Hexarelin (HEX), a synthetic hexapeptide, has a strong and reproducible GH-releasing activity in man after intravenous, subcutaneous, intranasal and oral administration. Its effect undergoes age-related variations, being reduced in elderly subjects. In spite of evidence in animals showing that the activity of GH-releasing peptides (GHRPs) is positively influenced by oestrogens, in young adults no sex-related difference has been found in the GH response to HEX or to other GHRPs. We aimed to clarify the influence of the menopause and oestrogens on the GH-releasing activity of HEX. We studied the GH response to the acute administration of the maximal effective dose of HEX (2 μg/kgi.v.) in 24 young women (YW, age: 27·3±0·5 years; body mass index (BMI): 20·7±0·3 kg/m2). 14 post-menopausal women (PW, age: 52·9±1·2 years; BMI: 23·2±0·9 kg/m2) and 14 aged women (AW, age: 68·9±1·5 years; BMI: 21·7±0·7 kg/m2). In 10 post-menopausal women the GH response to HEX was also studied after 3 months of transdermal oestradiol treatment (delivery 50 μg/die). Basal oestrogen and GH levels in PW were lower than those in YW (oestrogen: 4·8±3·6 vs 42·0±3·4 pg/ml (mean±s.e.m.), P< 0·001; GH: 1·5±0·5 vs 2·9±0·6 μg/l, P< 0·02) and similar to those in AW (oestrogen: 1·3±0·4 pg/ml; GH: 0·9±0·2 μg/l). IGF-I levels in PW were not different from those in YW (174·4±11·9 vs 195·5±14·9 μg/l) and higher than those in AW (109·8±15·8 μg/l, P<0·01). The GH response to HEX in PW (areas under the curve±s.e.m.: 453·6±56·0 μg.min/l) was lower (P<0·002) than that in YW (1630·4±259·7 μg.min/l) while it did not differ from that in AW (781·8±189·3 μg.min/l). In PW 3-month oestrogen administration increased oestradiol levels (38·3±5·9 vs 0·8±0·4 pg/ml, p<0·001) making them similar to those recorded in YW, while it failed to modify both basal GH and IGF-I levels (GH: 1·8±0·6 vs 1·5±0·7 μg/l; IGF-I: 164·6±14·3 vs 175·0±12·3 μg/l). Also the GH response to HEX was not modified by oestradiol treatment (518·4±125·6 vs 425·4±69·3 μg.min/l). In conclusion, present data confirm the strong GH-releasing effect of Hexarelin in humans and demonstrate that its activity is already reduced in post-menopausal women to an extent overlapping that in elderly women. Moreover, oestrogen treatment is not able to restore it. Thus, the lack of oestrogens does not seem to account for the reduced somatotroph responsiveness to GHRPs in the post-menopausal period.