John H. MacIndoe

Psychosexual effects of three doses of testosterone cycling in normal men.

BACKGROUND Testosterone is receiving increased attention for contraceptive and therapeutic indications. The potential psychosexual side effects of testosterone therapy and withdrawal are unclear. METHODS Healthy men between the ages of 21 and 40 years were recruited via advertisement for a randomized, controlled, double-blind study of acute and withdrawal effects of three doses of testosterone. Two weeks of placebo injections were followed by one of three randomized weekly doses of testosterone cypionate (100 mg, 250 mg, or 500 mg) for the next 14 weeks. Twelve weeks of placebo injections followed during the withdrawal phase of the study. Psychosexual effects were monitored throughout the study. RESULTS All doses of testosterone demonstrated only minimal effects on measures of mood and behavior during acute and withdrawal phases for all study completers. There were no effects on psychosexual function. There was no evidence of a dose-dependent effect on any measure. One noncompleter on 500 mg of testosterone developed a brief syndrome with symptoms similar to an agitated and irritable mania. CONCLUSIONS Doses of testosterone up to five times physiologic replacement dose appear to have minimal risk of adverse psychosexual effects in the majority of normal men; however, beginning at around 500 mg per week of testosterone cypionate, a minority of normal men may experience significant adverse psychological effects. Because illicit anabolic steroid users may use larger doses of multiple drugs under less restrictive conditions, our study may significantly underestimate the psychological effect of steroid use in the community.

Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men

PURPOSE We investigate and define the effects of exogenous testosterone on the normal prostate. MATERIALS AND METHODS A total of 31 healthy volunteers 21 to 39 years old were randomized to receive either 100, 250 or 500 mg. testosterone via intramuscular injection once a week for 15 weeks. Baseline measurements of serum testosterone, free testosterone and prostate specific antigen (PSA) were taken at week 1. Semen samples were also collected for PSA content and prostate volumes were determined by transrectal ultrasound before testosterone injection. Blood was then drawn every other week before each testosterone injection for the 15 weeks, every other week thereafter until week 28 and again at week 40. After the first 15 weeks semen samples were again collected, and prostate volumes were determined by repeat transrectal ultrasound. RESULTS Free and total serum testosterone levels increased significantly in the 250 and 500 mg. dose groups. No significant change occurred in the prostate volume or serum PSA levels at any dose of exogenous testosterone. Total semen PSA levels decreased following administration of testosterone but did not reach statistical significance. CONCLUSIONS Despite significant elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.

The effect of exogenous testosterone on total and free prostate specific antigen levels in healthy young men

PURPOSE We evaluated the effect of exogenous testosterone administration on serum total and free prostate specific antigen (PSA) in healthy young men. MATERIALS AND METHODS Nine volunteers received either 100, 250 or 500 mg. testosterone by intramuscular injection each week for 15 weeks. Blood was drawn every other week for 28 weeks and at week 40. Serum total and free PSA, and total and free testosterone were measured and compared to baseline values. RESULTS Significant elevations in total and free testosterone occurred but no significant change in serum total and free PSA was detected. CONCLUSIONS Serum PSA is not responsive to elevated serum testosterone levels in healthy young men. PSA metabolism in the normal prostate is unclear but our findings may have implications for differentiation of pathological conditions of the human prostate.

The Effects of Anabolic Steroids on Driving Performance as Assessed by the Iowa Driver Simulator

The effect of physiologic (100 mg/wk) and supraphysiologic (250 and 500 mg/wk) doses of testosterone cypionate (TC) on automobile driving were studied using the Iowa Driver Simulator. Six normal subject volunteers were studied off TC and on TC once steady-state concentrations were achieved after at least three weeks of dosing. Despite the administration of supraphysiologic testosterone doses, an increase in aggressive driving behavior was not detected. Likewise, corresponding psychometric testing using the Buss-Durkee Hostility Inventory to assess aggression was unable to detect any change in aggression in the test subjects. Although aggressive driving behavior may be increased by testosterone administration, the drug itself may not be responsible for these effects. Supraphysiologic doses greater than 500 mg/wk and a semi-controlled research environment may be necessary to produce this effect since case reports of AAS abuse causing altered driving behavior may be multifactorial in nature.

DEHYDROEPIANDROSTERONE AND ESTRONE 17-KETOSTEROID REDUCTASES IN MCF-7 HUMAN BREAST CANCER CELLS

SummaryThe identification of several steroid-transforming enzymes within human breast cancers has led to speculation that the growth of some hormone-responsive tumors might be mediated in part by intracellularly derived estrogens. Reports that MCF-7 human breast cancer cells can transform both estrone (E1)1 to estradiol (E2) and dehydroepiandrosterone (DHEA) to the estrogenic steroid 5-androstenediol (AED), have prompted us to investigate the 17-ketosteroid reductase activities (17-KSRs) which mediate these potentially important reactions. Enzyme assays were performed by quantifying the amounts of [3H]AED or [3H]E2 former from [3H]DHEA or [3H]E1, respectively, by various subcellular preparations from MCF-7 cells under a variety of experimental conditions. DHEA 17-KSR was found to be localized exclusively within cytosol, whereas the E1 17-KSR activity appeared to be nearly equally divided between the soluble and particulate cytoplasmic subfractions. The particulate E1 17-KSR appeared capable of utilizing NADH or NADPH, whereas both the cytosolic form of this enzyme and the soluble DHEA 17-KSR activity showed a strict requirement for NADPH. Although both of the soluble 17-KSRs also showed similar pH optima, several other features suggested that they are different enzymes in MCF-7. E1 did not inhibit the conversion of DHEA to AED, and DHEA did not interfere with the transformation of E1 to E2, indicating that major differences in substrate specificity exist between the two cytosolic activities. Furthermore, DHEA 17-KSR activity within cytosol stored at −20°C deteriorated almost completely over twelve weeks of storage, whereas E1 17-KSR activity remained stable. Finally, although both enzymes were found to be subject to product inhibition, AED inhibited DHEA 17-KSR competitively, whereas cytosolic E1 17-KSR activity was inhibited by E2 in noncompetitive fashion. Studies of the oxidation of E2 to E1 by MCF-7 cells showed that this transformation is catalyzed by both soluble and particulate 17-hydroxysteroid oxidases which utilize either NAD or NADP as cofactor. Having previously reported the presence of a particulate NADP(H)-linked androstenedione (AE) 17-ketosteroid oxidoreductase in MCF-7, we now suggest that at least three different enzymes, one particulate and two soluble forms, participate in the conversion of 17-ketosteroids to their hormonally active 17-hydroxysteroid derivatives within this cell line. The restricted substrate requirements of each enzyme provide a rationale for developing selective enzyme inhibitors which could provide important investigational tools and potentially effective therapeutic agents.

Development of a new human breast cancer cell line Ia-270.

SummaryA new human breast cancer cell line (Ia-270) has been isolated from a malignant pleural effusion from a woman with metastatic infiltrating ductal carcinoma of the breast. This cell line contains cytoplasmic estrogen (ER) and progesterone (PR) receptors. Following estradiol (E2) administration, PR synthesis is augmented and a higher level of saturation density is reached. In an athymic mouse, the cell line produced a tumor morphologically similar to the primary tumor. The results of isoenzyme and karyotype analyses demonstrate Ia-270 to be of human origin and free of HeLa cell contamination. The cell line has been maintained in continuous culture since April 1982 and may provide a usefulin vitro system for studying the biology of human breast cancer.

Testicular Contractile Cells and Sperm Transport**Supported by Grant CA 09110-03 from the National Cancer Institute, Department of Health, Education and Welfare (to J. L. H.); Grant X044 from the Department of Medicine, University of Iowa (to J. H. M.); and Research Project Grant U-300 from Utah State University (to L. C. E.).

Information bearing on the presence function and possible physiologic control of the contractile cells of the testis is consolidated. The cells are true muscle cells and contractile fibroblasts. Smooth muscle is most important in capsules of rabbits and dogs less so in humans and rats. In humans only vascular innervation has been seen in testicular tunica although innervation has been suggested to be present. Isolated rat rabbit and human testes contract in presence of ganglion stimulants. This is evidence for innervation. However no cell bodies of the sympathetic nervous system are known to exist. All of the prostaglandins (PGs) thus far tested initiate tonus increases and phasic contractions in nonmotile isolated rabbit testes. PGE1 potentiates contractions caused by other agents such as epinephrine. The smooth muscle of the rabbit testicular capsule depends on extracellular calcium for its contractility. A stimulatory agent as PGE2 is also needed. The laminar propria of seminiferous tubules from all mammals contains cells that resemble smooth muscle. Evidence is presented in support of the role for testicular contractile elements in the emptying of sperm from the testes. As with smooth muscle in other organs testicular muscle cells can facilitate emptying ducts of their secretory products in this case spermatozoa.