[Efficient OP management. Suggestions for optimisation of organisation and administration as a basis for establishing statutes for operating theatres]. / Effizientes OP-Management Vorschläge zur Optimierung von Prozessabläufen als Grundlage für die Erstellung eines OP-Statuts.

Economic aspects have gained increasing importance in recent years. The operating room (OR) is the most cost-intensive sector and determines the turnover process of a surgical patient within the hospital. Thus, optimisation of workflow processes is of particular interest for health care providers. If the results of surgery are viewed as a product, everything associated with surgery can be evaluated analogously to a manufacturing process. All steps involved in producing the end-result can and should be analysed with the goal of producing an efficient, economical and quality product. The leadership that physicians can provide to manage this process is important and leads to the introduction of a specialised "OR manager". This position must have the authority to issue directives to all other members of the OR team. An OR management subordinates directly to the administration of the hospital. By integrating and improving management of various elements of the surgical process, health care institutions are able to rationally trim costs while maintaining high-quality services. This paper gives a short introduction into the difficulties of organising an OR. Some suggestions are made to overcome common shortcomings in the daily practise. A proposal for an "OR statute" is presented that should be a basis for discussion within the OR team. It must be modified according to individual needs and prerequisites in every hospital. The single best opportunity for dramatic improvement in effective resource use in surgical services lies in the perioperative process. The management strategy must focus on process measurement using information technology and feed-back implementing modern quality management tools.However, no short-term effects can be expected from these changes. Improvements take about a year and continuous feed-back of all measures must accompany the reorganisation process.

Structure-function studies of linear and cyclized peptide antagonists of the GnRH receptor.

Structurally new analogs of the peptidic GnRH receptor antagonist Cetrorelix as well as conformationally constrained cyclized deca- or pentapeptides were synthesized and selected peptides evaluated comprehensively. To understand how structural variations of the antagonistic peptide effect pharmacodynamic properties, binding affinities and antagonistic potencies toward the human and rat GnRH receptor were determined. Whereas large substituents in position 6 of linear peptides are compatible with high binding affinity (K(D) < 0.5 nM), all cyclized peptides except the cyclo[3-10] analog D-52391 depicted low binding affinity (K(D) > 10 nM). Binding affinity and antagonistic potency in vitro correlated for all peptides and surprisingly no discrimination between human and rat receptor proteins was observed. Since receptor residues W(101) and N(102) are involved in agonist and antagonist binding, equally potent but structurally different antagonists were tested for binding to the respective W(101)A and N(102)A mutants. In contrast to linear decapeptides, residues N(102) and W(101) are not involved in binding of D-23938 and W(101) is the critical residue for D-52391 binding. We conclude that although equally potent, peptidic GnRH receptor antagonists do have distinct interactions within the ligand binding pocket. Finally, selected antagonists were tested for testosterone suppression in male rats. The duration of testosterone suppression below castration levels differed largely from 1 day for Ganirelix to 27 days for D-23487. Systemic availability became evident as the most important parameter for in vivo efficacy.

GnRH agonists and antagonists stimulate recovery of fertility in irradiated LBNF1 rats.

The goal of this study was to determine whether both gonadotropin-releasing hormone (GnRH) agonists and antagonists could enhance fertility in rats given sterilizing doses of irradiation, to quantify the levels of fertility, and to measure their relative effectiveness in stimulating recovery of spermatogenesis. Irradiated rats were treated with either the GnRH agonist Lupron or the GnRH antagonist Cetrorelix, which have different mechanisms of action. The antagonist suppressed luteinizing hormone (LH), reducing intratesticular testosterone from 75 ng/g-testis to about 5 ng/g-testis, whereas the agonist reduced intratesticular testosterone only moderately to about 20 ng/g-testis, presumably by direct action on the Leydig cell since LH was elevated. These differences were reflected in Leydig cell morphology. When hormone treatment was started immediately after 3.7-Gy irradiation, fertility was normal at week 20 in the agonist-treated rats and was near normal in antagonist-treated rats, whereas irradiated-only rats were sterile. At week 22 in the GnRH antagonist-treated rats, testicular weights and sperm counts were maintained at greater than 80% of control values; in GnRH agonist-treated rats, they were slightly but significantly lower than in GnRH antagonist-treated rats, and in irradiated-only rats, they were very low. When the treatment was initiated 10 weeks after 5-Gy irradiation, after spermatogenesis had ceased, fertility was restored at week 30 to subnormal levels in 83% of GnRH agonist- and 50% of GnRH antagonist-treated rats. Testis weights and sperm counts were restored to about 50% and 20% of control levels, respectively. The percentages of tubules with differentiated germ cells were higher in all groups of antagonist-treated rats than in those of agonist-treated rats. Thus, both GnRH agonists and antagonists produced dramatic recovery of spermatogenesis and fertility in irradiated rats, although there were differences in mechanism and perhaps also in effectiveness.

Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines.

The family of GH secretagogues (GHS) includes synthetic peptidyl (hexarelin) and nonpeptidyl (MK-0677) molecules possessing specific receptors in the pituitary and central nervous system as well as in peripheral tissues, including the heart and some endocrine organs. A gastric-derived peptide, named ghrelin, has recently been proposed as the natural ligand of the GHS receptors (GHS-Rs). The presence of specific GHS-Rs has now been investigated in nontumoral and neoplastic human breast tissue using a radioiodinated peptidyl GHS ([(125)I]-Tyr-Ala-hexarelin) as ligand. Specific binding sites for GHS were detected in membranes from several types of breast carcinomas, whereas a negligible binding was found in fibroadenomas and mammary parenchyma. The highest binding activity was found in well-differentiated (G1) invasive breast carcinomas and was progressively reduced in moderately (G2) to poorly (G3) differentiated tumors. [(125)I]-Tyr-Ala-hexarelin bound to tumor membranes was displaced by different unlabeled GHS such as hexarelin, Tyr-Ala-hexarelin, human ghrelin, and MK-0677 as well as by desoctanoyl-ghrelin and hexarelin derivative EP-80317, which are devoid of GH-releasing properties in vivo. In contrast, no competition was seen between radiolabeled Tyr-Ala-hexarelin and some peptides (CRF and insulin-like growth factor I) structurally and functionally unrelated to hexarelin or when GHRH and SRIF were tested in the displacement studies. The presence of specific GHS binding sites was also demonstrated in three different human breast carcinoma cell lines (MCF7, T47D, and MDA-MB231), in which, surprisingly, no messenger RNA for GHS-R1a was demonstrated by RT-PCR. In these cell lines, ghrelin (as well as hexarelin, MK-0677, EP-80317, and even desoctanoyl ghrelin) caused a significant inhibition of cell proliferation at concentrations close to their binding affinity. In conclusion, this study provides the first demonstration of specific GHS binding sites, other than GHS-R1, in breast cancer. These receptors probably mediate growth inhibitory effects on breast carcinoma cells in vitro.

Comparison of cryopreservation outcome with human pronuclear stage oocytes obtained by the GnRH antagonist, cetrorelix, and GnRH agonists.

This retrospective study was performed to examine the implantation and pregnancy rates of frozen-thawed pronuclear stage oocytes obtained with the use of a GnRH antagonist, Cetrorelix (Cetrotide((R)) ASTA-Medica, Frankfurt/M, Germany) used in a multidose protocol with hMG, and to compare these results with those obtained after a conventional long GnRH analogue protocol (Decapeptyl-Depot, Ferring, Kiel, Germany). The study population consisted of 31 infertile couples with frozen-thawed pronuclear stage oocytes after ICSI treatment using the GnRH antagonist Cetrorelix (Cetrorelix((R))) and 31 infertile couples with frozen-thawed pronuclear stage oocytes after ICSI treatment using the long GnRH analogue protocol. Patients underwent ICSI after down regulation with a GnRH agonist (Decapeptyl) and stimulation with hMG, or a GnRH antagonist (Cetrorelix) and hMG. The supernumerary pronuclear stage oocytes were cryopreserved and transferred in a later mildly stimulated cycle. The implantation and pregnancy rates for frozen-thawed pronuclear stage oocytes derived from the GnRH antagonist compared with the GnRH agonist were 3.26% versus 3.73% (P=1.0000) and 8.33% versus 10.25% (P=1.0000), respectively. To our knowledge we report here the first pregnancies obtained by the transfer of cryopreserved pronuclear stage embryos generated from ICSI using a GnRH antagonist in the collecting cycle. The use of Cetrorelix in a multiple dose protocol in combination with hMG does not demonstrate a negative effect on viability, implantation potential or pregnancy outcome as compared to 2PN conceptuses obtained from a long GnRH agonist-hMG protocol.

The LHRH antagonist cetrorelix: a review.

In those clinical situations in which an immediate and profound suppression of gonadotrophins is desired, LHRH agonists have the disadvantage of producing an initial stimulatory effect on hormone secretion. Therefore, the use of GnRH antagonists which cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the receptors is much more advantageous. One of the most advanced antagonist produced to date is Cetrorelix, a decapeptide which has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in a variety of animal species and in clinical studies as well. Clinical trials in patients suffering from advanced carcinoma of the prostate, benign prostate hyperplasia, and ovarian cancer are currently in progress and have already shown the usefulness of this new treatment modality. In particular, the concept that a complete suppression of sex-steroids may not be necessary in indications such as uterine fibroma, endometriosis and benign prostatic hyperplasia represents a promising novel perspective for treatment of these diseases. Following completion of phase III trials in controlled ovarian stimulation for IVF regimens, Cetrorelix was given marketing approval and, thus, became the first LHRH antagonist available clinically.

Gonadotropin-releasing hormone analogs stimulate and testosterone inhibits the recovery of spermatogenesis in irradiated rats.

We investigated the effects of GnRH analogs, different doses of testosterone (T), an androgen receptor antagonist (flutamide), and combinations of these on the recovery of spermatogenesis after irradiation. Treatment with a GnRH agonist (Lupron) for 10 weeks after irradiation reduced the intratesticular T concentration (ITT) to 4% of that in irradiated rats and serum FSH to undetectable levels without altering serum LH levels. Injection of a GnRH antagonist (Cetrorelix) at 3 weeks after irradiation suppressed LH, FSH, and ITT to <7%, 32%, and 10%, respectively, of levels in irradiated-only rats within 2 weeks; suppression was maintained for approximately 3 to 4 weeks. The percentage of tubules with differentiated germ cells (repopulation index, RI) was <0.6% at weeks 10 to 20 after irradiation. Spermatogenic recovery was induced by both the GnRH agonist (RI = 58% at week 10; 91% at week 20) and antagonist (RI = 70% at week 13). There was a dose-dependent suppression of testicular germ cell repopulation when T was combined with GnRH analogs. The ability of T to abolish the spermatogenic stimulatory effect of the GnRH antagonist was evident by the similar RI obtained for irradiated rats given antagonist + T or T alone. This suppression of GnRH-induced recovery of spermatogenesis by T could be reversed by flutamide. The RI best correlated with the degree of ITT suppression. In ITT-suppressed rats, the RI also showed an inverse correlation with serum T levels. Thus, T and/or its androgenic metabolites either directly or indirectly inhibit spermatogenic recovery after irradiation through an androgen receptor-mediated process. In addition, there was a close negative correlation between RI and FSH levels, and hence, a spermatogenic inhibitory role for FSH in the irradiated rats cannot be ruled out.

Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anesthetized rats.

Pulmonary absorption of the decapeptide cetrorelix acetate was studied in rats by a non-surgical intratracheal instillation method. The pharmacological effect (decrease of testosterone plasma concentration) following intratracheal (i.t.) instillation was determined in four groups of seven rats each at three different concentrations (0.5, 1.0 and 2.5 mg/kg body weight). The applied doses reduced testosterone plasma concentration to subnormal level (

Enhancement of A spermatogonial proliferation and differentiation in irradiated rats by gonadotropin-releasing hormone antagonist administration.

The initial changes in the numbers, proliferation, and differentiation of A spermatogonia in irradiated rats after the administration of a GnRH antagonist, which is known to induce differentiation in this system, were investigated. LBNF1 rats were given 6 Gy of gamma-irradiation; some were treated with the GnRH antagonist Cetrorelix beginning 15 weeks after irradiation. Although the spermatogonia in the irradiated rats without hormone treatment continue to proliferate (labeling and mitotic indexes of 24% and 18%, respectively), they underwent apoptosis (apoptotic indexes of 21% by the terminal transferase-mediated end labeling assay and 9% by nuclear morphology), resulting in a constant number of A spermatogonia. Whole mount analysis of clones ofA spermatogonia revealed that larger clones were more likely to undergo apoptosis than mitosis. Hormone administration decreased the intratesticular testosterone concentration to 6% of the level in irradiated rats within 1 week. Concomitantly, there was a decrease in spermatogonial apoptotic indexes to 43% of levels in irradiated-only rats, leading to an increases in their numbers by 150%, their diameters by 11%, and their labeling indexes by 31%. The sizes of the mitotic clones gradually increased, and clones of more than eight cells appeared at week 3 of hormone treatment. A spermatogonial differentiation began at week 4, and by week 6.6, differentiation occurred in 30% of the tubules. Thus, suppression of intratesticular testosterone by the GnRH antagonist may be responsible for the immediate changes in spermatogonial numbers and kinetics, but several additional steps are required before differentiation begins, which did not occur until week 4.

The luteal phase of nonsupplemented cycles after ovarian superovulation with human menopausal gonadotropin and the gonadotropin-releasing hormone antagonist Cetrorelix.

OBJECTIVE: To analyze the luteal phase of six patients undergoing controlled ovarian hyperstimulation (COH) with hMG and a new GnRH antagonist, Cetrorelix, without receiving luteal phase supplementation. DESIGN: Phase II study involving the first six patients who did not receive luteal phase support. SETTING: Tertiary referral center. PATIENT(S): Six healthy women undergoing COH for assisted reproductive techniques. INTERVENTION(S): Oocyte retrieval was performed 36 hours after hCG administration, followed by embryo transfer 2 days later. No luteal phase supplementation was given. MAIN OUTCOME MEASURE(S): Serum E2, progesterone, LH, and FSH concentrations were measured. RESULT(S): The length of the luteal phase was < or =12 days in three of the six patients. One of the patients in whom the luteal phase was >12 days had a low serum progesterone concentration (2.9 ng/mL) on day 10. Serum LH concentrations decreased after the preovulatory hCG injection in all patients. However, a progressive increase in LH was observed after day 7, reaching normal values. CONCLUSION(S): Corpus luteum function seems to be impaired in cycles that are stimulated with hMG and the GnRH antagonist Cetrorelix.

Treatment of uterine fibroids with a slow-release formulation of the gonadotrophin releasing hormone antagonist Cetrorelix.

A depot preparation of the third-generation gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix (SB-75) was used for preoperative treatment in twenty premenopausal patients with symptomatic uterine fibroids who were to undergo surgery. In a prospective, open, randomized setting 60 mg of Cetrorelix pamoate salt was administered i.m. on cycle day 2. Patients were randomized for a second dose of 30 or 60 mg of Cetrorelix depot, which was administered according to the degree of oestradiol suppression (<50 pg/ml) on treatment day 21 or 28. Surgery was done after 6 or 8 weeks of treatment, depending on second dosage administration. Weekly transvaginal sonography (TVS) and magnetic resonance imaging (MRI) before and after treatment was performed, for fibroid volume assessment. Sixteen patients showed satisfactory suppression of gonadotrophins and sex steroid secretion, avoiding any initial flare-up effect. In these patients a mean shrinkage rate of largest fibroid volume of 33.5% at the end of treatment could be observed according to TVS, while the mean shrinkage rate obtained after 14 days of treatment was 31.3%. In good responders (shrinkage >20%) largest fibroid volume at day 14 was approximately 56.7% of basic assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to TVS assessment were not statistically significant. The avoidance of any initial flare-up in gonadotrophin secretion may explain this extremely fast reduction in fibroid size. The advantages of GnRH antagonist treatment in this indication consist in the short treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by using an improved slow release preparation.

Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix.

The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.

High loading and low maintenance doses of a gonadotropin-releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle-stimulating hormone, and testosterone in normal men.

The GnRH antagonist cetrorelix effectively suppresses serum LH, FSH, and testosterone (T) in normal men without major side-effects. However, as with other available GnRH antagonists, relatively high doses of 10 mg/day were required for sustained reduction of T levels during 1-week administration in normal men. Therefore, we investigated whether a suppression of LH, FSH, and T achieved by initial high dose cetrorelix can be maintained by continued low dose injections. Sixteen young male volunteers were randomly assigned to four study groups (n = 4/group). Twelve men were injected s.c. with 10 mg cetrorelix at 0800 h for 5 days, followed by injections of 2 mg/day (group I), 2 x 1 mg/day (group II), and 1 mg/day (group III) up to the end of the 3-week injection period. For the control, group IV was given daily placebo injections for 3 weeks. Morning and evening blood samples were obtained daily for 4 weeks and then at increasing time intervals up to week 13. Initial injections of 10 mg/day cetrorelix suppressed LH, FSH, and T effectively. This initial reduction of serum levels was maintained during the following low dose maintenance injections in all groups. In comparison to the initial suppression, significantly lower levels of LH, FSH, and T near the assay detection limits were measured during study weeks 2 and 3. The results show that compared to previous long term studies, much lower daily doses of the GnRH antagonist are sufficient for effective suppression of LH, FSH, and T after initial high loading dose injections. In addition to competitive receptor blockage, other mechanisms of GnRH antagonist action, such as receptor down-regulation, appear to be involved during long term administration in men.

Pharmacological studies with cetrorelix (SB-75), a potent antagonist of luteinising hormone-releasing hormone.

The antitumour and hormone-suppressive effects of the luteinising hormone-releasing hormone LH-RH antagonist Cetrorelix (D-20761) and its pamoate salt (D-20762) were investigated in the model of the DMBA-induced mammary carcinoma of female rats and by testosterone determinations in normal male rats. Treatment with single high doses of D-20761 induced a rapid decrease of tumour weights with a dose-dependent duration of action. Strong antitumour effects were also observed by applying different multiple dose schedules, including a initial high dose (3.16 mg/kg, s.c.) followed by a low maintenance dose (31.6 micrograms/kg, s.c.). The stability of the molecule against degrading enzymes led to the idea of using the poorly soluble pamoate salt for facilitating a sustained release of active compound. This salt indeed induced a prolonged suppression of tumour growth and of testosterone levels. In conclusion, we found that Cetrorelix is a highly effective LH-RH antagonist which should be further developed for the treatment of hormone-dependent diseases.

Hormone profiles under ovarian stimulation with human menopausal gonadotropin (hMG) and concomitant administration of the gonadotropin releasing hormone (GnRH)-antagonist Cetrorelix at different dosages.

PURPOSE: The premature LH surge in ART programs seems to be avoided by daily administration of the GnRH-antagonist Cetrorelix during the midcycle phase in controlled ovarian hyperstimulation with hMG. The dosage necessary for sufficient suppression of the pituitary gland is not yet defined. METHODS: To elucidate this question three daily dosages (3, 1, 0.5 mg) were administered and the hormone profiles obtained as well as the number of oocytes retrieved, the fertilization rate, and the consumption of HMG were compared. RESULTS: No premature LH surge could be observed at any of the three dosages administered. Both gonadotropins were deeply suppressed. The fertilization rates of the oocytes obtained were 45.3% in the 3-mg group, 53.1% in the 1-mg group, and 67.7% in the 0.5-mg group. The average uses of hMG ampoules were 30 in the 3-mg group, 27 in the 1-mg group, and 26 in the 0.5-mg group. CONCLUSIONS: Cetrolix, 0.5 mg/day, administered during the midcycle phase of controlled ovarian hyperstimulation with hMG is enough to prevent completely the premature LH surge. Perhaps even lower dosages would be sufficient. Regarding fertilization rates and use of hMG, the lower dosage seems to be the most favorable.

Preserved pituitary response under ovarian stimulation with HMG and GnRH antagonists (Cetrorelix) in women with tubal infertility.

OBJECTIVE: To examine the pituitary response in patients undergoing short-term application of the GnRH antagonist Cetrorelix in the mid-cycle phase for hypophysial suppression of premature LH surges within an IVF-program. DESIGN: Twenty patients suffering from primary or secondary tubal infertility were stimulated with hMG from cycle day 2. From day 7 till ovulation induction Cetrorelix was administered in two different dose regimens (15 patients 3 mg s.c. daily; 5 patients 1 mg s.c. daily). Three hours before ovulation induction a GnRH test was performed using 25 micrograms of native GnRH and the pituitary response examined by measurement of the serum LH concentration after 30 min. RESULTS: Premature LH surges could be avoided in the 3-mg group and in the 1-mg group, respectively. Due to this, none of the cycles had to be cancelled. Oestradiol profiles and ultrasound demonstrated a satisfactory follicular maturation. All patients showed pronounced suppression of the serum LH levels before ovulation induction. The mean increase of serum LH due to the performed GnRH test was 10 mIU/ml for the 3-mg group, while the average maximum in the 1-mg group was about 32.5 mIU/ml. CONCLUSIONS: The pituitary response is preserved by the treatment with the GnRH antagonist Cetrorelix. The extent of suppression of the adenohypophysis, as expressed by the different reactions on GnRH test, can be modulated by the dosage administered. This should allow ovulation induction by GnRH or one of its agonists instead of hCG, which could be beneficial in patients at high risk of Ovarian Hyperstimulation Syndrome (OHSS) and those suffering from Polycystic Ovary Disease (PCOD).

Development and applications of luteinizing hormone-releasing hormone antagonists in the treatment of infertility: an overview.

Luteinizing hormone-releasing hormone (LHRH) plays a crucial role in controlling the ovarian cycle in women. By modification of the molecular structure of this decapeptide, analogues were synthesized with agonistic or antagonistic effects on the gonadotrophic cells of the anterior pituitary gland. The agonists, after an initial stimulatory effect ('flare up'), lead to desensitization of the gonadotrophic cells and a reduction in the number of LHRH receptors on the cell membrane ('down-regulation'), while the antagonists produce an immediate effect by competitive blockade of the LHRH receptors. After administration of LHRH antagonists, the serum levels of FSH and LH decrease within hours. Nevertheless, the adenohypophysis maintains its responsiveness to an LHRH stimulus ('pituitary response') after pretreatment with an antagonist. This different pharmacological mechanism of LHRH antagonists makes possible new approaches to ovarian stimulation and to the therapy of sex steroid dependent diseases. The premature LH surge, the main cause of cancellation during induction of superovulation in assisted reproduction technology (ART) programmes, can be abolished by short term application of an LHRH antagonist associated with a reduced human menopausal gonadotrophin (HMG) requirement for ovarian stimulation. A future approach to ART might be based on the combination of pretreatment with an LHRH antagonist and ovulation induction by native LHRH or an agonist. The severe side effects encountered with early LHRH antagonists, such as anaphylactoid reactions due to histamine release, are almost completely eliminated in modern antagonists, especially Cetrorelix which is presently used clinically in controlled phase II clinical studies.

Evaluation of the in vitro and in vivo activity of the L-, D,L- and D-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75).

The objective of this study was to examine the in vivo and in vitro gonadotropin-inhibiting potencies, edematogenic activities and the receptor binding affinities of the D-Cit6, D,L-Cit6 and L-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75) [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH- RH. In order to demonstrate the suppressive effects of two different diastereomers of SB-75 and their racemic mixture on LH and FSH release, [D-Cit6] SB-75 was injected subcutaneously in doses of 2.5 and 10 micrograms/rat, [D,L-Cit6]-SB-75 in doses of 5 and 20 micrograms/rat and [L-Cit6] SB-75 in doses of 12.5 and 50 micrograms/rat to castrated male rats. Two hours after administration, there was no difference in LH levels between rats injected with the L-form and control animals, indicating a low activity and/or a rapid enzymatic degradation of this peptide. The (1:1) diastereomeric mixture was only about half as potent in suppression of LH release compared to [D-Cit6] SB-75. Serum FSH levels were suppressed significantly (p < 0.01) for more than 48 h after the administration of 10 micrograms [D-Cit6] SB-75 and 20 micrograms of [D,L-Cit6] SB-75, respectively. [D-Cit6] SB-75 administered at a dose of 2 micrograms/rat induced 100% inhibition of ovulation, while 4 micrograms/rat of the D,L-Cit6 peptide were necessary to produce the same effect.(ABSTRACT TRUNCATED AT 250 WORDS)

[GnRH antagonists in gynecology: initial results within the scope of controlled ovarian hyperstimulation]. / Die GnRH-Antagonisten in der Gynäkologie: Erste Ergebnisse im Rahmen der kontrollierten ovariellen Hyperstimulation (COH).

OBJECTIVE: Applicability of the GnRH-antagonist Cetrorelix within controlled ovarian hyperstimulation (COH) to avoid the premature LH-surge should be examined. METHODS: 35 patients suffering from tubal infertility were stimulated for In Vitro Fertilization (IVF) by human menopausal gonadotrophins (HMG) and concomitant administration of Cetrorelix in different dosages (3 mg, 1 mg, 0,5 mg). RESULTS: No premature LH-surge could be observed. CONCLUSIONS: Short term administration of the GnGR-antagonists avoids the occurrence of a premature LH-surge.