Faculty Bibliography

Adrenal hypoplasia congenita (AHC) is an X-linked disorder that typically presents with adrenal insufficiency during infancy. Hypogonadotropic hypogonadism (HHG) has been identified as a component of this disorder in affected individuals who survive into childhood. Recently, AHC was shown to be caused by mutations in DAX-1, a protein that is structurally similar in its carboxyterminal region to orphan nuclear receptors. We studied two kindreds with clinical features of AHC and HHG. DAX-1 mutations were identified in both families. In the JW kindred, a single base deletion at nucleotide 1219 was accompanied by an additional base substitution that resulted in a frameshift mutation at codon 329 followed by premature termination. In the MH kindred, a GGAT duplication at codon 418 caused a frameshift that also resulted in truncation of DAX-1. Baseline luteinizing hormone (LIT), follicle-stimulating hormone (FSH), and free-alpha-subunit (FAS) levels were determined during 24 h of frequent (q10 min) venous sampling. In patient MH, baseline LH levels were low, but FAS levels were within the normal range. In contrast, in patient JW, the mean LH and FSH were within the normal range during baseline sampling, but LH secretion was erratic rather than showing typical pulses. FAS was apulsatile for much of the day, but a surge was seen over a 3-4-h period. Pulsatile gonadotropin releasing hormone (GnRH) (25 ng/kg) was administered every 2 h for 7 d to assess pituitary responsiveness to exogenous GnRH. MH did not exhibit a gonadotropin response to pulsatile GnRH. JW exhibited a normal response to the first pulse of GnRH, but there was no increase in FAS. In contrast to the priming effect of GnRH in GnRH-deficient patients with Kallmann syndrome, GnRH pulses caused minimal secretory responses of LH and no FAS responses in patient JW. The initial LH response in patient JW implies a deficiency in hypothalamic GnRH. On the other hand, the failure to respond to pulsatile GnRH is consistent with a pituitary defect in gonadotropin production. These two cases exemplify the phenotypic heterogeneity of AHC/HHG, and suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels

Perimenopause, which occurs when a woman's body begins producing less estrogen and progesterone, can begin at different ages for different women, with some women developing symptoms as early as their mid-thirties. Low-dose oral contraceptives help most women relieve perimenopausal symptoms, such as hot flashes

To determine if the use of hormone replacement therapy (HRT) in postmenopausal women influences the size of uterine leiomyomas, we report a series of 14 cases of postmenopausal women with uterine leiomyomas that were monitored with transvaginal pelvic ultrasound before and then at a mean of 19.7 +/- 6.3 months after initiating HRT. A small group of seven postmenopausal women with uterine leiomyomas not treated with HRT were also evaluated at two time points (9.6 +/- 1.7 months apart). There were no significant changes in mean uterine or myoma volumes from the time of the initial to follow-up ultrasound in the postmenopausal women treated with HRT. Neither the type of estrogen or progestin preparation nor the HRT regimen (sequential versus continuous combined) affected the mean uterine or myoma volume. There were also no significant changes in the mean myoma volume in the small group of postmenopausal women not on HRT during this interval of time; however, the mean uterine volume decreased. The use of HRT in postmenopausal women with uterine leiomyomas does not seem to significantly increase uterine or myoma size, but may prevent the overall uterine size from shrinking postmenopausally, although larger prospectively designed studies are needed to confirm these findings. Therefore, perhaps following the less time-consuming sonographic measurement of the overall uterine volume is adequate, and may be even preferable, for monitoring these patients rather than using the more labor-intensive serial measurement of the volume of each individual myoma

Vaginal atrophy can be reversed for most women through systemic hormones. Those women who cannot take systemic hormones can get relief of symptoms with local estrogen therapy, which ideally should be locally effective without significant systemic absorption and without endometrial stimulation. An estradiol-releasing vaginal ring was therefore tested for efficacy, safety and patient acceptability in a 15-week open-label, randomized parallel group trial with blinded evaluations of the cytological response data. Conjugated estrogen vaginal cream was used as a reference control. The primary objectives of the study were to evaluate whether the two treatments were equivalent regarding improvement in urogenital atrophy, improvement in physicians's overall evaluation of product performance on urinary and/or vaginal changes, and improvement in patient's assessment of urinary and/or vaginal symptoms. A secondary objective was to assess frequency of endometrial overstimulation during estrogen replacement therapy, to be measured by a progestogen challenge test. The ring and cream treatment produced an equivalent effect on the vaginal mucosa, and equivalence was also found in physician's and patient's assessments of both vaginal and urinary symptomatology. Both treatments were equally effective in improving the vaginal pH toward levels normally seen in fertile women (< 5.0). With regard to endometrial stimulation, significantly more patients had bleedings at progestogen challenge test after 3 months of treatment with cream than with the ring. The ring, however, was given significantly better overall product acceptability ratings by the patients. It can therefore be seen as an equally effective, but significantly more acceptable, new administration form for treatment of urogenital disorders due to estrogen deficiency, with a more favourable safety profile than vaginal cream