Biomedical subjects

F Labrie

Publications and source records attributed to F Labrie.

At least 379 records · Page 21Linked to original sources

PubMed1988

Effects of the aromatase inhibitor 4-hydroxyandrostenedione and the antiandrogen flutamide on growth and steroid levels in DMBA-induced rat mammary tumors.

Using dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat as model, comparison was made of the effect of treatment for 20 days with the aromatase inhibitor 4-hydroxyandrostenedione (4-OH-A) (7.5 mg, twice daily) or the antiandrogen flutamide (5 mg, twice daily) on tumor growth as well as on plasma and tumor content of estrogens, androgens, and their precursors and metabolites. Tumor number and size were markedly decreased following treatment with either drug, the effect of treatment being more important on size than number, and on new tumors which developed during treatment than on tumors already present at start of treatment. Treatment with the aromatase inhibitor 4-OH-A caused a parallel decrease in plasma and tumor levels of pregnenolone (Preg), progesterone (P), and 17-OH P, while there was a marked increase in dehydroepiandrosterone (DHEA), androst-5-ene-3 beta,17 beta-diol (delta 5-diol), androstenedione (delta 4-dione), testosterone (T), androstane-3 alpha, 17 beta-diol (3 alpha-diol), and androstane-3 beta,17 beta-diol (3 beta-diol), with no significant change in dihydrotestosterone (DHT) and 17 beta-estradiol levels. The marked increase in tissue T content coupled to a decrease in P levels could well contribute to the inhibition of tumor growth induced by 4-OH-A. Flutamide, on the other hand, caused a marked fall in plasma and tissue levels of Preg, 17-OH Preg, P, and 17-OH P, with no significant change in the concentration of the other steroids, thus suggesting a possible role of the fall in tissue P levels in the inhibition of tumor growth. Since both drugs are potent inhibitors of DMBA-induced tumor growth in intact animals, better knowledge of their mechanism of action should add to our understanding of the multiple endocrine factors controlling the growth of these tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1988

A study of LH-RH receptors in the pituitary gland of the winter flounder (Pseudopleuronectes americanus Walbaum).

A study using an iodinated [D-Ser(tBu)6,Pro9-NHEt]LH-RH (Buserelin), demonstrated the presence of a single class of high-affinity (KD = 2.90 nM), high-capacity LH-RH binding sites in pituitaries obtained from sexually mature male and female winter flounder. Displacement curves for unlabeled Buserelin and other preparations of mammalian and fish LH-RH, but a lack of competition for structurally unrelated peptide hormones, indicated the hormone specific nature of the fish pituitary LH-RH receptor preparation. Compared with native mammalian LH-RH and salmon LH-RH, Buserelin and an analog of salmon LH-RH, [D-Arg6,Trp7,Leu8,Pro9-NHEt]LH-RH, had significantly higher binding affinities for the flounder pituitary receptor correlating with results of previous studies demonstrating the superagonist biological activity of LH-RH analogs in trout and goldfish.

Animals↗

PubMed1988

Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today's therapy of choice.

One hundred and ninety-nine patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 26 months (3-59 months). The objective response to the treatment was assessed according to the criteria of the U.S. NPCP. There was a 5.7-fold increase (26.3 vs 4.6%) in the percentage of patients who achieved a complete response compared with the results obtained in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 12 of the 186 evaluable patients (6.5%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in the same five studies using monotherapy. The duration of response was also significantly improved in the patients who received the combination therapy while the death rate was decreased by approximately two-fold during the first 4 yr of treatment. In fact, while an approximately 50% death rate is observed at 2 yr in all studies using monotherapy, the same 50% death rate is delayed by 2 yr in the present study. It should be mentioned that at the time of relapse under combination therapy, the treatment is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide. The marked (5.7-fold) improvement in the rate of complete objective responses coupled with the three-fold decrease in the number of non-responders, the increased duration of the positive responses and the two-fold decrease in the death rate during the first 4 yr of treatment are obtained with the combination therapy using Flutamide and castration, thus improving the quality and duration of life with no or minimal side-effects. By blocking the androgen receptors in the prostatic cancer tissue, the antiandrogen decreases the action of the androgens of adrenal origin and thus inhibits the growth of a large number of tumors which, otherwise, would continue to be stimulated by the adrenal androgens left after medical or surgical castration.

Aged↗

PubMed1988

Characteristics of flutamide action on prostatic and testicular functions in the rat.

The effect of daily treatment with the pure antiandrogen Flutamide has been studied either alone or in combination with the LHRH agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (LHRH-A), on testicular and prostatic functions in adult male rats. Treatment for 10 days with Flutamide (5 mg/rat, twice daily) caused a marked stimulation of plasma testosterone (T) associated with a significant increase in plasma gonadotropin concentrations and inhibited plasma PRL levels. Testicular weight is not changed following antiandrogen administration but testicular LH/hCG receptor levels are markedly decreased with no change in FSH receptor levels. Moreover, Flutamide treatment alone produces an important inhibition of ventral prostate and seminal vesicle weights associated with a significant decrease in prostatic beta-adrenergic receptor levels but no change is observed in specific ornithine decarboxylase (ODC) activity. Daily LHRH-A treatment at the dose of 1 microgram/day for 10 days decreases plasma T to levels comparable to those found in orchiectomized men (0.30 +/- 0.5 ng/ml). This effect is associated with an almost complete loss of testicular LH/hCG receptors, a decrease in testicular weight, a significant increase in plasma gonadotropins and a marked inhibition of plasma PRL concentration. A relatively smaller inhibition of ventral prostate and seminal vesicle weights follows treatment with the LHRH agonist alone, this effect being accompanied by a significant reduction in beta-adrenergic receptor concentration but no change in prostatic ODC activity. Combination of the two drugs, however, caused a potent inhibitory effect on both ventral prostate and seminal vesicle weight to values similar to those found in castrated rats. The prostatic weight loss is accompanied by a marked fall in ODC activity and in the concentration of beta-adrenergic receptors. The present data clearly show that combined treatment with an LHRH agonist and a pure antiandrogen is highly effective in inhibiting, not only prostatic growth, but also two androgen-sensitive parameters of prostatic activity.

Anilides↗

PubMed1988

Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice.

In order to assess the androgenic activity of synthetic progestins currently used as "antiandrogens" for the treatment of prostate cancer in men, the effect of a series of these compounds has been studied in mice on the growth of the androgen-sensitive Shionogi tumor. Female mice (DD/S strain) were inoculated subcutaneously with 10(6) viable cells and divided into groups who received, respectively, the synthetic "progestins" medroxyprogesterone acetate (MPA), megestrol acetate (MEG), cyproterone acetate (CPA) or chlormadinone acetate (CMA), compared with the non-steroidal antiandrogen Flutamide (Flu), each administered at the twice-daily dose of 250 micrograms. Each synthetic "progestin" exerted a marked stimulatory effect on the growth of the tumor. The most impressive effect on growth was observed with MPA. In fact, in MPA-treated mice, tumor size was 17 times larger than control at 4.92 +/- 0.36 cm2/mouse 21 days after inoculation. CPA, CMA and MEG also stimulated the growth of this androgen-sensitive tumor, the percentages of stimulation of tumor size being 3.1-, 3.2- and 11.0-fold above control, respectively, on day 21, while Flu had no significant stimulatory effect. The present data clearly show that all the above-mentioned progestins have variable levels of stimulatory activity on the growth of the androgen-sensitive Shionogi tumor and indicate that such drugs are unlikely to be recommendable for the treatment of prostate cancer.

Androgens↗

PubMed1988

Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture.

A series of compounds designed to block the action of androgens in target tissues, and called antiandrogens, have been developed for the treatment of androgen-sensitive diseases, especially prostate cancer, hirsutism, precocious puberty and deviant sexual behavior. In order to further assess the androgenic activity of these compounds, we have studied their effect on the growth of an androgen-sensitive clone of the mouse mammary carcinoma Shionogi SC-115 cells in culture. Hydroxy-flutamide did not affect the doubling time (7.40 +/- 0.09 vs 7.20 +/- 0.12 days) characteristic of these cells. However, all of the other compounds tested stimulated cell growth. Thus, in the presence of cyproterone acetate, cells had an accelerated growth rate and shorter generation time of 6.28 +/- 0.06 days (P less than 0.01). In the presence of 1 microM spironolactone, the generation time was 4.96 +/- 0.04 days (P less than 0.01). With chlormadinone acetate, the doubling time was reduced to 3.79 +/- 0.08 days while for megestrol acetate, the doubling time was 3.63 +/- 0.04 days (P less than 0.01). The synthetic progestin Medroxyprogesterone acetate had the most potent androgenic effect reducing the doubling time to 1.85 +/- 0.05 days (P less than 0.01). For comparison, dihydrotestosterone gave a doubling time of 1.76 +/- 0.07 days. When hydroxy-flutamide (5 microM) was added simultaneously with each "progestin", the ED50 value of action of all the compounds was increased in a competitive manner, thus indicating that the mitogenic effect on cell growth of all compounds is mediated by the androgen receptor. Of all the compounds used, only hydroxy-Flutamide was devoid of any androgenic activity and thus meets the criteria of a pure antiandrogen.

Androgens↗

PubMed1988

Castration levels of plasma testosterone have potent stimulatory effects on androgen-sensitive parameters in the rat prostate.

In order to assess the biological significance of low serum androgens comparable to those which remain after castration in men treated for prostate cancer. Silastic depots continuously releasing predetermined doses of testosterone (T) have been implanted into castrated adult male rats in the absence or presence of simultaneous treatment with the pure antiandrogen Flutamide. Quite remarkably, a 3- to 5-fold increase in prostate weight (P less than or equal to 0.001) was observed at plasma T concentrations comparable to those found in the serum of castrated men. Although of lower magnitude, castration levels of plasma T also caused a significant stimulation of seminal vesicle weight (P less than 0.01). This dramatic stimulatory influence of "castration" levels of plasma T on ventral prostate and seminal vesicle weight can be explained by the 13- to 15-fold higher intraprostatic level of the active androgen dihydrotestosterone (DHT) compared to the plasma T concentration. In fact, a near-maximal intraprostatic concentration of DHT is reached at concentrations of plasma T of 0.2-0.5 ng/ml and a positive correlation was found between prostatic DHT concentration and ventral prostate weight. Prostatic growth and DHT concentrations were also positively correlated with ornithine decarboxylase (ODC) activity, an enzyme highly sensitive to androgens in the rat ventral prostate. In fact, a dramatic (30-fold) increase in ODC activity was observed at plasma T values corresponding to those found in castrated men. The level of prostatic beta 2-adrenergic receptors fell within 10 days of castration and an increase in beta 2-adrenergic receptor concentration was observed with low doses of T, thus indicating that beta 2-adrenoreceptor levels are also a sensitive parameter of androgenic activity in the rat prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

The rise in testicular androgens during the first days of treatment with an LHRH agonist in the dog can be blocked by aminoglutethimide or ketoconazole.

Up to day 6 of treatment of adult dogs, daily subcutaneous administration of 50 micrograms of the LHRH agonist [D-Trp6, des-Gly-NH2-10]LHRH ethylamide causes up to a 3-fold increase in serum testosterone (T) concentration which is followed by a progressive decrease to castration levels (less than or equal to 0.2 ng/ml) at later time intervals (up to 21 days, the last time interval studied). Both aminoglutethimide and ketoconazole, two inhibitors of steroid biosynthesis, cause a 30-40% rise in serum T when administered alone. However, either drug administered in combination with the LHRH agonist completely blocks the transient rise in serum T observed when the LHRH agonist is administered alone. On the other hand, the LHRH agonist prevents the secondary rise in steroid secretion observed when either of the two inhibitors of steroid secretion is used alone. Administration of the pure antiandrogen Flutamide alone or in combination with LHRH-A and an inhibitor of steroid biosynthesis does not influence serum T levels. When the serum levels of pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone, dehydroepiandrosterone (DHEA), androstenedione (delta 4-dione), androst-5-ene-3 beta, 17 beta-diol (delta 5-diol), T, dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol, androstane-3 beta. 17 beta-diol and 17 beta-estradiol (E2) are analyzed in detail, it can be seen that both aminoglutethimide and ketoconazole not only prevent the rise in serum steroids observed during the first 8 days of treatment with the LHRH agonist but that both compounds enhance the inhibitory effect of the LHRH agonist at later time intervals. A predominant inhibitory effect of ketoconazole is exerted on 17,20-desmolase activity. Aminoglutethimide has little influence on the loss of serum LH bioactivity induced by the LHRH agonist while ketoconazole stimulates the concentration of serum bioactive LH in the absence or presence of simultaneous treatment with the LHRH agonist. The present data clearly demonstrate that aminoglutethimide or ketoconazole can prevent the rise in serum androgens accompanying the first days of treatment with an LHRH agonist in the dog. Moreover, after 3 weeks of treatment, the inhibitory effect of the LHRH agonist on serum androgen levels is enhanced by addition of aminoglutethimide or ketoconazole. Moreover, Flutamide does not interfere with the inhibitory action of the LHRH agonist, aminoglutethimide or ketoconazole, thus suggesting that maximal inhibition of androgen action is likely to be achieved by a combination of these drugs.

Aldehyde-Lyases↗

PubMed1988

Important prognostic value of standardized objective criteria of response in stage D2 prostatic carcinoma.

One hundred and eighty-six previously untreated patients with clinical stage D2 prostate cancer have been followed according to the criteria of objective response of the National Prostatic Cancer Project (NPCP). All patients received combination therapy with the antiandrogen Flutamide and the LHRH agonist (D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (or surgical castration, 10 patients) as first treatment. Forty-nine patients (26.3%) achieved a complete response as best response while 56 (30.1%) and 69 (37.1%) patients had partial and stable responses, respectively, and only 12 patients (6.5%) did not respond to treatment. The median times required to achieve stable, partial and complete responses were 155, 183 and 401 days, respectively. The best response achieved has a major influence on the probability of continuing response and survival. While the 50% probability of continuing response is more than 3 years for the complete responders, it is reduced to 630 and 517 days for partial and stable responders, respectively. While the non-responders have a median life expectancy of 10.0 months, this value is increased to 30.3 and 37.8 months for the stable and partial responders, respectively. The best probability of survival is for the complete responders with a 95.9% probability of survival at 3 years. There is no significant correlation between the time required to achieve a best response (phase 1) and the duration of the response before progression occurs (phase 2) or the time between progression and death (phase 3) for any of the categories of responses. A longer period of time required to achieve a complete response is associated with a longer survival. When analysis is made, in an attempt to predict response, of the baseline characteristics of the patients before treatment, a low number of bone metastases and better performance status are associated with a greater chance of achieving a complete response while partial, stable and progression responses cannot be predicted from the baseline characteristics. The present data show the importance of standardization of the objective criteria of response to treatment in advanced prostate cancer. Thus, the patients who achieve a complete response have a much more favorable prognosis while partial and stable categories of response have a closely similar prognosis which is inferior to the complete responders. Moreover, the present data indicate that the stable category of response has an important prognostic value which is almost superimposable and not statistically different from the partial response in terms of duration of response and survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1988

Combination therapy with flutamide and [D-Trp6]LHRH ethylamide for stage C prostatic carcinoma.

Sixty-seven previously untreated patients presenting with clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average duration of treatment of 23.5 months. Only five patients have so far shown treatment failure with 91.8% of the patients still in remission at 2 years. Three patients have died from prostate cancer while three have died from other causes, 93.5% of the patients being alive at 2 years. Local control was achieved rapidly in all except one patient. Urinary obstruction and hydronephrosis were corrected in all cases. When comparing to recent data obtained after single endocrine therapy (orchiectomy or estrogens), or radiotherapy, the rate of treatment failure at 2 years is 3.5-fold lower after combination therapy (8.2%) than monotherapy (28.4%). The death rate at 2 years following start of the combination therapy is 6.5% while it is on average 22.2% (3.4-fold higher) in the studies using monotherapy (orchiectomy or estrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of the disease permits a better response which is possibly explained, at least in part, by the lower degree of dedifferentiation and heterogeneity of the tumors.

Acid Phosphatase↗

PubMed1988

Androgens modulate epidermal growth factor receptor levels in the rat ventral prostate.

In order to further understand the factors which influence the normal or pathologic growth of the prostate, we have characterized the receptor for epidermal growth factor (EGF) in the rat ventral prostate and have studied the hormonal regulation in this receptor. EGF binds to a single class of saturable, high affinity binding sites in total prostatic homogenate. Scatchard analysis of the binding data reveals an apparent dissociation constant (KD) of 0.93 +/- 0.08 nM and a number of sites of 4.01 +/- 0.24 fmol per mg protein. Among the peptides tested, only native EGF can displace bound [125I]EGF. Castration stimulates the concentration of prostatic EGF receptors from 25.5 +/- 3.0 to 43.4 +/- 5.4 fmol/100 mg tissue in intact and castrated animals, respectively (P less than 0.01). Treatment of castrated rats with dihydrotestosterone (DHT) inhibits the rise in prostatic EGF receptor concentration induced by orchiectomy, while estradiol, progesterone or the dopaminergic agonist CB-154, have no effect. Combined administration of DHT with the other above-mentioned steroids or CB-154 does not modify the inhibition of prostatic EGF receptor concentration induced by the androgen in castrated animals. When the data are expressed as changes in EGF receptor number in the total prostate, DHT treatment reverses the inhibitory effect induced by castration and yields an EGF binding capacity comparable to that measured in intact animals. Chronic treatment with a pure antiandrogen or a potent LHRH agonist (LHRH-A) alone has no significant effect on EGF receptor concentration in prostatic tissue, although, secondary to a reduction in prostatic weight, total prostatic EGF binding capacity is reduced following antiandrogen or LHRH-A treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗

PubMed1988

A pure antiandrogen does not interfere with the LHRH agonist-induced blockade of testicular androgen secretion in the dog.

Daily subcutaneous administration of 50 micrograms of the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6]LHRH ethylamide in adult dogs causes a transient increase in the serum testosterone (T) concentration which reaches a maximum at 200% above control on days 2-4 of treatment and progressively decreases to 7% of the pretreatment value on day 21, the last time interval studied. After a transient increase, the concentration of serum bioactive luteinizing hormone (LH) was progressively decreased on days 11 and 19, thus suggesting that in analogy with human findings, the loss of LH bioactivity is responsible for the inhibition of testicular steroidogenesis induced in the dog by LHRH agonists. Of major significance is the finding that the changes in serum T levels observed during the first 3 weeks of treatment, as well as the complete inhibition of the intratesticular concentration of sex steroids observed at the end of this period of treatment with the LHRH agonist were not affected by simultaneous administration of flutamide (125 mg per os every 8 h). Such findings indicate that at the dose used, the LHRH agonist is in full control of gonadotropin secretion, thus completely overcoming feedback influences. Since the administration of the antiandrogen flutamide does not decrease the efficacy of the LHRH agonist as blocker of testicular androgen biosynthesis, the present data support the use of a pure antiandrogen in order to neutralize the effect of the transient rise in testicular androgen secretion which always accompanies the first days of treatment with LHRH agonists in patients with advanced prostate cancer.

Anilides↗

PubMed1988

Full oestrogenic activity of C19-delta 5 adrenal steroids in rat pituitary lactotrophs and somatotrophs.

Oestrogens are known to exert specific stimulatory effects on basal and dopamine (DA)-inhibited prolactin (PRL) release as well as on PRL cell content in rat adenohypophysial cells in primary culture. Recently, we have demonstrated that classical oestrogens increase growth hormone (GH) release and cellular GH content in rat pituitary somatotrophs. Since there is evidence that 5-androstene-3 beta, 17 beta-diol (delta 5-diol), a metabolite of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) can induce typical oestrogenic responses in target tissues, we have investigated the effect of C19 adrenal steroids and compared them to that of 17 beta-oestradiol (E2) on the above-indicated parameters. Following a 72-h incubation, maximal concentrations of E2, delta 5-diol and DHEA caused a similar increase in PRL cell content at respective EC50 values of 0.020, 14 and 115 nM. The sensitivity of lactotrophs to DA action was decreased by approximately 4-fold after a 48-h exposure to maximal concentrations of delta 5-diol or DHEA. The time course of the antidopaminergic effect of delta 5-diol and DHEA was almost superimposable to that of E2. A 72-h incubation with 5 microM DHEA-S, a concentration within the range of blood levels found in women, doubled (P less than or equal to 0.001) cellular PRL accumulation. On the other hand, androstenedione (delta 4-dione) was without effect on any of the parameters measured. All stimulatory effects induced by maximal effective concentrations of delta 5-diol, DHEA or DHEA-S were competitively inhibited by simultaneous incubation with the antioestrogen LY156758. The amplitude of the stimulatory effects of delta 5-diol and DHEA on GH cell content as well as on spontaneous GH-releasing factor (GRF)-induced GH release was superimposable to that observed with E2. The effect of the steroids on GH cell content was exerted at 0.016 nM (E2), 12 nM (delta 5-diol) and 250 nM (DHEA). Simultaneous incubation with LY156758 completely blocked the effect of maximally effective concentrations of E2, delta 5-diol and DHEA in somatotrophs. Furthermore, a physiological concentration of DHEA-S (5 microM) enhanced spontaneous as well as GRF-induced GH release. On the other hand, delta 4-dione as well as testosterone and dihydrotestosterone did not alter GH release. The present data demonstrate that delta 5-diol, DHEA and DHEA-S can exert full oestrogenic effects in lactotrophs and somatotrophs, thus supporting their potential oestrogenic role under both physiological and pathological conditions.

Androgens↗

PubMed1988

Glucocorticoids stimulate the growth of mouse mammary carcinoma Shionogi cells in culture.

The relative potency of a series of glucocorticoids to stimulate the growth of a cloned cell line (SEM-1) derived from the androgen-sensitive Shionogi mouse mammary carcinoma is proportional to their known affinity for the glucocorticoid receptor. The stimulatory action of glucocorticoids is not inhibited by the pure antiandrogen hydroxyflutamide while the antiglucocorticoids RU25593 and RU38486 cause 100% and 80% inhibitions of the activity of triamcinolone acetonide, respectively, thus indicating that the stimulatory effect of glucocorticoids on Shionogi cell growth is mediated by the glucocorticoid receptor. Such data indicate that not only androgens but also glucocorticoids should be taken into account when assessing the endocrine control of the growth of these mammary carcinoma cells.

Adrenocorticotropic Hormone↗

PubMed1988

Adrenal precursor C19 steroids are potent stimulators of growth of androgen-sensitive mouse mammary carcinoma Shionogi cells in vitro.

Since there is convincing evidence for a role of adrenal steroids as precursors of active sex steroids in peripheral tissues, especially prostate cancer, we have studied the effect of the four main adrenal steroids, namely dehydroepiandrosterone sulfate (DHEA-S), DHEA, 5-androstene-3 beta,17 beta-diol (delta 5-diol) and 4-androstene-3,17-dione (delta 4-dione) on the growth of an androgen-sensitive clone (SEM-1) of the mouse mammary carcinoma Shionogi. From a control doubling time of 6.69 +/- 0.03 days, 0.1 microM DHT, 1.0 microM delta 4-dione, 10 microM delta 5-diol, 10 microM DHEA-S and 10 microM DHEA decreased generation time to 1.60 +/- 0.01, 1.69 +/- 0.01, 1.95 +/- 0.01, 4.37 +/- 0.02 and 5.66 +/- 0.03 days, respectively (P less than 0.01 vs. control). The same compounds exerted their stimulatory effects on cell growth at the following ED50 values: 0.06 nM, 16 nM, 90 nM, 150 nM and 16 microM for DHT, delta 4-dione, DHEA, delta 5-diol and DHEA-S, respectively. The stimulatory effect of all compounds was inhibited in a competitive manner by the pure antiandrogen hydroxyflutamide. Further evidence for an action of the adrenal steroids through the androgen receptor is indicated by competition of [3H]testosterone uptake in the tumor cells at the following IC50 values: 0.21 nM, 0.63 nM, 50 nM, 75 nM and 680 nM for DHT, testosterone, delta 4-dione, delta 5-diol and DHEA, respectively. The present data show that the four main adrenal steroids present in the serum of adult men can exert potent stimulatory effects on the growth of an androgen-sensitive cancer cell line through an androgen receptor-mediated mechanism.

Androgens↗

PubMed1988

The luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6, des-Gly-NH2(10)]-LHRH ethylamide, has no direct effect on spermatogenesis in the rat.

Treatment of intact rats with luteinizing hormone-releasing hormone (LHRH) agonists has been shown to produce atrophy of a variable number of testicular seminiferous tubules. These findings raised the question of a possible direct versus indirect action of LHRH agonists on spermatogenesis. To answer this question, we treated hypophysectomized rats with the LHRH agonist [D-Trp6, des-Gly-NH2(10)]-LHRH ethylamide, dihydrotestosterone (DHT), or a combination of these two compounds for a period of 1 mo. Treatment of hypophysectomized animals with the LHRH agonist alone had no significant effect on the atrophy of seminiferous tubules found after hypophysectomy. DHT, however, maintained spermatogenesis at 80% of the level seen in intact animals. When DHT and the LHRH agonist were administered in combination, the stimulatory effects of DHT were observed with no significant interference caused by the LHRH agonist. This study shows that an LHRH agonist has no direct effect on the morphology of the seminiferous tubules in the absence of the pituitary gland and strongly suggests that the atrophy observed in the testis after LHRH agonist treatment in intact animals is mediated by the LHRH agonist-induced changes in luteinizing hormone secretion and/or direct action of the peptide on Leydig cells.

Animals↗

PubMed1988

Benefits of combination therapy with flutamide in patients relapsing after castration.

Two hundred and nine patients with biopsy-proven stage D2 prostatic carcinoma showing disease progression after orchiectomy or treatment with DES (stilboestrol) or an LHRH agonist alone received combination therapy with the pure antiandrogen flutamide. In patients treated with DES, the oestrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. The objective response to therapy was assessed according to the criteria of the US NPCP. Thirteen patients had a complete response to treatment, while partial and stable responses were achieved in 20 and 39 patients respectively (total objective response rate of 34.5%). The mean duration of response was 24 months. In the non-responders the median survival was 8.1 months with a 17% probability of survival at 2 years; the probabilities of survival at 2 years of the patients who showed partial and stable responses were 87 and 67% respectively. All patients who achieved a complete response are still alive. Combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.

Aged↗

PubMed1988

Androgens exert selective effects on protein kinase C induced LH and FSH release in rat anterior pituitary cells in culture.

This study compares the selective effect of androgens on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release induced either by LH-releasing hormone (LH-RH) or by protein kinase C activation in rat anterior pituitary cells in culture. In control cells, phorbol-12-myristate-13-acetate (PMA) stimulated the release of radioimmunoassayable LH and FSH in a dose-dependent manner at an ED50 value of 5.95 +/- 1.45 nM. The maximal release of gonadotropins induced during a 3-hour incubation with PMA was 40-60% of that induced by LH-RH. Preincubation of the cells for 2-4 days with 10 nM 5 alpha-dihydrotestosterone (DHT) decreased by approximately 60% the subsequent release of LH induced by 100 nM LH-RH or by 500 nM PMA during a subsequent 3-hour incubation. The inhibitory effect of DHT was completely suppressed by coincubation with the antiandrogen hydroxyflutamide. DHT exerted a similar inhibitory effect on LH release induced by another stimulator of protein kinase C activity, namely 1-oleoyl-2-acetylglycerol. The potent inhibitory action of DHT on LH-RH- or PMA-induced LH release was exerted at an ED50 value of approximately 10 pM. Contrary to the effect on LH, the FSH response to LH-RH or to PMA was increased by preincubation with 2 nM DHT, the stimulatory effect of the androgen being completely antagonized by hydroxyflutamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗