Estradiol (E₂) drives growth-hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ER is expressed in GH releasing-hormone (GHRH) neurons and GH-secreting cells (somatotropes). Moreover, estrogen regulates receptors for somatostatin, GH-releasing peptide (GHRP, ghrelin) and GH itself, while potentiating signaling by IGF-I. Given this complex network, one cannot a priori predict the selective roles of hypothalamic vis-a-vis pituitary ER pathways. To make such a distinction, we introduce an investigative model comprising: (i) specific ER blockade with a pure antiestrogen, fulvestrant, that does not penetrate the blood-brain barrier; (ii) graded transdermal E₂ administration, which doubles GH concentrations in postmenopausal women; (iii) stimulation of fasting GH secretion by pairs of GHRH, GHRP-2 (a ghrelin analog) and L-arginine (to putatively limit somatostatin outflow); and (iv) implementation of a flexible-waveform deconvolution model to estimate the shape of secretory bursts independently of their size. The combined strategy unveiled that: (a) E₂ prolongs GH secretory bursts via fulvestrant-antagonizable mechanisms; (b) fulvestrant extends GHRH/GHRP-2-stimulated secretory bursts; (c) L-arginine/GHRP-2 stimulation lengthens GH secretory bursts whether or not E₂ is present; (d) E₂ limits the capability of L-arginine/GHRP-2 to expand GH secretory bursts, and fulvestrant does not inhibit this effect; and (e) E₂ and/or fulvestrant do not alter the time evolution of L-arginine/GHRH-induced GH secretory bursts. The collective data indicate that peripheral ER-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity.