Estrogen in the etiopathogenesis of BPH.

BACKGROUND: While the androgen-dependence of the prostate gland has long been accepted, the participation of estrogen, mediated via the stroma in the elicitation of benign prostatic hyperplasia (BPH), has only recently been recognized. Its mode of action is still uncertain. METHODS: This review first outlines the regulation of gene expression via hormones, growth factors, and other ligands in the coordination of cell growth, differentiation, and function. Focus is next directed to factors particularly involved in phosphorylation of estrogen receptors. Then, the access of sex steroids, especially of estrogen to the cell and to the transduction machinery, is described, preparatory to examining the hypotheses by which this access causes the process of BPH to occur. RESULTS: It becomes clear that the necessary phosphorylative activities which transmit signals to nuclear receptors and thence transcription of target genes can be performed by steroids or mimicked by proxy molecules and by cross-talk between discrete pathways. The character and concentration of the available estrogen are determined by the extent of its biosynthesis, its penetration of the cell, and its subsequent metabolism. In addition, the estrogen affects its own access through stimulation of facilitating peptide hormones, prolactin, and sex hormone-binding globulin. Finally, the induction of BPH is shown to be determined by the androgen/estrogen ratio and the change in stromal/epithelial balance accompanying aging. CONCLUSIONS: Despite a growing knowledge of hormone levels, metabolism, and activities in the prostate, and the variety of processes and factors they affect, our explanation of BPH is still fanciful.

Prostate stroma: physiology.

BACKGROUND: The separate structural and functional activities of the prostatic stroma were only recently discovered and are still poorly understood. METHODS: This review summarizes recent literature on the structure, and on the angiogenic, contractile, proliferative, and secretory activities mediated by the prostatic stroma and its agents. RESULTS: The stroma undergirds the acinar epithelium through its fibromuscular substance. Neovascularization of its hypoxic cells, a process driven by cytokines, especially vascular endothelial growth factor, provides fuel for glycolytic empowerment of smooth muscle contraction, growth, and secretion. Signals from the stromal complement of cholinergic and adrenergic fibers, modulated by also-elaborated nitric oxide, provide tight regulation of uroflow. Apparently, autonomic control is independent of that of the powerful endothelin, secreted by the epithelium. Superimposed on these intrinsic elements of prostatic stromal control are the effects of steroid hormones and their effectors. CONCLUSIONS: The illumination of the stroma's role in prostatic physiology, coupled with advances in knowledge of its pharmacology, should aid in our understanding, management, and prevention of prostatic disease.

Figuring out why we breathe.

This paper chronicles the evolution of present understanding of cardiopulmonary physiology and attempts to illuminate both the thought and innovation of all the participating pioneers. Early on, the rate of progress was determined by advances in anatomy-the definition of the vascular system and its relationships to the heart and lungs. It was held back by concerns, especially religious, with the pneuma, and by ignorance of the inability of air and blood to circulate together, and of blood's capability to transport gases within its cells. These stumbling blocks were set aside successively by the advent of microscopic anatomy (red cells and capillaries), chemistry (hemoglobin structure and function; the fact that air is a mixture of gases of different properties; processes of combustion; and the theory of the conservation of matter), and physics (Bohr effect; molecular structure of hemoglobin). Only though access to these facts and principles have we been able to approach some inborn errors and to design molecular prostheses such as oxygen-carrying microspheres and polyethylene glycol-hemoglobin.

Roles of estrogen and SHBG in prostate physiology.

Heretofore, the function of estrogen in the prostate, other than as an antiandrogen, has been unclear. In this review of a growing fund of knowledge about both estrogen and the plasma protein, sex hormone-binding globulin (SHBG), or testosterone-estradiol binding globulin (TeBG), the hypothesis is proposed that estrogen, mediated by SHBG, participates with androgen in setting the pace of prostatic growth and function. It is suggested that the estrogen not only directs stromal proliferation and secretion, but also, through IGF-I, conditions the response of the epithelium to androgen.

TRH: mediator of prolactin in the prostate?

Thanks to our preoccupation with androgen ablative therapy, no significant progress has been made in combating prostate cancer (PCa) in 50 years. Also, there have been only limited advances in medical treatment of benign prostatic hyperplasia (BPH). The intent of this essay is to explore the mode of participation of prolactin (Prl) in prostatic physiology in the hope that such knowledge will reveal new avenues through which both BPH and PCa can be opposed-even prevented. An especially novel aspect of this study is the recognition of the presence and androgen- and prolactin-dependent concentration of the tripeptide, thyrotropin-releasing hormone (TRH) in prostatic tissue. It is hypothesized that, whereas TRH is the hypothalamic stimulus of hypophyseal Prl secretion, it may, in the prostate, serve as the mediator of Prl's independent and androgen-dependent controls of the gland's growth and function. Through an overview of these relationships, methods are suggested both for their study and for their adaptation to early detection and prevention of imminent pathogenesis.

Na+,K(+)-ATPase: the actual androgen receptor of the prostate?

While the nucleus may play a secondary role in androgen regulation of prostatic functional and structural development, I propose that, in the fully developed gland, the pace of all metabolism, biosynthesis, secretion and reparative proliferation in the gland is coupled to and set by the action of androgen on the Na+,K(+)-ATPase of the plasma membrane. This report identifies the three questions which must be asked and affirmatively answered to verify this hypothesis: 1. Straightforward procedures for the unambiguous demonstration of the coupling of (Na+,K+)-ATPase activity to glycolysis, oxidative metabolism, protein synthesis, cell alkalinization and citrate synthesis/secretion and that addition of androgen in vitro boosts the rates of the enzyme and all its coupled processes. 2. Demonstration that the stimulatory effect of the androgen is on the specific catalytic activity of each (Na+,K+)-ATPase molecule, not on the number of these enzyme units present. 3. Provision of means to show a likely mechanism for this activation; viz. shift in enzyme conformation.

Training physicians to be doctors--teachers and healers, problem-solvers and decision-makers.

With the scientific advances made in medicine during the past 200 years, the training of physicians in America has changed from that of a mentor/apprenticeship relationship to one in which students are part of an impersonal, mass production process. From a historical perspective, it is contended that basic science and rote memorization of medical theory have subsumed the art of medicine. As a result, students are overloaded with irrelevant facts, few of which they carry over in their professional practice of medicine. To alter this teaching approach and, hence, the quality of physicians, medical school curricula should incorporate recommendations found in the General Professional Education of Physicians Report, among other sources. These recommendations, which have been incorporated successfully in the curriculum at the University of New Mexico School of Medicine, for example, include: establishing goals that may be coordinated interdepartmentally; reestablishing the physician/mentor for each student; using a small-group, interactive, problem-solving, clinically oriented approach to teaching; measuring each student's ability to not only retain knowledge but, more importantly, apply such information to actual clinical problem-solving and decision-making situations; admitting liberal arts graduates--not premedical students--to medical schools; and recruiting and training faculty members who have the time to each and the ability to emphasize biomedicine rather than their special discipline. These changes will make students more than physicians. They will be "real doctors," individuals who not only possess knowledge but can apply it in their daily practice of medicine.

Prostate plasma membrane receptor: a hypothesis.

Based on 50 years of emerging knowledge about and changing views of prostate biochemistry and physiology and especially on the belief that there is an underlying mechanism of androgen control, the hypothesis is developed and tested that the rates of proliferation, biosynthesis, metabolism, and secretion are modulated through the hormone-sensitive Na, K-ATPase of the plasma membrane. These preliminary experiments, constituting a novel synthesis of technologies from endocrinology, intermediary metabolism, and membrane transport, attempt to explain the extraordinary production and secretion of citrate and how this may be coupled to sustaining prostate cell number and function. Attention is focused on learning where androgen is bound and how it interacts with the Na,K-ATPase. Both the dissimilar properties of epithelial and stromal cells in the separate regions of the acinus and the changing environment of growth factors in which these cells are bathed help account for their unlike reactivities during development and ongoing mature function. Little wonder that one hormone can have so many effects!

The prostate plasma membrane as an androgen receptor.

The pivotal role of the cell nucleus in androgenic control of target organs, such as the prostate, has become increasingly suspect. Equally qualified receptor activities have been found in the cytosol, endoplasmic reticulum, and plasma membrane. It is presently difficult to explain how a sex steroid can manage proliferation, metabolism, biosynthesis and secretion, all through chromatin-directed signals. In my search for a more satisfactory mediator of androgen action, I discovered that the sodium-potassium-dependent ATPase of the prostate plasma membrane binds androgen, and is activated by the hormone's presence to serve as a metabolic pacemaker. This paper is my terminal status report on one aspect of this hypothesis; namely, the nature and site of androgen binding, with clues as to the mode of action. SDS-PAGE indicates that androgen can be bound to the beta-subunit of prostatic Na,K-ATPase. Selective enrichment of the enzyme by reversible coupling to either concanavalin A or a DHT-affinity column support this conclusion. Several studies show the dynamic effect of androgen binding: increased ouabain binding; enhancement of this binding by facilitated phosphorylation; spectroscopic evidence of conformational shifts, possibly consequences of these suggested activities for regulation, especially of metabolism, are examined.

Prolactin effect on the permeability of human benign hyperplastic prostate to testosterone.

While it has been known for over 30 years that prolactin (Prl) synergizes with androgen in the support and stimulation of prostatic growth and metabolism, the evidence that this is accomplished through increasing access of the steroid to the cellular machinery of the gland has arisen only since about 1970. There is widespread uncertainty as to how the Prl effect takes place: by 1) increasing the free steroid concentration in the blood; 2) facilitating the uptake of protein-bound androgen; 3) increasing, by metabolism or receptor-binding, the concentration gradient that can support passive diffusion of the steroid across the plasma membrane; or 4) modification of the fluidity of the membrane itself to increase the solubility of the steroid in the lipoprotein and, thus, the ease of penetration of the cell. The present study attempted to learn if Prl is an effective stimulus of androgen uptake when the first three options are not operative. Using an equilibrium exchange procedure to track the uptake of [17 alpha-3H]-testosterone ([17 alpha-3H]-T) into minced benign hyperplastic human prostate tissue and the irreversible metabolism of the entering steroid to [17 alpha-3H]-dihydrotestosterone [17 alpha-3H]-DHT, it was found that the rate of production of the 5 alpha-reduced metabolite, during a 1-hr incubation in vitro, was directly proportional to the concentration of ovine Prl over the dose range of 0-160 ng/ml. The clinical significance of Prl mediation of steroid uptake is discussed, and suggestions are made as to how the Prl might alter the permeability of the plasma membrane.

Interaction of prolactin and testosterone in the human prostate.

Three experiments were performed to determine whether human prolactin (hPr) affects prostatic uptake and metabolism of testosterone (T). 1) Patients with prostatic cancer were infused twice with radio-labelled androgens, the first time with basal hPR, the second time with oral thyrotrophin-releasing hormone (TRH)-elevated hPr. In 5/7, significant increases in metabolic clearance of dihydrotestosterone (DHT) and in conversion of T to DHT accompanied increased hPR. 2) The incorporation of labelled T into minced benign prostatic hypertrophy (BPH) tissue from subjects with high (40 ng/ml) hPR was measured and was found to be more than twice the uptake into tissue from those with low hPR (6.5 +/- 1.9 ng/ml). 3) Uptake and metabolism in vivo of a bolus of 3H-T by BPH and carcinomatous prostates was measured and was far greater in subjects whose hPR was elevated by chlorpromazine than in untreated controls. It is concluded that prolactin increases prostatic uptake and metabolism of T. It is suggested that the best management of prostatic cancer should include depletion of prolactin as well as androgen.

Comparative performance of three radioimmunoassays for prostatic acid phosphatase.

Three commercial radioimmunoassays and one enzymatic assay for prostatic acid phosphatase (PAP) have been tested on 122 patients to determine their relative specificity, sensitivity, and diagnostic value. Each of the three radioimmunoassays was found to have special merits. For distinguishing Stage IV prostatic cancer from normal patients without prostatic disease, the Smith Kline (SKF) and New England Nuclear (NEN) assays provide more significant differences. The SKF test also best distinguishes all stages of prostatic cancer from benign prostatic hyperplasia (BPH), but is inferior to the Malinckrodt (MAL) assay for contrasting Stage IV prostatic cancer from BPH. Values obtained with the NEN assay best distinguish the stages of prostatic cancer. Only with the MAL assay are significantly higher PAP values obtained in patients with metastases to bone than those without positive bone scans. Viewed from the point of sensitivity, the SKF assay proves best at all levels of specificity examined in detecting all stages (I-IV), and Stage IV prostatic cancer. By none of the assays can estrogenized Stage III and IV cancer patients be distinguished from those not on estrogen.

Benign prostatic hyperplasia in an XX man.

A sixty-nine-year-old white phenotypic male who was being investigated for a myeloproliferative disorder, was found to have an XX karyotype in all cells examined in bone marrow, lymphocytes, and skin fibroblast cultures. Despite essentially no testosterone in the plasma, he also suffered from severe prostatic hyperplasia, a finding not reported previously in patients with this genotype. While endocrine studies showed normal follicle-stimulating hormone, the luteinizing hormone level was twice the upper limit of normal and estrogens were in the normal female range. Except for complete absence of Leydig cells, testicular histology resembled that usually found in Klinefelter syndrome. The patient died of the combined effects of the myeloproliferative disease and urinary tract obstruction. The mechanism of occurrence of the sex chromosome anomaly as well as the cause and implication of the unusual finding of prostatic hyperplasia are discussed.

Derivation and determination of a human prostatic epithelial index.

The approximate percentage of epithelium (Iepith) in a sample of human prostate tissue can be estimated by assaying the specific activity of epithelial marker enzymes, beta-glucuronidase or arginase. There is a good correlation between epithelial density and beta-glucuronidase activity per unit of tissue protein.