Radiosurgery with the use of protons beams in patients with Cushing's disease: hormonal monitoring of delayed results

The present paper deals with late results of the treatment of patients with Cushing's disease by proton beam irradiation of the pituitary gland. Retrospective analysis included results of hormonal assays in 197 patients (161 women and 36 men) with verified Cushing's disease who had undergone proton therapy at the Endocrinological Research Centre. The age of the patients prior to irradiation varied from 17 to 54 years (mean 29±12.1). Duration of the follow up period ranged from 1 to 24 years. Each patient was first examined 6 month after irradiation, then annually for 5 years, and thereafter during episodic visits to the clinic of Endocrinological Research Centre. Trophic hormones (ACTH, GH, prolactin, LH, FSH, TSH) as well as cortisol, estradiol, testosterone, and free thyroxin were determined in peripheral blood; in addition, free cortisol was measured in daily urine. ACTH and cortisol were measured twice daily (at 8 a.m. and 11 p.m.) to characterize diurnal dynamics of these hormones. Complete remission of the primary disease was documented based on the results of hormonal assays in 164 (83.6%) patients 0.5-3 (mean 1.5±1.8) years after irradiation; remission without subsequent impairment of the pituitary trophic activity was achieved in 43 (21.8%) patients. Different combinations of post-treatment side effects (hypopituitarism) were recorded in 100 (50.1%) patients while 54 (27.4%) others had only one function affected by radiation. The following disorders of hormonal function of the pituitary and peripheral glands developed: adrenal insufficiency in 58 (29.7%) patients, secondary hypothyroidism in 66 (22.8%), hypogonadism in 93 (47.4%), and hyperprolactinemia in 72 (36.7%). Adrenal insufficiency was the first adverse event to develop after proton therapy (within 0.5-12.0, mean 2.5±2.3, years). It was followed by elevation of prolactin levels and decrease of gonadotropins (within 1.0-7.2, mean 3.0±2.9, years and 0.8-11.8, mean 3.0±3.1, years respectively). Secondary hypothyroidism was the last to develop (within 1.3-12.3, mean 5.0±3.2, years after treatment). It is concluded that biochemical monitoring hormonal changes coupled to the evaluation of the patient's clinical conditions is a very important component of long-term (throughout the lifespan) dynamic observation of patients with Cushing's disease necessary for the timely detection of manifestations of hypopituitarism and initiation of relevant treatment.