PubMed Health⌕ Search

Biomedical subjects

F Labrie

Publications and source records attributed to F Labrie.

At least 433 records · Page 24Linked to original sources
PubMed1986

Loss of luteinizing hormone bioactivity in patients with prostatic cancer treated with an LHRH agonist and a pure antiandrogen.

Chronic treatment of adult men with LHRH agonists causes a decrease in serum testosterone and 5 alpha-dihydrotestosterone to castrate levels. In the presence of such low levels of circulating testicular androgens, the concentration of serum LH measured by radioimmunoassay (RIA) sometimes remains normal or is only partially inhibited. In order to assess the biological activity of circulating LH, we have used the mouse interstitial cell assay. Blood samples were obtained from patients with prostatic carcinoma treated with the LHRH agonist [D-Trp6] LHRH ethylamide in combination with the pure antiandrogen Flutamide (Euflex). While serum LH levels measured by RIA were only partially reduced from 2.2 +/- 0.3 (SEM) to 1.1 +/- 0.1 ng/ml after 3 months of therapy, bioactive LH was markedly inhibited from 0.43 +/- 0.04 to 0.030 +/- 0.007 ng/ml, thus causing the ratio of biologically active to radioimmunoassayable LH to drop from 0.26 +/- 0.03 to 0.03 +/- 0.01. In the same patients, serum testosterone levels were decreased from 3.91 +/- 0.51 to 0.14 +/- 0.05 ng/ml after 3 months of treatment. In patients treated for 6 months, the bio/immuno ratio was still reduced at 0.032 +/- 0.005. These data show a marked loss of LH biological activity during treatment of adult men with an LHRH agonist and an antiandrogen. The close parallelism observed between serum testosterone and bioactive LH levels suggests that the loss of biological activity of the gonadotrophin is mainly, if not exclusively, responsible for the inhibition of testicular androgen secretion observed during chronic treatment with LHRH agonists.

Adenocarcinoma↗
PubMed1986

Ocular toxicity of Anandron in patients treated for prostatic cancer.

Approximately 65% of patients with prostatic cancer treated by the combination therapy using a gonadorelin (LHRH) agonist or orchidectomy in association with the antiandrogen Anandron complained of a delay in recovering vision after bright illumination (sun, television, bright light). Detailed ophthalmological examination revealed an increase in the photostress recovery time to an average of 9 min, while the upper limit of normal is 1 min 20 s. When treatment was changed from Anandron to the other pure antiandrogen flutamide, the value of the photostress recovery time markedly decreased and the visual symptoms rapidly disappeared. Since uninterrupted administration of the antiandrogen is of the outmost importance for the successful therapy of prostatic cancer, the availability of a compound such as flutamide that has no side effect other than those due to hypoandrogenicity should greatly facilitate compliance by the patients and the success of the treatment.

Aged↗
PubMed1986

Treatment of prostate cancer with gonadotropin-releasing hormone agonists.

It is now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3 beta, 17 beta-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2-0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0-10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗
PubMed1986

Stimulation of growth hormone release and synthesis by estrogens in rat anterior pituitary cells in culture.

We have investigated the potential effect of estrogens in the control of GH secretion in rat anterior pituitary cells in primary culture. We have found that a 72-h preincubation with 17 beta-estradiol (E2) caused an approximately 2- to 3-fold stimulation of basal and GH-releasing factor (GRF)-induced GH release as well as cellular GH content at EC50 values of 44, 35, and 15 pM, respectively. Estrone and estriol also increased GH release at respective EC50 values of 100 and 250 pM. The stimulatory effects of these steroids on GH release and cellular GH content were competitively blocked by simultaneous incubation with the antiestrogen LY156758. In contrast to thyroid and glucocorticoid hormones, a 72-h pretreatment with E2 failed to potentiate GRF-induced cAMP accumulation or enhance the sensitivity of the GH response to GRF. However, E2 increased the stimulatory effect of submaximal concentrations of dexamethasone on spontaneous and GRF-induced GH release as well as on total GH, but did not further increase the effect of maximal dexamethasone concentrations. As determined by a 60-min pulse labeling with [35S]methionine performed after a 72-h preincubation with E2, GH and PRL synthesis were increased by about 50% above control values (P less than 0.005). The present data clearly indicate for the first time that E2, at physiological concentrations, exerts a stimulatory effect on spontaneous and GRF-induced GH release as well as on cellular GH content, probably resulting, at least in part, from stimulation of GH synthesis.

Animals↗
PubMed1986

Serum luteinizing hormone (LH) biological activity in castrated patients with cancer of the prostate receiving a pure antiandrogen and in estrogen-pretreated patients treated with an LH-releasing hormone agonist and antiandrogen.

We recently reported almost complete disappearance of serum LH biological activity in previously untreated patients with advanced prostatic cancer receiving combined therapy with a LHRH agonist and a pure antiandrogen. This decrease in LH bioactivity was most likely responsible for the fall of circulating testosterone to castration levels during such treatment. Since patients previously treated with high doses of estrogens or orchiectomy before receiving combined therapy had a less favorable response to the new treatment, we measured serum LH levels by RIA and the mouse interstitial cell bioassay in these 2 groups of patients. Serum samples were obtained from 14 men with advanced prostatic cancer treated from 9-41 months (24 +/- 9 months) with diethylstilbestrol before receiving 500 micrograms/day LHRH agonist ([D-Trp6]LH/RH ethylamide) in combination with 3 daily oral doses of 250 mg pure antiandrogen flutamide and from 21 men castrated for at least 9 months (32 +/- 26 months) before receiving the antiandrogen alone. In previously castrated patients, both bio- and immunoactive LH serum levels were elevated and did not change during at least 3 months of antiandrogen treatment. In estrogen-pretreated men, however, bioactive LH concentrations declined from 1.2 +/- 0.5 (+/- SEM) to 0.04 +/- 0.01 ng/ml after 1 month of combined treatment and remained low thereafter, while serum LH levels, measured by RIA, did not significantly decline (1.4 +/- 0.5 vs. 0.9 +/- 0.1 ng/ml on days--2 and 30, respectively). This decrease in LH biopotency caused the biological to immunological activity ratio to fall from 0.5 +/- 0.2 before the onset of the combined therapy to 0.05 +/- 0.01 after 3 months. Thus, estrogen pretreatment did not prevent the ability of the LHRH agonist-antiandrogen combination to decrease serum LH biological activity. Moreover, the absence of an effect in castrated patients receiving antiandrogen alone indicates that the LHRH agonist, and not flutamide, was responsible for the effects of the combined therapy.

Aged↗
PubMed1986

Stimulation of the circulating levels of glycoprotein hormone alpha-subunit after combined administration of a luteinizing hormone-releasing hormone (LHRH) agonist and flutamide in patients with cancer of the prostate.

To ascertain whether the immunoreactive luteinizing hormone (LH) levels measured following the combined treatment may represent cross-reaction of the LH antiserum with LH subunits, we have examined the effects of therapy on the serum levels of free alpha- and free LH-beta-subunits in intact, castrated, and estrogen-treated patients. In previously untreated patients receiving the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide in association with the pure antiandrogen Flutamide, serum-free alpha-subunit levels were stimulated from 0.09 +/- 0.02 to 3.10 +/- 0.84 ng/ml after 5 days, and declined slowly afterwards to 1.33 +/- 0.20 ng/ml after 3 months of combined treatment. In patients pretreated from 12 to 24 months (17.5 +/- 1.0 months) with diethylstilbestrol (DES) prior to receiving the combined therapy, free serum alpha-subunit concentration followed a similar pattern, rising from 0.22 +/- 0.03 to 1.78 +/- 0.28 ng/ml after 15 days of combined treatment, and declining thereafter to 0.81 +/- 0.10 ng/ml after 3 months. Free LH-beta-subunits were below the detection limit in most previously untreated patients and in all DES-treated patients. After correcting for the cross-reactivity of the alpha-subunit in the LH RIA, immunoassayable LH serum levels in previously untreated patients were only slightly reduced from 0.81 +/- 0.06 ng/ml before the onset of the combined treatment to 0.52 +/- 0.05 ng/ml after 3 months. On the contrary, bioactive serum LH levels were drastically inhibited from 0.43 +/- 0.04 to 0.03 +/- 0.01 ng/ml after the same duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗
PubMed1986

[Combined anti-androgen treatment in adenocarcinoma of the prostate: first use of a new therapeutically efficacious principle in hormone-dependent cancer].

Since the first observation reported by Huggins et al. in 1941, hormonal treatment of advanced prostatic cancer has been directed primarily at neutralizing testicular androgens by orchiectomy or estrogen therapy. These two approaches yielded a 60 to 80% positive response rate in the many studies carried out over the last forty years. However, responses were short-lived and the disease recurred rapidly in nearly every case. A possible reason for these limited results may well be related to the fact that a unique characteristic of man as compared to other species is a high level of secretion of adrenal steroids that act as precursors and are converted into androgens within the prostatic tissue itself. Complete neutralization of both testicular and adrenal androgens is therefore mandatory to achieve total suppression of the influence of androgens on the carcinoma. To accomplish this goal, we have used a combination of an LHRH agonist (or orchiectomy) and a pure antiandrogen in fifty-two previously untreated patients with prostatic carcinoma and bone metastases (stage D2). Average duration of treatment was eighteen months (six to thirty-two months). An objective positive response assessed according to the criteria set forward by the National Prostatic Cancer Project (NPCP) was recorded during the first treatment months in every case, a significant improvement over the 60 to 80% positive response rate following previous treatments confined to neutralization of testicular androgens by orchiectomy or estrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1986

Stimulation of cell proliferation and estrogenic response by adrenal C19-delta 5-steroids in the ZR-75-1 human breast cancer cell line.

We have examined the effect of androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and its precursors, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3 beta-sulfate (DHEAS), on the growth of the estrogen-sensitive human breast cancer cell line, ZR-75-1. While the cell number was increased up to 4-fold by maximal concentrations of estradiol, delta 5-diol maximally stimulated cell proliferation by approximately 3-fold. Since the half-maximal stimulation achieved by delta 5-diol is observed at 2.5 nM and the normal range of plasma concentrations of this steroid in women is 1 to 3 nM, it is most likely that the stimulatory effect of delta 5-diol has physiological significance. DHEA and DHEAS were much less effective than delta 5-diol in stimulating the proliferation of ZR-75-1 cells, the maximal effect on cell number being 75% at the maximal dose used, namely 10 microM. The mitogenic effects of estradiol and delta 5-diol were competitively inhibited by the antiestrogen LY156758 (keoxifene), while the effects of DHEA and DHEAS were completely abolished by the antiestrogen. The effects of DHEA and delta 5-diol on cell proliferation are not likely to be mediated via their conversion to estrone or estradiol, since androstenedione had no effect, while testosterone and dihydrotestosterone decreased cell number by about 20%. The number of specific progesterone binding sites was increased 3.7-, 3.2-, and 2.0-fold by delta 5-diol, DHEA, and DHEAS, respectively. The relative potency of the C19-delta 5-steroids to increase the number of progesterone-specific binding sites was comparable to their ability to stimulate cell proliferation. Direct competition experiments performed with intact cells in monolayer culture showed that, under conditions of minimal metabolism, only delta 5-diol could significantly compete with estradiol for cellular estrogen-specific binding sites with an apparent dissociation constant of 11 nM, thus suggesting that physiological concentrations of C19-delta 5-steroids of adrenal origin could exert an estrogenic stimulation of breast tumor growth without involvement of the aromatase pathway. The present data suggest not only that estrone derived from androstenedione could play a role in estrogen-sensitive breast cancer in women but that delta 5-diol could well be the most important estrogen in breast cancer in women.

Androstenediol↗
PubMed1986

[Cancer of the prostate: biologic bases for the use of an antiandrogen in its treatment].

Although orchiectomy, estrogens and LHRH agonists suppress testicular androgens, they are without effect on adrenal androgens which are converted into dihydrotestosterone in the prostate. It is therefore necessary to develop substances able to block the action of all androgens, whatever their source, on target organs. The non-steroid, Anandron (RU 23908), when administered orally, gives rise to a high and sustained plasma level of intact compound that inhibits testosterone binding to its receptor. This inhibition, however, occurs not only in the prostate but also in the pituitary. The negative feedback action of androgens is thus inhibited by Anandron resulting in an increased secretion of testosterone and explaining the necessity of combining Anandron with castration (whether surgical or medical by an LHRH agonist). Anandron opposes, on the one hand, the action of adrenal androgens and, on the one other, of the testosterone surge that occurs during the early days of treatment with the LHRH analog. The efficacy of the combined treatment has been demonstrated experimentally. Clinical trials are presently underway.

Androgens↗
PubMed1985

Long term treatment with luteinising hormone releasing hormone agonists and maintenance of serum testosterone to castration concentrations.

Serum concentrations of luteinising hormone and testosterone were measured by radioimmunoassay one, two, four, seven, and 24 hours after the subcutaneous administration of 500 micrograms of the luteinising hormone releasing hormone agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide in patients who had previously received daily treatment with these peptides for 0, 1, 6, 12, 18, and 24 months. No increase in the serum concentrations of luteinising hormone or testosterone were detected at any time between one and 24 months' treatment. The data show that daily subcutaneous administration of the two luteinising hormone releasing hormone agonists used at the appropriate dose can maintain concentrations of serum androgens equivalent to those after castration during long term treatment.

Bone Neoplasms↗
PubMed1985

Vasopressin rapidly stimulates phosphatidic acid-phosphatidylinositol turnover in rat anterior pituitary cells.

In cultured rat anterior pituitary cells, the agonist [Asu1,6, Arg8]vasopressin (AVP-A) increased by 1.5-fold 32Pi incorporation into phosphatidic acid (PA), as early as 15 s after its addition. Increased phosphatidylinositol (PI) labeling became significant 4 min after AVP-A addition. Dose-response measurements with AVP-A showed ED50 values of 76 and 62 nM for PA and PI labeling, respectively. Peptide corticotropin-releasing factor (CRF) (0.1 microM) did not affect the stimulatory effect of AVP-A on PA and PI labeling. These data suggest that stimulation of PI metabolism in corticotrophs may be one of the early events involved in the stimulation of ACTH release induced by vasopressin.

Animals↗
PubMed1985

Increase in plasma ACTH after dopaminergic stimulation in rats.

The effects of a dopaminergic agonist, apomorphine, and a dopaminergic antagonist, haloperidol, on plasma ACTH, and corticosterone levels were evaluated in adult male rats. Subcutaneous administration of apomorphine in the dose range of 50-500 micrograms X kg-1 significantly increased plasma corticosterone levels. Acute treatment with apomorphine (250 micrograms X kg-1) resulted in an elevation of plasma ACTH concentration, peak values being reached 15 min after the injection. The apomorphine-induced rise in plasma ACTH levels was completely inhibited by pretreatment with haloperidol (1 mg X kg-1). A stimulatory role for dopamine receptors in the control of pituitary ACTH release in the rat is suggested.

Adrenocorticotropic Hormone↗
PubMed1985

Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate.

Flutamide is approximately 2-fold more potent than cyproterone acetate in reversing the stimulatory effect of dihydrotestosterone (DHT) on ventral prostate weight. Even at the highest dose of cyproterone acetate, prostate weight remains 40% above control while flutamide completely reverses the stimulatory action of DHT, thus suggesting some partial androgenic activity of cyproterone acetate. Megestrol acetate, on the other hand, is devoid of any antiandrogenic activity and it even increases the stimulatory effect of DHT on prostate weight. While flutamide completely reverses the inhibitory effect of DHT on plasma LH levels in castrated animals, cyproterone acetate reverses the value of this parameter by only 30% while megestrol acetate further inhibits plasma LH levels at all the doses used. Both cyproterone acetate and megestrol acetate inhibit adrenal weight to approximately 25% of control, thus indicating their glucocorticoid activity. As direct measure of androgenic activity, cyproterone acetate and megestrol acetate increased prostate weight in castrated animals by 60 and 100%, respectively (P less than 0.01) while flutamide had no effect. The present data show that cyproterone acetate and megestrol acetate, in addition to their well-known progestational and glucocorticoid action, have intrinsic androgenic activity. Since it is the only compound having pure antiandrogenic activity, flutamide provides the best scientific arguments for its successful use for the treatment of androgen-sensitive diseases.

Adrenal Glands↗
PubMed1985

Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs.

Estrogens increase both basal and LHRH-induced LH release in rat anterior pituitary cells in culture. Following 48 h of preincubation with 1 nM 17 beta-estradiol, the maximal LH response to LHRH is increased 1.5-fold while the ED50 value of LHRH action is decreased 2.5-fold from 500 to 200 pM. The maximal 3-fold stimulation of 0.3 nM LHRH-induced LH release by 17 beta-estradiol is exerted at a KD value of 14.4 pM. Keoxifene (300 nM) completely blocks the potent stimulatory effect of 17 beta-estradiol up to 1 nM, the highest concentration of the estrogen used. As shown by the complete reversal of the stimulatory effect of 0.1 and 1.0 nM 17 beta-estradiol by keoxifene at IC50 values of 7.7 and 34 nM respectively, the antiestrogen interacts competitively with 17 beta-estradiol at the estrogen binding site. When present alone, keoxifene shows no estrogenic activity. The present data show that keoxifene acts as a pure antiestrogen on the control of LHRH-induced LH release in rat pituitary gonadotrophs.

Animals↗
PubMed1985

Inhibition of ovulation during discontinuous intranasal luteinizing hormone-releasing hormone agonist dosing in combination with gestagen-induced bleeding.

Four groups of eight or nine normal cycling volunteers with regular menstrual cycles had daily blood sampling during two pretreatment, two treatment, and two posttreatment cycles. Intranasal doses of 100, 200, and 300 micrograms of (D-Ser[TBU]6-des-Gly-NH210) luteinizing hormone-releasing hormone (LH-RH) ethylamide were administered every 12 hours and compared with a 400-micrograms dose given every 24 hours during two periods of 21 days followed by a drug-free interval of 7 days. Five milligrams of medroxyprogesterone acetate was taken orally on days 17 to 21. Serum luteinizing hormone was elevated during the first 2 weeks of treatment, and serum follicle-stimulating hormone was increased only during the first 2 days of treatment. At 100 to 300 micrograms/12 hours serum estradiol was stimulated up to preovulatory levels, whereas at 400 micrograms/24 hours most values were in the early follicular phase range. Ovarian ultrasonography revealed the transient development of preovulatory-like follicles in 8 of 12 studied cycles. Serum progesterone values were less than 2 ng/ml in 57.3%, between 2 and 5 ng/ml in 27.9%, and greater than 5 ng/ml in 14.7%. Withdrawal bleeding occurred during the pause in 97% of treatment cycles. Nine of 13 breakthrough bleedings happened in the groups given 100-micrograms and 300-micrograms/12 hours. Recovery cycles showed slightly prolonged follicular phases with normal luteal phases. No changes were observed in routine laboratory measurements. In conclusion, intermittent administration of appropriate LH-RH agonist dosing in combination with a progestogen would effectively block ovulation while preserving adequate cyclic estradiol secretion and could be an alternative contraceptive approach.

Administration, Intranasal↗
PubMed1985

Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival.

Eighty-seven previously untreated patients with clinical stage D2 (bone metastases) prostate cancer have received the combination therapy with a pure antiandrogen and an LHRH agonist (or orchiectomy) as first treatment in a multicentre study for up to 34 months (average = 16.2 months). A positive objective response assessed according to the criteria of the US NPCP has been observed in all cases. Pain disappeared in all patients within 1 month and performance become normal in all (including 2 bedridden patients) within 4 months. Progression of the disease after a period of remission has been observed in only 8 patients. Only one patient has died from prostate cancer while 3 have died from other causes. The probability of continuing response and survival at 2 years for the patients who receive the combination treatment (Kaplan-Meier's method) is 81 and 91%, respectively. By contrast, in the randomized group who had orchiectomy alone, 4 of 7 have died from prostate cancer (P less than 0.05 as compared to combination therapy). In addition to a marked improvement in the remission rate and survival, combination therapy maintains a good quality of life, hot flashes and a decrease or loss of libido being the only side-effects.

Acid Phosphatase↗
PubMed1985

The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form.

In order to determine whether the high affinity state or the low affinity state of the dopamine receptor mediated the inhibition of release of PRL by dopamine agonists, a large number of dopaminergic agonists (n = 31) and antagonists (n = 24) were tested for their potencies to inhibit the binding of [3H] spiperone to porcine anterior pituitary tissue, and for their potencies to affect the release of PRL from rat anterior pituitary cells in culture. All agonists (except bromocriptine, ergocryptine, and dihydroergocryptine) inhibited [3H]spiperone binding in two phases: one phase occurred at nanomolar or subnanomolar concentrations (representing the high affinity state of the dopamine receptor) and the other phase occurred at much higher concentrations of agonist (the low affinity state of the dopamine receptor). The dissociation constants (K) for each drug at each state were derived by computer, with the program LIGAND. It was observed that the agonist K values for the high affinity state were virtually identical with those agonist concentrations inhibiting PRL release; the K values for the low affinity state were about 2 orders higher. These data suggest that the high affinity state of the D2 dopamine receptor is the functional state which mediates the inhibition of PRL release.

Animals↗