Evidence that dopamine acts via kisspeptin to hold GnRH pulse frequency in check in anestrous ewes.

Recent work has implicated stimulatory kisspeptin neurons in the arcuate nucleus (ARC) as important for seasonal changes in reproductive function in sheep, but earlier studies support a role for inhibitory A15 dopaminergic (DA) neurons in the suppression of GnRH (and LH) pulse frequency in the nonbreeding (anestrous) season. Because A15 neurons project to the ARC, we performed three experiments to test the hypothesis that A15 neurons act via ARC kisspeptin neurons to inhibit LH in anestrus: 1) we used dual immunocytochemistry to determine whether these ARC neurons contain D2 dopamine receptor (D2-R), the receptor responsible for inhibition of LH in anestrus; 2) we tested the ability of local administration of sulpiride, a D2-R antagonist, into the ARC to increase LH secretion in anestrus; and 3) we determined whether an antagonist to the kisspeptin receptor could block the increase in LH secretion induced by sulpiride in anestrus. In experiment 1, 40% of this ARC neuronal subpopulation contained D2-R in breeding season ewes, but this increased to approximately 80% in anestrus. In experiment 2, local microinjection of the two highest doses (10 and 50 nmol) of sulpiride into the ARC significantly increased LH pulse frequency to levels 3 times that seen with vehicle injections. Finally, intracerebroventricular infusion of a kisspeptin receptor antagonist completely blocked the increase in LH pulse frequency induced by systemic administration of sulpiride to anestrous ewes. These results support the hypothesis that DA acts to inhibit GnRH (and LH) secretion in anestrus by suppressing the activity of ARC kisspeptin neurons.

A controversy: linking atypical femoral fractures to bisphosphonate therapy.

Several cases have been reported of unusual spontaneous fractures with minimal trauma in the subtrochanteric and diaphyseal areas of the femur linked to long-term bisphosphonate use. After encountering three such patients, we conducted a review of published cases. The average age of these individuals were 68 years and approximately 25% had received concomitant glucocorticoids. Histomorphometric bone biopsy studies performed in some individuals have suggested that severe suppression of bone turnover may be the underlying cause; however, cause and effect has not been firmly established. Moreover, population studies have found this type of fracture rare and not increased in patients who have received bisphosphonate treatment. Physicians should continue to use bisphosphonate agents as a primary treatment for osteoporosis.