphenoidal surgery) with urinary-free cortisol (UFC) levels 1.5 times the upper limit of the normal reference range were randomized to subcutaneous pasireotide 600?mcg (n =?82) or 900?mcg (n =?80), twice daily. The primary outcome was UFC levels below or at the upper limit of the normal reference range. There was approximately a 50% reduction in median UFC levels in the second month of the study, and UFC levels stabilized through to the end of the study for all participants [17].

1.1.2 Retinoic Acid

1.1.2.1 Physiology

Regulation of Corticotroph Physiology by Retinoic Acid

The normal corticotroph cell has a POMC promoter gene, which is critical in POMC synthesis and eventual ACTH secretion. In normal physiology, there are retinoid-sensitive mediators (transcription factors) required for the activation of the POMC promoter gene, namely, activator protein 1 (AP-1) and nuclear receptor 77 (Nur77). Retinoic acid (RA), by binding to its nuclear RA receptors inhibits AP-1 and Nur77 expression, thus preventing the activation of the POMC promoter gene [18, 19]. It should be noted that chicken ovoalbumin upstream promoter transcription factor 1 (COUP-TF1) protects AP-1 and Nur77 from direct inactivation by RA...