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To study the bioavailability of dehydroepiandrosterone (DHEA) administered by the oral and percutaneous routes, three groups of 12 postmenopausal women aged 60-70 years received two capsules of 50mg of DHEA orally before breakfast daily for 14 days or applied 4 g of a 10% DHEA cream or gel at the same time of the day on a 30 cm x 30 cm surface area on the thighs. Detailed serial blood sampling over 24h was performed following 1st and 14th DHEA administration for measurement of DHEA and nine of its metabolites by liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS). Serum levels of estrone (E1) and estradiol (E2) did not change following DHEA administration by any of the three formulations, while serum androstenedione (4-dione), testosterone, DHEA sulfate (DHEA-S), E(1)-S, androsterone glucuronide (ADT-G) and 3alpha-androstanediol-G (3alpha-diol-G), increased in all cases, the effect on these parameters being more important after oral than percutaneous administration due to the metabolism of DHEA into these metabolites in the gastrointestinal tract and liver. No qualitative differences in DHEA metabolism are observed between the oral and percutaneous routes of DHEA administration while the levels of all steroids remain on a plateau during the 24h period during chronic percutaneous DHEA administration. The present data show that DHEA is transformed into active androgens and estrogens in peripheral intracrine tissues with no or minimal release of the active steroids E(1), E(2) or testosterone in the circulation. Moreover, DHEA is preferentially transformed into androgens rather than into estrogens. Most importantly, the present data show that changes in serum DHEA following oral or percutaneous DHEA administration are not a valid parameter of DHEA action since the increase in serum DHEA is at least 100% greater than the increase in the formation of active androgens and estrogens and thus much higher than the potential physiological effects.

PURPOSE This clinical trial is aimed at evaluating the impact of prostate cancer screening on cancer-specific mortality. SUBJECTS AND METHODS Forty-six thousand four hundred and eighty-six (46,486) men aged 45–80 years registered in the electoral roll of the Quebec city area were randomized in 1988 between screening and no screening. Screening included measurement of serum prostatic specific antigen (PSA) using 3.0 ng/ml as upper limit of normal and digital rectal examination (DRE) at first visit. At follow-up visits, serum PSA only was used. RESULTS Seventy-four (74) deaths from prostate cancer occurred in the 14,231 unscreened controls while 10 deaths were observed in the screened group of 7,348 men during the first 11 years following randomization. Median follow-up of screened men was 7.93 years. A Cox proportional hazards model of the age at death from prostate cancer shows a 62% reduction (P

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER α and ER β compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER α and ER β while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER α and ER β and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER β , this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER β activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. When human breast cancer ZR-75-1 xenografts were grown in nude mice, EM-800 led to a complete inhibition of the stimulatory effect of estrogens in ovariectomized mice while tamoxifen was less potent and even stimulated the growth of the tumors in the absence of estrogens, thus illustrating the stimulatory effect of tamoxifen on breast cancer growth. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 had no stimulatory effect on alkaline phosphatase activity, an estrogen-sensitive parameter. Raloxifene, droloxifene, hydroxytoremifene and hydroxytamoxifen, on the other hand, all stimulated to various extent, the activity of this enzyme. The stimulatory effect of all four compounds was blocked by EM-800, thus confirming their estrogenic activity in human endometrial tissue. When administered to ovariectomized animals, EM-800 prevents bone loss, the effect on bone mineral density, trabecular bone volume, and trabecular separation being 5–10 times more potent than raloxifene. EM-800 lowers serum cholesterol and triglyceride levels in the rat as well as in women. In a Phase II study performed in patients with breast cancer showing failure on tamoxifen, 1 patient had a complete response while 5 patients had a partial response and stable disease for at least three months has been observed in an additional 13 patients for a total of 19 positive responses out of 43 evaluable patients (44.2%). No significant secondary effect related to the drug was observed. A phase 3 international clinical trial is currently being performed in tamoxifen failure patients where EM-800 (SCH 57050) is compared to Arimidex. The detailed information obtained at the preclinical level with EM-652 or EM-800 indicates that these orally active compounds are highly potent and pure antiestrogens in the mammary gland and endometrium while they prevent bone loss and lower serum cholesterol and triglyceride levels. Preclinical and clinical data clearly suggest the interest of studying this compound in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer in which settings they should provide additional benefits on bone and lipids.

It is believed that the only possibility of an important decrease in death from prostate cancer is the diagnosis and treatment of the disease at a localized stage. As a response to this need, the present study was started in a population of 46 193 men aged 45–80 years registered in the electoral roll of Quebec City and its metropolitan area. These men were randomized between screening and no screening in a study aimed at assessing the impact of prostate cancer screening on cancer-specific death. At first visit, screening included measurement of serum prostatic specific antigen (PSA) using 3.0 ng/ml as the upper limit of normal, and digital rectal examination. Transrectal ultrasonography of the prostate was performed only if PSA and/or digital rectal examination were abnormal. At follow-up visits, only PSA measured annually was used as a screening test during the recent years. The prostate cancer death rates during the 8-year period of this study were 48.7/100 000 and 15/100 000 man-years in the unscreened...

The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.

Objective To assess the effect of neoadjuvant combination therapy withthe antiandrogen flutamide and a luteinizing,hormone-releasing hormone (LHRH) agonist administered for 3 months before radical prostatectomy, compared with surgery alone in early stage prostate cancer. Methods A sample of 161 randomly screened patients diagnosed as having stage B(134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the antiandrogen flutamide and an LHRH agonist before radical prostatectomy. Results Neoadjuvant combination therapy before radical prostatectomy decreasedcancer-positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery. Although, on average, the final stage determined by histopathologic examination of the surgical specimen was more advanced than predicted at initial diagnosis in 33.8% of control patients, an opposite observation was made in the group of men who received the 3-month neoadjuvant combination therapy where the final stage, instead of being more advanced, was less advanced than at diagnosis in an average of 21.1 % of men for a net 54% improvement of staging in favor of combination therapy. Organ-confined disease, on the other hand, increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.8% increase in the incidence of organ-confined disease. No cancer was found in 6 (6.7%) prostatectomy specimens from the treated group. Conclusions Although long-term follow-up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer.

It is well recognized that aging in men is accompanied by a decline in the serum levels of some adrenal and testicular steroids, but little or no attention has focused on the multiple steroid metabolites that are formed by steroid-converting enzymes in target tissues. In the present study, we have examined in detail the serum concentrations of a large series of adrenal and testicular steroids and their most significant metabolites produced in intracrine peripheral tissues. The serum concentrations of 26 conjugated and unconjugated C21-, C19-, and C18-steroids were measured in 2423 men aged 40-80 yr. The serum concentrations of the major circulating adrenal C19-steroids, namely dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), androst-5-ene-3 beta, 17 beta-diol and its sulfate, and androstenedione, decreased by about 60% between the ages of 40-80 yr. The small decrease in the serum concentrations of progesterone and pregnenolone in the presence of increased levels of cortisol and markedly decreased levels of DHEA, androst-5-ene-3 beta, 17 beta-diol, and their polar metabolites suggests that adrenal 17,20-lyase is particularly affected by aging. In addition to a marked decline in the serum concentrations of adrenal C19-steroids, a smaller, but significant, decrease occurred in serum testosterone. However, serum dihydrotestosterone levels remained constant, but the glucuronidated derivatives of dihydrotestosterone metabolites (androstane-3 alpha, 17 beta-diol glucuronide, androstane-3 beta, 17 beta-diol glucuronide, and androsterone glucuronide) were reduced by 45-50%, suggesting that 5 alpha-reductase activity in peripheral tissues may show a compensatory increase during aging. Analysis of the fatty acid esters of DHEA (DHEA-FA) also revealed that these nonpolar steroids markedly decrease between 40-80 yr of age, although such a decrease in DHEA-FA levels was smaller than that in DHEA and DHEA-S, suggesting that the formation of DHEA-FA may be specifically increased during aging. In summary, the present study suggests that in contrast to the marked decline in activity of steroidogenic enzymes in the adrenals and the small decrease in the testis, the activity of the steroid-converting enzymes present in peripheral tissues does not decrease during aging. In fact, the marked decrease in DHEA formation by the adrenals leads to a decrease of about 50% in total androgens in men between the ages of 40-80 yr. Such a decrease probably affects many physiological processes during aging.

A series of 115 previously untreated patients displaying clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide; the average follow-up was 3.9 years. Twenty-eight patients showed treatment failure with a probability of disease-free survival of 91.2% at 2 years. Twenty patients died from prostate cancer and 10 from other causes, the survival probability being 93.4% at 2 years. Local control was achieved rapidly in all patients. Urinary obstruction and hydronephrosis were corrected in all cases. When compared with data obtained after single endocrine therapy (orchiectomy or oestrogens) or radiotherapy, the treatment failure rate at 2 years was more than 3.0-fold lower after combination therapy (8.8%) than monotherapy (28.4%). The death rate 2 years after the start of combination therapy was 6.6% and was on average 22.2% (3.6-fold higher) in the studies using monotherapy (orchiectomy or oestrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of disease permits more efficient control of local disease and a decreased rate of progression to metastatic disease.

Three hundred and sixty-three 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 -Trp 6 ,des-Gly-NH 2 10 ]LHRH ethylamide (or orchiectomy) for an average of 771 days (24–2607 days). Only 31 of the 308 evaluable patients (10.1%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in five recent studies using monotherapy. The median survival achieved using monotherapy is approximately 24 months while, in the present study, it is increased to 41.2 months, thus giving an additional 17 months of survival with the combination therapy. It should be mentioned that at the time of relapse, combination therapy is continued and, addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide and hydrocortisone. While our studies showing the advantages of combination therapy with pure antiandrogen in advanced prostate cancer have been confirmed by independent large-scale randomized studies, our preliminary data clearly suggest the interest of downstaging early stage prostate cancer by temporary combination therapy prior to radical prostatectomy.

This clinical trial is aimed at evaluating the impact of prostate cancer screening on cancer-specific mortality.Forty-six thousand four hundred and eighty-six (46,486) men aged 45-80 years registered in the electoral roll of the Quebec city area were randomized in 1988 between screening and no screening. Screening included measurement of serum prostatic specific antigen (PSA) using 3.0 ng/ml as upper limit of normal and digital rectal examination (DRE) at first visit. At follow-up visits, serum PSA only was used.Seventy-four (74) deaths from prostate cancer occurred in the 14,231 unscreened controls while 10 deaths were observed in the screened group of 7,348 men during the first 11 years following randomization. Median follow-up of screened men was 7.93 years. A Cox proportional hazards model of the age at death from prostate cancer shows a 62% reduction (P0.002, Fisher's exact test) of cause-specific mortality in the screened men (P = 0.005). These results are in agreement with the continuous decrease of prostate cancer mortality observed in North America.

Purpose To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. Patients and Methods Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for ≥ 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for ≥ 3 months, and 7 patients (16%) had stable disease for ≥ 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. Conclusion EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

BACKGROUND The 11,811 first visits and 46,751 annual follow-up visits performed since 1988 were analyzed in order to assess the efficacy of serum prostatic specific antigen (PSA) and digital rectal examination (DRE) for diagnosis of prostate cancer. METHODS At first visit, screening included DRE and measurement of PSA using 3.0 ng/ml as upper limit of normal, demonstrated as optimal value in the course of the study. Transrectal echography of the prostate (TRUS) was performed only if PSA and/or DRE was abnormal. For elevated PSA, biopsy was performed only if PSA was above the value predicted from prostatic volume measured by TRUS. At follow-up visits, it was decided during the course of the study to use PSA alone. RESULTS PSA was above 3.0 ng/ml in 16.6% and 15.6% of men at first and follow-up visits, respectively. Prostate cancer was found in 2.9% of men invited for screening at first visit and in only 0.4% of men at follow-up visits for a 7.1-fold decrease at follow-up visits done up to 11 years. PSA alone allowed to find 90.5% and 90.0% of cancers at first and follow-up visits, respectively, compared to 41.1% and 25.0% by DRE alone. In the presence of normal PSA, 344 and 1,919 DREs are needed to find one prostate cancer at first and follow-up visits, respectively. A significant improvement in stage of the disease is found at follow-up (215 cancers) compared to first visits (337 cancers). Comparison made between men invited for screening and those who were not invited but screened showed no significant difference in terms of incidence and prevalence of prostate cancer as well as diagnosis of cancer as a function of age or as a function of PSA, DRE, and TRUS data. The cost for finding one case of prostate cancer is estimated at Can $2,420 and Can $7,105 (first and follow-up visits, respectively, when PSA is used as prescreening). CONCLUSIONS PSA used as prescreening and followed by DRE and TRUS when PSA is abnormal is highly efficient in detecting prostate cancer at a localized (potentially curable) stage since 99% of the cancers diagnosed were at such a localized stage, thus practically eliminating the diagnosis of metastatic and noncurable prostate cancer. The approach used is highly reliable, sensitive, efficient, and acceptable by the general population. The detection of clinically nonsignificant cancer is an exception. Prostate 45:19–35, 2000. © 2000 Wiley-Liss, Inc.

BACKGROUND The 46,193 men aged 45 to 80 years registered in the electoral roll of Quebec City and its Metropolitan area were randomized in November 1988 between screening and no screening in a study aimed of assessing the impact of prostate cancer screening on cause-specific death. METHODS At first visit, screening included measurement of serum prostatic specific antigen (PSA) using 3.0 ng/ml as upper limit of normal and a digital rectal examination (DRE). Transrectal echography of the prostate (TRUS) was performed only if PSA and/or DRE was abnormal and biopsy was then done, only if PSA was above the predicted PSA value. At follow-up visits, PSA alone was used as prescreening. RESULTS 137 deaths due to prostate cancer occurred between 1989 and 1996, inclusively, in the 38,056 unscreened men while only 5 deaths were observed among the 8,137 screened individuals. The prostate cancer death rates during the eight-year period were 48.7 and 15 per 100,000 man-years in the unscreened and screened groups, respectively, for a 3.25 odds ratio in favor of screening and early treatment (P < 0.01). CONCLUSIONS If PSA screening is started at the age of 50 years (or 45 years in the higher risk population), annual or biannual PSA alone is highly efficient to identify the men who are at high risk of having prostate cancer. Coupled with treatment of localized disease, this approach demonstrates, for the first time, that early diagnosis and treatment permits a dramatic decrease in deaths from prostate cancer. Prostate 38:83–91, 1999. © 1999 Wiley-Liss, Inc.

This study analyzes in detail the serum concentration of the active androgens and estrogens, as well as a series of free and conjugated forms of their precursors and metabolites, after daily application for 2 weeks of 10 mL 20% dehydroepiandrosterone (DHEA) solution on the skin to avoid first passage through the liver. In men, DHEA administration caused 175%, 90%, 200% and 120% increases in the circulating levels of DHEA and its sulfate (DHEA-S), DHEA-fatty acid esters, and androst-5-ene-3 beta,17 beta-diol, respectively, with a return to basal values 7 days after cessation of the 14-day treatment. Serum androstenedione increased by approximately 80%, whereas serum testosterone and dihydrotestosterone (DHT) remained unchanged. In parallel with the changes in serum DHEA, the concentrations of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, and androstane-3 beta,17 beta-diol-G increased by about 75%, 50%, and 75%, respectively, whereas androsterone-sulfate increased 115%. No consistent change was observed in serum estrone (E1) or estradiol (E2) in men receiving DHEA, whereas serum E1-sulfate and E2-sulfate were slightly and inconsistently increased by about 20%, and serum cortisol and aldosterone concentrations were unaffected by DHEA administration. Almost superimposable results were obtained in women for most steroids except testosterone, which was about 50% increased during DHEA treatment. This increase corresponded to about 0.8 nM testosterone, an effect undetectable in men because they already have much higher (approximately 15 nM) basal testosterone levels. In women, the serum levels of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, androstane-3 beta,17 beta-diol-G, and androsterone-sulfate were increased by 125%, 140%, 120% and 150%, respectively. The present study demonstrates that the serum concentrations of testosterone, DHT, E1, and E2 are poor indicators of total androgenic and estrogenic activity. However, the esterified metabolites of DHT appear as reliable markers of the total androgen pool, because they directly reflect the intracrine formation of androgens in the tissues possessing the steroidogenic enzymes required to transform the inactive precursors DHEA and DHEA-S into DHT. As well demonstrated in women, who synthesize almost all their androgens from DHEA and DHEA-S, supplementation with physiological amounts of exogeneous DHEA permits the biosynthesis of androgens limited to the appropriate target tissues without leakage of significant amounts of active androgens into the circulation. This local or intracrine biosynthesis and action of androgens eliminates the inappropriate exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects of DHEA.

Modulation of androgen receptor (AR) expression during neoadjuvant endocrine therapy in human prostates of patients with localized prostate cancer was investigated by immunohistochemistry. In 8 of 15 untreated prostatectomy specimens, the majority of prostatic glandular cells displayed nuclear immunostaining for AR, whereas only 1 of 26 pretreated cases displayed a similar glandular AR expression. Expression of AR in the prostatic stromal compartment of nontreated cases proved to be quite heterogeneous, since 4 of the 15 (27%) examined specimens did not show stromal AR expression. After preoperative neoadjuvant therapy, this value was 68%, although this difference did not reach statistical significance. Prostatectomy specimens of the treated patients contained carcinomas with a higher Gleason score than those of untreated patients. AR expression in carcinomas of treated patients was diminished (P= 0.05), which may be attributed to their relatively lower differentiation grade. The data strongly suggest that neoadjuvant hormone therapy reduces AR expression by nonneoplastic prostatic glandular cells and carcinoma cells by a selective, but incomplete, elimination of AR-positive cells.

Prostate cancer is the second cause of cancer death in men in the Western world; its medical and social impact is comparable to that of breast cancer in women. Although it is well recognized that early treatment is the only possibility for reducing the high rate of death from prostate cancer, screening and even early treatment are controversial issues due mainly to arguments based upon old literature and lack of awareness of the significant advances recently made in this field. As it is well known that surgical removal of organ-confined prostate cancer cures the disease, and it has been demonstrated that annual screening with prostate-specific antigen coupled with digital rectal examination followed, when indicated, by transrectal ultrasonography of the prostate more than doubles the proportion of organ-confined disease, screening alone offers the possibility of at least doubling the number of patients curable from prostate cancer or the potential for a cure to an estimated 45% of prostate cancer patients compared to a maximum of 20% in the absence of screening. It is important to mention that screening does not detect small and insignificant cancers, especially when random biopsies are not performed routinely. The critical volume of prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in diameter, if spherical. Such a tumor should increase serum prostate-specific antigen by 0.5 ng/mL. Contrary to the belief that screening detects cancers that are too small, the fact is that screening detects prostate cancer too late or nonorgan- or nonspecimen-confined cancer in 35-50% of cases. There is, thus, a narrow window when prostate cancer can be detected at a curable stage, and even the best available screening techniques cannot succeed in all cases. It should be mentioned that the recent improvements of the technique of radical prostatectomy have markedly improved the acceptability of surgery. Concerning the recent publicity related to watchful waiting, it is essential to indicate that all such reports support the notion that prostate cancer grows slowly, but steadily and irremediably, with increasing malignancy and risk of distant metastases and death if sufficient time is allowed. Another serious limitation of watchful waiting is that the available prognostic factors have a large margin of error and cannot predict with certainty the rate of progression of the tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Das Prostatakarzinom wurde zum haufigsten mannlichen Tumor und ist die zweithaufigste Todesursache nordamerikanischer Manner. Man erwartet fur 1994 200000 Neuerkrankungsfalle am Prostatakarzinom in den Vereinigten Staaten und rechnet mit dem Tumortod von 38000 Mannern (Boring et al. 1994). Das Prostatakarzinom ist daher ein groseres sozialmedizinisches Problem (Brown et al. 1994), das mit steigender Lebenserwartung zunimmt (Chisholm 1981).

Since the observations reported by Huggins and his colleagues (1941), the standard treatment of advanced prostate cancer has been a choice between orchiectomy and estrogens (Huggins and Hodges 1941; Nesbit and Baum 1950; Jordan et al. 1977; Mettlin et al. 1982; Murphy et al. 1983). Following such neutralization of testicular androgens, a positive response is observed in 60%–80% of patients for a limited time interval, thus leaving 20%–40% of patients in progression without any effect of treatment. Moreover, in the 60%–80% of patients who initially respond, relapse of the disease is usually seen within 6 to 24 months (Resnick and Grayhack 1975) and 50% of them are expected to die within the next 6 months (Johnson et al. 1977; Slack and Murphy 1984).

Sixty-three healthy post-menopausal women participated in the study aimed at determining the efficiency of percutaneous administration of estradiol (E2) giving physiological plasma levels of the estrogen to provide an efficient relief of climacteric and urogenital symptoms. Among these women, 31 had previous hysterectomy and were randomly allocated to one of the two estrogen replacement therapies while, similarly, the 32 women having an uterus were randomly divided between two groups who received in addition to estrogens, micronized oral progesterone. As estrogen, women received either E2 by percutaneous administration (Oestrogel) or oral conjugated estrogens (Premarin). With Oestrogel, serum E2 and estrone levels were within those seen during premenopause and showed a ratio close to 1.0. Climacteric symptoms were reduced or eliminated similarly in all groups. No changes was noticed on the concentration of serum angiotensinogen with Oestrogel therapy while a 2.5-fold increase was found in women receiving Premarin. As indicated by the 24-week endometrial biopsy, the progestational response induced by oral progesterone at the dose used was sufficient in twenty out of thirty-two women to cause endometrial atrophy, thus suggesting the need for higher amounts of micronized progesterone in a proportion of women. The present data also indicate that Oestrogel provides efficient relief of climacteric and urogenital symptoms without exerting any detectable effect on hepatic function while maintaining the ratio of serum E2/E1 at the physiological value of 1.0.

Sixty-three postmenopausal women were assigned to four treatment groups and received either Premarin or percutaneous 17 beta-estradiol (Oestrogel) alone or in combination with micronized progesterone (Utrogentan). The oral administration of estrogen alone to hysterectomized women resulted in: 1) a significant increase in triglyceride levels in plasma and all major lipoprotein fractions, 2) a significant increase in very low density lipoprotein cholesterol, 3) a significant decrease in low density lipoprotein (LDL) cholesterol but not LDL apo B concentration, 4) a significant increase in all the lipid components of high density lipoprotein (HDL) as well as apo AI, 5) and a significant increase in HDL2 cholesterol. In contrast, percutaneous administration of estrogen to hysterectomized women only increased HDL2 cholesterol and the triglyceride and cholesterol content of the whole HDL fraction. These results suggest that the route of estrogen administration is important in determining effects on lipoprotein metabolism. The same two estrogens were given to women with natural menopause, along with utrogestan, a micronized progesterone. The simultaneous administration of Utrogestan reversed the HDL cholesterol elevating effect of percutaneous estrogen alone, but it had no effect on other plasma lipoproteins. On the other hand, utrogestan in combination with oral estrogen had several potential beneficial effects on plasma lipoproteins. This combination did not negate the effects of oral estrogen alone on HDL, rather it further increased the concentrations of HDL cholesterol and apo AI. It also did not negate the LDL cholesterol lowering effect of oral estrogen alone. Furthermore, utrogestan lowered the magnitude of hypertriglyceridemia induced by oral estrogen alone. These results suggest that Utrogestan has lower potency of androgenic action and has desirable effects when given in cyclic combination with estrogen.

Acute or chronic treatment of adult male rats with luteinizing hormone-releasing hormone (LHRH) or its agonist leads to a loss of testicular LH and prolaction receptors accompanied by decreased testis seminal vesicle and ventral prostate weight. The inhibition of testosterone formation is due to a blockage of the steroidogenic pathway at the level of 17-hydroxylase and 1720-desmolase activities. The testicular desensitization is accompanied by a decreased pituitary responsiveness LHRH. Although the inhibitory effects at the testicular level could be explained by endogenous LH release induced by the LHRH agonist with secondary testicular desentization the LH-relasing peptides also exert direct inhibitory effects on gonadotropin receptors at the testicular level. Moreover LHRH and its agonists bind to a specific LHRH receptor in interstitial cells. Chronic treatment with LH agonists leads to marked degenerative changes in the seminiferous tubules almost all tubules showing signs of histologic damage after 4 weeks of treatment. Single administration of an LHRH agonist by the intranasal route in normal adult men casuses a transient inhibition of plasma testosterone levels with a temporary loss of diurnal cyclicity whereas preliminary data obtained in patients with cancer of the prostrate show inhibition of both testosterone and dihydrotestosterone plasma levels. Such data suggest the potential use of LHRH agonists in male contraception and for the treatment of cancer of the prostrate. (authors)

Several experimental studies have suggested that diet can alter the production and metabolism of steroids in men. The purpose of this study was to determine the levels of unconjugated steroids and steroid glucuronides as well as sex hormone-binding globulin (SHBG) among normal adult men who were either omnivorous or vegetarians. The participants were white volunteers ranging from 25-35 years of age and the blood samples were taken between 0900 h and 1000 h and between 1600 h and 1700 h for two consecutive days. No significant statistical change was found in plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone and estradiol levels. Vegetarian group showed a higher levels of sex hormone-binding globulin (SHBG) while the free androgen index (FAI; calculated by the ratio testosterone/SHBG) was lower in this group. Although the concentrations of androsterone glucuronide were higher in vegetarian group, the vegetarians had a 25-50% lower level of androstane-3 alpha, 17 beta-diol glucuronide and androstane-3 beta,17 beta-diol glucuronide. Our data further indicate that both, androstane-3 alpha,17 beta-diol glucuronide and androstane-3 beta,17 beta-diol glucuronide concentrations are significantly correlated with SHBG levels and with the FAI values. The increases in androstane-3 alpha,17 beta-diol glucuronide and androstane-3 beta,17 beta-diol glucuronide levels in the omnivorous group are probably a consequence of the elevation of the FAI. Our data suggest that in a vegetarian group, less testosterone is available for androgenic action.

At doses which have no or minimal inhibitory effect when administered alone, the LHRH agonist [D-Ser(TBU)6,des-Gly-NH10(2)] LHRH ethylamide (HOE-766) and the antiandrogen RU-23908 administered simultaneously cause a marked inhibition of ventral prostate and seminal vesicle weight after 5 months of treatment. The effect of the LHRH agonist is due to a blockage of the testicular steroidogenic pathway. The same LHRH agonist administered to adult men with cancer of the prostate causes a marked inhibition of serum testosterone and dihydrotestosterone to castration levels within 1-2 weeks. Administration of the pure antiandrogen to men with cancer of the prostate already receiving the LHRH agonist does not interfere with the LHRH agonist-induced blockage of androgen biosynthesis: Moreover, objective signs of remission of the disease were rapidly observed in 8 out of 10 patients. The ease of application of this new form of hormonal therapy which neutralizes androgens from all sources should facilitate its early administration and thus minimize the development of metastases and androgen-resistant cell clones.

Thirty sec after the intrajugular injection of [ 3 H] methionine-enkephalin (met-enkephalin) in the rat, the radioactivity was already distributed in an apparent volume of 53 ml and the metabolic clearance rate calculated from the characteristics of the plasma disappearance curve was 10 ml/min. As shown by partition chromatography plasma extracts obtained 15 sec after injection of [ 3 H] met-enkephalin, only 5% of the total radioactivity migrated as the intact pentapeptide, while no detectable intact pentapeptide remained 2 min after injection, thus indicating a half-life of [ 3 H] met-enkephalin of the order of 2 to 4 sec. Incubation of rat cerebral tissue with [ 3 H] met-enkephalin indicates that the first step in the breakdown of met-enkephalin in both plasma and brain tissue is cleavage of the Tyr-Gly amide bond. These data offer an explanation for the low activity of met-enkephalin after intraventricular or intravenous administration.

A single dose of 0.5 μg β-endorphin injected intraventricularly in unanesthetized male rats bearing chronic intraventricular and intrajugular cannulae led to a 7-fold stimulation of plasma prolactin (PRL) levels 10 to 20 min after injection of the peptide, whereas a dose of 500 μg methionine-enkephalin (met-enkephalin) led to only a 4-fold stimulation of plasma PRL levels. Combined with our previous data, the present findings show that β-endorphin and met-enkephalin have a more potent and more rapid stimulatory effect on PRL than GH release after intracerebral injection. These data suggest a possible role of endogenous opiate-like peptides in the control of both PRL and GH secretion.

Treatment of adult male rats with the potent LHRH agonists [D-Leu6, des-Gly-NH210]LHRH ethylamide or [D-Ala6. des-Gly-NH210]LHRH ethylamide led to a marked reduction of testicular LH and prolactin receptor levels accompanied by decreased plasma testosterone levels and testis, seminal vesicle and prostate weight. Maximal inhibitory effects were seen at a dose of 50 ng. After a single injection, maximal inhibitory effects were seen at 2–4 days with return toward normal levels at later time intervals. Similar results were obtained with LHRH itself although 5 μg was required for maximal effects. When the LHRH analog was administered twice a week at the 100 ng dose, degenerative signs appeared in the seminiferous tubules after one week while at four weeks, degenerative changes were so advanced that almost all germ cells had disappeared leaving only Sertoli cells.

Sertoli cell monolayers were prepared from 19-day-old rat testes. On day 7 of culture cells were incubated for 24 hr in the presence or absence of ovine follicle stimulating hormone (oFSH). Cells were harvested, and adenylyl cyclase responses of the membrane particles to FSH, human chorionic gonadotropin (hCG), isoproterenol, and fluoride (F-) were examined in the presence of either GTP or the nonhydrolyzable guanylyl nucleotide GMP-P(NH)P. Culturing the cells in presence of FSH caused a hormone specific desensitization of FSH-responsive adenylyl cyclase, whereas responses to isoproterenol and fluoride were unaffected. Activation of Sertoli cell adenylyl cyclase by GTP and GMP-P(NH)P showed no difference between cells preincubated with or without FSH, indicating that FSH did not change the activity of the G/F (or N) component or its interaction with the catalytic subunit of the adenylyl cyclase. FSH-responsive adenylyl cyclase in cultured Sertoli cells has been shown to be selectively desensitized by homologous hormone. The mechanism may involve alteration or loss of the FSH receptor or changes in the "coupling" of the FSH receptors to the G/F component of the adenylyl cyclase, since there was no alteration in the guanylyl nucleotide and fluoride activation.

Assessment of the role of endogenous LH release and direct gonadal action of LHRH agonists in the loss of gonadal LH receptors induced by treatment with gonadotropin-releasing peptides was first made by comparing the effect of single administration of 1 �g of ID-Ala’, des-Gly-NH2 ‘#{176} I LHRH ethylamide, ED-Ala’) LHRH-EA, 12 h before or immediately after hypophysectomy (HYPOX) on LH receptor levels measured 48 h after surgery in male and female adult rats. While administration of the LHRH agonist before HYPOX leads to a 50% loss of testicular LH receptors, only a 20% decrease is seen in HYPOX animals, thus suggesting a predominant role of endogenous LH release in the desensitization process in male animals. Treatment with increasing doses (1 to 100 ng/day) of another LHRH agonist, [D-Ser(TBU)’ I LHRH-EA, causes a 90% loss of testicular LH receptors in intact rats at the highest dose used (100 ng daily for 9 days) while the same treatment decreases LH receptors by only 35% in HYPOX animals. As measured by the steroidogenic response to 10 �g 0LH in vivo, while treatment of intact animals with [D-Ser(TBU)’ I LHRHEA leads to a marked blockage of the testicular steroidogenic pathway at the level of 17-hydroxylase and 17,20-desmolase activities with a corresponding increase of 5o-reductase activity, minimal or no signs of changes of enzymatic activity are seen after identical treatment in HYPOX animals. Chronic treatment (1 month) with the LHRH agonist in intact rats leads to degenerative changes of the seminiferous tubules, while no effect is observed in HYPOX animals, thus suggesting the essential role of the pituitary gland. Moreover, adrenalectomy does not influence the inhibitory effect of treatment with LHRH agonists on the loss of testicular LH receptors in HYPOX animals, thus eliminating the role of the adrenals in the action of LHRH agonists. Contrary to the results obtained in male animals, single administration of the LHRH agonist in female rats has similar inhibitory effects on ovarian gonadotropin receptors when administered either before or after hypophysectomy. Moreover, treatment with increasing doses of ED-Ser(TBU)’ I LHRH-EA leads to a similar inhibition of ovarian LH receptor levels in intact and HYPOX female animals. The present data show that LHRI-I agonist-induced endogenous LH release plays a predominant role in the desensitizing effect of treatment with LHRH agonists on testicular LH receptors and steroidogenesis as well as on inhibition of spermatogenesis; in the female, the direct gonadal effect, at least on LH and FSH receptors, appears to play a more important role than in male animals.

Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat are well known to be hormono-dependent. Daily injections of an LHRH agonist, [D-Ala6, des-Gly-NH2(10)]LHRH ethylamide (LHRH-A), 1 microgram daily, for 38 days results in a 35% decrease in the number of tumors present at the beginning of the experiment compared to a decline of 45% after ovariectomy and of 8% in the control group. This is accompanied by a marked reduction in ovarian LH and FSH receptors. LHRH-A treatment also resulted in reduction in the number of progesterone and prolactin receptors in the tumors. In addition, an increase in plasma LH and FSH and a decline in plasma prolactin (PRL) concentrations are observed. The mechanisms by which the LHRH agonist induces its antitumoral effect probably relate to an ovarian desensitization to LH and FSH with a concomitant decrease in circulating levels of estrogen and prolactin, two well known stimuli for the growth of DMBA-induced mammary tumors.

The effects of chronic treatment with hCG (100 I.U. s.c. every second day) on testicular morphology, LH receptor levels and concentration of steroid intermediates of the δ4 and δ5 biosynthetic pathways were studied in adult rats for periods extending from one to 12 weeks. Treatment with hCG causes a decrease in testis weight, a maximal inhibitory effect being observed after two and four weeks of treatment. At these time intervals, the loss of testis weight is accompanied by degenerative changes in most seminiferous tubules and hypertrophy of Leydig cells. Administration of hCG for one week leads also to an almost complete loss of LH binding sites and to a marked stimulation of the levels of testicular steroids of the A and pathways, as well as to an increase in weights of secondary reproductive organs. The initial increment of testicular steroid levels is followed after two weeks of hCG administration by an apparent decrease of 17, 20-desmolase activity suggested by a reduction in the levels of androst-5-ene-3β, 17β-diol, androstenedione, testosterone, and 5α-dihydrotestosterone and an increase in the concentrations of pregnenolone, 17-OH-pregnenolone, progesterone and 17-OH-progesterone. Plasma and pituitary LH levels are maximally reduced at one and four weeks of treatment, respectively, while plasma and pituitary FSH levels are only slightly reduced after four weeks of hCG administration. The effects of hCG on all of the above-mentioned parameters, except for testicular morphology and testis weight, are completely reversible at the eight and 12 week intervals. This transiency in the effects of hCG is accompanied by a gradual increase in plasma levels of hCG antibodies. The present data show that chronic treatment of adult rats with hCG induces a marked degeneration of the seminiferous tubules and an inhibition of spermatogenesis that accompanies the well-known loss of testicular LH receptors and inhibition of the steroidogenic pathway.

One hundred and eighty-six previously untreated patients with clinical stage D 2 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 -Trp 6 , des-Gly-N H 2 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. The presence of a low number of bone metastases is a major prognostic factor which favors complete responses and suggests the advantages of early treatment before dissemination of the disease.

MORPHINE stimulates prolactin and growth hormone secretion1,2, so the identification of brain peptides with opiate-like activity (methionine-enkephalin and leucine-enkephalin)3 raised the possibility that these peptides, beside their role as modulators of pain4, could also be involved in the control of neuro-endocrine functions. We did in fact find that Met-enkephalin administered intraventricularly led to a stimulation of prolactin and growth hormone release5–7. β-Endorphin (β-LPH61–91) was, however, found to be 500 to 2,000 times more potent than Met-enkephalin (β-LPH61–65) in stimulating the release of the pituitary hormones. Since both peptides show similar affinity for the opiate receptor when binding studies are performed at 0 °C in conditions of minimal enzymatic degradation8,9, the markedly different biological activities of the two peptides after intracerebral injection are likely to be due to a more rapid inactivation of Met-enkephalin. We show here that the two analogues resistant to enzymatic degradation, [D-Ala2]Met-enkephalin and [D-Ala2]Met-enkephalinamide can stimulate prolactin and growth hormone release after intraventricular injection at a level of potency which is 500 to 5,000 times higher than that of the natural Met-enkephalin molecule.

A single injection of the luteinizing hormone (LH)-releasing hormone (LHRH) agonist [D-Ala6,des-Gly-NH2(10)]LHRH ethylamide to female rats on diestrus I produced a marked reduction in ovarian LH/human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) receptor levels, uterine weight, and plasma progesterone levels measured 2 days later on expected proestrus. A maximal inhibitory effect was seen after a dose of only 40 ng of the peptide. No consistent effect of the LHRH analog was seen on ovarian prolactin receptors. When the analog was injected on day 7 of pregnancy, the inhibition of ovarian LH/hCG receptors was of shorter duration and was much less sensitive than that in nonpregnant animals. These data indicate that ovarian LH and FSH receptors levels are highly sensitive to changes in endogenous gonadotropin secretion and suggest that the gonadotropin surge occurring spontaneously on proestrus may play an important role in the regulation of ovarian gonadotropin receptors during the estrous cycle.

The effect of further adrenal androgen blockade with aminoglutethimide (AG) plus low dose hydrocortisone (HC) was studied in 119 patients with clinical stage D2 prostate cancer who previously progressed after standard hormone therapy and were under progression while receiving the combination therapy with Flutamide and castration. Using the objective criteria of the US NPCP, 1 complete, 2 partial and 14 stable responses were obtained for a total response rate of 14.3%, while 102 patients continued to progress. The 50% probability of survival was 21.0 months for the responders and 9.2 months for the non-responders. The present data indicate that further androgen blockade with AG + low dose HC is well tolerated and can be of benefit to a significant proportion of patients in progression at a very late stage of the disease.

In order to achieve a more complete blockade of androgens of both testicular and adrenal origins, 223 patients with advanced prostate cancer (stage D2 with bone metastases) received the combination therapy with the antiandrogen Flutamide and the LH-RH agonist [D-Trp6,des-Gly-HN10(2)] LH-RH ethylamide as first treatment. As assessed by the objective criteria of the US NPCP, a positive response was obtained in 94% of patients, thus leaving only 6% of patients with no response at the start of treatment while, following standard therapy, 20-40% of patients do not respond to treatment. The duration of response was increased while longer survival (an advantage of approximately 14 months compared to standard therapy, 38.5 vs approximately 24 months) was achieved with no or minimal side effects. Highly positive results were also obtained using the combination therapy in stage C prostate cancer patients while temporary treatment with the combination therapy in stages A and B prostate cancer facilitated radical prostatectomy. The present data supported by the results of independent studies indicate that combination therapy should be the treatment for all patients with advanced disease and possibly also at earlier stages of prostate cancer in combination with surgery.

A possible effect of LII or hCG on testicular prolactin receptor levels was investigated in hypophysectomized adult rats. Hypophyseetomy leads to a progressive decrease of testicular prolactin receptor content to ‘\�25% of that of controls 12 days after surgery. In animals injected3 times a day for 10 days with highly purifiedpreparations of ovine LII or hCG, prolactin receptor levelsincreasedfrom 21 4 to 41 ± 4 and 71 7 fmol/testis, respectively (P

While the intact male adult rats respond to LH with a predominant increase of testicular and plasma testosterone levels, the response to LH stimulation in animals treated with the LHRH agonist, [D-Ser(TBU) 6, des-Gly-NH2(10)] LHRH ethylamide is characterized by a major production of 5 alpha-androstane-3 alpha, 17 beta-diol. The marked increase of 5 alpha-androstane-3 alpha, 17 beta-diol levels in the presence of a 90% decrease of testosterone concentration strongly suggests that 5 alpha-reductase and 3 alpha-hydroxysteroid oxidoreductase activities are increased during testicular desensitization induced by treatment with the LHRH agonist.

In the present study we have examined the effects of gonadotrophin releasing hormone (LHRH), sex steroids and glucocorticoids on the binding of LHRH to receptors in the pituitary of male intact and castrated rats. In intact rats, LHRH (10 microgram/day) treatment for 11 days caused a significant increase in LHRH binding, whereas testosterone (500 microgram/day) or oestradiol (50 microgram/day) were inhibitory. 17-hydroxyprogesterone and dexamethasone were without effects. In castrated rats, LHRH caused a marginal decrease in LHRH binding. Much greater inhibition was observed with testosterone and oestradiol. 17-hydroxyprogesterone reduced binding to that of intact controls, whereas dexamethasone was ineffective. When different doses of sex steroids were tested, both oestradiol, testosterone and 5 alpha-dihydrotestosterone inhibited LHRH in a dose-dependent manner. The lowest doses of steroids causing significant inhibition of LHRH binding in castrated animals were 0.5, 50 and 500 microgram/day for oestradiol, 5 alpha-dihydrotestosterone and testosterone, respectively. The present study shows that pituitary receptors for LHRH are regulated both by sex steroids and LHRH itself.