Continuous Kisspeptin Administration in Postmenopausal Women: Impact of Estradiol on Luteinizing Hormone Secretion.

Context: Kisspeptin stimulates the reproductive endocrine cascade in both men and women. Circulating sex steroids are thought to modulate the ability of kisspeptin to stimulate gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release. Objective: To probe the effects of sex steroids on kisspeptin-stimulated GnRH-induced LH pulses. Participants: Eight healthy postmenopausal women. Intervention: Subjects underwent every-10-minute blood sampling to measure GnRH-induced LH secretion at baseline and in response to a continuous kisspeptin infusion (12.5 µg/kg/h) over 24 hours. A subset of the participants also received kisspeptin (0.313 µg/kg) and GnRH (75 ng/kg) intravenous boluses. Results: Postmenopausal women are resistant to the stimulatory effect of continuous kisspeptin on LH secretion. Postmenopausal women receiving estradiol replacement therapy are also resistant to kisspeptin initially, but they demonstrate a significant increase in LH pulse amplitude in direct proportion to the circulating estradiol concentration and duration of kisspeptin administration. Conclusions: Kisspeptin administration has complex effects on GnRH, and by extension, on LH secretion. The ability of kisspeptin to affect LH secretion can be modulated by the ambient sex-steroid milieu in a time- and dose-dependent manner.

Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty.

CONTEXT: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. OBJECTIVE: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal. PARTICIPANTS: Six men with congenital IHH and evidence for reversal. INTERVENTION: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg). RESULTS: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin. CONCLUSIONS: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.

Prospective study of health-related quality of life for children with brain tumors treated with proton radiotherapy.

PURPOSE: We describe the health-related quality of life (HRQoL) of a cohort of children with brain tumors treated with proton radiotherapy. PATIENTS AND METHODS: We recruited 142 pediatric patients with brain tumors (age 2 to 18 years) and parents of such patients treated with proton radiation at Massachusetts General Hospital from 2004 to 2010. HRQoL was assessed using the PedsQL core, brain tumor, and cancer modules (range, 0 to 100). Assessments took place during radiation and annually thereafter. We examined correlations of HRQoL with disease, treatment, and cognitive and behavioral data. RESULTS: Overall reports of HRQoL during treatment were 74.8 and 78.1 for child self-report (CSR) and 67.0 and 74.8 for parent proxy report (PPR) for the core and brain tumor modules, respectively. PPR demonstrated lower HRQoL scores than CSR, but the two were highly correlated. Higher HRQoL scores were significantly associated with Wechsler Full Scale Intelligence Quotient scores (administered via the age-appropriate version) and better scores on two behavioral measures. Disease type also correlated with PPR core total HRQoL score at the beginning of treatment: medulloblastoma or primitive neuroectodermal tumors, 57.8; germ cell tumors, 63.5; ependymoma or high-grade glioma, 69.8; low-grade glioma, 71.5; and other low-grade neoplasms, 78.0 (P = .001). Craniospinal irradiation and chemotherapy were negatively correlated with HRQoL. CONCLUSION: This is the first study to our knowledge of HRQoL in a cohort of children with brain tumors treated with proton radiation. This prospective study demonstrates the effect of disease type and intensity of treatment on HRQoL. It further suggests that where CSR is not possible, PPR is appropriate in most circumstances.