No abstract

We have studied the effect of increased cholinergic tone on the GH response to growth hormone-releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 micrograms i.v. GHRH (1-29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl-hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl-hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl-hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.

OBJECTIVE To determine the long-term effects of external beam megavoltage radiotherapy (RT: 4500 cGy via three portals at 180 cGy or less total daily dose) on endocrine function in prolactinomas. DESIGN Longitudinal study following radiotherapy with periodic re-assessment at regular intervals, at least 2 months off dopamine agonist therapy. PATIENTS Thirty-six female patients, age range 19-50 years, with either macroprolactinomas (12 patients) or microprolactinomas (24 patients), but without significant suprasellar extensions. MEASUREMENTS Clinical appraisal, and anterior and posterior pituitary assessment: basal levels at yearly intervals or less, with dynamic screening with TRH, LHRH and hypoglycaemic stimulation every 2-3 years. RESULTS Before RT, serum prolactin (PRL) levels ranged from 1150 to 34,000 mU/l; after RT (mean 8.5 years, range 3-14), serum PRL fell to normal (i.e. less than 360 mU/l) in 18 of the 36 patients (50%), and to just above the normal range (378-780 mU/l) in a further 10 (28%). Two patients had PRL levels at their last follow-up higher than those at presentation, with one patient showing evidence of tumour recurrence on CT scan. A total of eight of the 36 patients (23%) developed post-RT gonadal deficiency by the end of follow-up at 8 +/- 3.1 years (+/- SD, range 3-11), but six were aged over 40 years at that time. GH deficiency was frequent, occurring in 94% of patients, usually from 2 to 3 years post-RT, while TSH deficiency and reduced ACTH reserve was uncommon (each 14%), and occurred later. In the subgroup of 12 patients with macroprolactinomas, results were broadly comparable. CONCLUSIONS Megavoltage RT produces a progressive fall in serum prolactin in the great majority of patients with prolactinomas, with a relatively low incidence of TSH or ACTH deficiency. As it is now clear that dopamine agonist therapy alone provides sufficient management for microprolactinomas, RT may be used for the long-term control of macroprolactinomas, together with interim dopamine agonist therapy. It allows pregnancy to be safely undertaken but, in view of the delayed onset of gonadal deficiency, its administration should be timed with respect to the desired onset of conception in women.

Fourteen patients presented with arrested pubertal development associated with prolactin-secreting pituitary tumours; serum prolactin ranged from 4000-104,300 mU/l in the ten females and 920-68,000 in four males. Skull X-ray showed a markedly expanded pituitary fossa in eight patients. CT scan and/or air encephalography showed macroadenomas in nine, of whom seven had large suprasellar extensions to their tumours, yet only five had complained of headache and only two had visual field defects. All were treated with bromocriptine (7.5-60 mg/day) which lowered prolactin substantially in all and into the normal range in 11 (range less than 60-3090, median 105 mU/l). Puberty thereafter progressed spontaneously in 13, but in one patient, whose prolactin did not suppress completely, menarche could be induced only with clomiphene. Anterior pituitary function improved on bromocriptine. In seven patients with macroadenomas, tumour shrinkage into the pituitary fossa was complete and in two others incomplete shrinkage was followed by transsphenoidal hypophysectomy. Seven patients received pituitary irradiation, six after bromocriptine-induced shrinkage and one after transsphenoidal surgery. At follow-up 6 months to 10 years (median 5 years) after presentation, ten remain on bromocriptine with a suppressed serum prolactin, one has a normal prolactin after surgery, and three are off bromocriptine with residual hyperprolactinaemia (418-4680 mU/l). To date, four females have become pregnant and one male has fathered two children. Prolactinomas are an important, albeit rare, cause of arrested puberty and should therefore be sought. Most patients respond well to bromocriptine, with or without pituitary irradiation.