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