The authors have suggested that dysfunction of a central structure (above the pituitary level) is the primary etiologic factor responsible for the production of the polycystic ovary syndrome. To investigate further the functional integrity of the hypothalamic pituitary axis, plasma levels of /β-endorphin, γ3-melanocyte stimulating hormone, and γ1-melanocyte stimulating hormone-like immunoreactivity were measured in six patients with polycystic ovary syndrome, and in ten women with normal ovarian function. The limit of sensitivity for the radioimmunoassays was 20 pg/mL. Plasma β3-endorphin was significantly higher in polycystic ovary syndrome than in control subjects: (mean ± SE) 60 ± 10 versus 30 ± 4 pg/mL, respectively (P<.05). γ3-Melanocyte stimulating hormone was detectable in four of six patients with polycystic ovary syndrome (mean for the whole group: 45 ± 15 pg/mL); it was undetectable in all the control subjects. Control of plasma β-endorphin and γ3-melanocyte stimulating hormone secretion in PCO was evaluated with metyrapone and dexamethasone. Overnight administration of metyrapone to polycystic ovary syndrome patients resulted in rises of β-endorphin and γ3-melanocyte stimulating hormone. Dexamethasone suppressed only partially (to basal concentrations) β-endorphin and γ3-melanocyte stimulating hormone levels. Plasma adrenocorticotropic hormone concentrations were within the normal range and displayed the expected changes in response to metyrapone and dexamethasone. The present report presents an additional central (hypothalamic-pituitary) abnormality in patients with the polycystic ovary syndrome.