C. Wayne Bardin

Inhibition of the action of sex steroids by gonadotropin-releasing hormone (GnRH) agonists: A new biological effect

Abstract Agonistic analogs of GnRH [ (imBzl)-D-His 6 , Pro 9 -NEt]-GnRH and ]D-Trp 6 , Pro 9 -NEt]-GnRH inhibit the testosterone-induced increase in weights of ventral prostate and seminal vesicles in castrated and in hypophysectomized-castrated rats. These peptides also inhibit the uterotropic action of estradiol in the ovariectomized rat. The results suggest that part of the antifertility and antitumor activity of GnRH and its agonists could be due to their ability to antagonize the biological actions of sex steroids.

Ornithine Decarboxylase mRNA in Mouse Kidney: A Low Abundancy Gene Product Regulated by Androgens with Rapid Kinetics

We have used ODC gene expression in mouse kidney as the biological marker for studies of early androgen action. Some of the characteristics of this regulation involve its strict androgen specificity, the dependency on functional androgen receptors, the lack of requirement for pituitary hormones, and the ability of physiological androgens to bring about activation of the ODC gene. Some recent findings have revealed an additional intriguing feature in the regulation of ODC gene expression in that androgen sensitivity of ODC stimulation is genetically regulated in the mouse kidney (unpublished observations). One of the mechanisms by which androgens regulate renal ODC synthesis is to increase the concentration of ODC mRNA. Increased accumulation of this mRNA was seen as soon as 6 hr after testosterone administration, and it peaked 24 hr posttreatment. In general, acute changes in immunoreactive ODC concentration and ODC mRNA accumulation had very similar kinetics, suggesting that androgens induced de novo synthesis of ODC by increasing the rate of ODC gene transcription. In addition, there was always a highly significant correlation between the catalytic enzyme activity and immunoreactive enzyme protein concentration indicating that androgens do not specifically regulate the active site of ODC by either activating or inhibiting the enzyme by posttranslational modifications. A typical feature of ODC in virtually all eukaryotic tissues is the extremely rapid turnover rate of the enzyme with a biological half-life of 10-30 min. However, no direct information on the turnover rate of ODC mRNA is currently available, although indirect experiments have assigned a half-life of about seven hours for this mRNA. The availability of cDNA clones for ODC mRNA measurements will now permit us to address this question more directly, and also to investigate a possible role of androgens in the stabilization of ODC mRNA. In this regard it is of interest to note that chronic treatment of mice with pharmacological doses of testosterone prolongs the half-life of ODC protein four- to tenfold.

Calcitonin Gene Expression in the Rat Uterus during Pregnancy

Publisher Summary The C cells of the thyroid gland are known as the major site of synthesis of calcitonin. This polypeptide hormone is released in response to hypercalcemia and mediates calcium homeostasis in both bone and kidney. This chapter presents a study that identifies the uterus as a novel site of calcitonin gene expression during preimplantation stages of pregnancy. The calcitonin synthesized in uterus acts in a paracrine or autocrine fashion to regulate calcium levels in certain uterine cells. Calcium controls many cellular processes, including muscle contraction, nerve conduction, and numerous enzymatic reactions. In the uterus, calcitonin regulates processes such as myocontraction and, therefore, plays a crucial role in embryonic implantation and maintenance of pregnancy. The antiprogestin RU486, which effectively blocks implantation and terminates pregnancy, also inhibits calcitonin expression. RU486-induced termination of pregnancy in preimplantation stage animals results from down regulation of certain genes, including calcitonin, which are primarily regulated by progesterone and may be crucial for implantation.

Intracellular Hormone Receptor Defects and Disease

Publisher Summary This chapter discusses the quantitative or qualitative defects in steroid and thyroid hormone receptors in humans. It also presents the current information about multiple receptor diseases. Receptor abnormalities have been divided into two categories—(1) those in which the defect is of primary nature, that is, the disorder has a proved or suggested genetic origin, and (2) those where the defect is acquired, that is, it results from adaptive mechanisms of often unknown nature. For better understanding, a general outline of the mechanism of action of steroid and thyroid hormones is presented in the chapter. Although hormone receptor defect inevitably implies hormone resistance, it is important to emphasize that all hormone resistance is not a consequence of a receptor abnormality. Hormone resistance may also derive from pre-receptor mechanisms, such as the presence of endogenous or exogenous hormone antagonists and antibodies to the hormone or hormone receptor.

Clinical Implications of Gonadotropin Rhythms

When radioimmunoassays for LH and FSH were devised, a number of investigators looked for cyclic variations of gonadotropin levels in human plasma. The lack of sensitivity of these initial assays and the failure to obtain frequent samples prevented the detection of variable LH secretion. Nankin and Troen (1) were the first to show that LH and, to some extent, FSH were secreted in a pulsatile fashion. Since these initial studies, numerous laboratories have confirmed that LH secretion is highly variable (2–5). In view of these observations, it was important to determine whether variable gonadotropin secretion occurred in patients and what were the implications of this mode of secretion for the clinician.