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.     

Scheduled administration of a gonadotrophin-releasing hormone antagonist (Cetrorelix) on day 8 of in-vitro fertilization cycles: a pilot study

To assess in a pilot study the ability of a single injection of a GnRH antagonist (Cetrorelix) to prevent premature luteinizing hormone (LH) surges in an in-vitro fertilization (IVF) embryo transfer programme when administered on a fixed day in the late follicular phase, ovarian stimulation was carried out in 11 women with two ampoules of human menopausal gonadotrophin per day beginning on day 2 of the menstrual cycle. A 3 mg dose of Cetrorelix was administered on day 8 of the stimulation cycle. A second injection was administered 72 h later if ovulation was not triggered in the meantime. We did not observe a premature LH surge in any of the cycles studied. The injection of 3 mg Cetrorelix was capable of preventing LH surge in all the patients studied, introducing a very simple treatment protocol. Among the patients who received two injections (n = 3), the day of the first administration was delayed in two subjects due to slow follicular maturation kinetics. Out of 11 patients, 10 had an embryo transfer. Four clinical pregnancies were obtained (40% per embryo transfer), of which 3 are ongoing (30% per embryo transfer). A simple administration protocol for a new GnRH antagonist (Cetrorelix) was able to prevent LH surges in the 11 patients studied.     

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.     

Improved oocyte quality is obtained with follicle stimulating hormone alone than with follicle stimulating hormone/human menopausal gonadotrophin combination

The aim of this study was to compare the efficacy of pure follicle stimulating hormone (FSH) with that of FSH/human menopausal gonadotrophin (HMG) combination in downregulated cycles. A total of 357 patients was evaluated retrospectively. Sixty percent of patients in the FSH group and 55% in the FSH/HMG group were new; the others were repeat patients. Ovulation was suppressed with leuprolide acetate in all patients, followed by either FSH (n = 218) or FSH/HMG (n = 119). There was no difference in patients' age, infertility factors, number of ampoules used, length of stimulation, oestradiol levels on day of human chorionic gonadotrophin (HCG) administration, number of oocytes recovered or the number of embryos transferred. Also, nuclear maturity at aspiration and fertilization rates were not different between the two groups. FSH stimulation resulted in a significantly higher percentage of mature oocytes that showed the typical 'mature' morphological characteristics (P < 0.0001). The clinical pregnancy rates per transfer were 40 and 28% in patients stimulated with pure FSH and FSH/HMG respectively (P < 0.05). The significantly higher number of immature oocytes matured in vitro in the FSH/HMG group (P = 0.001) suggests a possible effect on in-vitro maturation, due to luteinizing hormone present in HMG. The difference in mature oocyte quality may be an important determinant in the higher pregnancy rates for the FSH-stimulated patients.     

Leptin concentrations in the follicular phase of spontaneous cycles and cycles superovulated with follicle stimulating hormone

It has been reported that oestradiol may play a role in the production of leptin from adipocytes. To investigate this relationship further, nine normally ovulating women were studied during two menstrual cycles, i.e. an untreated spontaneous cycle and a cycle treated with follicle stimulating hormone (FSH) from cycle day 2 until the day of human chorionic gonadotrophin (HCG) injection. Serum leptin values on cycle day 2 did not differ significantly between the spontaneous and the FSH cycles. In the spontaneous cycles, leptin values declined gradually and significantly up to day 7 and then increased progressively up to the day of luteinizing hormone (LH) surge onset, at which point they achieved the highest values. In the FSH cycles, serum leptin values increased gradually and significantly up to day 6, remaining stable thereafter, and were in the midfollicular phase significantly higher than in the spontaneous cycles. Significant positive correlations were found between mean values of leptin and mean values of oestradiol during the second half of the follicular phase in the spontaneous cycles and during the first half in the FSH cycles. A significant negative correlation was found between these two parameters in the spontaneous cycles during the first half of the follicular phase. Serum leptin levels were significantly higher in the midluteal than in the follicular phase in both cycles. These results demonstrate for the first time significant changes in leptin values during the follicular phase of the human menstrual cycle and a significant increase during superovulation induction with FSH. It is suggested that oestradiol may be involved in the regulation of leptin production in women.     

Developmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinizing hormone

We previously demonstrated, in luteinizing hormone (LH)-deficient macaques, that follicular growth and maturation occurred with administration of exogenous (recombinant human) follicle stimulating hormone (r-hFSH) alone, and that the oocytes recovered fertilized at a notably higher rate than their counterparts from animals receiving both r-hFSH and r-hLH (Zelinski-Wooten et al., 1995). Here, the developmental potential of embryos produced from animals treated with r-hFSH alone or in combination with r-hLH was evaluated. Embryos (n = 127) were cryopreserved, thawed and either co-cultured on buffalo rat liver cells until the hatched blastocyst stage or transferred to synchronized recipients. Although embryos from each treatment group demonstrated a similar ability to develop to hatched blastocysts with a definitive inner cell mass, a significant difference was seen in cryosurvival (56 versus 78%) and in developmental rate to the hatched blastocyst (12 versus 10 days) between embryos from the r-hFSH alone and the combination group respectively. Pregnancies resulted following oviductal embryo transfers in both groups, with corpus luteum rescue occurring on days 12-16 of the luteal phase. In summary, r-hFSH alone during the pre-ovulatory interval is adequate for the gametogenic events required to produce embryos that develop either in vitro or in vivo; however, exposure to r-hLH may improve embryo viability and the rate of development.     

Pregnancy and birth after high serum progesterone concentrations during the follicular phase in an in-vitro fertilization cycle with gonadotrophin-releasing hormone agonist suppression

This case illustrates the possibility of achieving a pregnancy and birth when elevated progesterone concentrations (> 4 ng/ml) are present during the follicular phase (from 6 days before human chorionic gonadotrophin injection) of a gonadotrophin-releasing hormone agonist/menotrophin cycle for in-vitro fertilization (IVF). The present patient underwent three IVF/embryo transfer cycles in which progesterone concentrations were repeatedly increased from the midfollicular phase onwards. A pregnancy was achieved after the first IVF attempt but ended in a miscarriage in the 19th week of gestation. During the second IVF attempt an endometrial biopsy taken on the day of oocyte retrieval revealed an endometrial advancement of 2 days. A successful pregnancy and birth was again achieved after the third IVF attempt although progesterone concentrations were considerably increased from 6 days before the ovulatory stimulus.     

Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone

The effects of profound suppression of circulating luteinizing hormone (LH) during the follicular phase of in-vitro fertilization cycles were explored in normal women during treatment with a gonadotrophin-releasing hormone analogue and exogenous purified follicle stimulating hormone. Ovarian responses to treatment and the capacity of supernumerary embryos to undergo blastocyst formation were examined in groups of patients defined by the concentration of plasma LH in the mid-follicular phase. Concentrations < or = 0.5 IU/I diagnosed the group with profoundly suppressed LH (相似文献   

First established pregnancy after controlled ovarian hyperstimulation with recombinant follicle stimulating hormone and the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462)

This case report describes the first established pregnancy after the use of gonadotrophin-releasing hormone (GnRH) antagonist, ganirelix (Org 37462; Organon), to prevent a premature luteinizing hormone surge during ovarian hyperstimulation with recombinant human follicle stimulating hormone (rhFSH). The pregnancy progressed normally and ended with the birth of a healthy boy and a girl after an elective Caesarean section at gestational age of 37 weeks. This case illustrates, for the first time, the use of a GnRH antagonist in combination with a pure FSH preparation for ovarian stimulation.     

Induction of the endogenous gonadotrophin surge for oocyte maturation with intra-nasal gonadotrophin-releasing hormone analogue (buserelin): effective minimal dose

From 1985-1987, a total of 34 couples undergoing superovulation for a single in-vitro fertilization (IVF) cycle with clomiphene citrate and purified follicle stimulating hormone (FSH) or human menopausal gonadotrophin (HMG) were randomly allocated doses of intra-nasal buserelin to induce an endogenous gonadotrophin surge, prior to oocyte collection. The doses ranged from a single 25 microg dose to 100 microg every 4 h for 20 h. In three cycles the treatment was abandoned because of a poor ovarian response. In the remaining 31 cycles buserelin was given to induce the endogenous gonadotrophin surge, but there was evidence of premature luteinization in eight cycles and a premature gonadotrophin surge in four cycles. Although a single dose as low as 40 microg induced a surge and resulted in a pregnancy, a single dose of 50 microg proved the most effective minimal dose consistently to induce a gonadotrophin surge and oocyte maturation. Recent reports using gonadotrophin-releasing hormone (GnRH) analogues to induce a gonadotrophin surge has prompted publication of this previously unpublished data.     

Human chorionic gonadotrophin and steroid concentrations in follicular fluid: the relationship to oocyte maturity and fertilization rates in stimulated and natural in-vitro fertilization cycles

The study investigates the relationship of follicular fluid steroids and human chorionic gonadotrophin to oocyte maturity and fertilization rates in stimulated and natural cycles. Oestradiol, progesterone, testosterone and human chorionic gonadotrophin were quantified in 129 samples of follicular fluid and the progesterone:oestradiol ratio calculated. Both stimulated cycles (short and long luteinizing hormone-releasing hormone/human menopausal gonadotrophin regimens) and natural cycles were compared. A total of 60 women were studied, 20 in each group. In the natural cycles, testosterone was significantly lower in follicles with intermediate oocytes (P = 0.015). Both oestradiol and testosterone were significantly lower in stimulated cycles compared to natural cycles (P = 0.032 and P = 0.034 respectively). In the ovarian stimulation cycles, the progesterone:oestradiol ratio was significantly higher when oocytes fertilized (P = 0.052). Moreover, in the stimulated cycles, oestradiol and human chorionic gonadotrophin were singnificantly lower in the short protocol compared to the long protocol. The data demonstrate that the hormonal milieu of the follicle is altered in down-regulated stimulated cycles to varying degrees, depending partially on the type of protocol used. Furthermore, the progesterone:oestradiol ratio, rather than individual hormone concentrations, may be a useful predictor of the fertilizing capacity of the oocytes.     

A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate

OBJECTIVE: To determine the relative efficacy of intrauterine insemination (IUI), direct intraperitoneal insemination, and intercourse in cycles stimulated with clomiphene citrate (CC) or human menopausal gonadotropins (hMG). DESIGN: A prospective randomized trial with a 2(3) factorial design with eight different treatment alternatives. Only one cycle per couple was performed. SETTINGS: The Departments of Obstetrics and Gynecology, Central Hospital, V?ster?s and Akademiska Hospital, Uppsala University, Uppsala, Sweden. PATIENTS: Of 157 randomized couples with unexplained infertility including 51 cases with minimal or mild endometriosis, 148 were selected for comparison. MAIN OUTCOME MEASURE: Pregnancy rate (PR). RESULTS: Follicular stimulation with hMG gave a higher PR than with CC in the insemination cycles, 19% (10/52) and 4% (2/49), respectively, but the PRs in intercourse cycles were not significantly different for hMG and CC, 13% (3/24) and 17% (4/23), respectively. Insemination cycles and intercourse cycles had a similar overall PR, 12% (12/101) and 13% (7/47), respectively. Furthermore, IUI and direct intraperitoneal insemination did not differ in efficacy. CONCLUSION: Follicular stimulation with hMG is more effective than CC in insemination cycles, but insemination as such seems to have no beneficial effect on the PR in stimulated cycles for treatment of unexplained infertility.     

ACTH, beta-endorphin, substance P, and corticotrophin releasing hormone in plasma and follicular fluid in hormonally stimulated menstrual cycles for in-vitro fertilization in the human

The differential diagnosis of psychiatric symptoms in encephalitis, especially in the early phase of the disease may be very difficult. It is particularly hard to distinguish it from the classic psychosis. The diagnostic problems have been presented on the basis of analysis of two case reports of the acute encephalitis in young persons. The presence of fever and pathological changes in the CSF were the most important indicators that helped to establish the diagnosis of encephalitis during the phase of acute psychopathological disorders.     

Follicle-stimulating hormone induces dose-dependant stimulation of immunoreactive inhibin secretion during the follicular phase of the human menstrual cycle

To determine whether FSH is a physiological regulator of the serum immunoreactive inhibin (INH) concentration during the follicular phase of the normal menstrual cycle, purified FSH (Metrodin) was administered in doses of 100 IU (n = 6), 150 IU (n = 5), and 200 IU (n = 5) to normal, regularly cycling volunteers between days 3-7 of the menstrual cycle. A control group (n = 5) received normal saline. There was a linear dose-related increase in serum INH (and in serum FSH) in response to the three doses of FSH, with 200 IU leading to a 107% increase in INH and a 68% increase in FSH. Serum estradiol rose in response to the two higher doses of FSH. There was a significant correlation between the actual increases in INH and estradiol (r = 0.53; P < 0.01). It was concluded that FSH stimulates INH in the follicular phase of the normal menstrual cycle, consistent with a physiological role for FSH in the regulation of granulosa cell production of inhibin.     

Perivitelline space granularity: a sign of human menopausal gonadotrophin overdose in intracytoplasmic sperm injection

The significance of the presence of coarse dark granules in the perivitelline space of oocytes has not been studied before. The study included 2288 intact oocytes [2063 in metaphase II (MII), 136 in metaphase I (MI), and 89 in germinal vesicle (GV)] retrieved in 206 intracytoplasmic sperm injection cycles stimulated by a long agonist protocol. The incidence of granules varied with oocyte maturity. It was detected in 34.3% and 4% of the MII and MI oocytes respectively, while none of the GV oocytes contained granules. The woman's age, hormonal values (oestradiol and progesterone), human chorionic gonadotrophin/oocyte retrieval interval, number of oocytes retrieved, and oocyte retrieval/injection interval were not related to the percentage of granular oocytes. Moreover, there was no correlation between the percentage of granular oocytes and the fertilization and cleavage rates, pregnancy outcome, as well as the implantation rate. Patients were divided into three groups according to the total human menopausal gonadotrophin (HMG) dose they received. There was a statistically significant difference between the three groups in the percentage of granular oocytes [17.4 +/- 5.2% versus 26.7 +/- 3.2% versus 45.4 +/- 4.2% in the low-dose (< 30 ampoules), intermediate dose (31-45 ampoules), and high-dose (> 45 ampoules) groups respectively]. We conclude that granularity in the perivitelline space is probably a physiological phenomenon related to the maturational events in oocytes and enhanced by exposure to high dosages of HMG.     

Comparative randomized controlled study between human follicle- stimulating hormone (FSH-HP) and human menopausal gonadotropins (hMG) in in vitro fertilization

Orotracheal fibreoptic intubation under general anaesthesia in children was studied in eleven consecutive patients of three months to eight-years-of-age without anticipated intubation difficulties. One case report is also included. Three fibrescopes with a different diameter were used in the study. The fibrescope used was chosen so that it fitted snugly in the tracheal tube. The fibreoscopy was prolonged in one patient due to mucus and two tries were needed. Resistance to the tracheal tube upon intubation was encountered in five patients, only one of these patients was older than two years. Fibreoptic intubation succeeded in nine patients. Two patients were intubated with the Macintosh laryngoscope. The problems encountered in children during orotracheal fibreoptic intubation under general anaesthesia are the same as with adults: easy fibreoscopy is not always followed by easy tracheal intubation, there may be prolonged fibreoscopy and failed intubations. Manipulation of the tracheal tube can lead to successful tracheal intubation and resistance to the tube is more common in smaller children.     

Long-term evaluation of implantation of fresh and cryopreserved human embryos following ovarian stimulation with buserelin acetate-human menopausal gonadotrophin (HMG) or clomiphene citrate-HMG

This study is a long-term evaluation of the total pregnancy potential of cohorts of fresh and cryopreserved sibling embryos from in-vitro fertilization (IVF) cycles stimulated with either the gonadotrophin-releasing hormone analogue buserelin (BUS) (long protocol) or clomiphene citrate (CC) both in combination with human menopausal gonadotrophin (HMG). Therefore a retrospective analysis was performed on patients who entered the IVF programme between January 1986 and July 1987 and who had triple embryo transfer in the collection cycle. Significantly more fertilized oocytes developed to good-quality embryos in the CC-HMG group (86.1%) than in the BUS-HMG group (80.8%). Transfer of the three morphologically best-looking embryos was performed in day 2 post-insemination in 106 CC-HMG and 80 BUS-HMG cycles. Supernumerary embryos were cultured for a further 24 h and multicellular embryos with up to 20% of fragments were frozen slowly with 1.5 M dimethylsulphoxide on day 3 post-insemination (162 embryos in CC-HMG cycles, 102 embryos in BUS- HMG cycles). Outcome was measured by embryo survival rate, embryo implantation rate and delivery rate in fresh and frozen embryo transfers. Delivery rates were 31.3 and 21.7% per fresh embryo transfer in BUS-HMG and CC- HMG cycles respectively. Fresh embryo implantation rates were significantly higher in collection cycles stimulated with BUS-HMG (17.9%) than in cycles stimulated with CC-HMG (11.3%). Implantation rates were significantly enhanced in embryos transferred in excess of one in cycles leading to pregnancy, perhaps indicative of higher embryo quality in BUS-HMG cycles. Almost all cryopreserved embryos have by now been thawed, so the contribution of frozen embryos to overall pregnancy rates can be evaluated. Overall morphological survival rates of frozen-thawed embryos have by now been thawed, so the contribution of frozen embryos to overall pregnancy rates can be evaluated Overall morphological survival rates of frozen-thawed embryos were similar for 140 embryos from CC-HMG cycles (50%) and 100 embryos from BUS-HMG cycles (46%). The percentage of fully intact embryos was, however, significantly lower in the BUS-HMG group (19%) than in the CC-HMG group (39.5%). Delivery rates were significantly lower following 30 transfers of frozen-thawed embryos from BUS-HMG-stimulated cycles (3.3%) than following 42 transfers of frozen-thawed embryos from CC-HMG cycles (19.1%). Embryo implantation rates were lower for frozen-thawed embryos from BUS-HMG cycles (2.3%) than from CC-HMG cycles (12.7%). Here we demonstrate that ovarian stimulation with the long protocol BUS-HMG instead of the CC-HMG protocol led to higher embryo implantation rates in collection cycles but to lower intact embryo survival rates and to lower embryo implantation rates for frozen sibling embryos. Despite the lower implantation rates with frozen embryos originating from the BUS-HMG protocol, there was no significant difference between total delivery rate per transfer from cycles stimulated with CC-HMG (30.2%) compared with BUS-HMG (33.8%).     

Increased interleukin-1 and interleukin-1 receptor antagonist levels in cervical mucus in the ovulatory phase in comparison with the follicular phase

Interleukin-1 (IL-1) receptor antagonist (IL-1ra) levels in the cervical mucus of women in the ovulatory phase are significantly higher than those in the follicular phase. IL-1 titers of women in the ovulatory phase are also significantly higher than those in the follicular phase. A positive correlation between IL-1ra and IL-1 levels in the cervical mucus was observed. Immunohistochemistry using an anti-IL-1ra monoclonal antibody revealed positive staining in the epithelial cells of the endocervix. These results suggest that IL-1ra from cervical epithelial cells protects the reproductive system from the toxicity of IL-1 produced in the endocervix.     

Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism

The incidence of hereditary nonpolyposis colorectal cancer (HNPCC) is not precisely known. Common estimates are 4 to 6% of all colorectal cancers (CRCs), but lower figures have been published. In an attempt to obtain an independent new estimate of this proportion and to identify more HNPCC families, we designed a new method. Based on the fact that age at diagnosis is considerably lower in hereditary than in sporadic CRC, a cohort of 227 CRC patients aged 44 years or younger diagnosed during the years 1985-1989 and reported to the Finnish Cancer Registry was chosen as probands. Pedigrees of the probands were constructed by combining information from the Finnish Population Register Center and Finnish Cancer Registry using only automatically processed data. Sixteen pedigrees were extended further by the help of parish registers. Six of these turned out to be new possible HNPCC families but none met the stringent criteria of the cancer syndrome. Our results can be interpreted to suggest that the proportion of HNPCC of all CRCs is between 0.5 and 0.9%, depending on the diagnostic criteria used. Modifications of our method should be useful in other research projects dealing with diseases in which a subset is due to genetically or environmentally determined susceptibility.     

Co-expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice

Bovine growth hormone (bGH) transgenic (Tg) mice have been shown to possess enhanced growth phenotypes and exhibit severe glomerulosclerosis. One amino acid substitution in GH, i.e. G119R in bGH or G120R in human (h) GH, results in GH antagonists (GHAs). GHA-Tg mice exhibit dwarf phenotypes and normal kidneys. In order to investigate the possibility of GHAs as pharmaceutical agents for the treatment of human diseases with excessive GH levels, we cross bred mice that express bGH with those that express hGHA. Double positive Tg mice were identified that express both genes although at different levels. Kidney histological studies revealed that the double positive Tg mice with high GHA/GH expression ratios possessed normal or near normal kidneys, whereas those with low GHA/GH ratios exhibited glomerulosclerosis similar to GH-Tg mice. Thus, co-expression of GH and GHA genes in vivo results in animal phenotypes and kidney histopathologies which are a reflection of the relative expression levels of each gene.