Luteinizing hormone-releasing hormone agonist and uterine leiomyoma: a pilot study.

Ten women with 12 uterine leiomyomas ranging from 7.5 to 420 cc (mean, 112.6 +/- 39.4) were treated with subcutaneous injections of the luteinizing hormone-releasing hormone agonist buserelin, 200 micrograms three times daily for 1 week and then 500 micrograms daily for the rest of the 6-month treatment period. Following initial stimulation the pituitary ovarian axis was suppressed after 3 weeks of treatment with mean serum estradiol ranging between 17 and 36 pg/ml. Seven uterine leiomyomas had a marked regression in size following treatment with luteinizing hormone-releasing hormone agonist; two were undetectable and the volume of the other five diminished by an average of 80%. One tumor did not respond to treatment, two regressed by 25%, and two, following an initial reduction of 65% and 50%, reenlarged during the last 2 months of treatment to 75% and 100% respectively of their initial volume. Luteinizing hormone-releasing hormone agonist is the first medication demonstrated effective in reducing the size of uterine myomas.

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.

PIP: 4 groups of 8 or 9 normal cycling volunteers with regular menstrual cycles had daily blood sampling during 2 pretreatment, 2 treatment, and 2 posttreatment cycles. Intranasal doses of 100, 200, and 300 mcg of luteninizing hormone-releasing hormone (LH-RH) ethylamide were administered every 12 hours and compared with a 400-mcg dose given every 24 hours during 2 periods of 21 days followed by a drug-free interval of 7 days. 5 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 100-300 mg/12 hours serum estradiol was stimulated up to preovulatory levels, whereas at 400 mcg/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 2-5 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. 9 of 13 breakthrough bleedings happened in the groups given 100-mcg and 300-mcg/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.

Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy.

Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.

Reversible hypogonadism induced by a luteinizing hormone-releasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis.

Ten women with endometriosis (stages I to IV) were treated with twice-daily subcutaneous injections of 200 micrograms of (D-Ser[TBU]6-des-Gly-NH2(10] luteinizing hormone-releasing hormone ethylamide (Buserelin) for 5 days followed by 400 micrograms intranasally three times daily for 25 to 31 weeks. Serum follicle-stimulating hormone levels returned to basal values on the second day of treatment, and serum luteinizing hormone levels progressively decreased to normal within 4 weeks. Serum estradiol decreased below early follicular phase levels within 7 to 30 days and continued to decrease to castrate levels. Light to moderate estrogen withdrawal bleeding was followed by amenorrhea with occasional bleeding or spotting in four women. Abdominal pain and dyspareunia disappeared or were ameliorated after 2 months of treatment. Resorption of endometrial implants was demonstrated by laparoscopy, and endometrial biopsy revealed atrophy or weak proliferation. Ovulation returned within 45 days, and two of four sexually active women became pregnant during cycles 3 and 5. The treatment was well accepted in spite of the expected hot flushes and vaginal dryness. Safety laboratory tests during and after treatment did not reveal any abnormalities. Reversible down-regulation of pituitary/ovarian function using repetitive luteinizing hormone-releasing hormone agonist administration can be a worthwhile approach to medical treatment of endometriosis.

Intranasal and subcutaneous treatment of central precocious puberty in both sexes with a long-acting analog of luteinizing hormone-releasing hormone.

The chronic administration of the long-acting LHRH agonist analog D-Ser(TBU)6-LHRH-EA10 (HOE 766, Buserelin) suppresses pituitary gonadotropin secretion. Since a similar analog was shown to be effective in the short term parenteral treatment of idiopathic precocious puberty in girls (10), we used Buserelin both intranasally and sc to treat patients of both sexes with idiopathic and secondary central precocious puberty to test its efficacy, safety, and potential for long term use. Six girls and two boys presented with advanced skeletal maturity, accelerated growth velocity, Tanner stage II-IV pubertal development, and pubertal levels of sex steroids and gonadotropins. Patients were treated for 6 months sc and up to 5 months intranasally. Optimal doses ranged from 10-20 micrograms/kg X day in girls and 30 micrograms/kg X day in boys, with marked individual variation. During sc therapy, there was significant suppression of growth velocity (P less than 0.001), serum gonadotropins (P less than 0.001), 17 beta-estradiol (P less than 0.005), and testosterone as well as clinical and behavioral improvement. The rate of bone maturation was reduced. All effects were reversed after discontinuation of therapy for 1 month in one girl. No reduction in efficacy was seen after changing four girls and one boy to intranasal therapy, but improved acceptability and compliance were reported by parents. Apart from withdrawal bleeding in one girl and transient acceleration of puberty in two patients during the initial phase of treatment, no serious unwanted effects occurred. Antibodies to native LHRH were not detected after 6 months of therapy. These results confirm the efficacy and safety of Buserelin by intranasal and sc routes in patients with sexual precocity and indicate a need for long term studies.

Suppression of testicular steroidogenesis by the GnRH agonistic analogue Buserelin (HOE-766) in patients with prostatic cancer: studies in relation to dose and route of administration.

Forty-six patients with prostatic carcinoma received the gonadotropin releasing hormone agonistic analogue (GnRH-A) Buserelin at doses ranging from 0.05 to 1.5 mg subcutaneously and/or 0.4 to 1.2 mg intranasally (i.n.) daily for 12-120 weeks. An increase in plasma testosterone (T) was seen in 19% of patients on day 7 of therapy; with continuation of treatment plasma T as well as DHT and E2 levels fell by more than 50% within 2-4 weeks in those patients receiving greater than or equal to 50 micrograms s.c. and/or greater than or equal to 1 mg in daily dose. Persistently low plasma T levels (less than 1 ng/ml) were reached in 60% of patients receiving 50 micrograms s.c. in 89% of those treated with 1.2 mg i.n. and in 100% of patients who received initially 1.5 mg s.c. X 7 days followed by 1.2 mg i.n. daily. The above data indicate the importance of dose and route of administration in achieving significant suppression of plasma sex steroids in patients with prostate cancer in whom Buserelin can be used as an alternative to castration or estrogens.

New hormonal treatment in cancer of the prostate: combined administration of an LHRH agonist and an antiandrogen.

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.

Gonadotroph and corpus luteum responses to two successive intranasal doses of a luteinizing hormone-releasing hormone agonist at different days after the midcycle luteinizing hormone surge.

Two successive intranasal doses (300 micrograms at 8:00 A.M. and 6:00 P.M.) of the luteinizing hormone-releasing hormone (LH-RH) agonist (D-Ser[TBU]6-des-Gly-NH2(10))LH-RH ethylamide (Buserelin) were administered on days 1 to 10 after the midcycle luteinizing hormone (LH) surge in 33 normally cycling women. Maximal stimulation of gonadotropins was observed at 4 hours and was of higher amplitude in the first 2 days after the LH surge. The response to the second dose was markedly blunted, showing pituitary refractoriness. On each day of treatment there was a progressive increase of serum estradiol, which was maximal (threefold) 4 hours after the second dose of Buserelin. Serum progesterone (P) levels were not significantly changed on days 1 to 4, but they were increased by 50% at 10 hours on days 5 to 10. Daily blood samples revealed that following treatment on days 1 to 4 after the midcycle LH surge, serum P profiles were lower than in control cycles, without change in the length of the luteal phase. Starting on treatment day 5, a precocious luteolysis was induced, as illustrated by an early fall in serum P levels and shortening of the luteal phase (1 to 4 days). All posttreatment control cycles were normal. The results of this time study indicate that an appropriate treatment with an intranasal Buserelin administered at any time between days 1 to 10 after the midcycle LH surge impair luteal function and could lead to a new postcoital contraceptive approach.

Gonadotropins and estradiol responses to single intranasal or subcutaneous administration of a luteinizing hormone-releasing hormone agonist in the early follicular phase.

Single increasing intranasal and subcutaneous doses of a potent luteinizing hormone-releasing hormone (LH-RH) agonistic analog (D-Ser[TBU]6-des-Gly-NH2(10))LH-RH ethylamide (Buserelin) were administered on day 2 or 3 of the follicular phase in 59 normal women. Groups of five or six volunteers received intranasal doses ranging from 50 to 1300 micrograms and subcutaneous doses varying between 0.3 and 30 micrograms of the LH-RH agonist. Maximal amplitude of the serum gonadotropin response is observed at 6 hours. A sixfold increase is obtained for luteinizing hormone (LH) at a 200 micrograms intranasal dose, whereas maximal follicle-stimulating hormone (FSH) stimulation (threefold) is reached at a lower dose (100 micrograms). A 1000-micrograms dose elicits a more prolonged stimulation, levels of FSH and LH being two and five times above control levels at 11 hours. Similar response curves are obtained by the subcutaneous route, a maximal stimulation being reached at 3 micrograms for FSH and at 10 micrograms for LH. Serum estradiol levels are maximally increased at 11 hours after administration of 10 and 200 micrograms of the analog by the respective subcutaneous and intranasal routes. Twenty-four-hour response curves of gonadotropins indicate that the efficacy of the intranasal route is approximately 3% to 5% of the subcutaneous route. These observations should provide information useful in the investigation of the antifertility effects and medical treatments using an intranasal LH-RH agonist in the human being.

Intranasal LHRH agonist (Buserelin) after ovulation: a post-coital contraceptive approach.

PIP: 10 groups of 4-7 volunteers with regular menstrual cycles participating in 3 protocols were recruited from among 20-40 year old women with no risk of pregnancy for this study of the effect of the luteinizing hormone releasing hormone (LHRH) agonist Buserelin on the onset of pregnancy. 50, 100, 200, 500, 1000, and 1500 mcg doses of Buserelin were administered by a nasal spray device between days 6-12 after the luteinizing hormone (LH) peak. To study the effect of the LHRH agonist treatment on the possible onset of a pregnancy, Buserelin was administered at varying times before and during increasing injections of human chorionic gonadotropin (hCG) mimicking the beginning of pregnancy. The results of the dose-effect study indicated that the corpus luteum is sensitive to a single but high intranasal dose of Buserelin. Administration of 2 successive smaller doses at mid-luteal phases has the same effect and appears preferable. When administered early in the luteal phase, pharmacological doses of LHRH agonist impair the establishment of a normal corpus luteum function leading to luteal phase insufficiency without shortening of the luteal phase. When administered at mid-luteal phase, the LHRH agonist treatment induces luteolysis leading to precocious menses, providing an approach for postcoital contraception in normally cycling women. Preliminary data indicate that LHRH agonist treatment after ovulation could have antifertility effects when administered before implantation. LHRH agonist treatment is ineffective when administered late in the luteal phase concomitantly with the injection of increasing amounts of hCG. Treatment early after ovulation might possibly prevent implantation or lead to impaired secretion of hCG. The mechanism of action of the antifertility effects of LHRH and its analogs remains to be clarified, but several explanations are currently under investigation.^ieng

New hormonal therapy in prostate cancer: combined use of a pure antiandrogen and an LHRH agonist.

Treatment with an LHRH agonist (HOE-766) alone causes an almost complete blockage of testicular testosterone formation in rat and man. In order to neutralize androgens of adrenal origin, a pure antiandrogen (RU-23908) was given in combination with the LHRH agonist in the rat. At doses where each drug has no or minimal effect alone, prostate and seminal vesicle weight were reduced to 9 and 15% of control after 5 months of combined treatment, respectively. Among the species studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis. Near castration levels of serum testosterone and 5 alpha-dihydrotestosterone are obtained within 1-2 weeks of daily subcutaneous administration of the LHRH agonist [D-Ser(tbu)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) in adult men with cancer of prostate. The decrease in serum androgen levels is accompanied by objective remission of the cancer in approximately 75% of cases. In a preliminary study where the LHRH agonist was administered in combination with the pure antiandrogen RU-23908, it was shown that the antiandrogen does not interfere with the LHRH-induced inhibition of serum androgen levels. The ease of application of this new form of hormonal therapy should permit its use at early stages of the disease and thus reduce the development of metastases and androgen-resistant cell clones.

New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens.

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Transabdominal ultrasonography in the evaluation of patients with advanced prostatic carcinoma: effects of castration and of chronic administration of a gonadotropin releasing hormone agonistic analogue.

Twenty-two patients with advanced prostatic carcinoma were subjected either to orchiectomy (group I, n = 5) or to chronic administration of a gonadotropin releasing hormone agonistic analogue D, Ser (TBU)6, des Gly-NH2(10) LHRH nonapeptide (HOE 766) (group 2, n = 17). Plasma testosterone was similar in both groups prior to treatment (group 1: 636 +/- 129.29, group 2: 580.85 +/- 37.57; X +/- SE). The levels attained in group I were significantly lower (P less than .05) than those of group 2 through eight weeks of follow-up but were similar by the third month. Prostatic size (cm2) as estimated by transabdominal ultrasonography did not differ between the two groups prior to treatment (group 1: 23.6 +/- 3.35, group 2: 21.4 +/- 1.97; X +/- SE). Both therapies resulted in a decrease of prostatic size that was significantly more pronounced (P less than .05) in group I compared with group 2 by the first and third month; by the six month, there was no statistical difference in the prostatic size attained with either therapeutic modality. Persistent suppression of prostatic size was documented in all patients of group 2 chronically (up to 24 months) treated with HOE 766 even when there was evidence of uninhibited or progressive bony metastases. The above data 1) indicate the efficacy of the HOE 766 in inducing medical castration and prostatic shrinkage in advanced carcinoma of the prostate, 2) document the usefulness of transabdominal ultrasound in the follow-up of such patients, and 3) suggest a relationship between the rapidity of tumor shrinkage and Leydig cell suppression.

Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma.

We have used the paradoxical antigonadal effects of LHRH agonists as a chemical castration in advanced prostatic cancer. We report early results of a phase II study on the clinical efficacy of the LHRH agonist D-Ser (TBU)6, des-Gly-NH2(10) LHRH administered to patients with stage D prostatic carcinoma. Following dose-range finding studies using either intranasal (IN) (200 micrograms twice/day or 500 micrograms twice/day) or subcutaneous (SC) administration (50 micrograms once/day, we developed a sequential combination of SC (500 micrograms three times/day for seven days) and IN regimen that was administered for 3 to 16 months to a group of 23 patients with stage D prostatic carcinoma. Initiation of therapy was associated with a clinical flare in one patient during the first week of treatment. Mean serum testosterone levels were already decreasing at one week and remained inhibited to levels inferior to 1 ng/ml after the first four weeks of treatment. Overall assessment shows that within the first six months of treatment, 26% patients were improved, 39% were stabilized, and 35% were nonresponders. Fourteen patients were followed during the next six months: 29% continued to respond, 29% escaped, 21% remained stable, and 21% were nonresponders. Histologic studies from castrated patients showed changes in spermatogenesis correlating to the degree and duration of suppression of testicular steroidogenesis without signs of toxicity. Preliminary observations on the combination of the pure antiandrogen RU 23908 with Buserelin (n = 5) or castration (n = 3) suggest that the addition of an antiandrogen does not seem to improve the patients nonresponding to other hormonal suppressive therapy (Buserelin) administered before (n = 3) or concomitantly with the antiandrogen (n = 2). Three relapsing castrate patients responded to the antiandrogen, but the response was temporary in two (eight to nine months of therapy). No side effects other than hot flashes and decreased potency are related to LHRH agonist alone or to the low-dose antiandrogen. Multicenter trials will be necessary to delineate the place of LHRH agonist alone or LHRH agonist combined with an antiandrogen in the treatment of prostatic cancer.

Sensitivity of luteinizing hormone and gonadal steroid responses to single intranasal administration of an LHRH agonist (Hoe-766) in young normal adult men.

PIP: While intranasal administration of the potent LHRH agonist [D-Ser (TBU)6, des-Gly-NH210] LHRH ethylamide, Hoe-766, at the doses of 50 or 100 mcg, has little effect on serum luteinizing hormone (LH) levels, doses of 200, 500, 1250, or 2500 mcg cause a rapid and marked stimulation. A near-maximal effect is seen at 30 minutes with a 4- to 5-fold stimulation of serum LH concentration. A progressive increase in serum testosterone (T) levels is observed on the day of treatment with doses of 200 mcg and higher of the LHRH agonist with an effect lasting for 24 hours at the 2 highest doses used. The increase in serum T levels at the 3 highest doses of Hoe-766 is followed by a decrease of androgen levels during the 1st-3rd posttreatment days. This temporary decrease of serum T levels is followed by a return to normal diurnal cyclicity and levels at later time intervals. An almost superimposable pattern is observed on serum 170H-progesterone levels: increase of serum levels lasting for up to 24 hours followed by loss of diurnal cyclicity and low concentration during the 1st-3rd posttreatment days. Plasma 17beta-estradiol concentrations are increased for 48 hours after administration of the 2 highest doses of Hoe-766 with a return to normal at later time intervals. The present data show that near-maximal stimulation of serum LH levels as well as 170H-progesterone, testosterone, 17beta-estradiol secretion can be achieved by doses of Hoe-766 ranging between 200-500 mcg by the intranasal route. Moreover, doses of Hoe-766 leading to a stimulation of LH and androgen secretion cause a transient loss of diurnal cyclicity and low levels of circulating T and 170H-progesterone lasting for 1-3 days with a complete return to normal at a later time. It is suggested that intranasal doses of Hoe-766 could be used chronically to inhibit androgen secretion in men for treatment of androgen-dependent diseases such as cancer of the prostate and benign prostatic hyperplasia.^ieng

Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists.

Ten patients with prostatic carcinoma--six with stage C and four with stage D disease--were treated for 6 weeks to 12 months with agonistic analogues of luteinizing hormone-releasing hormone (LH-RH). [D-Trp6]LH-RH was given subcutaneously once daily at a dose of 100 microgram and [D-Ser(But)6]des-GlyNH2(10)-LH-RH ethylamide (HOE 766) was given subcutaneously (50 microgram once daily) or intranasally (500 microgram twice daily). In all patients, mean plasma testosterone levels showed a 75% suppression by the third week of treatment and remained low thereafter. This was followed by a decrease or normalization of plasma acid phosphatase levels by the second month of treatment and a 47% decrease in serum alkaline phosphatase by the 10th week of treatment in all but one patient. In patients with stage C disease presenting with prostatism or urinary outflow obstruction, there was a noticeable clinical improvement. In two such patients, a decrease in the size of the prostate was confirmed by ultrasonography. In patients with stage D disease manifested by diffuse bone metastases, there was relief of bone pain, and in one patient treated for greater than 12 months the improvement was documented by radioisotope bone imaging. It is concluded that superactive agonistic LH-RH analogues hold promise as therapeutic agents in patients with androgen-sensitive prostatic adenocarcinoma. Furthermore, the analogous of LH-RH may be used to assess the responsiveness of patients to surgical castration. Long-term administration of LH-RH analogues could become an alternative to surgical castration and estrogen therapy for the treatment of hormone-dependent prostatic carcinoma.

New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen.

In order to block the influence of androgens from all sources on the growth of prostatic cancer, we have used a new hormonal therapy based on medical castration achieved with the potent LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) combined with the administration of a pure antiandrogen that neutralizes the action of adrenal androgens as well as those still secreted in low amounts by the testis during LHRH agonist treatment. This study was performed in ten patients with advanced prostatic carcinoma (9 at stage D2 and one at stage C). Bone pain, prostatism and general well-being were 60 to 90% improved within one month after starting treatment in all patients. After 2 months of treatment, minimal bone pain remained only in one patient who was originally bedridden. Bone scanning showed a 70 to 90% decrease in uptake after 3 to 5 months of treatment in the patients studied. Acid phosphatase levels were 60 to 90% reduced after 2 months of treatment in 3 out of the 4 patients who had elevated levels before therapy. Marked objective and subjective improvement was thus rapidly observed in 9 out of 10 patients treated with the combined therapy, while, in the other patient at stage C, subjective improvement could be documented. Although preliminary, this study indicates that a combined hormonal therapy which neutralizes all androgenic influences on peripheral tissues is of potential benefit in prostatic cancer. Moreover, the ease of application as well as the lack of secondary effects of the present approach should make possible its use early in the disease and should thus minimize the development of metastases and androgen-resistant cell clones. Randomized prospective studies on this potentially beneficial therapy are warranted.