[For the reasonable use of clomiphene citrate for unexplained infertilities].
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Biomedical subjects
Publications and source records attributed to P Merviel.
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Over-responsive patients are at risk of ovarian hyperstimulation, which may lead to severe complications. The choice of ovarian stimulation protocol or the use of a coasting (gonadotrophins suspension) with its associated risk of too strong ovarian response will be discussed herein. As for in vitro fertilization stimulation protocols, the best are probably those which use steadily increasing low doses of gonadotrophins, associated to GnRH agonists (low-dose protocols) or those which complete a double hypophyseal inhibition (estro-progestative association and GnRH agonists). GnRH antagonists may also reduce the risk of ovarian hyperstimulation, by estradiol drop. Outside the context of in vitro fertilization GnRH continuous administration or low -dose gonadotrophin stimulation are the best options. A coasting will be performed when an excess follicle response is documented. Under strict hormonal follow-up and within four days it allows achieving a high rate of pregnancy with a lower risk of hyperstimulation. Compared to other therapies of hyperstimulation syndrome, the coasting allows to avoid cycle cancellation or freezing of all embryos.
OBJECTIVE: A prospective open study was conducted to evaluate the prepubic (TPP) route of TVT. PATIENTS AND METHODS: 164 patients suffering from stress or mixed urinary incontinence were operated by prepubic route mainly under spinal anaesthesia. The incision is more proximal and para-uretral dissection directed more lateral to reach ischiopubic bone. The tape is introduced while keeping the needle tip close to bone to perforate between bone and ischiocavernous muscle. Then the needle is brought forwards to get its tip in vertical position and pushed under vulva to supra pubic area. A cough test is done with more pulling than in TVT since in TPP the pulling forces will act more frontally and laterally. Evaluation included detailed clinical examination with stress test, pads, endoscopic and urodynamic assessments and questionnaires in order to detect prognostic factors and to have a global treatment policy for associated low urinary tract symptoms and prolapse. RESULTS: Mean follow-up time was 20 months (14-30). No significant intraoperative complications occurred. All patients urinated the first day. The mean postvoid residual urine was 45 ml. Objective cure rate was achieved in 135 (82.3%) patients and 7 (4.3%) patients were improved while failure was observed in 22 (13,4%) patients. From patients'point of view success and satisfaction rates were 85.4% and 86%. No significant modification of sexual activity occurred. DISCUSSION AND CONCLUSION: TPP is a simple technique with very low risks and the preliminary results are consonant with those of other published techniques.
Gonadotrophin-releasing hormone (GnRH) plays a key role in the secretion of gonadotrophins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate steroidogenesis and folliculogenesis. Two GnRH antagonists, Cetrorelix and Ganirelix, deprived of histaminergic side-effects, have been introduced into ovarian stimulation protocols to prevent premature LH surges and proved their safety in clinical trials. At present, most of the published studies have not found significant differences in follicular recruitment, oocyte quality, and so on, except for a decrease in pregnancy and implantation rates in in vitro fertilization and embryo transfer (IVF-ET) cycles when the GnRH antagonist rather than the agonist was used. This decrease in pregnancy rates was in relation with a necessary learning curve of the physicians. Another possibility is the impact of the GnRH antagonist on endometrium through its GnRH receptor; this effect was cancelled after cryopreserved embryo transfers because the pregnancy rates were similar between GnRH antagonist and agonist in this case. GnRH antagonists were also interesting in poor responders and polycystic ovarian syndrome, where the agonists have not permitted to obtain the better results in IVF-ET cycles. Similarly, the GnRH antagonists could prevent the LH surge in the intrauterine insemination cycles.
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The diagnosis of cancer in a pregnant woman raises serious problems for the obstetrician and the oncologist. Many diagnostic and therapeutic procedures cannot be implemented during gestation due to the risk of fetal complications. At the same time postponing radiotherapy or chemotherapy until after delivery would expose the patient to excessive risk. Optimal management practices remain to be fully described and few randomized studies have addressed the problem. There is the additional question of how best to preserve fertility.
Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane and proliferate to form aggregates called trophoblast cell columns (TCCs). They subsequently invade the decidua and differentiate into interstitial and endovascular trophoblasts. The influence of the decidua on EVT differentiation is controversial. We therefore compared the pattern of trophoblast differentiation marker expression in viable intrauterine and tubal pregnancies, as decidual cell markers (prolactin [PRL] and insulin-like growth factor binding Protein-1 [IGFBP1]) were only expressed in endometrial implantation sites. Extravillous trophoblast differentiation in anchoring villi from uterine and ectopic pregnancies exhibited a comparable phenotypical switch: alpha6 integrin subunit, E-cadherin, EGF receptor, Ki 67 and connexin 40 were localized in the proximal part of the TCC, while alpha5beta1 and alpha1 integrins, c-erb B2, hPL and HLA-G were expressed by invasive cytotrophoblasts. The cyclin-dependent kinase inhibitors p16 and p57 were mainly detected in invasive cytotrophoblasts some distance from the columns. However, the TCC was markedly longer in tubal pregnancy than in intrauterine pregnancy. These findings suggest that the decidua is not necessary to trigger EVT invasion, but that it is likely to limit the extent of the TCC and to accelerate the onset of EVT migration.
The objectives of this study were to determine the mean plasma inhibin A and B kinetics in normoovulatory patients treated by GnRH agonist and rec-FSH and to compare their predictive value with that of plasma estradiol on retrieved oocytes number and pregnancy rate. The study was carried out retrospectively in 36 normoovulatory IVF patients stimulated by GnRH agonist from D21 and rec-FSH from D2 of the following cycle. Two groups of 18 patients (having obtained or not a pregnancy) were paired for age and cause of infertility. Estradiol was measured by direct immunoassay. Inhibin A and B were measured by ELISA (Serotec Limited, Oxford, UK). Inhibin A was correlated with estradiol until P-2 (P0: day of follicles aspiration). Inhibin B rose earlier, its concentration reached its maximum at P-5. Plasma estradiol and inhibin A kinetics were not different among pregnant and nonpregnant women. There was a trend for a broader plasma Inhibin B surface under the curve in pregnant than in nonpregnant women. Estradiol and Inhibin A were correlated to the oocytes number at the end of stimulation (P-2 and D10). Inhibin B was correlated earlier than estradiol and inhibin A, at P-8 and D7. Plasma inhibin A did not demonstrate a better predictive value than estradiol neither of the oocytes number nor the chance of pregnancy. Inhibin B could be useful for early decision of cycle cancellation or stimulation adjustment.
The association of breast cancer with pregnancy is rare. It is defined as the occurrence of breast cancer during pregnancy or during the year following delivery. Patient management must be ensured by a multidisciplinary team including gynecologists, obstetricians and clinical oncologists.
OBJECTIVE: To study the relation between serum human chorionic gonadotrophin (hCG) levels measured at 15-18 weeks and gestational disorders, assess their correlation with the artery uteroplacental Doppler (AUD) at 24 weeks among nulliparas, and assess the predictivity of the hCG/hPL (human placental lactogen) ratio for pre-eclampsia. STUDY DESIGN: Retrospective study of two groups of women younger than 38 years old: one with an elevated serum hCG level (2 MoM (multiples of the median) or more) and a normal fetal karyotype (group A), and the other with a lower hCG level (group B). Within each group, we studied the nulliparas separately (respectively groups AO and BO). We analyzed the double screening, elevated hCG levels with abnormal AUD, for the predicting of hypertensive disorders. RESULTS: Elevated hCG levels were significantly (p<0.05) more prevalent among women who developed gestational diabetes (groups A and AO) and among nulliparas with pregnancy-induced hypertension and pre-eclampsia (AO). Among nulliparas, the combination of the hCG assay and a subsequent Doppler increased the positive predictive value (PPV) of the assay from 19 to 75%, without reducing its negative predictive value (NPV) for gestational vascular disorders. The hCG/hPL ratio did not improve the predictivity of the hCG assay alone for pre-eclampsia. CONCLUSIONS: An hCG level of 2 MoM or more at 15-18 weeks identifies a group of women at risk of gestational vascular disorders; it therefore ought to lead to an AUD at 24 weeks. This double screening should be able to define a population of women at risk of developing a hypertensive disorder, who could thus benefit from a preventive treatment, as aspirin.
Fetal cells exist in maternal blood and can be utilized for prenatal diagnosis. These cells are present from the sixth week of gestation, with frequency increasing as gestation advances, to many years after the birth. Enrichment of trophoblast cells, erythroblasts and lymphocytes was performed with various density gradient techniques and either magnetic activated or fluorescent activated sorting techniques. The abnormalities were detected by fluorescent in-situ hybridation (FISH) with chromosome-specific DNA probes for the detection of trisomy 21, trisomy 18, Klinefelter syndrome 47 XXY, or by polymerase chain reaction (PCR) for the detection of fetal sex, certain Mendelian disorders (as beta-globin mutations), HLA polymorphisms and fetal Rhesus D blood type. However others studies were necessary to determine the sensitivity and specificity of this technique as a noninvasive alternative to conventional methods of prenatal cytogenetic diagnosis.
The implantation of the human embryo is a double paradox, immunological and biological. The immunological paradox is that it consists of a heterologous graft in which the uterine immune system (via the cytokines) and the embryo's antigenicity (HLAG) collaborate to make possible both implantation and the maintenance of the pregnancy. The biological paradox arises because several different mechanisms must be successively implemented for these two epithelia to fuse and then for one to allow invasion by the other (that is, the for the endometrium to be decidualized by the trophoblast): preparation of the endometrium throughout the menstrual cycle under the influence of estrogens and then progesterone, with the involvement of growth factors (EGF, TGF and IGF), neoangiogenesis (estradiol, FGF and VEGF), recognition by the trophoblastic cells of the various components of the decidua and of the extracellular matrix (integrins and cadherin) and the progressive invasion of the decidua, to the depth of the spiral arteries (by the trophoblastic secretion of metalloproteases). A defective or excessive trophoblastic invasion can result in complications of pregnancy: early spontaneous miscarriage, preeclampsia and growth retardation of vascular origin in the case of defects, placenta accreta or percreta in the case of excess.
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This is the perfect example of the problems which are the consequences of the actual medicine. We carried out an ovocyte donation study at the Tenon Hospital, in Paris, between 1994 and 1999 involving 177 cryopreserved thawed embryo transfers among 300 recipients. This study enables us to stress the ethical difficulties posed by the so called bioethical laws of 1994. Simultaneously two consequences became clearly evident: a paucity of donors, and the necessity to only transfer frozen embryos due to decree of 1996 upon sanitary security that imposes the quarantine of embryos for six months. On the other hand, the use of this method has yielded important new information regarding embryo implantation and the importance of ovocyte quality that is closely correlated to donor age.
UTERINE DISORDERS: Because they can prevent implantation, anomalies within the uterine cavity play an important role in fertility. The uterine disorders most often observed during hysteroscopy and implicated in infertility are adhesions, septa, polyps, submucous myomas, adenomyosis, endometritis, anomalies of the cervical canal, and lesions of the uterotubal junction. EXPLORATIONS: Hysterosalpingography can be used to evaluate tubal permeability but provides inadequate information about the uterine cavity (numerous false-positives and false-negatives). Pelvic ultrasound is especially helpful for diagnosing interstitial anomalies in the uterus. HYSTEROSCOPY: Diagnostic hysteroscopy also has a place in infertility investigations, for it allows direct visualization of the uterine cavity, the endometrial mucus (endometritis, adenomyosis), and the cervical canal. The examination is practiced on a out-patient basis, without anesthesia, using appropriate small-caliber instruments and irrigation with physiological saline. Surgical hysteroscopy is used to treat these anomalies. Patients receive general anesthesia. A high-frequency, low-voltage electric current is used, and glycine for irrigation. This procedure allows resection of submucous myomas and polyps and of septa and adhesions. Some groups use laser beams and irrigation by physiological saline for these treatments. Coagulation of a superficial focal spot of adenomyosis is not useful in infertility therapy. RESULTS: As assessed by the percentage of patients with each indication who subsequently became pregnant, the results of surgical hysteroscopy have been satisfactory: 62 per cent (%) of cases after myomectomy, 66% after section of uterine septa, and 61% after treatment of complicated adhesions. A new exploration of the uterine cavity will be necessary sometime after the surgery to verify the absence of any iatrogenic disorders (adhesions, myomatous fragments).
Many reports suggested that the high rate of miscarriage in women with polycystic ovaries may be due to increased urine and/or plasma LH concentration. In fact, with the exception of pulsatile GnRH, any treatment likely to increase the plasma LH level results in unchanged or rather low miscarriage rates. Conversely, a reduction in this rate by GnRH agonists is not conclusive. Excess weight may also increase the risk of miscarriage. In women with incipient ovarian failure, the miscarriage rate is mainly linked to age. No stimulation has been found to be effective in these patients. There is a need for more extensive evaluation in GnRH analog microdoses, recombinant FSH and GnRH antagonists. Oocyte donations from younger women are difficult to obtain because of the lack of donors in France.
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