Administration of agonistic and antagonistic analogues of LH-RH induce anovulation in Macaca fasicularis

This study was designed to compare the effects of [N-Ac-D-Trp^1,3, D-p-Cl-Phe², D-Phe⁶, D-Ala¹⁰] (A-LH-RH), an inhibitory analogue, and D-Trp⁶-LH-RH, an agonist of LH-RH, administered to normally cycling cynomologous monkeys. Animals were divided into three groups (n = 5 each), each group receiving one of the following daily during the first 25 days of the menstrual cycle: 1) 20 μg of D-Trp⁶-LH-RH daily. 2) 1 mg of A-LH-RH, and 3) vehicle. Ovulation was established by serial laparoscopies and serum estradiol measurement. Controls presented normal cycles, as evidenced by ovulation day, luteal phase length and hormone levels. Ovulation was completely inhibited during drug administration in all animals of groups 1 and 2. Luteal phase length of all monkeys that ovulated was normal. The present data, therefore, not only show evidence for a consistent anovulatory effect of agonistic and antagonistic analogues of LH-RH in non-human primates, but also open a new approach for non-steroidal contraception.     

The GIFT experience: an evaluation of the outcome of 115 cases

The outcome of a series of 115 patients undergoing GIFT by minilaparotomyis described, their duration of infertility ranging between3 and 19 years. Ovarian stimulation was carried out using clomiphenefrom day 3 and HMG from day 6, and HCG was used to induce follicularmaturation. A maximum of four oocytes, two per oviduct with100 000 spermatozoa, were replaced. Thirtysix pregnancies wereestablished. The highest incidence of pregnancy was obtainedin cases of unexplained infertility (42%) and endometriosis(28%), and the lowest with male factors (13%). The most matureoocytes gave the best results. There were eleven miscarriages(30.5%) and two ectopic pregnancies (5.5%). Eleven of the 23deliveries involved multiple births.     

Studies on chorionic gonadotrophin hormone in rhesus monkeys--disappearance rates

The disappearance rate of macaque chorionic gonadotrophin (MCG)was investigated in six pregnant monkeys. The animals were hysterectomizedwith a rapid initial ligature of the uterine and ovarian vesselswith minimal uterine manipulation. The entire procedure lasted<2 min. Blood samples were drawn before and after the hysterectomy(5, 20, 30, 45, 60, 90, 120 min), and MCG was measured in serumby radioimmunoassay. For all animals, a progressive decrease(rate of disappearance) of MCG values in serum was found, whichappeared to follow a double exponential curve. Averaged curvesproduced disappearance rates of T ¹ = 17.2 h for the first compartment(72 h), and TT 22= 87.1 h for the second compartment (156 h).The results suggest that the disappearance of MCG after interruptionof pregnancy in the rhesus monkey is very similar to that occurringin humans. These data demonstrate that the rhesus monkey isan excellent animal model to study the dynamics of placentalhormone secretion in humans     

Temporal changes in FSH and LH concentrations following the administration of a potent LH-RH inhibitory analogue ( [N-Ac-D-Trp1, 3, D-p-Cl-Phe2, D-Phe6, D-Ala10]-LH-RH) to oophorectomized rhesus monkeys

A series of studies was performed in order to assess the antigonadotropic potency of an inhibitory analogue of LH-RH (IA-LH-RH) ( [N-Ac-D-Trp1, 3, D-p-Cl-Phe2, D-Phe6, D-Ala10]-LH-RH) in oophorectomized rhesus monkeys. I) Single administration of 1 mg IA-LH-RH im resulted in a prompt and significant decrease of serum levels of FSH and LH which lasted for at least 24 h. A specific rebound of serum LH to higher concentrations than baseline occurred in all animals at +48 or +72 h. II) Exogenous LH-RH at a dose of 150 micrograms was administered iv 2 or 18 h after the injection of 1 mg IA-LH-RH. Blood was drawn at 0, 10, 20, 30, 60, 120 and 180 min post LH-RH. The rise in LH and FSH levels observed in the control animals was not altered when LH-RH was administered 2 h after the antagonist, but it was significantly inhibited and delayed when LH-RH was given 18 h after the LH-RH inhibitory analogue. These results show that antagonistic analogues of LH-RH are potent inhibitors of gonadotropin concentrations in non-human primates. Their potential use in conditions in which inhibition of gonadotropin secretion and/or release is desired is discussed.     

Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10]-LH-RH) in the rhesus monkey

Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12 h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12 h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.     

Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.     

Volume Contents

Intramedullary tumors are rare, accounting for only about 4% of all CNS neoplasms. Although surgery represents the most effective treatment, recurrence may occur. As a large proportion of intramedullary malignancies occur in children, who are more sensitive to the deleterious effects of irradiation, chemotherapy assumes an important role. This article describes the most common intramedullary tumors and the role of chemotherapy.     

Tubal embryo transfer as a treatment for infertility due to male factor

Transvaginal follicular aspiration (TVA) with ultrasonically guided needles allows the transfer of in vitro generated embryos to the fallopian tubes (TET), performing only one surgical procedure in the process. Up to now, this approach has been used to treat 16 couples with infertility due to severe male factor. Follicular development was induced with a combination of clomiphene citrate and human menopausal gonadotropin (hMG) or follicle-stimulating hormone and hMG. Follicles were aspirated by TVA 36 hours after an injection of human chorionic gonadotropin 10,000 IU intramuscularly. A total of 169 oocytes were recovered (10.5 +/- 6.9 X +/- SD) from the 16 patients. There was failure of fertilization in 6 cases. In the remaining 10, a TET was performed 44 to 50 hours after TVA, utilizing embryos at the pronuclear stage. Six pregnancies resulted from the 10 transfers. This technique combines the advantages of proof of fertilization with a more adequate tubal embryo development and entrance to the uterine cavity that may determine and increase chance of implantation.     

Mini-Percoll: a new method of semen preparation for IVF in severe male factor infertility

Conventional methods of semen preparation for IVF, such as swim-up sedimentation, regular Percoll gradients, are not very effective in the treatment of severe oligoasthenozoospermia (total motile count less than 5 X 10(6)). For these cases, a new method of sperm preparation consisting of a reduced volume of a discontinuous Percoll gradient (mini-Percoll) has been utilized. The results obtained were analysed by comparing mini-Percoll versus resuspension in two groups of patients with severe male factor infertility. In the mini-Percoll group, a statistically significant improvement (P less than 0.001) was obtained in the post-treatment seminal parameters of motility, progression and proportion of normal forms. In the resuspension group (n = 12), only eight of 108 oocytes inseminated were fertilized (7%), while in the mini-Percoll group (n = 29), 124 out of 336 oocytes were fertilized (40%) (P less than 0.001). Furthermore, in the mini-Percoll group, a higher pregnancy rate (25 versus 7%) and low abortion rate (22 versus 33%) were observed. Although more studies are necessary to confirm these preliminary data, mini-Percoll seems to be a valid laboratory tool for semen samples of extremely poor quality.     

Optimisation of sonourethrography: the clamp method

Purpose

To describe the clamp method for performing retrograde sonourethrography (RSUG) and contrast-enhanced voiding sonourethrography (CE-VSUG) via the transperineal approach in male adults.

Materials and methods

Prospective study of 113 males (14-86 years) with urethral strictures confirmed by urethrography who received sonourethrography via the clamp method between 2011 and 2015. The characteristic parameters of the quantitative variables were calculated and a comparative analysis of the qualitative variables was conducted using the McNemar test.

Results

RSUG was performed successfully in all the cases (n = 113) and detected 49 cases with anterior urethral strictures; the strictures in the proximal bulbar cone in five of them (10.2%) were not visualised on retrograde urethrography (RUG) (p < 0.05). CE-VSUG was performed successfully in 97 cases and observed posterior urethral strictures in 82; the bladder neck strictures in 6 of them (7.3%) were not observed on voiding cystourethrography (VCUG) (p < 0.05). Retrograde bladder filling was achieved in approximately 6 min.

Conclusion

The clamp method enables RSUG and CE-VSUG to be performed simply, effectively and painlessly by a single operator. It also allows the evaluation of cases with urethromeatal alterations (stricture, hypospadias and meatotomy).

Key Points

? The clamp method enables RSUG to be performed simply and painlessly. ? The clamp method requires only one operator and allows assessing urethromeatal alterations. ? RSUG shows greater capacity for detecting anterior urethral strictures than RUG. ? The clamp method achieves retrograde bladder filling in approximately 6 min. ? CE-VSUG shows greater capacity for detecting strictures than VCUG.