John L. Kirkland

Familial Cystic Parathyroid Adenomatosis

Although the commonest familial form of primary hyperparathyroidism is parathyroid hyperplasia, a few families have manifested parathyroid adenomas. We describe a family in which four members developed cystic parathyroid adenomas. Although calcium levels returned to normal after resection of the adenoma, a second adenoma would often develop several years later (we have termed this temporal sequence adenomatosis). Each adenoma had a cystic histologic appearance, and three of four normal-sized parathyroid glands also contained many cysts. No other endocrine tumors have appeared, but in three patients the hyperparathyroidism was complicated by fibrous maxillary or mandibular tumors that resembled ossifying fibromas rather than the brown tumors generally found in patients with hyperparathyroidism. Each patient with an adenoma was hypercalciuric, but two were obligate carriers of hypocalciuric hypercalcemia. This familial occurrence of the rare cystic parathyroid adenoma suggests the presence of a distinct hereditary syndrome. The genetic basis may be the simultaneous inheritance of familial hypocalciuric hypercalcemia and another trait that may increase the urinary excretion of calcium.

Regulation of uterine epidermal growth factor (EGF) receptors by estrogen in the mature rat and during the estrous cycle

Previous work has shown that the immature rat uterus contains epidermal growth factor (EGF) receptors and that tissue levels of this receptor are increased by the administration of exogenous estrogens. This study was undertaken to determine if estrogen administration also elevated EGF receptor levels in the mature animal and if the growth factor receptor levels varied in concert with endogenous estrogens throughout the estrous cycle. In the mature, castrate rat administration of estradiol, but not non-estrogenic steroids, causes a 2-3-fold elevation of uterine EGF receptors as judged by ligand binding. This increase is maximum in 18 h and is due to an increase in the number of binding sites. In cycling animals EGF receptor levels are low at metestrus, rise at diestrus, reach a maximum (approximately twice metestrus values) at proestrus, and then return at estrus to metestrus levels. These changes in EGF receptor levels parallel changes in plasma estrogens and occupied nuclear estrogen receptor reported by other workers. These results indicate that uterine EGF receptors are increased by exogenous estrogens in both mature and immature animals, and support a physiological role for estrogens in the regulation of this growth factor receptor.

Estrogen regulates expression of the jun family of protooncogenes in the uterus

Treatment of immature female rats with estradiol increases uterine levels of c-jun and jun-B mRNAs approx. 10-fold. This effect is specific for estrogenic steroids. The induction of jun transcripts is blocked by actinomycin D but not puromycin, suggesting that the hormonal effect is due at least in part to transcriptional activation. The hormone effect is rapid and peak levels of jun mRNAs are seen within 3 h after treatment. Inductions of jun and fos transcripts in the uterus by estradiol exhibit similar dose response curves (maximum responses at 4 micrograms/kg). Estradiol also elevates uterine levels of jun-D, and this induction is insensitive to puromycin. In vivo treatment with the phorbol ester TPA rapidly elevates uterine levels of fos, jun, and myc transcripts, indicating that expression of these protooncogenes is under non-estrogenic as well as estrogenic regulation in this target tissue. These results suggest that multiple members of the jun and fos protooncogene families may play a role in amplifying the uterine response to estrogens.

Hypoparathyroidism and T cell immune defect in a patient with 10p deletion syndrome

At least a dozen cases of partial deletion of the short arm of chromosome 10 have been described since the first report in 1975) Pertinent physical findings in these children include down-slanting palpebrai fissures, ear anomalies, frontal bossing, micrognathia, and developmental delay. We report an additional child with 10p deletion who initially presented with hypocalcemia and was later discovered to have a T cell defect. Whether or not this immune defect is categorized as partial DiGeorge syndrome, this patient does have an immune defect primarily involving the T cell system, associated with a chromosomal deletion.

Interactions between estrogen and EGF in uterine growth and function.

The rat uterus contains specific, high-affinity EGF receptors which possess a tyrosine kinase activity. As demonstrated autoradiographically, these receptors are present in the epithelial, stromal and myometrial cells of the uterus. Estrogen treatment in vivo produces a 2-3-fold increase in EGF receptor levels in the immature rat, the immature mouse and the ovariectomized adult rat; furthermore, EGF receptor levels vary throughout the estrus cycle in concert with levels of occupied nuclear estrogen receptor. This estrogen-induced increase in EGF receptor is preceded by an increase in the level of EGF receptor mRNA as judged by Northern blot analysis. In general, there is a good correlation between estrogen-induced DNA synthesis and EGF receptor levels in the uterus, although in certain situations EGF receptor levels are elevated without a subsequent increase in DNA synthesis. These observations suggest that an increase in tissue EGF receptor levels is important in estrogen-induced uterine growth, but that this increase in receptor levels alone is not sufficient to stimulate DNA synthesis. In addition to its possible role in tissue growth, we have shown very recently that EGF causes contraction of myometrial smooth muscle in a completely in vitro organ bath system. The qualitative nature of this contractile response is distinct from that produced by other classical uterotonic agents. The physiological significance of this uterine response to EGF remains to be elucidated.

Evidence for thyroid hormone receptors in uterine nuclei

Nuclear preparations from the rat uterus contain specific, high affinity binding sites for T3, with the properties expected of a thyroid hormone receptor. The Kd value for the binding of T3 to these sites is 9.3 +/- 0.1 x 10(-10) M and the maximum number of binding sites is 0.11 +/- 0.02 pmoles T3 bound per mg of DNA. Competition experiments with Triac, D-T3, T4, and rT3 compared to L-T3 revealed relative affinities of 87%, 22%, 15%, and 1.6% respectively. T3 binding sites solubilized from uterine nuclear preparations by high salt extraction sediment at 3.6 S and are destroyed largely by trypsin treatment. Estradiol treatment of ovariectomized rats for 3 days did not alter the quantity of T3 binding sites expressed on the basis of DNA content. These results suggest that uterine nuclei contain a specific T3 receptor and raise the possibility that this hormone may have direct effects on the uterus.

Serum gonadotropin levels in female adolescents with congenital adrenal hyperplasia

Summary Adolescent females with congenital adrenal hyperplasia frequently have menstrual disorders. An investigation of the hypothalamic-pituitary-gonadal axis in three patients under good control was performed by determining serum levels of LH and FSH. The lack of midcycle peaks in those with a history of poor control and cyclicity observed in one with good control suggest that postnatal exposure to adrenal androgens can disrupt the normal hypothalamic-pituitary-gonadal axis.

Effect of a Diabetic State on Myometrial Ultrastructure and Isolated Uterine Contractions in the Rat

Abstract Alterations in rat myometrial ultrastructure and in vitro uterine contractile responses to oxytocin were examined in estradiol-treated (40 μg/kg) euglycemic and streptozotocin-induced (85 mg/kg) diabetic rats. Myometrial morphology was examined 18, 24, and 36 hr after estradiol administration. At the time points examined, nuclei of myometrial cells from euglycemic and diabetic rats were pleomorphic and contained large areas of heterochromatin dispersed throughout the nuclei. Mitochondria were round to oval in shape and contained a dense matrix with cristae that extended across the mitochondria. Myofilaments were found in both euglycemic and diabetic cells but the relative number of myofilaments in diabetic cells appeared to be less than the number found in myometrial cells removed from euglycemic animals. The number of free cytoplasmic ribosomes in diabetic cells also appeared to be less than those found in euglycemic cells. In order to determine if apparent differences in the number of myofilament found in diabetic myometrial cells could be correlated with changes in uterine contractile responses to hormones, oxytocin dose-response curves (10-8 to 10-5 M) were examined in isolated uteri removed from saline-injected and estradiol-injected (24-hr pretreatments) euglycemic and diabetic rats. The maximal contractile responses (milligrams tension developed per milligrams tissue) in saline-injected euglycemic and diabetic rats were 49 ± 5 and 36 ± 4, respectively, while maximal contractile responses in estradiol-injected euglycemic and diabetic rats were 68 ± 7 and 45 ± 5, respectively. Maximal contractile responses induced by oxytocin in estradiol-treated diabetic uteri were significantly smaller than the contractile responses measured in euglycemic estradiol-treated uteri. This study demonstrates that estradiol-induced changes in both myometrial cell morphology and in vitro uterine contractile responses to oxytocin are altered in diabetic rats.

Intranasal nafarelin: an LH-RH analogue treatment of gonadotropin-dependent precocious puberty

The agonistic analogues of luteinizing hormone releasing hormone decrease biochemical findings and clinical signs of gonadotropin-dependent precocious puberty. We tested a new analogue, nafarelin acetate, in 15 girls with gonadotropin-dependent precocious puberty. The hydrophobic nature and potency of this compound allow it to be administered by intranasal inhalation. Laboratory assessment of vaginal cytology, estradiol and urinary gonadotropin levels, and growth velocity revealed that nafarelin acetate 800 to 1200 micrograms/day diminished these values during a 6-month treatment period. These results suggest gonadotropin-dependent precocious puberty in girls can be treated with intranasal administration of nafarelin acetate.

Identification of Y chromatin directly in gonadal tissue by fluorescence in situ hybridization (FISH): Significance for Ullrich‐Turner syndrome screening in the cytogenetics laboratory

The presence of Y chromatin in individuals with Ullrich-Turner syndrome (UTS) confers a risk for gonadoblastoma. In mosaic cases, little is known about Y chromatin distribution in gonads. Fluorescence in situ hybridization (FISH) is a direct approach to assess the extent of Y chromatin mosaicism in gonads. Gonadal tissue from four patients with mosaic karyotypes were analyzed by routine cytogenetics and FISH with X and Y centromere probes. Y chromatin was present in gonads in varying percentages in these patients. The distribution of Y chromatin in gonads of UTS individuals did not completely correlate with that found in blood lymphocytes. The finding of Y chromatin in the blood samples from these patients prompted the development of a screening strategy in our cytogenetics laboratory to detect low-level Y chromatin mosaicism in patients with UTS.