Corticotrophins (corticotropin and tetracosactide)

Structures and nomenclature

Natural ACTH (corticotropin) is a polypeptide consisting of 39 amino acids. Its hormonal activity is related to the first 24 amino acids in a sequence that is found in both animal and human pituitary glands. The differing sequences of the remaining 15 amino acids in animals can lead to antibody formation and hence to allergic reactions when animal hormones are injected into humans. From 1970 onwards, therefore, even highly purified corticotropin preparations of animal origin were largely displaced by the so-called “synthetic ACTH” or “synthetic corticotropin,” better known by its generic name of tetracosactide (rINN), which contains only the first 24 amino acids, hence avoiding much of the antigenicity of the complete molecule. Collectively, corticotropin and tetracosactide are known as the corticotrophins.

Since the development of tetracosactide, other modifications to the corticotropin molecule have been made, and some clinical work has been done with products containing fewer than 24 amino acids, for example 1–18. However, none has proved more usable than tetracosactide. The replacement of some naturally occurring amino acids by others may intensify or prolong the effect of the polypeptide.

Production and elimination

Fluctuations in the rates of secretion of glucocorticoids from the adrenal cortex are determined by variations in the rate of release of corticotropin from the anterior pituitary, and this in turn is controlled by the hypothalamic corticotropin-releasing hormone (CRH). Since release of CRH is affected by circulating glucocorticoid concentrations, a negative-feedback control operates to keep the system in balance. It follows from this that if glucocorticoids are administered exogenously they will operate through this feedback to suppress adrenal function.

The mode of inactivation and excretion of corticotropin is still almost completely unknown; its biological half-life has been variously assessed as several minutes or several hours.

Uses

Corticotrophins can be used diagnostically to investigate adrenocortical insufficiency. Corticotropin has also been used therapeutically in most of the conditions for which systemic glucocorticoids are indicated, although such use is now fairly limited. However, corticotropin is used in certain neurological disorders, such as infantile spasms and multiple sclerosis. The main indications for corticotropin and tetracosactide are thus diagnostic rather than therapeutic; for the latter purpose they are being increasingly replaced by CRH.

General adverse effects and adverse reactions

Corticotrophins share all the adverse effects of glucocorticoids, including impaired immunity, but they do not depress adrenocortical function. In addition, the melanocyte-stimulating hormone (MSH) sequence in the corticotropin molecule can result in hyperpigmentation, and induction of androgen secretion can lead to virilization. Corticotrophins also have additional unwanted effects of their own, such as myoclonic encephalopathy and adrenal hemorrhage. Hypersensitivity reactions occur occasionally, but have become less frequent since older preparations of animal origin were phased out. Tumor-inducing effects have not been observed.

Tetracosactide has been evaluated in a retrospective study using the medical records of 135 patients (73 boys and 62 girls) with West syndrome who had been treated and examined regularly for more than 1 year. There were adverse effects in 57 patients, leading to withdrawal of therapy in 23. The most common adverse effects that caused withdrawal were respiratory infections (74%), gastrointestinal infections (35%), hypertension (65%), dysrhythmias (48%), irritability and increased muscle tone (17%), and hypokalemia (17%) [ ].

Cardiovascular

Corticotropin has been reported to cause enlargement of cardiac tumors in tuberous sclerosis [ ].

• A female infant with tuberous sclerosis had multiple large cardiac tumors in the left and right ventricles. Corticotropin was given (dose not stated; once a day for 2 weeks, tapering over 3 months) at 4 months for infantile spasms. At 6 months a heart murmur was detected. Echocardiography showed pronounced enlargement of the tumors in both ventricles and a small tumor extending from the upper portion of the interventricular septum into the left ventricular outflow tract. An electrocardiogram showed 2–3 mm ST segment depression in leads I, aVL, and V4-6. Gated single photon emission CT showed low perfusion at the lateral and inferior regions of the left ventricle, indicating myocardial ischemia. Corticotropin was withdrawn and 3 months later the patient was asymptomatic. An echocardiogram showed that the tumors had reduced in size, and there was concomitant improvement in the electrocardiogram.

There is a risk of myocardial hypertrophy in children on prolonged treatment with ACTH [ ], an effect that could reflect increased androgen secretion and thus be more likely to occur than with glucocorticoids.

Hypertension, with or without simultaneous hypertrophic myopathy, is a common feature of adrenal stimulation that seems to be common with depot tetracosactide but not simple tetracosactide [ ]. During treatment for infantile spasms, hypertension occurred more often in those treated with high doses [ ], and changes in cardiac function, such as left ventricular shortening fraction, can occur early and sometimes before systolic hypertension [ ].

Respiratory

Corticotropin and to a lesser extent tetracosactide can cause asthma in sensitive subjects [ ]. The question as to whether tetracosactide or glucocorticoids should be preferred for the treatment of chronic asthmatic bronchitis has been discussed mainly with respect to adverse effects, particularly adverse endocrine effects and effects on growth. An earlier belief that corticotropin might be more effective in children has not been confirmed.

Nervous system

In 138 Japanese patients with West syndrome treated with low-dose tetracosactide, the initial effects on seizures and long-term outcome were not related to dose (daily dose 0.005–0.032 mg/kg, 0.2–1.28 IU/kg; total dose 0.1–0.87 mg/kg, 4–35 IU/kg) [ ]. There were moderate or severe adverse effects in 30% of the patients. There was slight loss of brain volume on CT/MRI scans in 64% of the patients, moderate loss in 23%, and severe loss in 4%. The severity of adverse effects correlated with the total dose of corticotropin, and the severity of brain volume loss due to corticotropin correlated well with the daily and total doses. The authors recommended a reduction in the dose of corticotropin in order to avoid serious adverse effects.

Brain shrinkage has been described as a possible adverse effect of corticotropin treatment of infantile spasms, and this has been confirmed using magnetic resonance imaging [ , ]. Changes in midline structures (volume reductions in the pons, corpus callosum, and cerebellum) seem to show that the beneficial effect of corticotropin in infantile spasms could be due to a direct effect on the brainstem. Cerebral shrinkage and subdural hematoma occurred after the administration of high doses of corticotropin for West syndrome (total dose 4.5–6.75 mg) and subdural hematoma occurred in two children (aged 2 and 5 months) during the administration of low doses of tetracosactide (0.01 mg/kg/day; total dose 0.24–0.26 mg) [ ].

Drowsiness, hypotonia, and irritability were observed in 37% of infants given corticotropin in a randomized comparison of corticotropin with vigabatrin in the treatment of infantile spasms [ ].

Myoclonic encephalopathy appears to be a specific, if rare, complication of corticotropin, not seen with the glucocorticoids [ ].