Somatostatin Analogs in Acromegaly

Abstract

Since their introduction into clinical practice, somatostatin analogs have been the medical therapy of choice for the treatment of acromegaly. Therefore, considerable data exist on their use for this purpose. This review summarizes the literature on somatostatin analog therapy of acromegaly and describes its efficacy in terms of the main goals for the treatment of acromegaly, i.e. normalization of hormone levels, GH and IGF-I, relief of the signs and symptoms of acromegaly, and pituitary tumor shrinkage. The side effects of somatostatin analogs and their role as primary therapy for acromegaly are also discussed. The review focuses on the data with the depot analogs because these formulations are most likely to be chosen in clinical practice. The native peptide somatostatin is widely distributed in the central nervous system and peripheral tissues (1–3). Somatostatin is processed from its precursor into its two biologically active forms, somatostatin-14 and somatostatin-28 (2). Native somatostatin has diverse physiological actions, including its role as a central nervous system neurotransmitter and neuromodulator, regulatory hormone in the gastrointestinal tract and pancreas, and inhibitor of GH and TSH release in the pituitary (2, 3). In vitro, native somatostatin retains its inhibitory effect on GH secretion in many GH-secreting tumors, and this led to the development of analogs of somatostatin for clinical use in the treatment of acromegaly (4). The two analogs of somatostatin available for clinical use are the cyclic octapeptides octreotide (Dphe-cys-phe-Dtrp-lys-thr-cys-thr-ol) and lanreotide (Dnal-cys-tyr-Dtrp-lys-val-cys-thr) (1, 5–7). Octreotide is the only analog currently available for clinical use in the treatment of acromegaly in the United States. Lanreotide has been used extensively in Europe for the treatment of acromegaly. Certain properties of these analogs, including their greater potency for GH suppression and longer half-life after peripheral administration than somatostatin, make them advantageous to the native hormone for the treatment of acromegaly. For example, octreotide is 45 times more potent at suppressing pituitary GH secretion than native somatostatin-14 (8) and has a half-life of 2 h when given sc (9). Somatostatin analogs and native somatostatin elicit their biological effects by activating somatostatin receptors. There are five distinct somatostatin receptors, types 1–5 (10). They are all G protein-coupled receptors, but differ in their regulatory/signaling pathways, tissue distribution, and the affinity to which the somatostatin analogs bind to them (6, 10). Relative to native somatostatin, the analogs have a narrowed spectrum of receptor activity that allows for greater specificity of GH suppression. Octreotide and lanreotide have greatest affinity for receptor subtypes 2 and 5, with their affinity for subtype 2 being about 10-fold higher than for subtype 5 (1). Receptor subtypes 2 and 5 are those through which endogenous somatostatin suppression of GH occurs (11) and are also the predominant types of somatostatin receptors found in GH-secreting pituitary tumors (12–15). A significant percentage of GH-secreting pituitary tumors are resistant to octreotide and lanreotide, and this may be explained in part by variable tumoral expression or reduced receptor density of subtypes 2 or 5 on the tumors of these patients (16). The first preparation of somatostatin analog available for clinical use was sc-administered octreotide. After sc injection, serum octreotide levels rise within 30 min and then fall over the next few hours. The maximal suppressive effect of octreotide on GH levels occurs between 2 and 6 h after the injection (17). GH levels rise between injections given every 8 h, but with continued treatment this rise is lessened (9). Importantly also, in somatostatin analog responsive patients, the suppressive effect on GH secretion does not wane with time. The typical dose of octreotide in its sc form is 100–250 μg thrice daily, but doses up to 1500 μg over a 24-h period can be given (18). Octreotide is also available in a long-acting release (LAR) preparation, octreotide LAR, in which octreotide is enclosed in microspheres of a slowly biodegrading polymer that allows for prolonged release of drug (19). After the injection of octreotide LAR, octreotide levels rise briefly, corresponding to release of octreotide from the surface of the microspheres. Octreotide levels then fall and begin to rise again about 7–14 d later after the injection and remain elevated for an average of 34 d (20). Steady-state conditions are usually achieved after two to three injections. GH levels fall and rise in response to the changing octreotide levels (20, 21). The usual starting dose of octreotide LAR is 20 mg with titration down to 10 mg or up to 30 or 40 mg, based on the response of GH and IGF-I levels. The manufacturer recommends monthly drug administration, allowing for an overlap of injectio