An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate.

A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.

Plasma progesterone and 17-hydroxyprogesterone in normal men and children with congenital adrenal hyperplasia.

Plasma 17-hydroxyprogesterone (17-OHP) concentrations in normal men averaged 0.094 mug/100 ml. Studies using suppressive doses of androgens and glucocorticoids showed that 90% of the 17-OHP originated from the Leydig cell. The 17-OHP production rate was 1.8 mg/24 hr. Plasma 17-OHP has a marked circadian variation, the 8 p.m. values being only 40% of the 8 a.m. values. Plasma luteinizing hormone measured in the same samples did not vary. The adrenal cortex has the capacity to synthesize and secrete 17-OHP and progesterone since adrenocorticotrophic hormone (ACTH) caused a fourfold increase in these plasma steroids. In children with congenital adrenal hyperplasia, plasma 17-OHP levels were 50-200 times those of normal men and plasma progesterone was increased 6- to 10-fold over normal men.

Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia.

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetite in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetite and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P =.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P =.06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.

Influence of fluoxymesterone on in vitro erythropoiesis affected by leukemic cells.

To investigate the influence of nonlymphocytic leukemic cells on normal erythropoietic burst-forming units (BFU-E), we cocultured leukemic cells at concentrations ranging from 0.5 to 5.0 X 10(5)/ml with 2 X 10(5) blood mononuclear cells or marrow nucleated cells from normal subjects in a BFU-E assay. The inhibitory effect of leukemic cells on burst formation by normal BFU-E was detected only at a high concentration (5 X 10(5)/ml). Leukemic-cell-conditioned medium (LCCM) was prepared by adding 1.25-10 X 10(6)/ml leukemic cells to culture medium. LCCM caused a dose-dependent inhibition of burst formation by normal BFU-E, but the medium prepared from normal cells did not. To examine the influence of fluoxymesterone (FM) on the inhibition of burst formation, we added 10(-10)-10(-7) M FM to the culture medium. Inhibition of burst formation by normal BFU-E was reduced from 73.4% to 58.2%-63.1%. These results suggest that FM stimulates proliferation and differentiation of normal BFU-E that are affected by inhibitory factors produced by leukemic cells.

Developmental study of androgen responsiveness in the submandibular gland of the mouse.

The development of androgen responsiveness in the submandibular gland of normal and androgen-resistant (Tfm) mice of different ages was studied after varying hormonal treatments. Total esteroproteolytic (tamase) activity of submandibular gland homogenates was used as a marker for androgen action. Newborn mice of all four genotypes (normal male, normal female, carrier Tfm females, and Tfm males) were resistant to androgen. However, at 3 weeks of age the capacity to develop a tamase response appears in normal and carrier Tfm animals given androgen and rapidly rise to maximal levels. The level in the normal animal is regulated thereafter primarly by the level of circulating androgen. In contrast, the tamase response in the Tfm male of all ages and under all androgen regimens was minimal.

Androgens directly stimulate proliferation of bone cells in vitro.

This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an androgen receptor mediated mechanism.

Effect of fluoxymesterone on the pituitary-gonadal axis: the role of testosterone-estradiol-binding globulin.

Four normal men and two agonadal men were given the oral synthetic androgen, fluoxymesterone (9alpha-fluoro-11beta, 17beta-dihydroxy-17alpha-methyl-4-androstene-3-one) for three days. Plasma testosterone (T), 17 alpha-hydroxyprogesterone (17-OHP), and LH were measured every 30 minutes on a control day and on the first day of treatment. Testosterone and LH were measured every six hours on the last day of treatment. During the first 24 hours of treatment the number of LH secretory episodes per day decreased from 10.5+/-2.5 (SD) to 6.2+/-2.9 (SD) (P less than 0.01), mean 24 hour LH decreased from 12.6+/-3.5 (SD) mlU/ml to 9.3+/-3.7 (SD) mlU/ml (P less than 0.01), and mean 17-OHP decreased from 2.33+/-1.4 (SD) ng/ml to 1.18+/-0.39 (SD) ng/ml (P less than 0.01) in all normal subjects. T was significantly decreased (P less than 0.01) from 464.5+/-76.4 (SD) ng/100 ml to 294.2+/-99.5 (SD) ng/100 ml. By the third day of treatment, LH had decreased further in four, and T in three of four normals. The number of LH spikes and the mean LH levels did not decrease in the agonadal patients. In vitro, using equilibrium dialysis, fluoxymesterone displaced T from plasma binding proteins with an apparent K=1.0 x 10(8) and 1.9 x 10(7) in female and male plasma, respectively, at 22 C; and 5.2 x 10(7) and 8.0 x 10(6) at 37 C. In polyacrylamide gel electrophoresis, a 500-fold molar excess of fluoxymesterone decreased the peak of TeBG-bound T by 45% (P less than 0.01). The in vitro data are consistent with the possibility that, in vivo, the displacement of T from TeBG by fluoxymesterone may play a role in the suppression of the pituitary-gonadal axis by synthetic oral androgens in vivo.

PIP: The effect of fluoxymesterone (9 alpha-fluoro-11 beta, 17 beta-dihydroxy-17 alpha-methyl-4-androstene-3-one) on the pituitary-gonadal axis and the role of testosterone-estradiol-binding globulin (TeBG) were investigated. 4 normal men and 2 agonadal men were given fluoxymesterone for 3 days. Plasma testosterone (T), 17 alpha-hydroxyprogesterone (17-OHP), and luteinizing hormone (LH) were measured every 30 minutes on a control day and on the 1st day of treatment. T and LH were measured every 6 hours on the last day of treatment. During the first 24 hours of treatment the number of LH secretory episodes/day decreased from 10.5 to 6.2 (p less than .01), mean 24-hour LH decreased from 12.6 mIU/ml to 9.3 mIU/ml (p less than .01), and mean 17-OHP decreased from 2.33 ng/ml to 1.18 ng/ml (p less than .01) in all normal subjects. T decreased from 464.5 ng/100 ml to 294.2 ng/100 ml (p less than .01). By the 3rd day of treatment, LH had decreased further in 4 and T in 3 of 4 normals. Mean LH levels and the number of LH spikes did not decrease in the agonadal patients. Fluoxymesterone displaced T in vitro from plasma binding proteins with an apparent equilibrium constant of 1 X 10(8) and 1.9 X 10(7) in female and male plasma, respectively, at 22 degrees C and 5.2 X 10(7) and 8 X 10(6) at 37 degrees C. In polyacrylamide gel electrophoresis a 500-fold more excess of fluoxymesterone decreased the peak of TeBG-bound T significantly (p less than .01, 45%). These in Vitro data are consistent with the possibility that, in vivo, the displacement of T from TeBG by fluoxymesterone may play a role in the suppression of the pituitary-gonadal axis by synthetic oral androgens in vitro.

Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human: the use of a sensitive radioimmunoassay.

A specific and sensitive radioimmunoassay for measuring unconjugated plasma dehydroepiandrosterone (DHA) has been developed and the results expressed in ng/100 ml. Mean values +/-1 SD were in mixed cord blood 593.3 +/- 186.5 in 21 females and 712.7 +/- 190.9 in 18 males. During the first day of life the peripheral plasma concentration of DHA was 917.6 +/- 317.8 in 22 female and 922.65 +/- 290 in 17 male neonates. During the first month of age, DHA levels decreased significantly and then more progressively throughout the first year of life. Mean levels observed between the first and 6th month of life were 147.1 +/- 53.6 in 15 girls and 151.6 +/- 62.7 in 28 boys. Between 6 and 12 months of age mean DHA levels were 90.9 +/- 43.3 and 68.14 +/- 30.9 in 11 girls and 24 boys, respectively. In 250 normal children, plasma DHA levels were very low between 1 to 6 years of age, but rising progressively thereafter without any sex difference long before any clinical sign of puberty. A circadian rhythm parallel to that of cortisol was observed as early as 5 years of age. Acute and chronic stimulation of ACTH confirmed the adrenal origin of DHA, while the results of hCG stimulation test and fluoxymesterone suppression test assessed the testicular participation to the DHA production.

Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma.

This report describes the binding of 70 synthetic compounds to both testosterone-binding globulin (TeBG) and corticosteroid-binding globulin (CBG). The ability of each compound to displace [3H]testosterone from TeBG and [3H]cortisol from CBG adsorbed from a plasma pool onto a solid phase matrix of Concanavalin A-Sepharose was determined under equilibrium conditions at physiological pH and temperature. From these data, the association constants of the compounds for binding to both TeBG and CBG were calculated and used to predict whether endogenous steroid transport would be altered by the therapeutic administration of the drug. Computer simulation predicted that by interacting with TeBG, therapeutic levels of danazol, methyltestosterone, fluoxymesterone, and norgestrel could displace 83%, 48%, 43%, and 16%, respectively, of the concentration of testosterone bound to TeBG in a normal man. Similarly, by interacting with CBG, therapeutic levels of prednisolone could decrease the concentration of cortisol bound to CBG by approximately 32% in both men and women, and despite relatively low affinity binding to TeBG (5 X 10(5) M-1), prednisolone could also displace small amounts of testosterone from TeBG. These results indicate that binding to steroid transport proteins should be considered among the in vivo effects of drugs on endogenous steroid hormone levels.

The effects of fluoxymesterone administration on testicular function.

Long term daily administration of fluoxymesterone (9alpha-fluoro-17alpha-methyl-11beta, 17beta-dihydroxyandrost-4-en-3-one) was associated with a modest suppression of sperm production and a profound suppression of testosterone levels in the absence of significant effects on plasma gonadotropin levels. Nine normal male volunteers took either 10, 20, or 30 mg of fluoxymesterone daily for twelve weeks. Plasma samples were obtained for testosterone, estrogen, LH and FSH levels at biweekly intervals before, during and for up to 12 weeks after fluoxymesterone treatment. Samples were obtained for dehydroepiandrosterone sulfate, testosterone binding globulin and free testosterone assays at representative times before, during and after treatment. Although lower sperm counts were observed at several points during both the treatment and follow up periods, significant consistent suppression of spermatogenesis could not be demonstrated. Reduced plasma testosterone levels were seen within 24 h after beginning fluoxymesterone, and further reductions were noted throughout the treatment period. Changes in plasma estrogen levels did not correlate with fluoxymesterone administration. Neither plasma LH nor plasma FSH levels were significantly altered by fluoxymesterone. A short term study utilizing a single dose of fluoxymesterone yielded similar findings. It is proposed that fluoxymesterone has a local effect on the Leydig cell which is not mediated by gonadotropins.

Androgen receptor abnormalities in identical twins with oligospermia. Clinical and biochemical studies.

Identical twin brothers presented with oligospermia, small testes, normal male phenotypes, elevated serum luteinizing hormone levels, and normal or elevated serum testosterone levels. Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens. Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother. In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone. Fluoxymesterone suppressed serum luteinizing hormone and serum testosterone/estradiol-binding globulin, and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone, the suppression of serum luteinizing hormone by testosterone was subnormal. Both subjects showed marked exaggeration of the serum 17-hydroxyprogesterone increase after administration of human chorionic gonadotropin, despite normal serum testosterone increases, suggesting a block in testicular 17,20-desmolase, which converts 17-hydroxyprogesterone to testosterone. These studies suggest that oligospermia and block of the enzyme 17,20-desmolase may be the earliest manifestations of androgen resistance, and the finding of the syndrome of oligospermia, normal male phenotype, and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder.

Long-term results of treatment with low-dose fluoxymesterone in constitutional delay of growth and puberty and in genetic short stature.

This prospective study was designed to assess growth response, side effects, other possible long-term effects, and final adult height in boys treated with the oral androgen, fluoxymesterone. From 1973 to 1984, eighty-two short boys (71 with constitutional delay of growth and puberty [CDGP] and 11 with genetic short stature [GSS]) were treated with daily oral doses of 2.5 mg of fluoxymesterone from 6 to 60 months. Final height assessment was made from 1989 to 1991. A group of 34 untreated boys (26 with CDGP and 8 with GSS) were also followed to assess the accuracy of the Greulich-Pyle and Bayley-Pinneau (GP-BP) and sexual maturity index height prediction methods. During treatment, each patient had a 1.7- to 2.5-fold increase in linear growth velocity. Accelerated velocity (over baseline) continued as long as the bone age was less than 14 years. No adverse androgenic effects (or undue acceleration of puberty) were observed. Final height exceeded pretreatment predictions for CDGP + GSS by 6.1 +/- 3.5 (SD) cm (GP-BP) and 5.4 +/- 3.2 cm (sexual maturity index). It is concluded that a daily oral dose of 2.5 mg of fluoxymesterone can be used to accelerate linear growth in boys with CDGP and GSS when needed to alleviate emotional problems secondary to slow growth and short stature without fear of compromising final adult height.

Treatment with anabolic steroids increases the activity of the mitochondrial outer carnitine palmitoyltransferase in rat liver and fast-twitch muscle.

Treatment of male rats with the anabolic steroids fluoxymesterone or methylandrostanolone increased the activity of the outer carnitine palmitoyltransferase in liver and fast-twitch muscle mitochondria. This effect was not potentiated by physical exercise and was not observed in heart and slow-twitch muscle mitochondria. Anabolic steroids did not affect the sensitivity of the liver enzyme to inhibition by malonyl-CoA. The data presented herein suggest that androgens may have an important physiological role in the regulation of fatty acid oxidation in liver and fast-twitch muscle mitochondria. In addition, our results are at odds with the notion that (most of) the metabolic effects of anabolic steroids on muscle are only evident when physical training is parallely performed.

Lack of effect of anabolic steroids on specific mRNAs of skeletal muscle undergoing compensatory hypertrophy.

Compensatory hypertrophy of the fast-twitch plantaris muscle (HP) was induced in male rats to determine whether the resulting translational activity of isolated polyribosomes could be modified in this process and by the androgen status. HP induced a significant increase in free androgen binding sites and a typical protein synthesis pattern characterized by a slow myosin light chain isozyme (LC-1S), an increase in fast isozymes (LC-1F,2F) and of beta-tropomyosin/alpha-tropomyosin ratio. The variations in receptor occupancy following castration and treatments with four anabolic steroids (AS) did not result in modification of the template activity of major HP mRNAs. These data suggest that the slight increase of steroid receptors found in HP remains insufficient to trigger an androgenic response in skeletal muscle.

Ultrastructural changes induced by anabolic steroids in liver of trained rats.

The effects of anabolic steroid treatment in association with endurance training on biochemical serum parameters and liver ultrastructure have been investigated in male rats. Values of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were not significantly affected by administration of high doses of fluoxymesterone or methylandrostanolone. Electron microscopic examination of hepatic tissue from treated animals revealed ultrastructural alterations of hepatocytes. The most prominent changes were swelling of mitochondria, which presented electron-lucent matrix and slightly defined cristae, and a marked increase in the number of lysosomes. These changes were evident in both sedentary and trained treated rats, indicating that liver cell damage is produced by anabolic-androgenic steroids despite the simultaneous realization of physical exercise. The alterations observed were not detected by means of conventional biochemical liver tests.

Effects of human chorionic gonadotropin, androgens, adrenocorticotropin hormone, dexamethasone and hyperprolactinemia on plasma sex steroid-binding protein.

This presentation reports the effects of androgens, glucocorticoids and some pituitary hormones on plasma sex steroid-binding protein (SBP). The latter was measured by a solid phase method after desteroidation of the plasma. An hCG test (1500 I.U. every other day X 7) was given to 60 boys. In the children with a normal testosterone (T) rise, plasma SBP decreased (% of basal values) either significantly (38.3 +/- 9.3%, group A; n = 29), or moderately (13.4 +/- 4.4%, group B; n = 9) or did not change (-1.6 +/- 6.4%, group C; n = 10). In the 3 infants tested at an age when SBP normally rise sharply, hCG partially prevented this rise. The administration of either fluoxymesterone (10 mg/m2 for 10 days) or depot-T (4 I.M. injections of 100 mg/m2 every 2 weeks) induced a significant drop (about 2-fold) in plasma SBP in a control group of infants or children, but did not change SBP in 3 infants with the androgen insensitivity syndrome. A single injection of 0.25 mg of ACTH did not significantly alter SBP levels. In contrast, at the end of a 3-day ACTH test (0.5 mg/m2 12 hourly X 6) SBP levels had significantly decreased (mean 35% fall) with no age or sex differences, and with no correlation with the cortisol levels reached. However, the lowering effect of ACTH on SBP levels is likely mediated by glucocorticoids, since its effect was reproduced by high doses (8 mg/day for 3 days) of dexamethasone given at once or after 3 days of treatment at lower dose (20 micrograms/kg BW). It would appear that the depressive effect of ACTH and/or dexamethasone is observed for a threshold dose of glucocorticoids (greater than 5-fold physiological levels) and a certain time (greater than or equal to 3 days) of exposure. The mechanism by which androgens and glucocorticoids lower SBP levels in vivo is not yet understood. From recent experiments, showing that both stimulate the secretion of SBP in hepatoma cells in vitro, it would appear that both hormones may alter SBP metabolism. In a selected population of hyperprolactinemic women, with normal weight and no hirsutism, plasma SBP levels were found in the normal female range. The discrepancy with previous studies in the literature may be explained by differences in the degree of hyperprolactinemia and/or associated hyperandrogenim. This study further documents the multifactorial and intricated hormonal influences involved in the regulation of plasma SBP in vivo.

Effect of anabolic steroids on mitochondria and sarcotubular system of skeletal muscle.

Soleus and extensor digitorum longus (EDL) mitochondria and sarcotubular system were examined in sedentary and trained (treadmill for 12 wk) male rats that were treated with fluoxymesterone or methandrostanolone (2 mg/kg, 5 days/wk, for 8 wk). Neither physical exercise nor anabolic/androgenic steroid administration resulted in a significant change in muscle wet weight. Treatment with the anabolizing androgens increased succinate dehydrogenase activity in fast-twitch muscle mitochondria; this effect was not enhanced by training and was not observed in soleus mitochondria. On the other hand, the content of the slow-twitch muscle in sarcotubular fraction was increased in sedentary rats by fluoxymesterone or methandrostanolone treatment, whereas no significant changes were found in EDL. The training program affected adenosinetriphosphatase (ATPase) activities in the sarcotubular fraction; Mg2(+)-ATPase was increased in both soleus and EDL, but Ca2(+)-ATPase was decreased only in soleus. However, in sedentary animals only the Mg2(+)-dependent activity of EDL was increased by anabolizing androgen treatment, and this change was not potentiated by additional training. The present data indicate that anabolic/androgenic steroids can affect mitochondrial and sarcotubular enzymes in skeletal muscle. The effects are muscle-type specific.

Inhibition of capacitation in the rabbit.

PIP: The effectiveness of antiestrogens and progestins in the inhibition of capacitation in the rabbit uterus and oviduct was studied. The agents tested were 8 mg/day nafoxidine HCL (NHCL), 4 mg/day fluoxymesterone (FM), 4 and 20 mg/day clomiphene citrate (CC), 8 mg/day testosterone (T), 8 mg/day dydrogesterone (D) 4 and 8 mg/day 20alpha-hyd roxyprogesterone (HP), 4, 8, 40, and 120 mg/day progesterone (P), 4 mg/day norethindrone (NE), and .5, 2, 5, and 20 mg/day chlormadinone acetate (CA). nhcl, fm, cc, d, hp (8 mg/day), NE, and CA reduced fertilization, though capacitation was still possible. The highest dose of P failed to inhibit capacitation in the oviduct. T and HP (4 mg/day) failed to reduce fertilization. However, CC and NE sharply reduced ovulation in all animals (an average of less than 1 egg per rabbit), while 20 mg/day of CC completely inhibited ovulation. CA accelerated the passage of some eggs to the uterus. 8 mg/day of HP, 1 mg/day of P, and 2 mg/day of CA completely inhibited capacitation in the uterus. The capacitation ability of the oviduct was not impaired by P, NE, or, CA. It was found that 2500 units of P were required to completely abolish the effect of 1 unit of estradiol. It is concluded that the contraceptive effect of the drugs tested are not due to inhibition of capacitation, but rather to faulty transport of sperm and eggs, inhibiti on of ovulation, and production of an environment in the female reproductive tract that is hostile to sperm.^ieng

Aberrant androgen action and increased size of tandem CAG repeat in androgen receptor gene in X-linked recessive bulbospinal neuronopathy.

Plasma levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after 3 or 6 days of administration of the synthetic androgenic hormone fluoxymesterone (10 mg/day) were measured in 26 patients with X-linked recessive bulbospinal neuronopathy (X-BSNP) and 22 age-matched male controls. The testosterone, LH and FSH levels in the controls were markedly suppressed after administration, but in the patients with X-BSNP, they were suppressed significantly less. The level of suppression varied considerably with the patients, and those of plasma testosterone and FSH were significantly correlated with the number of CAG repeats in the androgen receptor gene. These findings suggest that the androgen action was aberrantly transduced in the target organs in the patients with X-BSNP and which is related to the elongated CAG repeat in the androgen receptor gene.

Evaluation of CEA and GCDFP-15 plasma level during hormonally induced cancer stimulation.

Preliminary clinical trials indicate that transient stimulation of breast and prostate cancer growth by hormonal means may enhance tumor sensitivity to chemotherapy. In none of these studies, however, has an attempt been made to measure parameters that might reflect perturbations in cell kinetics induced by the treatment schedules. While conducting two, controlled, randomized clinical trials in advanced breast cancer and prostate cancer using a similar approach, we have measured plasma levels of two tumor markers, carcinoembryonic antigen (CEA) and breast gross cystic disease fluid protein (GCDFP-15). These served as a possible means of monitoring hormonal stimulation of tumor growth. Both markers failed to increase following administration of estrogens to patients with breast cancer and of androgens to men with prostatic carcinoma. In contrast, transient stimulation of tumor growth probably occurred as shown by exacerbation of symptoms and, in patients with prostate cancer, rise in acid phosphatase. We conclude that CEA and GCDFP-15 are not useful for monitoring pertubations in tumor cell kinetics induced by hormone stimulative protocols.