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Highly glycosylated FSH: available clinical results and investigational issues

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Highly glycosylated FSH: available clinical results and investigational issuesG├╝rgan Timur

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PREMATURE PUBARCHE IN MEDITERRANEAN GIRLS: HIGH PREVALENCE OF HETEROZYGOUS CYP21MUTATION CARRIERS

Paris – DGYE-2009-0185 [ID 451583]

Aim of the study: This study investigated the prevalence and consequences of heterozygous CYP21A2 mutations in PP girls.
Main finding: We investigated 36 French Mediterranean girls with isolated PP. We performed synacthen testing with 17OHP and 21-deoxycortisol evaluation, along with molecular analysis of the CYP21A2 gene in girls with abnormal elevation of one of these two adrenal steroids. Three girls (8.3%) had NCAH, secondary to compound heterozygosity that associated at least one severe mutation for the 3 girls. A heterozygous mutation of the CYP21A2 gene was confirmed by molecular biology in eight girls (22%); a deletion of the CYP21A2 gene was found in one of them. Biological hyperandrogenism was found in the prepubertal CYP21A2 mutation carriers, whereas the four heterozygous girls who were followed long enough to have reached pubertal age presented biological and clinical hyperandrogenism.
Conclusions:
We underline the high prevalence of heterozygous CYP21A2 mutations in girls with PP and demonstrate the usefulness of systematic screening by synacthen testing, both to improve their future clinical management and to prevent the transmission of classical adrenal hyperplasia to future offspring. Because of the severe metabolic and cardiovascular consequences of hyperandrogenism, long-term follow-up of these heterozygous patients is mandatory.

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ROLE OF ESTRADIOL IN CORTISOL-INDUCED REDUCTION OF LUTEINIZING HORMONE PULSE FREQUENCY.

Endocrinology. 2009 Jun;150(6):2775-82.

Oakley AE, Breen KM, Tilbrook AJ, Wagenmaker ER, Karsch FJ.

Precise control of pulsatile GnRH and LH release is imperative to ovarian cyclicity but is vulnerable to environmental perturbations, like stress. In sheep, a sustained (29 h) increase in plasma cortisol to a level observed during stress profoundly reduces GnRH pulse frequency in ovariectomized ewes treated with ovarian steroids, whereas shorter infusion (6 h) is ineffective in the absence of ovarian hormones. This study first determined whether the ovarian steroid milieu or duration of exposure is the relevant factor in determining whether cortisol reduces LH pulse frequency. Prolonged (29 h) cortisol infusion did not lower LH pulse frequency in ovariectomized ewes deprived of ovarian hormones, but it did so in ovariectomized ewes treated with estradiol and progesterone to create an artificial estrous cycle, implicating ovarian steroids as the critical factor. Importantly, this effect of cortisol was more pronounced after the simulated preovulatory estradiol rise of the artificial follicular phase. The second experiment examined which component of the ovarian steroid milieu enables cortisol to reduce LH pulse frequency in the artificial follicular phase: prior exposure to progesterone in the luteal phase, low early follicular phase estradiol levels, or the preovulatory estradiol rise. Basal estradiol enabled cortisol to decrease LH pulse frequency, but the response was potentiated by the estradiol rise. These findings lead to the conclusion that ovarian steroids, particularly estradiol, enable cortisol to inhibit LH pulse frequency. Moreover, the results provide new insight into the means by which gonadal steroids, and possibly reproductive status, modulate neuroendocrine responses to stress.

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ESTRADIOL-17{BETA} INHIBITS GNRH-INDUCED CA2+ IN GONADOTROPES TO REGULATE NEGATIVE FEEDBACK ON LH RELEASE.

6) Endocrinology. 2009 May 28

Iqbal J, Latchoumanin O, Sari IP, Lang RJ, Coleman HA, Parkington HC, Clarke IJ.

In pituitary gonadotropes, estrogens have biphasic actions to cause an initial negative feedback followed by a positive feedback on LH secretion, but the mechanisms involved are not clearly understood. To investigate the feedback effects of estrogen, we used mixed ovine pituitary cell cultures (48-72h) which were treated with 10(-9)M estradiol-17beta (E2) or vehicle followed by a pulse of 10(-9)M GnRH. more

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CIRCADIAN REGULATION OF KISS1 NEURONS: IMPLICATIONS FOR TIMING THE PREOVULATORY GNRH/LH SURGE.

Endocrinology. 2009 May 14

Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS.

The preovulatory GnRH/LH surge depends on the presence of estradiol (E2) and is gated by a circadian oscillator in the suprachiasmatic nucleus (SCN) that causes the surge to occur within a specific temporal window. Although the mechanisms by which the clock times the LH surge are unclear, evidence suggests that the SCN is linked to GnRH neurons through a multi-synaptic pathway that includes neurons in the anteroventral periventricular nucleus (AVPV). more

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