Distribution of α-integrin subunits in fetal polycystic kidney diseases

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by β1-integrins, a subfamily of integrin receptors, formed by the association of the β1-chain with different α-subunits. To date, no study on α-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of α-integrin subunits (α1, α2, α3, α5, and α6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in α1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits α2, α3, and α6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the α1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of α2, α3, and α6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases. Received May 28, 1996; received in revised form October 2, 1996; accepted October 25, 1996     

Polycystic kidney disease genes and polycystins

Conclusion The past decade has seen extraordinary progress in the study of autosomal-dominant polycystic kidney disease. The 2 major genes for this disorder have been identified. Animal models of ADPKD have been produced. The molecular basis of the disease has been characterized. ADPKD is a “second-hit” disease, much like many cancer predisposition syndromes. This has profound implications for our understanding. The progression of ADPKD in individual patients is likely related more to their individual rate of acquisition of second hits at thePKD1 orPKD2 locus than to the inherited germ line mutation itself. Therapeutic approaches will perhaps now be considered, which will include interventions that may limit the rate at which somatic mutations occur in the kidney. The major focus of research at present is to elucidate the normal functions ofPKD1 andPKD2. Protein binding partners are being sought for both proteins. The possible calcium channel function ofPKD2 is being investigated. The downstream effects of cellular deficiency of either protein are likely to yield many clues. Modifying genetic factors that may independently affect disease progression are likely to be identified using the several mouse models. Perhaps the next decade will bring great strides in understanding and in potential therapy for this common disease. This paper was presented at the 2nd International Forum “The Frontiers of Nephrology,” Tokyo, May 10, 1998.     

血清IGFBP-3、PDGF及bFGF联合检测对多囊卵巢综合征患者妊娠结局的预测价值

目的 探究血清胰岛素样生长因子结合蛋白-3(IGFBP-3)、血小板来源生长因子（PDGF）及碱性成纤维细胞生长因子（bFGF）联合检测对多囊卵巢综合征（PCOS）患者妊娠结局的预测价值。方法 选取2021年5月—2022年12月在沧州市中心医院接受治疗的150例PCOS孕妇作为PCOS组,另选取同期在该院产检健康的90例孕妇作为对照组。比较两组血清IGFBP-3、PDGF及bFGF水平;根据PCOS组孕妇的妊娠情况分为妊娠结局良好组119例和妊娠结局不良组31例,统计PCOS患者妊娠结局情况并比较血清IGFBP-3、PDGF、bFGF水平;绘制受试者工作特征（ROC）曲线分析血清IGFBP-3、PDGF和bFGF对PCOS的预测价值。结果 PCOS组血清IGFBP-3水平低于对照组（P <0.05）,PDGF、bFGF水平均高于对照组（P <0.05）。妊娠结局不良组血清IGFBP-3水平低于妊娠结局良好组（P <0.05）,PDGF、bFGF水平均高于妊娠结局良好组（P <0.05）。ROC曲线分析结果显示,血清IGFBP-3、PDGF、bFGF水平预测PC...     

Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis

Both Fas (APO-1, CD95), an apoptosis-inducing receptor, and its ligand, Fas ligand (FasL, CD95L), have been localized to the ovary. Granulosa cell apoptosis occurs in antral follicular atresia. In polycystic ovary syndrome (PCOS), antral follicles accumulate with some atretic features. The ovarian expression of Fas and FasL was examined in PCOS by immunohistochemistry and correlated with immunodetection of apoptotic cells. Fas immunostaining was present in pre-antral follicle oocytes, some primary and secondary pre-antral follicle granulosa cells, and both granulosa and theca of antral follicles. Thecal staining persisted with advancing atresia, while granulosa staining declined. In antral follicles, abundant Fas-positive cells co-localized with scattered nuclei immunopositive for apoptosis. Ovarian vascular myocytes were strongly Fas-immunopositive. FasL immunostaining was present in pre-antral follicles in oocytes and variably in granulosa. In antral follicles, granulosa and thecal FasL staining increased with advancing atresia. Normal control ovaries showed follicular Fas and FasL staining patterns similar to those in PCOS, but vascular staining was less prominent. In one healthy follicle, Fas immunostaining was seen in the oocyte and weakly in mural granulosa and theca interna. The results suggest that in PCOS, an alteration in Fas-mediated apoptosis, does not cause abnormal folliculogenesis, but may promote ovarian vascular remodelling.     

Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells

BACKGROUND: The present study was conducted to investigate the effect of androstenedione, insulin and LH on human granulosa cell oestrogen and progesterone production. We postulated that elevated concentrations of androstenedione, insulin and LH may be important modulators of granulosa cell steroidogenesis. METHODS: Granulosa cells obtained in connection with IVF procedures were cultured for a total of 4 days in serum-free medium containing androstenedione (10(-6) mol/l). We tested the effect of androstenedione (10(-5) mol/l) on insulin (0-800 microIU/ml), LH (1-10 ng/ml) as well as on insulin + LH-stimulated oestrogen and progesterone production. RESULTS: Insulin increased the basal secretion of steroid hormones, and furthermore augmented LH-stimulated oestrogen and progesterone accumulation in granulosa cell cultures. Androstenedione (10(-5) mol/l) stimulated basal oestrogen production, but significantly reduced (32-58%) insulin + LH-stimulated oestrogen and progesterone secretion (P < 0.05). CONCLUSION: These results suggest that high androstenedione concentrations may act directly to impair insulin augmentation of LH-stimulated oestradiol and progesterone production in cultured human granulosa luteal cells. This is compatible with the hypothesis that high androgen levels may inhibit oestrogen production in polycystic ovary follicles, and as such may contribute to anovulation and infertility in women with polycystic ovary syndrome.     

Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome

Thirty-two women with polycystic ovary syndrome (PCOS) wereallocated to two antiandrogen treatment regimens; 28 women completedthe trial. Twenty women were treated with ethinyloestradioland cyproterone acetate (EO-CA) cyclically for 6 months andeight women were treated with the gonadotrophin releasing hormone(GnRH) analogue, goserelin for 6 months. Effects on hirsutism,insulin sensitivity (estimated by glucose clamp technique),blood lipids and hormones were measured. Women treated withEO-CA showed a reduction in hirsutism (P <0.05), and decreasedserum androgen concentrations (P <0.001) as well as reducedinsulin sensitivity (P <0.05). In women treated with goserelin,serum androgen concentrations also decreased (P <0.001),but there was no significant reduction of hirsutism. This group,however, showed an improved insulin sensitivity (P <0.05)despite an unchanged body mass index. Bone mineral density wasunaltered in both treatment groups. The reduction in androgenconcentrations caused by EO-CA was not paralleled by increasedinsulin sensitivity, most probably due to the effect of ethinyloestradiolper se. In contrast, the reduction in androgen concentrationsby goserelin was accompanied by an improved insulin sensitivity.     

Ovulation induction: a mini review

Ovulation induction is the method for treating anovulatory infertility. For patients with hypogonadotrophic hypogonadism, the treatment involves administration of both FSH and LH, while HCG is injected for follicle rupture. Pulsatile GnRH has the same effectiveness as gonadotrophins and the advantage of the low multiple pregnancy rate. In polycystic ovary syndrome (PCOS), the first treatment choice is clomiphene citrate. With this drug, in properly selected patients, the cumulative pregnancy rate approaches that of normal women. Low-dose protocols of FSH are the second line of treatment, effective in inducing monofollicular development. Laparoscopic ovarian drilling can be an alternative but not as a first choice treatment in clomiphene-resistant patients. Other treatments, such as pulsatile GnRH and GnRH agonists, are hardly used today in PCOS. However, in obese women with PCOS, weight loss and exercise should be recommended as the first line of therapy. Newer agents including aromatase inhibitors and insulin sensitizers, although promising, need further evaluation.     

Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin

To assess the risk of miscarriage after in-vitro fertilization(IVF) with respect to age, cause of infertility, ovarian morphologyand treatment regimen, a retrospective analysis was performedof the first 1060 pregnancies conceived between June 1984 andJuly 1990 as a result of 7623 IVF cycles. Superovulation inductionwas achieved with human menopausal gonadotrophin (HMG) and/orpurified follicle stimulating hormone (FSH) together with eitherclomiphene citrate or the gonadotrophin hormone-releasing hormone(GnRH) agonist buserelin, the latter either as a short ‘flare’regimen or as a ‘long’ regimen to induce pituitarydesensitization. There were 282 spontaneous abortions (26.6%)and 54 ectopic pregnancies (5.1%). The mean age of women withongoing pregnancies was 32.2 (SD 3.9) years compared with 33.2(SD 4.1) years in those who miscarried, which were significantlydifferent (P = 0.008). There was no relation between the miscarriagerate and the indication for IVF. The miscarriage rate was 23.6%in women with normal ovaries compared with 35.8% in those withpolycystic ovaries [P = 0.0038, 95% confidence interval (CI)4.68–23.10%]. There was no difference in the miscarriagerate between treatment with HMG or FSH. Women whose ovarieswere normal on ultrasound were just as likely to miscarry ifthey were treated with clomiphene or with the long buserelinprotocol. Those with polycystic ovaries, however, had a significantreduction in the rate of miscarriage when treated with the longbuserelin protocol, 20.3% (15/74), compared with clomiphenecitrate, 47.2% (51/108) (P = 0.0003, 95% CI 13.82–40.09%).     

A controlled study comparing patients with and without polycystic ovaries undergoing in-vitro fertilization

The outcome of in-vitro fertilization and embryo transfer (IVF—ET)was compared in 76 patients with polycystic ovaries (PCO) diagnosedon pre-treatment ultrasound scan, and 76 control patients whohad normal ovaries and were matched for age, cause of infertilityand stimulation regimen. Despite receiving significantly lesshuman menopausal gonadotrophin (HMG), patients with PCO, ascompared with controls, had significantly higher serum oestradiollevels on the day of human chronic gonadotrophin administration(5940 ± 255 versus 4370 ± 240 pmol/1, P < 0.001),developed more follicles (14.9 ± 0.7 versus 9.8 ±0.6, P < 0.001) and produced more oocytes (9.3 ± 0.6versus 6.8 ± 0.5, P = 0.003). However, fertilizationrates were reduced in the PCO patients (52.8 ± 3.4% versus66.1 ± 3.4%, P = 0.007). There was no significant differencein cleavage rates. The pregnancy rate/embryo transfer was 25.4%in the PCO group and 23.0% in the group with normal ovaries.There were three high order multiple pregnancies in the PCOgroup compared with none in the group with normal ovaries. Ofthe PCO patients, 10.5% developed moderate/severe ovarian hyperstimulationsyndrome (OHSS) compared with none of the controls (P = 0.006).Patients with and without PCO undergoing IVF have comparablepregnancy and livebirth rates. However, it is important to diagnosePCO before ovarian stimulation is initiated as these patientsare more likely to develop moderate or severe OHSS following1VF—ET.