Heterogeneity of prolactin and TSH response to TRH in hypotonadotropic hypogonadism.

To evaluate prolactin and TSH secretion in isolated gonadotropin deficiency, thyrotropin-releasing hormone (TRH), in a dose of 500 microgram, was administered iv to fifteen male subjects with this disorder. In 4 out of 8 untreated patients, TRH-mediated prolactin release was significantly blunted and this attenuated response was not improved in one patient after treatment with testosterone for 1 year. In 7 patients who were treated with testosterone for 2 to 8 years, four failed to show a normal prolactin response after TRH injection. TRH-induced TSH secretion, on the other hand, was attenuated in two out of 8 untreated and in two of 8 treated patients with hypogonadotropic hypogonadism. The decreased TSH reserve was not necessarily associated with the poor prolactin response to TRH. It was concluded that heterogeneity exists in TRH-mediated prolactin and TSH release in "isolated" gonadotropin deficiency syndrome.

Prepubertal XY gonadal dysgenesis.

Two children had prepubertal XY gonadal dysgenesis. A 7-year-old girl with clitoral enlargement had a left ovarian tumor that contained a dysgerminoma; the right gonad proved to be a gonadoblastoma. The second child (a 2-year-old girl) showed poor physical development and slight virilization of the genitalia. Her bilateral dysgenetic gonads were removed at exploratory laparotomy. The occurrence of gonadal tumors in XY gonadal dysgenesis is increased. It is probably related to the hypergonadotropinism existing from childhood as well as to genetic predisposition of the cryptorchid testis in the presence of a Y chromosome. Our first patient is one of the youngest who had XY gonadal dysgenesis iwth gonadoblastoma reported. The indication of prophylactic gonadectomy in XY gonadal dysgenesis is emphasized.

LH-RH agonist, Zoladex (Goserelin), depot formulation in the treatment of prostatic cancer. Randomized dose-finding trial in Japan.

Ninety patients with advanced prostatic cancer (15 with stage B, 23 with stage C, and 52 with stage D) were randomized to receive 0.9, 1.8, or 3.6 mg, respectively, of Zoladex depot subcutaneous injection every 28 days for 12 weeks. The serum levels of LH, FSH, and testosterone were elevated after the first injection, and followed by a significant decrease. The suppression of testosterone levels in the blood to castrate levels was observed in all patients except two treated with 0.9 mg. Objective response (CR and PR) was seen in 63.6% (0.9 mg), 47.8% (1.8 mg), and 68% (3.6 mg) of patients according to the Japanese Prostatic Group Criteria. Subjective improvement (performance status, analgesic consumption) was also observed in 75-88% of patients but without a statistically significant difference between each dose group. Only minor adverse effects were found during the treatments. The drug was detected dose dependently in the blood by radioimmunoassay. These results suggest that endocrine therapy with Zoladex depot in doses of 3.6 mg subcutaneously every 4 weeks is a useful alternative to surgical castration in patients with prostatic cancer.

Leuprorelin acetate depot: results of a multicentre Japanese trial. TAP-144-SR Study Group.

The clinical efficacy and safety of 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks was evaluated in a collaborative study of 81 patients with untreated prostatic cancer. Efficacy of treatment was assessed using criteria based on a meeting of the Prostatic Cancer Study Group funded by the Japanese Ministry of Health and Welfare and using National Prostatic Cancer Project criteria. Japanese criteria enabled evaluation of individual parameters, unlike the National Prostatic Cancer Project system which classified a patient as unevaluable if one evaluation parameter was unavailable. Leuprorelin acetate depot suppressed serum luteinizing hormone, follicle stimulating hormone and testosterone concentrations. Objective response rates of the prostate, bone metastases, serum prostatic acid phosphatase and soft tissue metastases, and subjective dysuria and pain responses were comparable to those found with conventional hormone therapy. Leuprorelin acetate depot was well tolerated, with no significant differences in response to the two doses.

[Retroperitoneal lymph node dissection for patients with advanced testicular tumor].

We examined the indication for retroperitoneal lymph node dissection (RPLND) for 30 patients with advanced testicular tumor and made the following conclusion. The sequence of RPLND and primary chemotherapy made no difference in the therapeutic effect for patients with stage II A non-seminomatous germ cell tumor (NSGCT). However, we thought it better to administer primary chemotherapy prior to RPLND to prevent dissemination of tumor cells. Viable tumor cells often remained in retroperitoneal residual tumors even after chemotherapy in the patients with NSGCT advanced beyond stage II B. Therefore, RPLND seemed to be necessary if residual retroperitoneal tumors were found after the chemotherapy. In patients with seminoma, RPLND did not seem to be necessary if the residual tumor was less than 3 cm in diameter or the reduction rate of the retroperitoneal tumor was more than 80% after the initial therapy (chemotherapy or irradiation therapy.

[Treatment of prostatic cancer with intranasal administration of LHRH analog, Buserelin (Hoe 766) study of the optimum dosage of intranasal application].

Patients with pathologically defined prostatic carcinoma (114 cases in 23 institutes) were subcutaneously administered 500 micrograms of Buserelin (Hoe 766) 3 times a day for 7 consecutive days, then randomized to intranasally administered 600 or 900 micrograms/day of Buserelin as maintenance treatment. We examined the clinical efficacy, safety and endocrinological effects of the drug by the intranasal dosage. Size of prostate decreased more than 25% in 21 cases (total 47 cases; measured at the start and 3 months treatment by ultrasonography. Complete response and partial response were observed in 13 cases (16.1%) by NPCP's criteria at 3 months Buserelin treatment. Grobal Improvement Rating (GIR) were respectively 64.3% (600 micrograms group) and 68.0% (900 micrograms group). Grobal Utility Rating (GUR) were respectively 85.7% (600 micrograms group) and 82.0% (900 micrograms group). No significance was observed in these two groups. Adverse reactions were observed in 21 cases (18.9%). Except in 1 case, they were slight and the Buserelin treatment could be continued. Objectively Safety Rating (OSR) was 92.8%. Five cases were treated for more than 2 years with Buserelin and these cases were well controlled. Buserelin was considered as an effective and safe drug to treat prostatic carcinoma.

[Coexistence of cyst and tumor in the same kidney: a case report].

A case of renal cyst associated with renal tumor is presented herein. A 40-year-old male patient visited our outpatient clinic for left renal cyst which had been found by ultrasonography on routine clinical examination. CT scan demonstrated an irregular area in the cyst wall measuring about 2 cm in thickness which showed enhancement of density with contrast medium. Magnetic resonance imaging (MRI) also demonstrated a round mass with abnormal signal on the cyst wall, protruding into the cyst cavity. Transabdominal radical nephrectomy was performed on 13 July 1987, and to the resected kidney was attached a cyst measuring 7 cm in diameter in the lower pole. Grossly, the cyst contained amorphous red-brown material which turned out to be old blood clots and the wall harbored a tumor (3.0 x 2.5 cm). Histologically, the tumor was renal cell carcinoma, the surface of which was covered with necrotic tissue. The coexistence of renal cyst and tumor is rare and 62 cases were collected from the Japanese literature including our case, and discussion was made in relation to the etiological factors.

[Transurethral removal of the ureter by the intussusception method in the treatment of renal pelvic and ureteral tumors].

Between August 1986 and December 1998, 19 patients who had renal pelvic and upper ureteral tumors were treated with nephrectomy and transurethral removal of the ureter using the intussusception method. Removal of the ureter failed in 5 patients because of excessive ablasion of the ureter or insufficient electro-resection around the ipsilateral ureteral orifice. Excluding those patients, the safety of the operation and the intravesical recurrence were compared with the outcome in 12 patients undergoing partial cystectomy for similar tumors. The mean operating time was not significantly shorter with the intussusception method compared with partial cystectomy (190.4 versus 251.3 minutes), but the mean blood loss was significantly smaller (187.5 versus 460.2 ml) and the intussusception method did not require a blood transfusion. The mean term of hospitalization was 20.3 days for patients treated by the intussusception method which was significantly shorter than that for patient undergoing partial cystectomy (25.4 days). Intravesical recurrence was found in seven patients (50%) treated by the intussusception method and the 1- and 5-year recurrence-free rates were 69.2% and 30.8% respectively. There was no significant difference in the recurrence-free rates between the two surgical techniques. These results suggest that the intussusception method is superior to partial cystectomy in decreasing the operating time, blood loss and term of hospitalization. It can be an attractive option in selected cases, without increasing the risk of intravesical recurrence.

[Metastatic renal tumor originating from esophageal carcinoma: a case report].

We report a case of renal metastasis from esophageal carcinoma. The patient was a 74-year-old man, who had undergone an operation for esophageal carcinoma thirteen months previously. He was admitted to our clinic for examination of a right renal mass. Computed tomography (CT) revealed an irregular low density area in the right kidney and angiography showed a hypovascular tumor. Partial nephrectomy was performed. Histological examination revealed squamous cell carcinoma and the diagnosis was metastasis of esophageal carcinoma. Metastatic renal tumors are rarely encountered clinically and, to our knowledge, the present case is only the 16th clinical report of the renal metastasis of esophageal carcinoma in Japan. However, metastasis to the kidney is relatively common at autopsy. It is the fifth most common site of metastasis following the lungs, liver, bones and adrenals. Consequently, patients with malignancy should be followed up while keeping renal metastasis in mind.

[The efficacy and safety of terazosin and tamsulosin in patients with urinary disturbance accompanying prostatic hypertrophy].

Terazosin (TE) and tamsulosin (TA) were allocated randomly to 38 patients who had urinary disturbance accompanying prostatic hypertrophy, and the efficacy and safety of the drugs were examined. Subjective symptoms due to I-PSS were improved significantly in both TE and TA groups. On the other hand, objective symptoms such as the maximum urinary flow and mean urinary flow were improved more in the TE group. TE showed hypotensive and cholesterol-decreasing effects in patients who also had hypertension and hyperlipemia. No unknown adverse reactions were observed in either groups, and the drugs were shown to be highly safe. TE was considered to be useful as the first choice drug for the patients with hypertension and or hyperlipemia and those with severe objective symptoms. TA was considered to be useful for the patients with impaired drug compliance or those with severe subjective symptoms though objective symptoms were not so severe.

[A case of ureterovesical malacoplakia that manifested hydronephrosis].

A 70-year-old woman visited a nearby physician with a chief complaint of fever and was admitted to a hospital with a diagnosis of acute pyelonephritis. After discharge, pyuria persisted and examination revealed an intravesical solid tumor. The patient was referred to this department for close examination and treatment. The right kidney was hydronephrotic. The intravesical tumor that was resected was solid yellowish-white and ranged from the neck of the uterus to both ureteral orifices. In addition, a grain-sized tumoral lesion, was found in the lower part of the ureter and was also resected. There was sclerotic thickening localized to the right intramural ureter, which had a slightly edematous interior. This was considered to be the cause of the hydronephrosis and a ureteral stent was put in place. Pathological diagnosis was given as malacoplakia. With this case, placement of a ureteral stent was chosen based on the findings of a minimal ureteral lesion, a narrow area of scarring in the intramural ureter as a probable cause of hydronephrosis, and a judgement of mild obstruction. A stent is less invasive for patients, but consideration should be given to urinary infection due to long-term placement recurrence of malacoplakia due to the increased risk of infection, and trouble with periodical exchanging of catheters due to aggravated scarring. Absence of pyuria or signs of recurrence after seven months' placement suggests that use of the stent was the best method.

[A case of emphysematous cystitis].

Emphysematous cystitis is a rare lower urinary tract infection. Patients with diabetes mellitus, neurogenic bladder, and recurrent urinary tract infection are generally at higher risk of this disease. A 71-year-old woman with neurogenic bladder was referred from the internal medicine department because of urinary retention. Abdominal radiography and computed tomographic (CT) scanning revealed a characteristic accumulation of air in the wall and lumen of the urinary bladder. Emphysematous cystitis was improved by antibiotic therapy and urinary drainage. CT scan was a sensitive method for detecting early signs and confirming the diagnosis.

[Endocrine therapy of prostatic carcinoma with slow release (depot) formulation of the LH-RH analog ICI 118630 (Zoladex)].

To investigate the clinical efficacy, safety and endocrinology of ICI 118630 (Zoladex) depot formulation at 3 different dose levels (0.9, 1.8 and 3.6 mg), 90 patients were randomized to receive either one of the 3 doses from April, 1985 to March, 1986 in 28 centers. The depot preparation was injected subcutaneously every 4 weeks 3 times (for up to 12 weeks). Clinical efficacy was evaluated in terms of tumor response and overall subjective response. In 70 patients eligible for tumor response evaluation, 14 out of 22 (63.6%) in the 0.9 mg group, 11 out of 23 (47.8%) in the 1.8 mg group, and 17 out of 25 (68.0%) in the 3.6 mg group showed clinical improvement, that is, either complete response or partial response. In 72 eligible patients for overall subjective response evaluation, clinical subjective improvement was observed in 75.0, 81.8 and 88.0% of the patients in the 3 groups, respectively. There was no significant difference between the groups. As for endocrinology, there were 75 eligible patients. Endocrinological effect was observed in 23 out of 25 (92.0%) in the 0.9 mg group, 100% in both 1.8 mg and 3.6 mg groups. There was no significant difference between the groups. Castration was achieved by week 3.5 +/- 1.7 of therapy on average and by week 2 in the earliest case. There was no significant difference in incidence of side effects between the 3 groups: 5 out of 26 (19.2%) in the 0.9 mg group, 8 out of 29 (27.6%) in the 1.8 mg group, and 2 out of 30 (6.7%) in the 3.6 mg group. Flares presented as an increase in bone pain in 2 and as ureteric obstruction in 2 all in the 1.8 mg group but none in the other 2 dose groups. These flares disappeared on further treatment with Zoladex. These patients showed a clinical-response. The blood level of Zoladex was dose dependent, reaching its peak at week 2 of therapy in all 3 dose groups. There was no evidence of accumulation. Since these results demonstrate that 3.6 mg produces medical castration earlier, it may well be considered as an optimal dose in men.

[Clinical experience with single and multiple subcutaneous administration of LHRH analog Buserelin (Hoe 766) in prostatic carcinoma: endocrinological study of optimum subcutaneous doses].

Seventy three patients with prostatic carcinoma (PC) and 7 patients with benign prostatic hypertrophy (BPH) in 12 institutes subcutaneously received single and multiple doses of Hoe 766, and clinical efficacy, safety and endocrine effects of drug were examined. In a single doses study, six doses were subcutaneously administered to 7 BPH and 3 with PC. Gonadotropin and testosterone levels in the blood were increased following all these doses. In a multiple study, 7 kinds of doses were given to 40 patients with PC. The optimum doses of subcutaneous injection was decided to be 500 x 3 micrograms/day based on gonadotropin and testosterone suppression. Objective response by NPCP's criteria was observed in 35.3% (complete response 5.9%, partial response 29.4%) following 3 months of Hoe 766 treatment. Adverse reactions were observed in 9 cases (12.8%): Treatment was discontinued in 3 cases (eruption in 2, nausea and vomiting in 1), and continued in 6 cases (8.6%) without any treatment required. Buserelin was thus considered to be an effective, safe drug to treat prostatic carcinoma.

[Hypothyroidism followed by interferon-alpha as adjuvant therapy of renal cell carcinoma: a case report].

A 58-year-old male patient was admitted to the hospital complaining of weight loss. Abdominal computerized tomographic (CT) scan disclosed a mass shadow in the left kidney. From the results of further examination, including drip infusion pyelography (DIP) and angiography, he was preoperatively diagnosed as having a left renal tumor. Left radical nephrectomy was performed on March 15, 1990. The lesion was histologically diagnosed as renal cell carcinoma (clear cell subtype, grade 2) confined by the renal capsule (stage I). No distant metastases were detected. Interferon-alpha was administered every other day as adjuvant chemotherapy. After the patient experienced muscle pain in his thighs and shoulders after exercise on February 11, 1991, the serum creatine phosphokinase (CPK) level progressively increased up to 2,329 U/l. On the basis of the results of various examinations reflecting thyroid gland function, he was diagnosed as having primary hypothyroidism due to Hashimoto's disease. Thyroid function improved after administration of triiodothyronine and thyroxine. Interferon has been reported to influence thyroid function, and, in this case, interferon-alpha therapy may have induced the primary hypothyroidism associated with Hashimoto's disease.

[Effects of etretinate on spermatogenesis and endocrine parameter function in man].

Nine adult men with psoriasis were treated orally with 50-75 mg/day aromatic retinoid, etretinate for more than 3 months. Semen analyses as well as measurement of serum levels of LH, FSH, prolactin, testosterone and estradiol were performed before and every month during the therapy for 3 months or more in order to study the effects of the drug on male reproductive function. Average sperm concentration at 2 months after the treatment by the drug was higher than the untreated value, although this was statistically not significant due to greater variations. Decrease in sperm count during the therapy was observed only in one patient. Sperm concentration of this case, however, was recovered and increased to higher levels after 6 months on the drug. No change was found in other semen parameters including sperm morphology. All hormone levels remained unchanged except for prolactin which increased. We conclude that etretinate did not cause suppression of spermatogenesis nor impairment of sperm motility or morphology as far as shown by the present observation periods.

[Clinical phase I and phase II study on a sustained release formulation of leuprorelin acetate (TAP-144-SR), an LH-RH agonist, in patients with prostatic carcinoma. Collaborative++ Studies on Prostatic Carcinoma by the Study Group for TAP-144-SR].

TAP-144-SR is a sustained release formulation of an LH-RH agonist, leuprorelin acetate (TAP-144), that has been newly developed in Japan. As a phase I study, a single subcutaneous dose of TAP-144-SR was given to 15 patients with prostatic cancer to investigate the safety, endocrinological effects, and serum levels of the drug. The patients were divided into four groups according to the dosage levels of 1.88 mg, 3.75mg, 7.5 mg and 15 mg. No serious side effects were noted in any of the patients treated with any dose. No patients exhibited signs of a local reaction at the site of injection. In two patients transient exacerbation of clinical symptoms owing to "flare up" was observed. Serum testosterone levels decreased to the castration level (less than 1.0 ng/ml) in all of the patients, although the time required to attain the castration level tended to be longer in the patients receiving 1.88 mg. Serum TAP-144 levels increased on the first day and gradually decreased thereafter. In the groups of patients that received 3.75 mg or more of TAP-144-SR, TAP-144 was detected in the serum up to 4 weeks after administration. Based on the results of the phase I study, 3.75 mg and 7.5 mg of TAP-144-SR were selected as the doses for the phase II study. The phase II study was carried out as a multi-center open trial. Patients with stage B-D prostatic cancer received subcutaneously either 3.75 mg (3.75 mg group) or 7.5 mg (7.5 mg group) of TAP-144-SR once every 4 weeks for a total of 3 doses over a period of 12 weeks. TAP-144-SR 3.75 mg was administered to 51 patients and 7.5 mg to 50 patients. Both of these doses were adequate to suppress serum LH and FSH levels. Serum testosterone was decreased to the castration level within 22 days after the first dose, and this suppression was maintained throughout the treatment period. Clinical response rate (CR + PR) was 21% in the 3.75 mg group and 22-24% in the 7.5 mg group according to the Criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria. The response rate by the criteria of Japanese Prostatic Cancer Study Group was 51% in the 3.75 mg group and 62% in the 7.5 mg group. Adverse reactions were noted in 26% of patients in the 3.75 mg group and 34% in the 7.5 mg group.(ABSTRACT TRUNCATED AT 400 WORDS)

[Male pseudohermaphroditism].

Male pseudohermaphroditism (MPH) is a complex variety of sexual differentiation disorders characterized by deficiency of masculinization of the internal and/or external genital organs in the presence of testicular development as the male gonad. This condition is caused by embryonic failure in the processes of male sexual development, which is a sequence of mechanisms originating from the genetic sex determination triggered by the SRY gene on the Y chromosome, followed by genital sex differentiation influenced by the fetal testis. Resulting phenotypical features of MPH vary from complete female to mostly normal but with some ambiguity in the maleness. Pubertal changes are also important factors related to etiology. Recent elucidation of detailed mechanisms of male differentiation and its derangements has been achieved in the era of molecular genetics. Classical classification of MPH, mainly based on anatomical and endocrinological findings obviously needs to subject to a complete revision. The newest version of MPH classification is reviewed and discussed in relation to etiological backgrounds of each type of the disorder. Main etiological factors are: failure of the SRY and its related genes involved in the testis determination; failure of anti-mülerian hormone (AMH) for normal involution of the female duct system; disordered production or function of androgen receptors essential for the fetal differentiation of the male genital organs; 5 alpha-reductase deficiency syndrome; defective responsiveness of the testis to gonadotropin due to Leydig cell agenesis; various types of enzyme defects involved in testicular androgen biosynthesis; fetal testicular dysgenesis syndromes occurring at various stages of embryogenesis; and other less clearly defined entities of MPH. Implications are that other types of sexual differentiation disorders than MPH, such as true hermaphroditism, gonadal dysgenesis and some other disorders that have been considered to be distinct entities, may have close linkage to MPH through dysgenetic process of gonadal development with subsequent degeneration and/or tumorigenesis. Molecular basis of these probably related disorders should be elucidated in the near future and some clues to preventive measures for these genetically determined malformations are awaited.

[Testicular endocrine function in patients with prostatic cancer receiving medical castration by long-term administration of LH-RH agonists].

Six patients with advanced prostatic cancer who had been treated by long-term administration of LH-RH agonistic preparations (Buserelin or Leupron) were tested for their pituitary-testicular endocrine functions. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL), estradiol (E2) and dihydrotestosterone (DHT) were measured consecutively. In all medically castrated patients, serum levels of LH, FSH, T, DHT and E2 were suppressed and particularly serum T levels were below the castration level of 1.0 ng/ml. On the other hand, serum PRL levels were unchanged after the long-term treatment with the agonists. Serum LH and FSH levels failed to respond to LH-RH stimulation after the treatment, whereas serum T responded to stimulation by human chorionic gonadotropin (hCG) to various degrees. It was remarkable that, in 4 out of 6 medically castrated patients treated up to more than 3 years, serum T response levels above 1.0 ng/ml were noted. It is suggested that testicular endocrine function to secrete T and DHT in patients under treatment with long-term LH-RH agonist administration are still preserved in response to hCG stimulation.

[A case of thymoma associated with prostatic cancer].

A case of prostatic cancer treated with an LH-RH analogue depo-preparation was found to have a mediastinal thymoma which was later removed by surgery. The association of thymoma and prostatic cancer has not been documented in the world literature, and it remains to be elucidated whether the occurrence of the both tumors is a coincidence or etiologically inter-related.