Somatostatin Health Benefits, Function & Side Effects

Somatostatin Analogs in Acromegaly

Somatostatin Health Benefits, Function & Side Effects

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 ly to be chosen in clinical practice.

Biology of somatostatin and somatostatin analogs

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).

Somatostatin analogs: pharmacodynamics

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, the response of GH and IGF-I levels. The manufacturer recommends monthly drug administration, allowing for an overlap of injections that will maintain sufficiently high octreotide levels.

However, the effect of LAR may be prolonged enough to maintain GH and IGF-I suppression up to 6 or 8 wk after an LAR injection, allowing lengthening of the dosing interval beyond every 4 wk in some patients (22, 23).

Lanreotide is also available in a slow release (SR) preparation where lanreotide is encapsulated in microspheres of biodegradable polymer. After injection of lanreotide SR, lanreotide levels remain elevated for about 11 d (24).

Thus, lanreotide has a shorter duration of suppression of GH levels than octreotide LAR, which requires lanreotide injections to be given at 10–14 d intervals, but the interval may need to be decreased or can be increased in some patients (22).

Criteria for assessing efficacy of somatostatin analogs

The efficacy of somatostatin analogs for the treatment of acromegaly needs to be assessed by a number of important criteria. First, efficacy should be assessed in terms of biochemical control of GH and IGF-I levels. In most studies, GH control has been defined as GH levels obtained at random or from a mean of eight hourly samples of less than 2.0 or 2.

5 μg/liter and in a fewer number of studies as glucose- suppressed GH levels of less than 1.0 μg/liter. It is important to note that with newer highly sensitive GH assays, GH levels less than 2.5 μg/liter do not necessarily ensure normalization of IGF-I levels and biochemical control in all patients (25). However, epidemiological data have shown that a GH level less than 2.

5 μg/liter (when GH is measured by polyclonal RIA) is associated with a reduction of the mortality in acromegaly (26, 27), and therefore this is the GH cutoff used in most somatostatin analog studies. Efficacy should also be assessed as normalization of IGF-I level that is increasingly recognized as an essential criterion for cure of acromegaly (28, 29).

Normalization of IGF-I level has been associated with a reduction of the excess mortality in acromegaly (30). Because most patients with acromegaly have macroadenomas at diagnosis, another crucial aspect of somatostatin analog therapy for acromegaly is their effect on pituitary tumor size.

Other important aspects of somatostatin analog therapy for acromegaly are their effect on the clinical signs and symptoms of acromegaly, the side effects of the analogs, and their efficacy as primary therapy.

Biochemical control

Although most patients treated with somatostatin analogs will have some fall in GH levels, many fewer patients have persistent suppression and normalization of GH levels.

In data combined from many studies of patients treated with depot somatostatin analogs as adjunctive therapy, GH levels were suppressed in 56% of patients treated with LAR (19, 20, 31–34) and 49% of those treated with lanreotide SR (Refs. 7, 24, 35–44 ; Table 1). Considerable variability does exist among the data from different studies (Table 1).

This variability may reflect the wide ranges in number of patients studied (8–149 patients) and in the duration of treatment (6–36 months).

Analysis of data from many studies shows that IGF-I levels with long-term somatostatin analog therapy were normalized in 66% of those treated with octreotide LAR (19, 20, 31–34) and 48% of patients who received lanreotide therapy (7, 24, 35–45). The percentage of patients achieving IGF-I normalization varied among studies (Table 1).

It is important to point out that approximately 90% of patients in the trials with octreotide LAR were preselected for octreotide responsiveness. In most cases, this was determined as acute suppression of GH to less than 5 μg/liter after sc injection of octreotide. By contrast, only about 10% of patients were reported to be similarly selected in lanreotide studies. The extent to which the selection bias in some studies influenced the reported efficacy figures is unknown.

Biochemical efficacy of somatostatin analog therapy for acromegaly

  . GH suppression4 . IGF-I normalization . Mean duration (range) . 
Adjunctive 
  somatostatin 
  analog 
  therapy5 
 Octreotide LAR6 56%1 66%1 20 months 
(47–75%)2 (41–75%)2 (12–36) 
(169/301)3 (204/309)3 
 Lanreotide SR7 49% 48% 18 months 
(14–78%) (30–63%) (6–24) 
(196/404) (199/417) 
Primary 50% 60% 16 months 
 somatostatin (27–77%) (28–90%) (3–39) 
analog therapy8 (108/216) (137/227) 

A number of studies have drawn comparisons among the efficacy of short-acting octreotide, octreotide LAR, and lanreotide SR.

Most studies comparing lanreotide and long-acting octreotide report somewhat greater efficacy with octreotide LAR, but all were sequential in which lanreotide treatment preceded octreotide LAR, so it is difficult to draw any firm conclusions from these data (46–49). One study from Jenkins et al.

(22), a short-term, prospective randomized study in unselected patients, reported that IGF-I levels were normalized in 56% of 11 patients 14 d after lanreotide injection and in 67% of 18 patients 4 wk after octreotide LAR injection.

A number of studies have compared the efficacy of sc octreotide and octreotide LAR. These studies, for the most part retrospective, have reported a similar efficacy for the two preparations (36, 39, 43, 44, 50). In clinical practice, however, it is expected that greater patient compliance with the depot form will result in better control with this formulation.

The efficacy of somatostatin analogs in combination with the dopamine agonists bromocriptine or cabergoline has been examined in a few small studies.

Overall, most studies, although not all, have shown that 10–20% of somatostatin analog-resistant patients have some further suppression of GH and/or IGF-I levels with the addition of a dopamine agonist to somatostatin analog therapy (51–55).

The comparative efficacy of a somatostatin analog combined with bromocriptine vs. cabergoline has not been assessed.

An improvement in the signs and symptoms of acromegaly occurs overall in 64–74% of patients treated with depot analog therapy (7, 20, 34, 37, 39, 41, 42, 44, 45). Studies have reported improvements to varying degrees in headache, soft tissue swelling, arthralgia, carpal tunnel syndrome, snoring, hyperhidrosis, fatigue, and malaise.

With depot somatostatin analog therapy, as has been shown for sc octreotide, more patients subjectively report improvement in the signs and symptoms of acromegaly than the number of patients whose GH/IGF-I levels normalize. Symptomatic improvement is ly due to lowering without complete normalization of GH/IGF-I levels in such patients.

Objective improvement in the clinical manifestations of acromegaly is also an important aspect of treatment of acromegaly. Manifestations of cardiovascular disease, the leading cause of mortality in these patients, can improve with somatostatin analog therapy.

A number of studies have shown improvements with somatostatin analog therapy in cardiac structure and function, including left ventricular mass index, left ventricular hypertrophy, and ejection fraction (56–60). Normalization of IGF-I has also been associated with improvement in cardiac performance on octreotide (61).

An improvement in sleep apnea can also occur in some patients with acromegaly treated with octreotide (62).

Tumor shrinkage

Another very important component of the efficacy of somatostatin analog therapy for acromegaly is its effect on tumor shrinkage (Table 2).

Overall, in combined data from patients receiving either the long-acting analogs or sc octreotide as adjunctive therapy, about 30% of patients had tumor shrinkage (19, 24, 31–33, 35, 37, 40, 41–43, 59, 63–65). Tumor size reduction was most often reported to be between 20 and 50%.

Tumor shrinkage data were available from trials in which approximately 90% of patients treated with octreotide LAR and about 10% of those treated with lanreotide SR were preselected for octreotide responsiveness.

As a result, we do not know whether the tumor shrinkage statistics would differ in the unselected overall population of patients with acromegaly treated with somatostatin analogs.

Fewer than 1% of tumors were reported to enlarge on somatostatin analogs, suggesting that clinically apparent tumor growth may be slowed with this therapy even in patients whose GH and IGF-I levels are not normalized. However, other factors, including prior radiotherapy and follow-up of not more than 3–4 yr in the studies to date, could have played a role in the apparent lack of tumor growth reported in patients treated with somatostatin analogs.

Tumor shrinkage on somatostatin analog therapy

Adjunctive somatostatin analog therapy1 . % of patients with tumor shrinkage . Total with shrinkage % (number) . 50% shrinkage . 
All analogs 12% 18% 

Source: https://academic.oup.com/jcem/article/87/7/3013/2846438

Somatostatin: ly the most widely effective gastrointestinal hormone in the human body

Somatostatin Health Benefits, Function & Side Effects

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Sandostatin (Octreotide Acetate): Uses, Dosage, Side Effects, Interactions, Warning

Somatostatin Health Benefits, Function & Side Effects

Sandostatin® (octreotide acetate) alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Sandostatin (octreotide acetate) also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism.

Cardiac conduction abnormalities have also occurred during treatment with Sandostatin (octreotide acetate) .

However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development of diabetes mellitus, hypothyroidism, and cardiovascular disease.

Although the degree to which these abnormalities are related to Sandostatin (octreotide acetate) therapy is not clear, new abnormalities of glycemic control, thyroid function and ECG developed during Sandostatin (octreotide acetate) therapy as described below.

Risk of Pregnancy with Normalization of IGF-1 and GH

Although acromegaly may lead to infertility, there are reports of pregnancy in acromegalic women. In women with active acromegaly who have been unable to become pregnant, normalization of GH and IGF-1 may restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with octreotide.

The hypoglycemia or hyperglycemia which occurs during Sandostatin (octreotide acetate) therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents.

Hypoglycemia and hyperglycemia occurred on Sandostatin (octreotide acetate) in 3% and 16% of acromegalic patients, respectively.

Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin (octreotide acetate) therapy was reported in one patient with no history of hyperglycemia.

In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin LAR® Depot (octreotide acetate for injectable suspension) are ly to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients.

In non-diabetics and Type II diabetics with partially intact insulin reserves, Sandostatin (octreotide acetate) Injection or Sandostatin (octreotide acetate) LAR Depot administration may result in decreases in plasma insulin levels and hyperglycemia.

It is therefore recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy with these drugs.

In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin (octreotide acetate) . Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic therapy.

In acromegalics, bradycardia ( < 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during Sandostatin (octreotide acetate) therapy. Other EKG changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R wave progression.

These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin (octreotide acetate) therapy resulted in worsening of CHF with improvement when drug was discontinued.

Confirmation of a drug effect was obtained with a positive rechallenge.

Several cases of pancreatitis have been reported in patients receiving Sandostatin (octreotide acetate) therapy.

Sandostatin (octreotide acetate) may alter absorption of dietary fats in some patients.

In patients with severe renal failure requiring dialysis, the half-life of Sandostatin (octreotide acetate) may be increased, necessitating adjustment of the maintenance dosage.

Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving Sandostatin (octreotide acetate) therapy, and monitoring of vitamin B12 levels is recommended during chronic Sandostatin (octreotide acetate) therapy.

Laboratory Tests

Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy:

Acromegaly: Growth Hormone, IGF-I (somatomedin C) Responsiveness to Sandostatin (octreotide acetate) may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours post dose. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made two weeks after drug initiation or dosage change.

Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P

VIPoma: VIP (plasma vasoactive intestinal peptide)

Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see PRECAUTIONS – General).

Carcinogenesis/Mutagenesis/Impairment of Fertility

Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin (octreotide acetate) .

No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure body surface area).

In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure body surface area) compared to an incidence of 8%-10% in the vehicle-control groups.

The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans.

There have been no reports of injection site tumors in patients treated with Sandostatin (octreotide acetate) for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females.

The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.

Sandostatin (octreotide acetate) did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure body surface area.

Pregnancy Category B

There are no adequate and well-controlled studies of octreotide use in pregnant women.

Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose body surface area and revealed no evidence of harm to the fetus due to octreotide.

However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly.

Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 mcg/day of Sandostatin (octreotide acetate) s.c.

or 20-30 mg/month of Sandostatin (octreotide acetate) LAR, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported.

Nursing Mothers

It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when octreotide is administered to a nursing woman.

Pediatric Use

Safety and efficacy of Sandostatin (octreotide acetate) Injection in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin (octreotide acetate) in pediatric under age 6 years.

In post-marketing report, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin (octreotide acetate) use in children, most notably in children under 2 years of age.

The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of Sandostatin (octreotide acetate) using the Sandostatin (octreotide acetate) LAR Depot formulation was examined in a single randomized, double-blind, placebo-controlled, six–month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin (octreotide acetate) LAR Depot administered by IM injection every four weeks was approximately 3 ng/ml. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m² in Sandostatin (octreotide acetate) LAR Depot-treated subjects compared to 0.0 kg/m² in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin (octreotide acetate) LAR Depot. No unexpected adverse events were observed. However, with Sandostatin (octreotide acetate) LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adults indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin (octreotide acetate) LAR Depot was 10 to 30 mg once a month.

Geriatric Use

Clinical studies of Sandostatin (octreotide acetate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Source: https://www.rxlist.com/sandostatin-drug.htm

Drugs & Medications

Somatostatin Health Benefits, Function & Side Effects

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octreotide acetate 500 mcg/mL (1 mL) injection syringe

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octreotide acetate 200 mcg/mL injection solution

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Source: https://www.webmd.com/drugs/2/drug-17226/octreotide-acetate-injection/details

Probable adverse effects of long term use of somatostatin analogues in patients with RA

Somatostatin Health Benefits, Function & Side Effects

  • somatostatin
  • rheumatoid arthritis

We would to comment on two pilot studies recently published in the Annals of the Rheumatic Diseases by Paran et al and Koseoglu and Koseoglu about the effects of otcreotide, a somatostatin (SOM) analogue, in patients with refractory rheumatoid arthritis (RA).

1,2 Both groups reported minor adverse effects as shown by routine clinical and laboratory assessment.

However, because these SOM analogues had some positive effects on disease activity in these difficult patients, they concluded that they might be used as disease modifying antirheumatic drugs (DMARDs) and that larger randomised controlled clinical trials were warranted.

Although we welcome research on new DMARDs, in this instance we feel obliged to point out some probable adverse effects of the long term use of SOM analogues in patients with RA that were not considered in these preliminary trials.

As reviewed by Paran et al, SOM has some immunomodulatory and analgesic effects and these constitute the rationale for the use of SOM analogues in the treatment of RA.

However, the main function of SOM is to regulate the production of growth hormone (GH) by inhibiting pituitary GH production in response to GH releasing hormone.

Consequently, systemic administration of SOM or its analogues causes GH deficiency.3

Although most of us recognise the consequences of GH deficiency in children (for example, dwarfism), its effects in adults are not as widely recognised. Studies on subjects with adult onset GH deficiency disclosed a complex syndrome that includes4:

  • Alterations in metabolism and body composition (excessive and centrally distributed body fat, osteopenia, and generalised muscle atrophy—that is, sarcopenia)

  • Decreased muscle strength and exercise capacity

  • Increased cardiovascular mortality

  • Reduced psychological wellbeing and quality of life.

These adverse effects are ameliorated by treatment with exogenous GH, clearly demonstrating that GH has an important role in adult life.4

These possible adverse effects of the long term use of SOM analogues are particularly relevant in patients with RA who already present with an impaired GH/insulin- growth factor I axis,5,6 sarcopenia, low bone mineral density, abdominal obesity,7 poor physical fitness,8 reduced quality of life,9 and high cardiovascular mortality.10

For these reasons, we suggest that if and when large, randomised controlled clinical trials of SOM analogues are conducted in patients with RA, they should include not only routine clinical and laboratory assessment, but also measures of body composition, physical fitness, psychologicalwellbeing, and cardiovascular health. This would be the only way to detect these serious adverse effects that might outweigh the benefits of SOM analogues in the treatment of RA.

Marcora et al raise an important point about the potential effect of somatostatin on the growth hormone axis and its ability to induce growth hormone deficiency.

Indeed, Calabresi et al have shown that intravenous somatostatin may decrease the mass and frequency of growth hormone secretory bursts in healthy volunteers, but this study is of short term treatment and uses the native somatostatin and not an analogue.

1 The native hormone binds all five somatostatin receptors, which may lead to significantly more side effects than the receptor subtype specific somatostatin analogues.2,3 The potential of somatostatin to induce growth hormone deficiency obviously cannot be evaluated in patients with acromegaly.

However, long term studies of somatostatin analogues in the treatment of endocrine tumours of the gastrointestinal tract have shown that they are safe, and that the most important adverse event is the development of gallstones.4 In these studies, growth hormone deficiency was not a matter of great concern.

We agree that future studies of somatostatin in patients with rheumatoid arthritis should include an appropriate evaluation of its hormonal effects. These future studies should also assess the optimal somatostatin analogue and the best dosage to use for both efficacy and safety.

  • somatostatin
  • rheumatoid arthritis

We would to comment on two pilot studies recently published in the Annals of the Rheumatic Diseases by Paran et al and Koseoglu and Koseoglu about the effects of otcreotide, a somatostatin (SOM) analogue, in patients with refractory rheumatoid arthritis (RA).

1,2 Both groups reported minor adverse effects as shown by routine clinical and laboratory assessment.

However, because these SOM analogues had some positive effects on disease activity in these difficult patients, they concluded that they might be used as disease modifying antirheumatic drugs (DMARDs) and that larger randomised controlled clinical trials were warranted.

Although we welcome research on new DMARDs, in this instance we feel obliged to point out some probable adverse effects of the long term use of SOM analogues in patients with RA that were not considered in these preliminary trials.

As reviewed by Paran et al, SOM has some immunomodulatory and analgesic effects and these constitute the rationale for the use of SOM analogues in the treatment of RA.

However, the main function of SOM is to regulate the production of growth hormone (GH) by inhibiting pituitary GH production in response to GH releasing hormone.

Consequently, systemic administration of SOM or its analogues causes GH deficiency.3

Although most of us recognise the consequences of GH deficiency in children (for example, dwarfism), its effects in adults are not as widely recognised. Studies on subjects with adult onset GH deficiency disclosed a complex syndrome that includes4:

  • Alterations in metabolism and body composition (excessive and centrally distributed body fat, osteopenia, and generalised muscle atrophy—that is, sarcopenia)

  • Decreased muscle strength and exercise capacity

  • Increased cardiovascular mortality

  • Reduced psychological wellbeing and quality of life.

These adverse effects are ameliorated by treatment with exogenous GH, clearly demonstrating that GH has an important role in adult life.4

These possible adverse effects of the long term use of SOM analogues are particularly relevant in patients with RA who already present with an impaired GH/insulin- growth factor I axis,5,6 sarcopenia, low bone mineral density, abdominal obesity,7 poor physical fitness,8 reduced quality of life,9 and high cardiovascular mortality.10

For these reasons, we suggest that if and when large, randomised controlled clinical trials of SOM analogues are conducted in patients with RA, they should include not only routine clinical and laboratory assessment, but also measures of body composition, physical fitness, psychologicalwellbeing, and cardiovascular health. This would be the only way to detect these serious adverse effects that might outweigh the benefits of SOM analogues in the treatment of RA.

Marcora et al raise an important point about the potential effect of somatostatin on the growth hormone axis and its ability to induce growth hormone deficiency.

Indeed, Calabresi et al have shown that intravenous somatostatin may decrease the mass and frequency of growth hormone secretory bursts in healthy volunteers, but this study is of short term treatment and uses the native somatostatin and not an analogue.

1 The native hormone binds all five somatostatin receptors, which may lead to significantly more side effects than the receptor subtype specific somatostatin analogues.2,3 The potential of somatostatin to induce growth hormone deficiency obviously cannot be evaluated in patients with acromegaly.

However, long term studies of somatostatin analogues in the treatment of endocrine tumours of the gastrointestinal tract have shown that they are safe, and that the most important adverse event is the development of gallstones.4 In these studies, growth hormone deficiency was not a matter of great concern.

We agree that future studies of somatostatin in patients with rheumatoid arthritis should include an appropriate evaluation of its hormonal effects. These future studies should also assess the optimal somatostatin analogue and the best dosage to use for both efficacy and safety.

Page 3

  • somatostatin
  • rheumatoid arthritis

We would to comment on two pilot studies recently published in the Annals of the Rheumatic Diseases by Paran et al and Koseoglu and Koseoglu about the effects of otcreotide, a somatostatin (SOM) analogue, in patients with refractory rheumatoid arthritis (RA).

1,2 Both groups reported minor adverse effects as shown by routine clinical and laboratory assessment.

However, because these SOM analogues had some positive effects on disease activity in these difficult patients, they concluded that they might be used as disease modifying antirheumatic drugs (DMARDs) and that larger randomised controlled clinical trials were warranted.

Although we welcome research on new DMARDs, in this instance we feel obliged to point out some probable adverse effects of the long term use of SOM analogues in …

Source: https://ard.bmj.com/content/61/12/1117

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