Miklós Koppán

Bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung carcinoma

Antagonists of bombesin/gastrin‐releasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/GRP on tumors such as small cell lung carcinoma (SCLC). Although several studies have addressed the intracellular events that follow the formation of the receptor‐ligand complex, the mechanism of action of BN/GRP antagonists remains unclear.

Endometriosis: Harmful survival of an ectopic tissue

Endometriosis results from implantation of endometrial tissue outside the uterine cavity. Endometriosis might remain asymptomatic and discovered accidentally. However, it may cause symptoms, which include chronic pelvic pain, bleeding, infertility, and increases susceptibility to development of adenocarcinoma. The most prevailing hypothesis is that endometriosis results from implantation of endometrial tissue that gains access to peritoneal cavity by retrograde flow during menstruation. The factors contributing to the establishment and persistence of the endometriotic lesions (plaques) most probably include abnormalities of the genital tract, genetic predisposition, hormonal imbalance, altered immune surveillance, inflammatory response and abnormal regulation of the endometrial cells. The mediators that contribute to survival and progression of endometriosis are likely involved in the development of the symptoms of this process. Genomic studies have started to delineate the wide array of mediators involved and the complex genetic background required in the development of endometriosis. This review summarizes our current knowledge regarding the pathogenesis of endometriosis, including progress made with transgenic animals, and a clinical perspective on the diagnosis and management of this common process.

Luteinizing hormone–releasing hormone (LH–RH) antagonist Cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors

In previous studies, we showed that LH-RH antagonist Cetrorelix inhibits the growth of DU-145 and PC-3 human androgen-independent prostate cancers in nude mice. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer with Cetrorelix at a dose of 100 microg/animal subcutaneously (s.c.) once a day. Tumor growth, serum and tumor levels of IGF-I and -II as well as the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of treatment, final volume and weight of DU-145 tumors in mice treated with Cetrorelix were significantly decreased compared with controls and serum IGF-1 showed a significant reduction. Therapy with Cetrorelix also reduced by 84% the levels of IGF-II in DU-145 tumor tissue compared with controls, but did not affect the concentration of IGF-I. RT-PCR analyses revealed a high expression of mRNA for IGF-II, but not for IGF-I in DU-145 tumors. Treatment with Cetrorelix decreased the expression of IGF-II mRNA by 78% (p < 0.01) as compared with controls. Our study indicates that LH-RH antagonist Cetrorelix may inhibit the growth of DU- 145 human androgen-independent prostate cancers by decreasing the production and mRNA expression of IGF-II by the tumor tissue. This also suggests that LH-RH antagonist Cetrorelix could interfere with the signal transduction pathways involving IGF-II, leading to tumor growth inhibition.

Lamprey Gonadotropin Hormone-Releasing Hormone-III has No Selective Follicle-Stimulating Hormone-Releasing Effect In Rats

Lamprey gonadotropin releasing‐hormone (LGnRH)‐III, a hypothalamic neurohormone recently isolated from sea lamprey, was reported to have a selective stimulatory effect on follicle‐stimulating hormone (FSH) release in rats and suggested to be the mammalian FSH‐releasing factor. In this study, we determined the relative luteinizing hormone (LH)‐ and FSH‐releasing potency of LGnRH‐III compared to mammalian gonadotropin‐releasing hormone (LHRH) in normal female rats, ovariectomized (OVX) and oestrogen/progesterone substituted rats and the superfused rat‐pituitary cell system. The specificity of LGnRH‐III for the mammalian LHRH receptor was investigated by blocking the receptor with an LHRH antagonist, MI‐1544. In vitro, LGnRH‐III dose‐dependently stimulated both LH and FSH secretion from rat pituitary cells at 10−7 to 10−5 M concentrations, while LHRH stimulated gonadotropin secretion at a 1000‐fold lower doses (10−10 to 10−8 M). The difference between its LH‐ and FSH‐releasing potency was similar to that of LHRH. LGnRH‐III bound to high affinity binding sites on rat pituitary cells with a Kd of 6.7 nm, Bmax=113±27 fmol/mg protein. In vivo, LGnRH‐III also stimulated both LH and FSH secretion in a dose‐dependent manner and, similar to LHRH, induced a greater rise in the serum LH than the FSH level. In normal cycling rats, it showed 180–650‐fold weaker potency than LHRH in stimulating LH secretion and 70–80‐fold weaker effect in stimulating FSH secretion. In OVX rats, LGnRH‐III demonstrated a similarly weak effect on both gonadotropins. It was found to be 40–210‐fold less potent than LHRH regarding LH release and 50–160‐fold weaker regarding FSH release. LHRH‐receptor antagonist MI‐1544 prevented both the LH‐ and the FSH‐releasing effect of LGnRH‐III both in vitro and in vivo. These results do not support the hypothesis that LGnRH‐III might be the mammalian FSH‐releasing factor but demonstrate that it is a weak agonist for the pituitary LHRH receptor and stimulates both gonadotropins in a dose‐dependent fashion.

Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome

OBJECTIVE To evaluate the effect of low-dose aspirin therapy on ovarian hyperstimulation syndrome (OHSS) in an unselected group of patients undergoing in vitro fertilization (IVF). DESIGN Randomized clinical trial. SETTING Division of Reproductive Medicine at the Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, Pécs, Hungary. PATIENT(S) Patients who underwent IVF between 2000 and 2006. INTERVENTION(S) Initiation of 3154 IVF cycles, for which gonadotropin-releasing hormone agonist was used in 2425 cycles; 1503 cycles randomly selected for low-dose aspirin treatment starting from the first day of controlled ovarian hyperstimulation compared with no treatment in the remaining 922 cycles. MAIN OUTCOME MEASURE(S) The incidence of severe or critical OHSS and the rate of clinical pregnancy. RESULT(S) During this time period, 45 cases of severe OHSS were detected. Only two of the OHSS patients had received aspirin previously. CONCLUSION(S) Based on our preliminary results, introduction of low-dose aspirin therapy during ovulation induction for the prevention of OHSS in high-risk patients should be considered.

Effects of perinatal asphyxia on the neurobehavioral and retinal development of newborn rats.

Perinatal asphyxia during delivery produces long-term deficits and represents a major problem in both neonatal and pediatric care. Several morphological, biochemical and behavioral changes have been described in rats exposed to perinatal asphyxia. The aim of the present study was to evaluate how perinatal asphyxia affects the complex early neurobehavioral development and retinal structure of newborn rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by cesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily during the first 3 weeks, and motor coordination tests were performed on postnatal weeks 3-5. After completion of the testing procedure, retinas were removed for histological analysis. We found that in spite of the fast catch-up-growth of asphyctic pups, nearly all examined reflexes were delayed by 1-4 days: negative geotaxis, sensory reflexes, righting reflexes, development of fore- and hindlimb grasp and placing, gait and auditory startle reflexes. Time to perform negative geotaxis, surface righting and gait reflexes was significantly longer during the first few weeks in asphyctic pups. Among the motor coordination tests, a markedly weaker performance was observed in the grid walking and footfault test and in the walk initiation test. Retinal structure showed severe degeneration in the layer of the photoreceptor and bipolar cell bodies. In summary, our present study provided a detailed description of reflex and motor development following perinatal asphyxia, showing that asphyxia led to a marked delay in neurobehavioral development and a severe retinal degeneration.

The effect of catecholamines, acetylcholine and histamine on progesterone release by human granulosa cells in a granulosa cell superfusion system

There are experimental data demonstrating the presence and actions of various neurotransmitters in the ovary, thus supporting the view that they might play a role in intraovarian regulatory mechanisms, although their exact function in the regulation of ovarian hormone secretion is unclear. The objective of the present study was to investigate the direct action of catecholamines, acetylcholine and histamine on progesterone secretion of human granulosa cells in a superfused cell system. Human granulosa cells were isolated from preovulatory follicular fluid using a Percoll gradient centrifugation method. Approximately 2 × 106 cells were mixed with Sephadex G-10 and were transferred into two chambers of the superfusion apparatus. The system was perfused with a culture medium and test materials were added to the system at a dose of 100 pmol/ml. The progesterone concentration of samples was measured using an 125I radioimmunoassay. Administration of epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine and histamine had no effect on progesterone release. However, acetylcholine produced a significant progesterone release, which could be blocked by atropine. The observed effect of acetylcholine on progesterone release of superfused human granulosa cells may reflect a physiological role of acetylcholine in the regulation of granulosa cell function during the menstrual cycle.

Inhibition of the UCI‐107 human ovarian carcinoma cell line by a targeted cytotoxic analog of somatostatin, AN‐238

Cytotoxic analogs of somatostatin (SST), such as AN‐238, which consists of 2‐pyrrolinodoxorubicin (AN‐201) linked to the SST carrier RC‐121, can be targeted to tumors that express SST receptors. Because SST receptors are present in ovarian carcinoma cells, the authors evaluated the effect of AN‐238 on the UCI‐107 ovarian carcinoma cell line.

Role of PACAP in Female Fertility and Reproduction at Gonadal Level – Recent Advances

Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, first isolated from hypothalamic extracts, but later shown in peripheral organs, such as endocrine glands, gastrointestinal system, cardiovascular system, and reproductive organs. PACAP plays a role in fertility and reproduction. Numerous studies report on the gonadal regulatory effects of PACAP at hypothalamo-hypophyseal levels. However, the local effects of PACAP at gonadal levels are also important. The present review summarizes the effects of PACAP in the ovary. PACAP and its receptors are present in the ovary, and PACAP plays a role in germ cell migration, meiotic division, follicular development, and atresia. The autocrine-paracrine hormonal effects seem to play a regulatory role in ovulation, luteinization, and follicular atrophy. Altogether, PACAP belongs to the ovarian regulatory peptides.

Effects of Pituitary Adenylate Cyclase Activating Polypeptide on Human Sperm Motility

Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide with diverse effects, was originally isolated as a hypothalamo-hypophyseal peptide. Subsequent studies showed highest levels of PACAP in the testis after the brain, suggesting that it influences the development and functioning of spermatozoa. Indeed, it has been proven that PACAP has an effect on spermatogenesis, both locally and via influencing the hypothalamo-hypophyseal–gonadal axis. The aim of the present study was to determine whether PACAP has an effect on human sperm motility and whether it is present in the human seminal fluid. Furthermore, the sperm head morphology was studied in mice lacking endogenous PACAP. Human samples were obtained from healthy adult volunteers and andrological patients. The effects of PACAP on the motility of human sperm cells were investigated using a computer aided sperm analysis system. In cases where the motility was lower, addition of PACAP to the samples increased the motility and the ratio of rapid progressive and medium progressive sperm motility groups. The presence of PACAP could not be detected in human seminal fluid samples by means of mass spectrometry. Investigating sperm head morphology with routine histology in PACAP deficient mice revealed that both the longitudinal and transverse diameters were significantly lower in PACAP deficient mice, without marked difference in the shape, as revealed by scanning electron microscopy.