Calcitonin [SED-15, 595; SEDA-30, 507; SEDA-31, 703; SEDA-32, 789]
The adverse effects of salmon calcitonin have again been reviewed [1R]. Salmon calcitonin nasal spray is thought to be safe. Hypersensitivity is the only contraindication. The systemic adverse reactions of flushing and nausea that occur with injections are rare. Local reactions due to nasal irritation are the most common adverse reactions.
Gonadotropins (gonadorelin, GnRH, and analogues) [SED-15, 1536; SEDA-30, 507; SEDA-31, 703; SEDA-32, 789]
A review of the use of gonadorelin analogues for precocious puberty showed that in general they were well tolerated [2R]. Headache and hot flushes were usually short-term problems. Local adverse events at the injection site occasionally required a change of therapy. Anaphylaxis has been described. Bone mineral density was not thought to be adversely affected in this group. In contrast gonadorelin therapy alone was not recommended for the management of idiopathic short stature, when the delay in puberty can compromise bone mineral density.
Cardiovascular
In 945 men with prostate cancer who were randomly allocated to external beam radiotherapy combined with goserelin acetate or to radiotherapy followed by goserelin only if there was relapse, the mean period of follow-up was 8.1 years, during which there were 574 deaths, 117 of which were due to cardiovascular disease [3C]. There was no increased risk of cardiovascular mortality in men who used adjuvant goserelin compared with those not using goserelin (8.4% versus 11%). The risk of cardiovascular disease has previously been reported to increase in men using GnRH agonists for prostate cancer.
Nervous system
Drug-induced chorea has previously been described with the use of the combined oral contraceptive, but the mechanism is uncertain. A case involving goserelin has been reported [4A].
•
A 77-year-old man complained of involuntary movements after taking goserelin for prostate cancer for 6 weeks. He continued therapy for about 10 months and his symptoms persisted, but 3 months after stopping goserelin the abnormal movements stopped.
Reproductive system
Ovarian hyperstimulation syndrome has been attributed to triptorelin [5A].
•
A 35-year-old woman with infertility received triptorelin 3.75 mg on day 21 of her menstrual cycle and 10 days later a scan showed 12 follicles measuring 16–19 mm in both ovaries. She had symptoms of nausea and abdominal bloating. •
A 26-year-old woman with infertility received triptorelin 3.75 mg and 2 weeks later developed abdominal heaviness; a scan showed bilateral follicles of 15–21 mm in both ovaries.
Ovarian hyperstimulation has been previously been reported but is uncommon after the sole administration of triptorelin.
In an uncontrolled study in 13 patients aged 30–42 years with endometriosis or menorrhagia, who took the aromatase inhibitor letrozole 2.5 mg/day for the first 5 days after receiving leuprolide acetate 3.75 mg intramuscularly, the initial increase in estrogen concentrations was not apparent [6c]. In a randomized study in healthy subjects, mean age 30 years, who received triptorelin 3.75 mg (two injections 4 weeks apart), with or without oral exemestane 25 mg/day for 56 days, there was no effect on the initial flare of FSH, LH, and estrogen, although there was subsequent increased suppression of estrogen [7c]. Of the 14 women who received placebo with triptorelin, 11 had hot flushes compared with nine of the 15 who took exemestane.
Musculoskeletal
Gonadorelin has been used for the management of endometriosis in adolescents [8R]. In this group the effect on bone mineral density can be minimized by using norethindrone acetate with or without estrogen at the same time.
Tumorigenicity
In an analysis of data from 54 362 women referred to Danish hospitals between 1963 and 1968 with infertility problems (median age at first evaluation 30 years), there were 156 patients with epithelial ovarian tumors, who were compared with a randomly selected subcohort [9C]. Various infertility therapies had been used. The risk of ovarian cancer was not increased after any use of gonadotropins (rate ratio = 0.83).
Drug formulations
In patients, mean age 73 years, with prostate cancer, a study of the use of leuprorelin acetate 11.25 mg injections every 3 months for 12 months (n = 58), compared with six monthly injections of depot leuprorelin acetate containing either 22.5 or 30 mg (n = 120), the results suggested no differences in adverse reactions [10C]. Flushing was the most common adverse reaction; it occurred in 43% of those who received 11.25 mg and in 34% of those who received 30 mg. Increased sweating was also slightly more common in those who received 11.25 mg. Injection site reactions were more common in those who received 30 mg, 12% versus 2%. Overall the frequency of adverse reactions was similar.
Somatropin (human growth hormone, hGH) [SED-15, 3163; SEDA-30, 508; SEDA-31, 705; SEDA-32, 791]
Cardiovascular
In 14 patients with growth hormone deficiency (aged 33–62 years, four men), who were given growth hormone at an initial dose of 0.015 mg/kg/week, the dose was then titrated depending on IGF-1 concentrations [11c]. Echocardiography was performed at baseline and at 24, 48, and 60 months. There was progressive increase in left ventricular mass from 116 to 174 g. The long-term effects of growth hormone replacement in adults are unknown.
In 122 men, mean age 70 years, who were randomized to testosterone gel 5 g/day (n = 61) or 10 g/day with different doses of growth hormone (0, 3, or 5 micrograms/kg/day) for 12 weeks, there was an increase in blood pressure, which persisted 4 weeks after the study ended [12c]. The blood pressure at 16 weeks was 130/76 mmHg compared with 117/68 mmHg at baseline.
In 10 patients (mean age 58 years, one man) with acromegaly, which was thought to have been cured, who were treated with growth hormone with the dose adjusted to normalize IGF-1 concentrations, and 10 patients with previous non-functioning pituitary adenomas, who also received growth hormone (mean age 54 years, one man), three of the former had cardiovascular events during 2 years; one patient died with a myocardial infarction after 5 months; two had cerebral infarctions at 2 and 6 weeks and continued growth hormone therapy [13c]. None of the patients with non-functioning pituitary disease had cardiovascular events. The numbers were small in this study, and the safety of using growth hormone in patients with previous acromegaly needs further evaluation.
Metabolism
A review of growth hormone therapy for adults with growth hormone deficiency has shown a correlation of growth hormone dose and duration with the development of impaired glucose tolerance [14R]. A meta-analysis of studies of growth hormone therapy for obesity in adults showed a small but significant increase in fasting plasma glucose concentrations [15M].
Pancreas
Pancreatitis has been attributed to growth hormone.
•
A 40-year-old man used growth hormone 0.6 mg/day for 2 weeks to enhance muscle development. He developed pancreatitis 10 days later. There was no other apparent risk factor [16A]. •
A 13-year-old girl with a craniopharyngioma was using growth hormone 0.033 mg/kg/day subcutaneously six times per week, levothyroxine, hydrocortisone, and an antidiuretic hormone analogue [17A]. She developed severe abdominal pain and was admitted 1 month later with persistent symptoms. The diagnosis was pancreatitis. Growth hormone was withdrawn and she recovered. Six months later growth hormone was restarted without recurrence of pancreatitis.
In the second case the authors speculated that the pancreatitis might have been related to a high cholesterol concentration (6.5 mmol/l) caused by the use of growth hormone.
Musculoskeletal
Of 19 patients with de Quervain's tenosynovitis, mean age 33 years, nine were using growth hormone for body building purposes [18c]. Four stopped using growth hormone when requested. The patients who were not using growth hormone responded to non-surgical treatment. Four of the five patients who continued growth hormone therapy required surgical therapy, compared with two of the four who stopped. Growth hormone may make de Quervain's tenosynovitis more difficult to treat.
Eight children with Hurler's syndrome, mean age 9 years, were treated with growth hormone, mean dose 0.32 mg/kg/week [19c]. There was radiographic data for six children. There was progression of scoliosis in one, kyphosis progression in one, and worsening of genu valgum in one. One child discontinued therapy owing to a slipped capital femoral epiphysis, which is not a typical feature of Hurler's syndrome.
In 39 children with isolated growth hormone deficiency and five with multiple pituitary hormone deficiencies (aged 8–16 years, 30 boys), who were treated with growth hormone 33 micrograms/kg/day, Southwick's angle was measured using pelvic X-rays at baseline, 1 year, and 2 years [20c]. Data were available for 28 patients at 1 year, of whom 17 had an increased angle. Data at 2 years were available for 10 patients, of whom nine had further progression. It is thought that an increased Southwick's angle is a marker for a risk of slipped capital femoral epiphysis, and growth hormone can increase the risk of epiphysiolysis.
Drug administration route
Inhaled growth hormone
In a randomized crossover trial, somatotropin inhalation powder was given to 22 children with growth hormone deficiency, mean age 11 years [21c]. Eight received inhaled growth hormone 8.4 mg/day or subcutaneous growth hormone 0.5 mg per day; six received inhaled growth hormone 16.8 mg/day or subcutaneous growth hormone 1.0 mg/day; and eight received inhaled growth hormone 33.6 mg/day or subcutaneous growth hormone 2.0 mg/day. Each treatment was given for 7 days. There were no effects on lung function in this short study.
Growth hormone receptor antagonists [SEDA-30, 510; SEDA-31, 707; SEDA-32, 794]
Liver
In a 40 week, open, randomized, controlled study in patients with acromegaly, who were inadequately treated with long-acting octreotide, adding pegvisomant therapy to octreotide was compared with changing to pegvisomant alone [22c]. The mean age of the 25 patients randomized to pegvisomant alone was 49 years, 10 of whom had diabetes. The 26 patients randomized to combined therapy had a mean age of 40 years and four had diabetes. Pegvisomant was begun at 10 mg/day and titrated, according to IGF-1 concentrations, to a maximum of 30 mg/day and a minimum of 5 mg/day. There were significant increases in liver enzymes to more than three times the upper limit of the reference range in one patient who received pegvisomant alone and in four who received combination therapy. Three patients using combination therapy had activities more than 10 times the upper limit, and they returned to normal or near normal on withdrawal. Liver function should be monitored, especially when combination therapy is used. Current recommendations suggest monthly liver function tests for the first 6 months of treatment, followed by 6-monthly tests [23R].
Tumorigenicity
Two boys and one girl with pituitary gigantism, who were not cured by surgery, a somatostatin analogue, and a dopamine receptor agonist, were given pegvisomant [24A]. One child, aged 5 years received 10 mg/day subcutaneously; the others, aged 10 and 11 years, received 20 mg/day. One child had a documented increase in tumor size and stopped taking pegvisomant after about 3 years; 3 months after the end of therapy there was no further increase in tumor size.
One patient in each group of a randomized control comparison of pegvisomant alone with pegvisomant plus long-acting octreotide had an increased pituitary volume at 40 weeks [22c]. Long-term surveillance of pituitary volume is required for patients receiving pegvisomant.
Melatonin and analogues [SED-15, 2245; SEDA-31, 708; SEDA-32, 794]
Melatonin analogues are under development with varying binding affinities for melatonin receptors [25R]. Large-scale evidence for their use in circadian rhythm sleep disorders is not yet available.
Ramelteon, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide (TAK-375), has four times the potency as melatonin at MT1 receptors and 17 times the potency at MT2 receptors. Adverse effects in trials so far suggest effects similar to placebo.
Agomelatine, N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, is a melatonin MT1 and MT2 receptor agonist. It is also an antagonist at 5-HT2C receptors.
Tasimelteon, (1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cycloproplyl]methyl] propanamide, has high affinity for melatonin MT1 and MT2 receptors.
Melatonin has been used in neonates at pharmacological doses without apparent adverse reactions, although studies are usually small [26R].
Circadin is a prolonged-release tablet containing melatonin 2 mg. It has received European Medicine Agency approval for treatment of primary insomnia. Adverse reactions are uncommon, but include headache, pharyngitis, back pain, and weakness. There do not appear to be withdrawal effects.
Drug–drug interactions
Melatonin is metabolized mainly by CYP1A, but CYP2C19 is also involved to a lesser extent [27r]. Melatonin concentrations can be increased by cimetidine, quinolones, and estrogens. They are reduced by carbamazepine and cigarette smoking.
Oxytocin and analogues [SED-15, 2657; SEDA-30, 511; SEDA-31, 708; SEDA-32, 795]
Observational studies
The use of oxytocin in low income countries has been reviewed [28R]. The use of oxytocin compared with no use of oxytocin in normal labor had a relative risk of 1.9 for stillbirth. The adjusted relative risk for neonatal resuscitation was 2–5.6. Oxytocin is useful for the management of postpartum hemorrhage, but it is important that in low resource settings its use does not result in increased harm to the neonate.
In 80 women, mean age 31 years, undergoing cesarean section, who were randomized to oxytocin 2 or 5 units as an intravenous bolus over 5–10 seconds after the delivery of a baby and cord clamping, followed by a continuous infusion of oxytocin 10 units/hour over 4 hours, 13 reported nausea after receiving 5 units compared with two who received 2 units [29C]. Mean arterial pressure fell more in those who were given 5 units (13 compared with 6 mmHg), and six patients had a reduction of more than 30 mmHg.
Electrolyte balance
Hyponatremia has been attributed to oxytocin [30A].
•
A 26-year-old woman in the second stage of labor received an infusion of oxytocin 10 U/l in 5% dextrose at a variable rate of 10–150 ml/hour. In the 5 hours after delivery, which was complicated by a retained placenta requiring general anesthesia for removal, she received isotonic fluid 5500 ml, 5% dextrose 3500 ml with oxytocin 50 U/l, hydroxyethyl starch 1000 ml, and 4 units of blood. She then received 5% dextrose 7500 ml with oxytocin 100 U/l over 15 hours; 24 hours later her serum sodium concentration was 113 mmol/l. She became unconscious and had a generalized convulsion. She subsequently made a full recovery.
Consideration of how oxytocin is infused to minimize the risk of hyponatremia is essential.
Skin
Extravasation of concentrations of oxytocin in the hand has reportedly caused vasoconstriction [31A].
•
A 24-year-old woman had vaginal bleeding at 15 weeks gestation. She received 2 units of packed erythrocytes and then 3 units of oxytocin through a cannula on the back of the hand. Within 30 minutes the hand had become edematous and cyanotic. Extravasation was apparent. The radial and ulnar pulses were not palpable and were faint on a Doppler scan. The hand was elevated and the symptoms gradually abated, with improvement of the pulses.
Thyrotropin-releasing hormone and thyrotropin
See Chapter 41.
Parathyroid hormone [SED-15, 2689; SEDA-32, 796]
Potential novel uses of parathyroid hormone therapy are being explored through its effects on the cardiovascular system, which include arterial vasodilatation [32R].
Observational studies
Women aged more than 45 years with low bone mineral density were randomized to hormone replacement therapy with (n = 90) or without (n = 90) 100 micrograms of subcutaneous PTH 1–84 [33c]. Those who received PTH 1–84 had more hypercalciuria (43%), hypercalcemia (14%), nausea (25%), vomiting (11%), and dizziness (10%). It was thought that they might not have had as great an increase in calcium concentrations as would have been expected, because of a tendency of hormone replacement therapy to lower calcium concentrations.
Somatostatin (growth hormone release-inhibiting hormone) and analogues [SED-15, 3160; SEDA-30, 510; SEDA-31, 709; SEDA-32, 796]
Adverse reactions to somatostatin analogues have been extensively reported. The asymptomatic effects have been reviewed [23R, 34R]. There are asymptomatic gallstones in 20–40, bradycardia in up to 25%, and conduction abnormalities in 10%. Somatostatin analogues may alter the absorption of other drugs, especially oral hypoglycemic agents, β blockers, calcium channel blockers, and ciclosporin, while effects on CYP isoenzymes may alter concentrations of quinidine, terfenadine, and warfarin. Somatostatin analogues should not be used with drugs that prolong the QT interval, such as cisapride.
Nervous system
In one case a high dose of octreotide may have altered the balance between brain dopamine and GABA, and thus caused Parkinson-like symptoms [35A].
•
A 31-year-old woman with carcinoid syndrome was given octreotide in doses that gradually increased over the years, so that after 4 years she was receiving 30 mg intramuscularly every 2 weeks and an additional 6–8 mg of subcutaneous octreotide each month. She developed slowness of movement and a tendency to bump into things. The dose of octreotide was reduced to 10 mg every 2 weeks and her neurological symptoms improved. The dose of octreotide was temporarily increased to 30 mg 2 weekly with a recurrence of symptoms.
Metabolism
In 112 patients with acromegaly (mean age 47 years, 51 men), who were treated with somatostatin analogues, there was an increase in fasting plasma glucose concentrations after 1 month, which correlated with a reduction in insulin concentrations [36C]. The fasting glucose concentration had returned to baseline by 3 months. At the end of 12 months the most important predictor of blood glucose concentration was control of growth hormone concentrations; 11 patients had improved their glucose tolerance status and 17 had worsened.
Octreotide [SEDA-30, 510; SEDA-31, 709; SEDA-32, 797]
Hematologic
Thrombocytopenia has been attributed to octreotide [37A].
•
A 53-year-old man with hematemesis and melena due to variceal bleeding was given octreotide 50 micrograms as an initial intravenous bolus, followed by 50 micrograms/hour as a continuous intravenous infusion. His platelet count fell from 144 to 4 × 109/l over the next 50 hours. The platelet count gradually increased after the octreotide was withdrawn at 72 hours. He was again given octreotide 3 months later, and the platelet count fell from 214 to 89 × 109/l. The octreotide was withdrawn and the platelet count returned to 221 × 109/l.
The mechanism of this effect is unknown.
Gastrointestinal
In 125 patients being treated with pelvic radiation for various cancers of the pelvis, randomly allocated to subcutaneous octreotide 100 micrograms on day 1 followed by depot octreotide 20 mg on days 2 and 29, or placebo, octreotide did not improve symptoms and may have worsened abdominal cramps, nocturnal bowel movement, and melena [38C].
Biliary tract
Nine subjects with Prader–Willi syndrome (mean age 15 years) received either octreotide 30 mg or saline intramuscularly every 4 weeks for 16 weeks. After a 24-week wash-out period, they then received the alternative therapy. Three developed gallbladder abnormalities on ultrasound by the end of the octreotide phase; two went on to have cholecystectomy 12–24 months later [39c].
Nails
Beau's lines, or onychomadesis, are seen in patients receiving certain drugs, and has been associated with octreotide [40A].
•
Beau's lines were noted in a 72-year-old lady with carcinoid syndrome who was receiving subcutaneous octreotide every 28 days. The distance of the lines from the proximal nail fold suggested that they had developed at around the time of octreotide injection, although there were only two lines when she had received four injections.