Long-term effects of the mammary carcinogen 7,12-dimethylbenz(a) anthracene on hypothalamic gonadotropin-releasing hormone and its pituitary receptor gene expression,during the promotion stage,in female Sprague-Dawley rats

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of these tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory luteinizing hormone (LH) surge and amplification of the preovulatory 17-estradiol surge, and gonadotropin-releasing hormone (GnRH) released in vitro. In this study, we examined the hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus (POA-AH) and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland. Sprague-Dawley rats, 55–60 days of age with regular estrous cycles, received a single dose of 15mg DMBA in 1ml sesame oil delivered by intragastric intubation. A first series of experiments was performed for the measurement of hypothalamic GnRH mRNA and pituitary GnRH Rc mRNA levels. A second series of experiments was performed for the measurement of pituitary GnRH receptor. In both experiments, animals were sacrificed by decapitation at 11.00, 16.00, 18.00 and 20.00h on each day of the 7th or 8th estrous cycle (28–32 days) after treatment. GnRH and GnRH receptor mRNAs were quantified using solution hybridization-RNase protection assay. The GnRH Rc was quantified using the 125I-D-Ala⁶-N-Met-Leu⁶-des-Gly¹⁰-ethylamide GnRH. DMBA-treatment produced no significant effect on the overall mean values of GnRH mRNA. GnRH mRNA levels in control rats rose significantly between 16.00 and 20.00h on proestrus and between 18.00 and 20.00h on diestrus I. DMBA-treated rats had a surge in GnRH mRNA levels at 18.00h on proestrus, and showed additional surges at 18.00h on diestrus II and estrus. GnRH receptor mRNA content in the anterior pituitary gland surged at 16.00h on certain days of the cycle in both groups of rats. In control rats, only the surge on diestrus II proved significant, whereas DMBA-treated rats exhibited significant surges on diestrus I, diestrus II and proestrus. GnRH receptor mRNA values were significantly lower on both days of diestrus in DMBA-treated rats compared with controls. GnRH Rc peptide content, like GnRH receptor in RNA surged at 16.00h in both groups with the exception of a marked fall on proestrus day for DMBA treated rats. A reduction in the amplitude of the surge was also seen on the day of estrous and to a lesser extend on the day of diestrus DII in DMBA treated animal. Overall, there was a disruption of the GnRH Rc pattern which culminate on the day of proestrus in DMBA-treated animals. Interestingly, the daily rise between 11.00 and 16.00h which is the more pronounced on the day of proestrus in control animals, was completely blunted in DMBA-treated rats. Overall, the results are consistent with the hypothesis that the carcinogen attenuates, directly or indirectly, preovulatory biosynthesis of the GnRH receptor and LH release.     

Interaction between Alpha-Fetoprotein Gene and Gonadotropin-Releasing Hormone and Effects on Brain Sexual Differentation: Molecular Function and Biological Process

Brain sexual differentiation is a present focus in sexuality research. Within the process, the alpha-fetoprotein gene (AFP) and gonadotropin-releasing hormone (GnRH) are found to be interacted and cause several effect on the sexual differentiation in animal model. However, the actual mechanism and interaction in human has never been clarified. Here, the author used a new gene ontology technology to predict the molecular function and biological process of the interaction between GnRH and AFP in human.     

Conservative Management versus Aspiration of Functional Ovarian Cysts Before Ovarian Stimulation for Assisted Reproduction

Purpose: To compare the efficiency of transvaginal ultrasound-guided functional ovarian cyst aspiration, withconservative management, in the outcome of patientsundergoing assisted reproductive technique (ART) (in vitrofertilization or intracytoplasmic sperm injection). Thesecysts were identified before ovarian stimulation begun andafter administration of a midluteal GnRH agonist. Methods: Fifty nine patients undergoing ART from January1, 1997 to February 28, 1999, who developed functionalovarian cysts were included. Aspirations of these cysts(n = 14) versus conservative management(n = 45) were compared. Total number of ovarian folliclesdeveloped, number of oocytes retrieved, estradiol levels onthe day of human chorionic gonadotropin, fertilization rate,number of good quality embryos transferred, implantation,and clinical pregnancy rate per cycle were evaluated. Results: No statistical differences were observed betweenthe two groups in any of the selected parameters. Conclusions: Cyst aspiration and conservative managementshowed similar implantation and pregnancy rates, in patientswho develop functional ovarian cysts after pituitarydown-regulation following luteal phase gonadotropin-releasinghormone agonist administration. Prospective studies areneeded to confirm this trend.     

GnRH拮抗剂配伍HMG方案对卵巢低反应患者IVF—ET治疗结局分析

目的探讨促性腺激素释放激素拮抗剂（GnRH拮抗剂）配伍HMG方案对卵巢低反应患者控制性超排卵的效果，及其对体外受精-胚胎移植结局的影响。方法研究对象为前次IVF—ET治疗失败，证明是卵巢低反应，要求再次IVF—ET治疗的患者，随机分为2组，实验组使用GnRH拮抗剂＋HMG方案，共21个周期，对照组使用GnRH激动剂短方案，共23个周期。将两组患者的年龄、基础FSH水平、Gn使用天数和剂量、hCG日血清E2水平、获卵数、受精率、临床妊娠率、胚胎种植率等进行比较。结果两组患者不孕年限、与前次IVF—ET间隔时间、周期取消率、Gn使用天数、HCG日E2水平、获卵数、受精方式、受精率，胚胎移植数等比较差异均无显著性（P〉0．05）。拮抗剂组与激动剂组的平均年龄分别为：（37．7±3．3）岁和（35．9±4．1）岁；平均基础FSH分别为：（14．21±6．76）μ／L和（10．04±4．60）μ／L。平均Gn使用量：拮抗剂组为（32．3±17．8）支，激动剂组为（39．8±12．2）支。拮抗剂组与激动剂组的临床妊娠和胚胎种植率分别为（42．1％vs10．5％）和（25．7％vs5．0％），两组患者的年龄、基础FSH、平均Gn用量、临床妊娠率、胚胎种植率等比较差异均有显著性（P〈0．05）。结论GnRH拮抗剂与HMG配伍，对卵巢低反应的患者是一种有效的超排卵治疗方案，可以提高IVF—ET的临床妊娠率和胚胎种植率，并且费用低廉。     

Characterization of binding sites for a GnRH-agonist (buserelin) in human breast cancer biopsies and their distribution in relation to tumor parameters

Summary Gonadotropin-releasing hormone analogs (GnRH-A) have been added to the armentarium in the therapy of hormone-dependent breast cancer in premenopausal women. The effect of chronic GnRH-A-treatment in premenopausal women is based on the suppression of the hypothalamus-pituitary-ovarian axis and the reduction of sex-steroid serum levels. In addition, a number of experimental and clinical data have been accumulated indicating a direct action of GnRH-A on breast cancer cells and tissue. In this study we analyzed 235 human breast cancer biopsies for specific GnRH-A-binding. We demonstrate high affinity GnRH-A binding sites in human breast cancer tissues. The evaluation of clinical data showed no correlation of the level of GnRH-A-binding with classical tumor parameters.     

High responders are not exempt from detrimental effects of prematurely rising progesterone levels in fresh embryo transfer cycles

Research question

Are high-responder IVF patients protected from the deleterious effect of prematurely elevated serum progesterone level on the probability of pregnancy?

Growth Hormone-Releasing Hormone (GHRH)-GH-Somatic Growth and Luteinizing Hormone (LH)RH-LH-Ovarian Axes in Adult Female Transgenic Mice Expressing Human GH Gene

We have examined alterations in the hypothalamo-pituitary GH-somatic growth axis and the hypothalamo-pituitary LH-ovarian axis in a line of transgenic ICR mice expressing human GH (hGH) under the influence of the whey acid protein promoter. Transgenic female mice weighed twice as much as control females and were infertile. The size of the anterior pituitary (AP) was that of the controls. In transgenic mice, acinar cells in the mammary and mandibular glands displayed hGH-immunoreactivity, and plasma hGH was detected by radioimmunoassay. In the medial basal hypothalamus (MBH) of transgenic females, the immunoreactive-GHRH level was decreased (P<0.01). There was a corresponding reduction in the number of GHRH-immunoreactive neurons in the arcuate nucleus (ARC) and in the immunostaining of GHRH nerve terminals in the median eminence. The level of somatostatin (SRIH) in the MBH was increased (P<0.05), and SRIH-immunoreactive neurons in the periventricular nucleus (PeV) were increased in size and number in transgenic mice. The MBH level of LHRH in transgenic animals was greater (P<0.01) than in controls, although there was no apparent difference in the number of LHRH-immunoreactive neurons or in LHRH level in the preoptic area. There are fewer SRIH- and LHRH-immunoreactive neurons in the ARC in transgenic mice. Cells in the AP for GH, PRL, and LH were fewer in transgenic mice. The ovary suffered disturbance of follicular development and of corpora lutea formation.     

Gonadotropin-releasing hormone agonistic analogues in the treatment of advanced prostatic carcinoma

Orchiectomy or chronic administration of the gonadotropin releasing hormone agonistic analogue D, Ser (TBU)⁶, des Gly-NH₂¹⁰ ethylamide (HOE 766) were employed as therapeutic maneuvers in 25 patients with advanced prostatic carcinoma. HOE 766 administration effectively suppressed plasma testosterone to castrate levels that persisted for as long as treatment continued. Surgical and medical castration resulted in a significant decrease in prostatic size; this became evident earlier for surgically than medically treated patients (P <.05), but no difference existed after the third month of treatment. Symptoms and signs of prostatism improved in practically all the patients. Among patients with stage D₂ disease, there was an improvement in five as far as bone radiological assessment was concerned. Alkaline phosphatase levels did not show appreciable changes in patients showing objective stable disease or partial response according to National Prostatic Cancer Project criteria. Radioimmunoassayable prostatic acid phosphatase levels became normal in two of two stage C, five of five stage D₁, and eight of seventeen patients with stage D₂ disease, a rise in prostatic acid phosphatase (PAP), in alkaline phosphatase, and deterioration in bone radiology were associated with clinical evidence of relapse; this occured despite persistently low levels of plasma testosterone. Serum thyroxine, cortisol, and prolactin levels remained unchanged following orchiectomy or chronic administration of HOE 766. Practically all patients complained of hot flashes and experienced a decrease in libido and potency, but none developed gynecomastia or thromboembolic episodes. The data indicate that HOE 766 can be used safely as an alternative to castration or estrogens for the treatment of patients with androgen-dependent prostatic cancer.     

Effect of gonadotropin-releasing hormone hypogonadism on insulin action as assessed by hyperglycemic clamp studies in men

OBJECTIVE: To investigate the effects of decreasing androgen levels on insulin action, in view of the relationship between hyperandrogenism and impaired insulin action in women with polycystic ovary syndrome. DESIGN: Prospective, clinical study. SETTING: University hospital. PATIENT(S): Ten normal healthy men. INTERVENTION(S): Gonadotropin-releasing hormone (GnRH) agonist, 3.75 mg, administered monthly for 3 months. MAIN OUTCOME MEASURE(S): Insulin action (M/I ratio). RESULT(S): The M/I ratio decreased from 0.24 +/- 0.04 to 0.17 +/- 0.04 after GnRH agonist therapy. CONCLUSION(S): In normal men, administration of a GnRH analogue was associated with a decrease in both testosterone levels and insulin action.