Biomedical subjects
Publications and source records attributed to P Fénichel.
Struma ovarii, a rare form of ovarian tumor, represents less than 3% of ovarian teratomas. The peak frequency occurs during the fifth decade of life. Diagnosis is usually a surprise of pelvic ultrasound or histological analysis. Surgery is the main mode of treatment and prognosis is excellent. Struma ovarii can be associated with thyroid biology abnormalities, or exceptionally become malignant, and thus managed as a thyroid cancer.
OBJECTIVES: To evaluate and compare the outcome of pregnancies in women with type 1 diabetes treated with continuous subcutaneous insulin pump or multiple insulin injections. PATIENTS AND METHODS: Thirty-three patients treated with pump, 23 with multiple injections. Were mainly investigated: glycemic control (HbA1C), fetal outcome (congenital malformations, preterm delivery, perinatal mortality), rates of gestational hypertension and cesarean section. RESULTS: HbA1C (1st, 2nd and 3rd trimester) with pump was not significantly different from that obtained with multiple injections (respectively, 7.5 +/- 1.24 vs 7.6 +/- 1.4; 6.34 +/- 0.6 vs 6.6 +/- 0.8; 6.6 +/- 0.7 vs 6.4 +/- 0.7). Fetal prognosis was also similar. The occurrence of gestational hypertension was linked to diabetic complications [OR 5,7, IC95% 1.24-25, p = 0.0025]. The rate of cesarean section (70% in women treated with pump) was influenced by diabetes duration. In planned pregnancy, independently of therapeutic device, HbA1C during organogenesis was better (6.9% +/- 0.78 vs 8.51 +/- 1.3, p < 0.0001) with no perinatal death and no major congenital malformation. DISCUSSION AND CONCLUSION: Fetal prognosis is not overall significantly different with insulin pump compared with intensified conventional therapy. The initiation of insulin pump therapy should not be systematic. Instead, the benefits risks ratio must be assessed resulting in a tailored prescription according to individual needs. This therapeutic choice should be discussed before conception, as planned pregnancy is a main prognostic factor. Diabetes duration and complications remain key factors for the prognosis.
Intensive use of radiochemotherapy has greatly improved the prognosis associated with cancer in young women patients. However, improvement of the vital prognosis is frequently associated with impairment of fertility and premature ovarian failure. Cryopreservation of ovarian tissues has been developed but effective secondary use of cryopreserved tissue by means of autograft or through in vitro follicular maturation need yet to be clarified even though first success seemed to be recently obtained. Infant ovaries have been considered to be less sensitive than adult ovaries, which has suggested that hypophysal blockage could protect adult ovaries against fertility impairment before and during radiochemotherapy. Non-randomized studies using LHRH agonists support such a hypothesis. However what we know about physiopathology of follicular destruction involving exaggerated apoptosis and several animal models do not fit with these results. By consequence randomized studies need to be performed to verify the benefit, which one could expect from such a systematic clinical use.
OBJECTIVES: The rise in the prevalence of type 2 diabetes in women of childbearing age leads to an increasing number of pregnant women with type 2 diabetes. But published data on fetal outcome are scarce. PATIENTS AND METHODS: In a prospective study from 1999 to 2002, we assessed fetal outcome (preterm delivery, perinatal mortality, congenital malformations) in 20 pregnancies associated with type 2 diabetes and compared the outcome to 40 pregnancies associated with type 1 diabetes. RESULTS: Women with type 2 diabetes are older (32 +/- 5 vs. 27 +/- 5, P = 0.003), more obese (body mass index: 28.3 +/- 4.8 vs. 22.8 +/- 5.5, P < 0.001) than women with type 1 diabetes. Their pregnancy usually is not planned (10% vs. 55%, P < 0.001). HbA1c during organogenesis is above 8% in 46.6% of type 2 vs. 26.4% of type 1 (P < 0.001). Compared with data obtained in the general population, a fivefold increase in preterm delivery (26.3% vs. 4.7%), a sevenfold increase in perinatal mortality (5% vs. 0.7%) and congenital malformations (15.8% vs. 2.2%) are observed. These results are similar to those obtained in type 1. In planned pregnancy, HbA1c during organogenesis is under 7% with no perinatal death and no major congenital malformation. DISCUSSION AND CONCLUSION: Pregnancy complicated by type 2 diabetes is a high-risk one, as much as in type 1 diabetes. Efficient pre-pregnancy care needs to be strongly encouraged in women with type 2 diabetes who also display many risk factors for adverse fetal outcome.
Hypoestrogenic hypergonadotrophic amenorrhea occurring before the age of 40 years is generally considered irreversible. The term "premature menopause" used to define this condition seems a misnomer, and "premature ovarian failure" (POF) is preferred on both a psychological and a physiological basis. POF is not uncommon considering the incidence rate of 1-2% of women during their theoretically reproductive life. These circumstances are particularly painful when a child is desired. However, since a long time the notion of permanent cessation of ovarian function is challenged and intermittent and transient return of ovarian function has been described with 5-10% chance of pregnancy often more than 12 months after the beginning of the amenorrheic status. A multicentric retrospective study conducted by the GEDO reports 27 pregnancies out of 518 patients waiting for an in vitro fertilization with oocyte donation because of POF or occult ovarian insufficiency. Considering this work and a literature review, we try to propose part of understanding of the basic POF physiopathology, and to examine the factors which could act on the prognosis and the clinical management.
The increasing prevalence of type 2 diabetes in women of childbearing age leads to an increasing number of pregnant women with type 2 diabetes. Pregnancy complicated by type 2 diabetes is a high-risk pregnancy, associated with birth defects and high perinatal mortality to the same extent as in type 1 diabetes. Until now, most attention was directed toward women with type 1 diabetes. Recent data stresses the urgent need to develop better screening and efficient care strategies in women with type 2 diabetes, who also display many risk factors for adverse fetal outcome. Family physicians, diabetologists and gynaecologists must be aware of this growing concern. Improvement of pregnancy planning, adequate metabolic control from conception to delivery and a multi-disciplinary team approach to care should improve fetal and maternal outcomes. Furthermore, diabetes screening in high-risk women prior to pregnancy is warranted.
Connexin43 (Cx43) is one of the most predominant gap junction proteins found in the testis. We used in situ hybridization and indirect immunofluorescence to study the distribution of Cx43 mRNA and protein in the rodent seminiferous epithelium. During mouse testis maturation, Cx43 mRNA and its corresponding protein were first detected in the adluminal compartment of the growing seminiferous tubules (early postnatal age: Day 12) to become progressively located in the basal compartment at later ages (Days 16, 19, 27). In seminiferous tubules of sexually mature animals, the intensity of the hybridization signal was stage-dependent, with a maximum at Stage VII compared with Stages V and IX of the spermatogenic cycle (p<0.05). The highest expression of Cx43 mRNA was observed in the supporting Sertoli cells and, to a lesser extent, in the most basally located and less mature germ cells (spermatogonia and spermatocytes). Consistent with these observations, in situ dye coupling was observed between Sertoli cells and basal germ cells. In a mutant mouse deficient for the retinoid X receptor beta, which exhibited abnormal spermatogenesis due to altered Sertoli cell function, Cx43 transcripts were markedly decreased in the seminiferous epithelium (p<0.01). The immunoreactive signal for Cx43 was significantly reduced in seminiferous tubules of the 3-month-old mutant mice (p<0.05) and undetectable in older animals. These data provide new information about the precise localization of Cx43 mRNA and protein in seminiferous tubules of immature and mature rodent testes. Moreover, they suggest that retinoids, through the RXRbeta receptors, could be involved in the control of Cx43 gene expression in Sertoli cells.
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Anti-Müllerian hormone (AMH) also known as Müllerian inhibiting substance or factor, is a Sertoli cell-secreted glycoprotein responsible in male embryos for Müllerian duct regression. However, its role in adults remains unknown. AMH seminal concentrations have been evaluated using an enzyme-linked immunoassay in three groups of young men: group 1, fertile donors (n = 18); group 2, obstructive azoospermia (n = 9) after vasectomy or associated with deferent duct agenesia; and group 3, non-obstructive azoospermia with spermatogenesis deficiency and normal karyotype (n = 23). AMH was present in seminal plasma of most fertile donors at concentrations ranging from undetectable (<3.5 pmol/l) up to 543 pmol/l (geometric mean: 153 pmol/l), higher than the serum level (range <3.5 up to 67 pmol/l, geometric mean: 10.7 pmol/l, n = 13). Seminal AMH concentrations were undetectable in all obstructive azoospermic patients, confirming its testicular origin. In non-obstructive azoospermia (group 3), seminal AMH concentration was lower (range <3. 5-68.5 pmol/l, geometric mean: 17 pmol/l) than in fertile donors (P < 0.003) without correlation with plasma follicle stimulating hormone values. In group 3, comparison of seminal AMH concentration and the results of histological analysis of testicular biopsies revealed that undetectable AMH found in 14 cases was associated in 11 of them with lack of spermatozoa, while detectable concentrations of AMH (10-68.5 pmol/l) found in nine cases were associated in seven of them with persistent spermatogenesis. In the adult, AMH is secreted preferentially towards the seminiferous lumen. Although its relationship with spermatogenesis requires further investigation, our results suggest that seminal AMH may represent a non-invasive marker of persistent hypospermatogenesis in cases of non-obstructive azoospermia which may indicate the likely success of testicular spermatozoa recovery before intracytoplasmic sperm injection.
The French study group on oocyte donation, named GEDO, reports the results concerning the oocyte donation activity in France during 1998, including information from all the centers in effective operation except one. These data describe the recipients' and donors' situation and give the analysis of the results obtained.
Fertilization includes sperm-oocyte recognition, adhesion, binding, fusion and egg activation. Integrin receptors, which are adhesion molecules, are expressed on sea urchin, mouse, hamster and human unfertilized oocytes. Potential sperm ligands have been identified. A role for integrins during fertilization is supported by inhibition of sperm-egg adhesion and/or fusion by means of anti-integrin monoclonal antibodies, Arg-Gly-Asp (RGD) or disintegrin-like peptides. In several cell-cell interactions, such as lymphocyte activation, viral fusion, bacterial infection or macrophage phagocytosis, integrins act as co-receptors after activation and, by clustering in a multimolecular complex, are able to transduce signals through cytoskeletal proteins and adaptor kinases. Experimental data suggest that they may act in a similar way during fertilization and may participate to initiation and/or propagation of the calcium signal via stimulation of phospholipase C gamma and inositol trisphosphate production.
Autoimmunity may be involved in idiopathic premature ovarian failure (POF). However, the frequency, physiopathology and potential reversibility of autoimmune oophoritis needs clarification. Using an ELISA against whole tissue homogenate as antigen, from human ovaries at different ages, positive circulating ovarian antibodies (AOA) were found in 59% of patients with primitive idiopathic POF (27/46); 20/27 were positive for IgG isotype, 9/27 for IgM and 8/27 for IgA. Specificity of AOA was examined (i) by comparison to different control groups; mean values of the three subclasses of immunoglobins were significantly higher in POF women than in normally cycling fertile young women (n = 23) and fertile young men (n = 17), in untreated Grave's disease (n = 35) or in women with positive antinuclear factor (n = 25); and (ii) by assessing possible cross-reaction; only six out of the 27 positive sera reacted with other tissues (thyroid, pancreas, adrenal), including four clinical polyendocrinopathies. Significance of AOA was explored (i) by comparison with postmenopausal women (n = 40) and older women (n = 15), who did not have enhanced ratios of AOA, thereby excluding a potential role of high FSH values; (ii) by analysing the factors time and surgery; no relation could be found either with the duration of amenorrhoea (6 months to 21 years) or with the history of an ovarian biopsy (12/47) in the absence of any associated pelvic surgery; and (iii) by screening for other immunological factors; familial or personal autoimmune disease (8/46), HLA DR3 (10/42), HLA DR4 (11/42), associated autoantibodies (thyroperoxidase, adrenal, beta islets, parathyroid, DNA, smooth muscles) (12/42). If one positive AOA isotype was present, a second immunological factor was found in 45% of cases. Spontaneous pregnancies during oestrogen therapy occurred in four cases, including three women with positive AOA. Circulating AOA detected by an ELISA may represent a practical and suitable marker for diagnosis of POF. Its use for prognosis and rational treatment needs further evaluation.
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The effects of an adenosine agonist with specificity for A2 receptors, on human sperm prepared for in vitro fertilization (IVF), were examined to verify physiological effects and possible pharmacological use. 5' -N-ethyl-carboxamidoadenosine (NECA), when added at 100 microM over 30 min in B2 medium, did not induce a spontaneous acrosome reaction after 0, 3, and 6 h capacitation in B2, nor did it modify sperm motility. However, NECA increased the number of capacitated spermatozoa able to respond (p < 0.05) to A23187 (10 microM) after 6 h preincubation in B2 medium. This effect was associated with an increase in cAMP production, which was measured by RIA after 10 and 20 min incubation with NECA in uncapacitated sperm, and with changes in the kinetics of protein tyrosine phosphorylation as revealed by Western blot. Phosphorylation of a 95-kDa protein was enhanced by NECA in uncapacitated sperm and inhibited in capacitating sperm (incubated 1 h in B2), whereas phosphorylation of a 50-kDa protein was systematically enhanced whatever the preincubation time. NECA can stimulate uncapacitated human sperm via cAMP production and protein phosphorylation/dephosphorylation without inducing an acrosome reaction or influencing motility. Cyclic AMP-dependent protein kinase A seems to positively control protein phosphorylation involved in human capacitation. Adenosine present in the tubal fluid or produced by the spermatozoon itself may influence capacitation in vivo through sperm A2 receptors. In cases of male infertility, use of NECA in sperm handling for IVF should be evaluated as a means to improve capacitation without increasing the possibility of a premature spontaneous acrosome reaction.
Progesterone has been tested in vitro with human spermatozoa to verify its physiological effects and its possible therapeutic use in cases of male infertility. Progesterone induced a rapid, dose-dependent influx of calcium in capacitated and non-capacitated spermatozoa with a half-maximally effective dose of 30 nM. The agonist, 19-nortestosterone, was much less potent that progesterone itself. Progesterone-induced calcium influx was not inhibited by a similar concentration (0.1 microgram/ml) of RU 486, a classical progesterone antagonist. The increase in intracytoplasmic calcium levels was unable to induce the acrosome reaction (AR) even after incubation for 5 h, when this was evaluated by double staining, using a monoclonal antibody GB24 raised against the inner acrosome membrane and ethidium homodimer as a vital probe. However, after incubation for 5 h, progesterone was able to enhance the tyrosine phosphorylation of a 95 kD sperm protein, which is phosphorylated progressively during capacitation in well-defined culture media. Incubation of spermatozoa with 1 or 10 micrograms/ml progesterone for 3 or 30 min did not induce major modifications of hyperactivated movement when analysed by computer-assisted semen analysis. Progesterone secreted by cumulus cells may physiologically increase sperm intracytoplasmic free calcium during capacitation. This priming effect may facilitate the acrosome reaction, induced by binding to the zona pellucida, without enhancing spontaneous acrosome reaction prematurely. It therefore seems useful to propose progesterone as a means of accelerating capacitation during in vitro fertilization in cases of male infertility.
Human gametes and pre-implantation embryos express selectively several complement regulatory proteins. Membrane cofactor protein (MCP, CD46) and decay accelerating factor (DAF, CD55) are regulators for C3 convertases and protectin (CD59) is an inhibitor of the membrane attack complex. These three proteins were identified on human sperm and found to be functional. CD55 and CD59 were both expressed by the plasmic membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not present on unfertilized oocytes but appeared at the 6/8 cell-stage embryo when human gene expression first occurs. Complement receptor 1 (CR1, CD35) and MHC class I antigens were not found on oocytes neither on embryos. Such a selective expression of complement regulatory proteins associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human gametes and pre-implantation embryos escape from complement-mediated damage during their travel through the female genital tract. Indeed uterine, tubal and follicular fluids contain all the components of the complement cascade, including classical and alternative pathways. Nevertheless participation of CD46 and CD59 in cell to cell interaction during fertilization and/or implantation cannot be excluded. CD59 is an adhesive molecule involved in the rosette phenomena and CD46 has been described as the human receptor for measles virus, which binds through a fusion protein. Monoclonal antibodies raised against these two proteins (CD46 and CD59) are able to inhibit heterospecific fertilization between zona-free hamster oocytes and human spermatozoa suggesting the role of these proteins during fertilization.
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