On the dynamics between gonadotrophin surge-inhibiting factor and gonadotrophin releasing hormone (GnRH): role of self-priming and desensitization in the luteinizing hormone response to GnRH after follicle stimulating hormone treatment

The effects were studied of follicle stimulating hormone (FSH)-induced production of gonadotrophin surge-inhibiting factor (GnSIF) on three phases of the pituitary responsiveness to gonadotrophin releasing hormone (GnRH): the unprimed, primed and desensitized phases. Rats were injected with FSH on two occasions during the oestrous cycle. Spontaneous luteinizing hormone (LH) surges were measured as well as GnRH-induced LH surges on the day of pro-oestrus during infusions with 100-4000 pmol GnRH/rat/10 h, in phenobarbital blocked rats. The spontaneous LH surges were attenuated or completely inhibited by the FSH treatment. FSH suppresses and prolongs the unprimed LH response and delays GnRH self-priming, especially during infusions with low concentrations of GnRH. This treatment does not affect the total LH response (area under curve) to the highest concentrations of GnRH and after ovariectomy. On the other hand, this response is suppressed during infusions with the lower concentrations of GnRH. Hence, FSH, via GnSIF, delays maximal priming of the LH response to GnRH, whereas the suppression of LH release is a consequence of the GnRH-induced progressed state of desensitization. The inconsistent effects of FSH on the mid-cycle LH surges are explained as a result of the interaction between the relative strengths of GnRH and GnSIF.     

Pre-ovulatory changes in steroidogenesis in ovaries from immature rats treated with pregnant mare serum gonadotrophin

The metabolism of progesterone in the 1000 g supernatant fraction of homogenates of ovaries from PMSG-treated immature rats was determined. As early as 52 h after a single injection of 50 i.u. PMSG, still before the LH surge, 5alpha-pregnane-3alpha, 20alpha-diol was identified as the main metabolite, together with small quantities of 3alpha-hydroxy-kalpha-pregnan-20-one and 5alpha-androstane-3alpha, 17beta-diol. Similar incubations of untreated rat ovaries at the same age did not produce 5alpha-pregnane-3alpha, 20alpha-diol. The quantities of 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-androstane-3alpha, 1mbeta-diol were reduced in PMSG-treated rat ovaries as compared with control ovaries. When progesterone metabolism was examined 64 h after PMSG administration, 5-7 h after the peak of LH surge but still before ovulation, 75% of the substrate was converted to 5alpha-pregnane-3alpha, 20alpha-diol, while 3alpha-hydroxy-5alpha-pregnan-20-one as well as 5alpha-androstane-3alpha, 17beta-diol could not be detected.     

Luteotropic effect of pregnant mare serum gonadotropin in cattle

The ability to accurately assess tumor size and orientation to surrounding vital structures is an important consideration during preoperative evaluation. The authors report on nine children with solid tumors (hepatoblastoma [1], neuroblastoma [2], adrenal cortical carcinoma [2], liver adenoma [1], primitive neuroectodermal tumor [PNET] [1], and stage V Wilms' tumor [2]) for whom tumor resectability was questioned because of the tumors' close proximity to major blood vessels (noted through conventional radiographic imaging). The children had scanning with spiral volumetric acquisition computerized tomography, (CT) which obtains images during continuous rotation of the x-ray source while the patient moves at a constant velocity through the gantry. This technique is rapid (18 to 30 seconds), and is similar with respect to radiation exposure; little or no sedation is required, and the contrast dose is lower than that of conventional CT. Three-dimensional reconstruction of spiral CT imaging provided useful information that allowed successful resection in all nine cases. The authors suggest that spiral CT may become an important imaging modality in the preoperative evaluation of pediatric solid tumors and that further evaluation of this new methodology is warranted.     

The effect of recombinant follicle stimulating hormone (Gonal-F) on endogenous luteinizing hormone secretion in women

Parenteral administration of follicle stimulating hormone (FSH) has been shown to lower luteinizing hormone (LH) concentrations in women undergoing ovulation induction. This study was designed to explore the physiological mechanism of this effect. Seven healthy women were recruited into a double-blind placebo-controlled study. LH secretion, after the administration of variable i.v. boluses (37.5, 75 and 150 IU) of recombinant FSH (Gonal-F), was evaluated. LH was measured at 10 min intervals for 2 h before and 4 h after the FSH/placebo infusion. LH pulse frequency and amplitude were evaluated and there was no significant difference between control and trial cycles for each subject. A linear regression analysis revealed that in the group receiving 150 IU FSH, the mean plasma LH concentration decreased significantly due to a reduction tonic LH secretion. This could be a result of the suppression of secretion or an alteration of clearance. This decrease was not seen in the other dosage groups, revealing that above a dosage threshold, FSH reduced non-pulsatile LH secretion. Therefore the effect of FSH in this study exposed the likely presence of two components of LH concentration: an FSH-sensitive, non-pulsatile tonic secretion and a gonadotrophin-releasing hormone-stimulated, pulsatile release that is unaffected by FSH. Although an indirect effect involving ovarian regulation is not excluded, the rapidity of the effect suggests that FSH acts directly on the pituitary gland.     

Luteinizing hormone response to gonadotrophin-releasing hormone in normal women undergoing ovulation induction with urinary or recombinant follicle stimulating hormone

Oestradiol enhances pituitary sensitivity to gonadotrophin-releasing hormone (GnRH) in normal women, while in women undergoing ovulation induction the putative factor gonadotrophin surge attenuating factor (GnSAF) attenuates the response of luteinizing hormone (LH) to GnRH. To study the relationships between oestradiol and GnSAF during ovulation induction, 15 normally ovulating women were investigated in an untreated spontaneous cycle (control, first cycle), in a cycle treated with daily i.m. injections of 225 IU urinary follicle-stimulating hormone (FSH) (Metrodin HP, uFSH cycle) and in a cycle treated with daily s.c. injections of 225 IU recombinant FSH (Gonal-F, rFSH cycle). Treatment with FSH started on cycle day 2. The women during the second and third cycle were allocated to the two treatments in an alternate way. One woman who became pregnant during the first treatment cycle (rFSH) was excluded from the study. In all cycles, an i.v. injection of 10 microg GnRH was given to the women (n = 14) daily from days 2-7 as well as from the day on which the leading follicle was 14 mm in diameter (day V) until mid-cycle (n = 7). The response of LH to GnRH at 30 min (deltaLH), representing pituitary sensitivity, was calculated. In the spontaneous (control) cycles, deltaLH values increased significantly only during the late follicular phase, i.e. from day V to mid-cycle, at which time they were correlated significantly with serum oestradiol values (r = 0.554, P < 0.01). Initially during the early follicular phase in the uFSH and the rFSH cycles, deltaLH values showed a significant decline which was not related to oestradiol (increased GnSAF bioactivity). Then, deltaLH values increased significantly on cycle day 7 and further on day v with no change thereafter up to mid-cycle. On these two days, deltaLH values were correlated significantly with serum oestradiol values (r = 0.587 and r = 0.652 respectively, P < 0.05). During the pre-ovulatory period, deltaLH values in the FSH cycles were significantly lower than in the spontaneous cycles. Significantly higher serum FSH values were achieved during treatment with uFSH than rFSH. However, serum values of oestradiol, immunoreactive inhibin, and deltaLH as well as the number of follicles > or = 12 mm in diameter did not differ significantly between the two FSH preparations. These results suggest that in women undergoing ovulation induction with FSH, oestradiol enhances pituitary sensitivity to GnRH, while GnSAF exerts antagonistic effects. The rFSH used in this study (Gonal-F) was at least as effective as the uFSH preparation (Metrodin-HP) in inducing multiple follicular maturation in normally cycling women.     

The effect of follicle stimulating hormone and epidermal growth factor on the developmental capacity of in-vitro matured mouse oocytes

Staphylococcus aureus produces and secretes a protein, Efb, that binds to fibrinogen, seems to be required for virulence, and may benefit the microorganism by delaying wound healing. Interactions of Efb with fibrinogen are influenced by divalent metal cations, including Ca2+. Increasing concentrations of Ca2+ increased the binding of fibrinogen to immobilized Efb, whereas binding of Efb to immobilized fibrinogen was decreased with increasing Ca2+ concentration. Studies with synthetic peptides showed that peptides from the carboxyl terminal half of Efb bound to soluble fibrinogen and enhanced the binding of fibrinogen to Efb. A peptide corresponding to a repeated sequence in the amino terminal half of the protein also bound fibrinogen and inhibited binding of fibrinogen to Efb. These results may provide clues to the biological function of Efb and aid in the rational design of agents to block the Efb fibrinogen interaction.     

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.     

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.     

Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism

The efficacy and safety of highly purified follicle stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) was studied in 60 men with hypogonadotrophic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotrophic hypogonadism and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynaecomastia. No local reactions at injection site were observed. In conclusion, the s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.     

The effect of diazoxide on uterine blood flow in pregnant sheep

Diazoxide, a labor inhibiting agent, was administered intravenously at various rates to seven pregnant, near-term sheep to evaluate its effect on cardiovascular and uterine hemodynamics. Uterine blood flow was measured with electromagnetic flow transducers. Rapid administration of diazoxide resulted in a profound maternal tachycardia with hypotension, an increase in uterine vascular resistance, and a significant decrease in uterine blood flow. With slow infusion of the drug, the changes in heart rate and blood pressure were minimized, uterine vascular resistance was decreased, and uterine blood flow was maintained. Therefore, slow infusion appears to be the preferred method for inhibiting labor with diazoxide.     

Effect of growth hormone administration on circulating levels of luteinizing hormone, follicle stimulating hormone and testosterone in normal healthy men

A new area of growth hormone (GH) therapy in adults is the treatment of infertility. The aim of this study was to evaluate the effects of pharmacological GH administration on the secretion of pituitary and gonadal hormones in normal men. Eight healthy men, 23-32 years of age (mean 28.1 years), with a normal body mass index were studied in a double-blind, placebo-controlled crossover design. All participants had a normal semen analysis before entering the study. Each participant was treated with placebo and GH (12/IU/day, Norditropin; Novo Nordisk, Denmark) during two different 14-day periods, separated by a 6 week washout period. Administration of GH for 14 days resulted in a significant increase in serum insulin-like growth factor I (IGF-I; P < 0.01) but no changes occurred in IGF-I values during placebo treatment. The concentrations of follicle stimulating hormone and luteinizing hormone displayed no change during the two periods and did not differ between the GH treatment period and the placebo period. The concentration of testosterone was unchanged during the placebo/GH periods and there was no difference between the GH treatment period and the placebo period. We conclude that GH treatment for 14 days in normal healthy men does not affect gonadotrophin or testosterone patterns.     

Purified urinary follicle stimulating hormone induces different hormone profiles compared with menotrophins, dependent upon the route of administration and endogenous luteinizing hormone activity

The effects of treatment of patients with gonadotrophin-releasing hormone analogue (GnRHa) combined with purified follicle stimulating hormone (FSH) for in-vitro fertilization (IVF) were investigated in detail to determine the influences of different administration routes and the degree of suppression of luteinizing hormone (LH). Responses to exogenous gonadotrophins were studied in infertile women (n = 60) with normal menstrual rhythm whose endogenous gonadotrophin activity was suppressed using a GnRHa in a long protocol. They were randomized to receive i.m. administration of human menopausal gonadotrophins (HMGim, Pergonal) or purified follicle stimulating hormone (FSH, Metrodin High Purity) administered either i.m. (MHPim) or s.c. (MHPsc). Responses were assessed by measuring plasma FSH, LH, oestradiol, testosterone and progesterone. After stimulation day 4, the MHPsc group showed significantly higher circulating concentrations of FSH than either the MHPim or HMGim group. However, the HMG group showed significantly higher oestradiol concentrations after stimulation day 5 than either MHP group. The differences in circulating oestradiol concentrations in the MHP-treated patients appeared to be strongly influenced by the mean circulating concentrations of LH in the follicular phase. The patients who showed mean follicular phase LH concentrations of < 1 IU/l showed longer follicular phases, lower circulating oestradiol and testosterone concentrations and also lower follicular fluid concentrations of oestradiol and testosterone, indicating a reduction in the normal follicular metabolism of progesterone to androgens and oestrogens under these conditions. This group of patients also showed longer follicular phases, which may have consequences for future clinical management.     

Effect of profound suppression of luteinizing hormone during treatment with gonadotrophin-releasing hormone analogue and purified follicle stimulating hormone upon development of cryopreserved embryos

In response to previously published evidence from monkeys, this study examined the influence of the degree of luteinizing hormone (LH) suppression during the follicular phase of the stimulation cycle, upon cryopreserved embryo survival and development. The LH concentration of the mid-follicular phase was assessed in 250 in-vitro fertilization (IVF) cycles treated with gonadotrophin-releasing hormone analogue (GnRHa) and either purified follicle stimulating hormone (FSH) or human menopausal gonadotrophin (HMG), and was related to the performance of cryopreserved embryos in 351 subsequent embryo transfer cycles. Rates of embryo survival, embryo development rates, implantation rates, and pregnancy rates were examined with respect to the LH concentration recorded in the mid-follicular phase. In contrast to experimental evidence from other primates, there was no significant influence of the follicular phase LH concentration upon any of the parameters examined.     

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.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle stimulating hormone

In contrast to the many detailed studies of Graafian follicles, the biology of small follicles in the human ovary is poorly understood and the trigger for follicular growth initiation remains unknown. No practical model exists to study preantral follicle growth in the human because of their slow growth rate and lack of an effective culture system. We therefore tested ovarian xenografts as a new strategy to study the early stages of ovarian follicular growth in vivo. Mice homozygous for severe combined immunodeficiency (SCID) and hypogonadism (hpg) received human ovarian xenografts under their kidney capsules. Follicle growth was assessed by morphology and proliferating cell nuclear antigen (PCNA) immunostaining. The grafts were recovered after 11 (short-term) and 17 weeks (long-term), and serially sectioned. During the last 6 weeks of long-term grafting, mice were randomized to receive either placebo or 1 IU of purified follicle stimulating hormone (FSH) s.c. on alternating days. After 11 weeks of grafting, the most advanced follicles had a maximum of two granulosa cell layers. In the absence of FSH administration, follicles did not progress beyond the two-layer stage even after 17 weeks of grafting, and the oestradiol levels remained undetectable. In the FSH-treated long-term grafts, follicles had grown to antral stages and resulted in oestradiol levels as high as 2070 pmol/l. Growth initiation indices did not differ between control and FSH-treated grafts. This study demonstrates that follicles can survive and grow in human ovarian tissue grafted under the renal capsules of immunodeficient mice for at least 17 weeks, and indicate that xenograft models are potentially useful for studying human follicle development. Using this physiological model, we showed that FSH is required for follicle growth beyond the two-layer stage, although growth initiation is independent of gonadotrophin stimulation.     

Relationships between the number of small follicles prior to superovulatory treatment and superovulatory response in Holstein cows

In order to determine relationships between the number of small follicles prior to superovulatory treatment and superovulatory response, a total of 55 superovulations were induced in Holstein cows. The ovaries were examined ultrasonographically once 0-1.5 days before the initiation of superovulatory treatment. The number of small follicles 3-6 mm in diameter on both ovaries before superovulatory treatment was found to be significantly correlated with the numbers of corpora lutea after superovulation (r = 0.440, P < 0.001), total ova recovered (r = 0.503, P < 0.001) and transferable embryos recovered (r = 0.482, P < 0.001). These results indicate that a single ultrasonographic examination of follicles 3-6 mm in diameter prior to superovulatory treatment can be utilized to predict superovulatory response.     

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   

Effects of thyrotropin, follicle stimulating hormone and luteinizing hormone on sIL-2R in vitro secretion from human peripheral blood mononuclear cells

The effect of thyroid stimulating hormone (TSH) or thyrotropin (0.06, 0.6, 6, and 60 microIU/ml), follicle stimulating hormone (FSH) and luteinizing hormone (0.1, 1, 10, and 100 mIU/ml) on soluble interleukin-2 receptor (sIL-2R) release in vitro from resting or phytohaemagglutinin (PHA) activated human peripheral blood mononuclear cells (PBMC) was evaluated. sIL-2R concentrations were measured in supernatants of cultured cells by quantitative sandwich enzyme immunoassay method (ELISA). TSH in a dilution of 0.6 microIU/ml and FSH in a concentration of 1 mIU/ml inhibited the secretion of sIL-2R only (p < 0.01) into supernatants from PHA activated PBMC cultures.