Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G proteincoupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.

Intensified peroxidation in the Graafian follicle may be a factor compromising the normal development of the oocyte. The aim of this study was to measure concentrations of three oxidative stress markers: conjugated dienes, lipid hydroperoxides and thiobarbituric acid-reactive substances, in preovulatory follicular fluids and sera of 145 women attending an in-vitro fertilization programme, and to correlate these concentrations with pregnancy outcome. Determinations were conducted either with or without an antioxidant (10 microM butylated hydroxytoluene) and an iron chelate (10 microM deferoxamine mesylate) to examine peroxidation associated with the methods used. Concentrations of conjugated dienes, lipid hydroperoxides and thiobarbituric acid-reactive substances in follicular fluid were all significantly lower than those in serum, both in the presence or absence of the antioxidant and iron chelate. These concentrations did not correlate with pregnancy outcome. In conclusion, the intensity of peroxidation in the Graafian follicle is much lower than that in serum. This gradient is the result of the lower rate of initiation of peroxidation in the follicular fluid, suggestive of the presence of efficient antioxidant defence systems in the direct milieu of the oocyte before ovulation. The concentrations of investigated oxidative stress markers in follicular fluid do not reflect the reproductive potential of oocytes.

Background and Purpose-Recent evidence suggests that physiological changes in the concentration of endogenous estrogens may influence stroke outcome. The purpose of this study was to determine a menstrual cycle-related profile of blood flow through the carotid arteries and its correlation with estrogen concentration. Methods-The flow velocity and cross-sectional area of the common carotid artery, internal carotid artery (ICA), and external carotid artery (ECA) were measured with duplex Doppler sonography throughout the menstrual cycle in 14 healthy women. Concentration of plasma 17␤-estradiol, progesterone, hematocrit, hemoglobin, and blood pressure were also determined. Results-In the follicular phase, the concentration of estrogen increased to reach a peak on day 14, whereas concentration of progesterone remained low. The mean and end-diastolic velocities in the ICA increased on average by 15% of their base values, along with increasing concentrations of estrogen (rϭ0.59 and 0.65, respectively). The profile of flow velocity changes in this artery corresponded to the profile of estrogen concentration. In contrast to the ICA, flow velocities in the ECA decreased from their base value, reaching their minimum in the luteal phase. The mean flow velocity in the common carotid artery increased on day 14 by just 2% of its base value. The lumen of the carotid arteries was stable throughout the cycle. Hematocrit, hemoglobin, and systolic blood pressure also remained unchanged. Conclusions-Increased

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