[Liver transplantation for hepatopulmonary syndrome complicating cirrhosis]. / Transplantation hépatique pour syndrome hépatopulmonaire compliquant une cirrhose.

Hepato-pulmonary syndrome (HPS) is a pulmonary vascular complication of cirrhosis quite frequent but often under-diagnosed, and characterized by intra-pulmonary capillary and pre-capillary vascular dilatations that may lead to severe hypoxemia. HPS is often asymptomatic but may induce a progressive dyspnea. HPS diagnosis is based on arterial gasometry that proves the hypoxemia and contrast-enhanced echo-cardiography revealing the vascular dilatations. Screening of HPS is recommended in every cirrhotic patient complaining of dyspnea or in every liver transplantation candidate. Indeed, the only effective treatment of HPS is liver transplantation; HPS patients receive exception-points in the MELD (Model for End-Stage Liver Disease) liver allocation score. The authors report herein the case of a 39-year-old male patient with a cirrhosis of unknown origin complicated by HPS which appeared as a disabling dyspnea. This patient underwent liver transplantation a year after HPS diagnosis and recovered completely.

Le syndrome hépatopulmonaire est une complication vasculaire pulmonaire de la cirrhose relativement fréquente et sous-diagnostiquée, caractérisée par des vasodilatations capillaires et pré-capillaires intrapulmonaires pouvant entraîner une hypoxémie sévère. Souvent asymptomatique, ce syndrome se révèle le plus souvent par une dyspnée d'apparition progressive. Le diagnostic est réalisé par une gazométrie artérielle prouvant l'hypoxémie et une échographie cardiaque de contraste démontrant l'existence de vasodilatations intrapulmonaires. Le dépistage du syndrome hépatopulmonaire est préconisé chez tout patient atteint de cirrhose présentant de la dyspnée et chez tout patient candidat à une greffe hépatique. En effet, le seul traitement efficace est la transplantation hépatique, et ces patients bénéficient d'ailleurs de points d'exception dans le calcul du score de MELD («Model for End-Stage Liver Disease¼). Nous rapportons ici le cas d'un patient de 39 ans atteint d'une cirrhose d'origine indéterminée compliquée d'un syndrome hépatopulmonaire qui s'est révélé par une dyspnée devenue rapidement invalidante. Ce patient a pu bénéficier d'une transplantation hépatique un an après le diagnostic de syndrome hépatopulmonaire, permettant ainsi une guérison complète tant sur plan hépatique que pulmonaire.

[An unusual interstitial pneumonitis]. / Une pneumopathie interstitielle inhabituelle.

We report the case of a twenty-six-years-old patient who developed acute silicosis after only five years of professional exposure. He also succeedingly presented in the course of the disease progressive massive fibrosis, rest hypoxia, and eventually spontaneous pneumothorax. Monopulmonary transplantation was finally successfully performed.

[Male infertility]. / Explorations en infertilité masculine.

In 2/3 of infertility problems, the male partner is, partially or entirely, responsible. His investigation starts with a careful history and is followed by a thorough physical examination. Then, comes the spermogram. In addition to an assessment of the number, motility, and morphology of spermatozoids, this examination must involve a spermocytogram, tests of anti-spermatozoid immunity, and a bacteriological analysis. The biological study of the seminal plasma is also of considerable value. Electron microscopy of sperm is valuable in asthenospermic men. A genetic and hormonal investigation is, nowadays, almost mandatory in all cases. Testicular biopsy with cryopreservation of testicular tissue and demonstration of a possible varicocele can also, in selected cases, be of great help. The overall strategy will be decided on the basis of the whole investigation.

[Successful PMA. Review of the activities of the Center for Medically Assisted Procreation of University of Liege, 1985-1997]. / La PMA qui réussit Bilan d'activité du Centre de Procréation Médicalement assistée de l'ULg, 1985-1997.

Assisted reproductive treatments (ART) hold an increasing place in the field of female infertility but also of male infertility with the development of new micromanipulative technologies. From January 1985 to December 1997, more than 3,000 ovarian punctures were achieved at the CPMA of the University of Liege and more than 40,000 oocytes were recovered. Global results show a take home baby rate of 23% per ovum pick-up and 27% per embryo transfer. Embryo cryopreservation offers an efficient solution to the problem of supernumerary embryos and opens the way for IVF-derived procedures such as oocyte or embryo donation, surrogate mother. The transfer of frozen-thawed embryos increases the total ongoing pregnancy rate per cycle of 31%. One of the aims of our Centre in the near future is the development of new technologies such as control of chromosomal abnormalities or genetic defect in preimplantation embryos and clinical applications of oocyte or ovarian tissue freezing.

The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features.

The multicentric study regroups 128 cases of the ovarian hyperstimulation syndrome (OHSS) in in-vitro fertilization (IVF) and 256 selected controls. Values of serum oestradiol obtained from different laboratories were found to be normally distributed after logarithmic transformation. Comparative study of clinical and biological characteristics indicates that among OHSS patients (i) mean age was lower; (ii) tubal indications for IVF were less frequent; (iii) polycystic ovary-like conditions (i.e. hyperandrogenism, anovulation, luteinizing hormone/follicle stimulating hormone ratio > 2) were more frequent. OHSS patients displayed ovarian hypersensitivity reflected by higher oestradiol peak concentrations in response to lower dosage of human menopausal gonadotrophin and by a steeper slope of oestradiol increment during stimulation. In these patients, the collection of greater numbers of fertilizable oocytes allowed replacement of more embryos with a good vitality score. Ongoing pregnancy rate was found to be higher among the OHSS patients. The following complications were recorded among OHSS cases: abdominal fluid at echographic examination or clinical ascites (86.7 and 71.1%, respectively); pleural and pericardial effusion (21 and 3%, respectively); haemoconcentration (71.1%); electrolytic disorders (6.2%). Although significantly different between groups, clinical and biological parameters under study showed considerable overlap of their distributions in control and OHSS cases. Therefore, these data must be submitted to discriminant analysis in order to derive a formula predictive of the risk of OHSS.

Pregnancy rates after transfer of embryos obtained from different stimulation protocols and frozen at either pronucleate or multicellular stages.

After in-vitro fertilization, 2161 supernumerary embryos were frozen with 1,2-propanediol and sucrose as cryoprotectants at either pronucleate or multicellular (2-6 blastomeres) stages. By the end of March 1990, 494 pronucleate stage embryos and 492 multicellular stage embryos had been thawed and 54 and 47% of them, respectively were considered suitable for transfer. Ongoing pregnancy and implantation rates were 17.9 and 10.7%, respectively for embryos frozen at the pronucleate stage and 5.5 and 4.7% for embryos frozen at the multicellular stage. Ovarian stimulation with human menopausal gonadotrophin (HMG) after pharmacological hypophysectomy with a gonadotrophin releasing hormone agonistic analogue (GnRHa) using a long protocol permitted us to freeze significantly more embryos per cycle (7.2 +/- 4.1) than stimulation with HMG and GnRHa in a short protocol (4.7 +/- 3.4) or stimulation with clomiphene citrate (CC) and HMG (2.7 +/- 1.9). Ongoing pregnancy rates after transfer during the stimulated cycles were similar for the three types of treatment (27.1, 27.3 and 32.1%, respectively). However, ongoing pregnancy rates after frozen-thawed embryo transfers were significantly higher when originating from GnRHa + HMG treatments (14.3 and 14.8%, respectively for long and short protocols) than when originating from CC + HMG treatment (5.6%). Embryo cryopreservation has permitted the ongoing pregnancy rate to increase from 28.4 to 36.9% (P less than 0.01) even though more than half of the embryos have not been thawed. We conclude that embryos obtained after stimulation with GnRHa + HMG and frozen at the pronucleate stage are more likely to result in a pregnancy.

Variations of luteinizing hormone serum concentrations after exogenous human chorionic gonadotropin administration during ovarian hyperstimulation.

Changes in luteinizing hormone (LH), estradiol, and progesterone (P) serum levels before and after preovulatory administration of human chorionic gonadotropin (hCG) were assayed in 30 patients stimulated with clomiphene citrate (CC) and human menopausal gonadotropin (hMG) and compared with LH variations in 43 patients submitted to pharmacological hypophysectomy with a gonadotropin-releasing hormone agonist (GnRH-a) and stimulation with hMG. In CC + hMG-treated patients, an endogenous LH surge occurred systematically 4.25 +/- 2.75 hours after hCG injection. Multiparametric analysis indicated an inverse correlation between the delay in the initial rise of the LH surge and the increase in P levels during the 6 hours after hCG administration. Gonadotropin-releasing hormone agonist + hMG treatment did not lead to an LH surge after hCG but to a significant fall in LH levels. Thus, exogenous hCG, administered before ovulation, induces an endogenous LH surge if pituitary function is not blocked by a GnRH-a, probably through an increase in P secretion.

[Treatment of ovarian polycystic syndrome in vitro. Physiopathogenetic considerations]. / Traitement des dystrophies ovariennes polykystiques au cours de fécondation in vitro. Considerations physiopathogeniques.

More than 60% of patients with polycystic ovary disease (PCO) cannot conceive after repeated ovulation inductions with Clomifene citrate although there is ovulation or more frequently follicle luteinization. Because of hyperstimulation, therapy with hMG has been superseded by low doses of purified FSH with variable results according to authors. It has been even claimed that there was no benefit to replace hMG with FSH. However, on the basis of the PCO physico-pathology, namely LH hypersecretion and androgen hyperproduction, it would be rational to associate the desensitization of the pituitary with LH-RH agonist and the ovary stimulation with variable doses of hMG or purified FSH. In the series where such therapy associating LH-RH agonists with purified FSH was applied, the results concerning suppression of LH and androgen secretion, and the occurrence of pregnancy were interesting. However, the risk of hyperstimulation still occurred. Thus, the first part concerns the critical review of these results while, in the second part, our experience in in vitro fecundation will be reported.

Inhibin and related peptides: mechanisms of action and regulation of secretion.

The structure of inhibin is known; it consists of a heterodimer composed of one alpha and one beta subunit. The homodimer of beta A (beta A-beta A) and the heterodimer beta A-beta B, called activin A and B, respectively, stimulate the release and synthesis of FSH by gonadotrophs. Inhibin exerts effects at the hypophyseal, hypothalamic, and gonadal levels. Produced by granulosa cells in the female and by Sertoli cells in the male, inhibin synthesis is stimulated by FSH and reduced by hypophysectomy and progesterone. At present, there is no evidence for a signal from germinal cells to modify inhibin production. Inhibin secretion evolves in parallel with follicular maturation and aromatase activity, whereas luteinization arrests its production. Nevertheless, important differences in the regulation of inhibin secretion seem to exist from one species to another. Sperm inhibin levels can be correlated with spermatozoa number. Administration of inhibin to sheep induces either anovulation or an increase in the rate of ovulation depending on the scheme of treatment.

[Male infertility and medically assisted procreation]. / Infertilité masculine et procréation médicalement assistée.

Three hundred thirty patients underwent in vitro fertilization in our centre since 1985. Fifty two percent of them presented an abnormal spermogram (sperm count less than or equal to 20 X 10/ml; mobility less than 40%; teratospermia greater than 60%). In those cases, lack of fertilization is statistically increased but pregnancy rate per transfer is similar to this observed with pure female cases. Sperm count, mobility and teratospermia influence the success rate but are not sufficient criteria of ability to fertilize. On the other hand, hamster test is without predictive interest.

[Paracrine regulation of testicular function]. / Régulation paracrine des fonctions testiculaires.

Spermatogenesis and spermiogenesis are controlled by FSH and testosterone but need also the participation of several paracrine and autocrine mechanisms of regulations. The relationships between peritubular, Sertoli and Leydig cells are currently investigated. High intratesticular testosterone levels are maintained by a binding to a protein called ABP which is synthetized by Sertoli cell and regulated by pituitary FSH. Leydig cell testosterone, peritubular cell P-Mod-S (protein modulating Sertoli function) and Sertoli cell FRP (follicle regulatory protein). Accumulation of testosterone results to aromatase activity modulation. Aromatization is stimulated by FSH, activin, alpha-MSH but is inhibited by aromatase inhibitor, inhibin, FSHBI (FSH binding inhibitor). Other molecules, growing factors, mitogenic factors, energetic substrates are synthetized in the testis under the control of germ cells. Understanding of these mechanisms of intratesticular regulation will permit to discover therapies capable of correcting certain fertility dysfunctions.

Inhibin and related peptides. Mechanisms of action and regulation of secretion.

The structure of inhibin is known: it consists in a heterodimer constituted by one alpha and one beta subunits. The homodimer of beta A or the heterodimer beta A or the heterodimer beta A-beta B called activin A and B stimulates the release and the synthesis of FSH by gonadotrophs. Inhibin displays actions at hypophyseal, hypothalamic and gonadal levels. Produced by granulosa cells in female and by Sertoli cells in male, inhibin synthesis is stimulated by FSH, and reduced by hypophysectomy and progesterone. At the present time, there is no evidence for a signal from germinal cells to modify inhibin production. Inhibin secretion evolves with follicular maturation as aromatase activity whereas luteinization arrests its production. Nevertheless it seems to exist large difference in the regulation of inhibin secretion from one species to the other. Sperm inhibin levels are correlated with spermatozoa number. Its administration to the sheep induce either an anovulation or an increase of ovulation rate according to the scheme of treatment.

Laminin and type III procollagen peptide in human preovulatory follicular fluid.

The levels of laminin P1 fragment, a marker of basement membrane, and of the aminoterminal sequence of type III procollagen, a marker of interstitial connective tissue, were measured in human preovulatory follicular fluids. The concentrations of these peptides correlated with progesterone levels but not with those of estradiol or testosterone. Immunocytochemical studies confirmed the remodeling of the perifollicular basement membrane and interstitial matrix during oocyte maturation. The studies suggest that monitoring of the ovarian connective tissue macromolecules could be useful for estimating follicular maturation.

Endocrine, paracrine and autocrine control of follicular development.

Development of a single follicle during the menstrual cycle is under control of hormones stimulating follicular maturation, ovulation and luteogenesis. Several factors intervene locally to prevent other follicles from developing at the same time as dominant follicle. These other follicles remain quiescent or evaluate to atresia. Atresia results from the action of several endocrine, paracrine and autocrine mechanisms which synergistically inhibit aromatase activity. The subsequent lack of estrogens reduces granulosa cell multiplication. The oocyte will not become fertilizable before the preovulatory peak of LH, after the resumption of meiosis and after reaching metaphase of the second meiotic division. Several factors are involved in the inhibition of spontaneous resumption of meiosis: cyclic nucleotides, sex steroids, somatostatin and oocyte maturation inhibitor(s) (OMI). Ovulation is related to breakdown of connective tissue synthesized by granulosa cells under the influence of FSH. Connective tissue lysis is dependent on proteolytic enzymes which are released and activated by FSH, LH and relaxin. A paracrine control could be involved in ovulation: LH induces the production of prostaglandin and relaxin by theca cells which, in turn, stimulate collagenase and proteoglycanase secretion by granulosa cells.