米非司酮配伍米索前列醇对母胎界面孕酮诱导阻断因子及孕酮受体表达的影响

目的 研究米非司酮配伍米索前列醇对母胎界面孕酮诱导阻断因子（PIBF）及孕酮受体（PR）表达的影响. 方法 应用免疫组织化学染色法检测米非司酮药物流产成功（药流成功组,n =30）、失败（药流失败组,n=30）及正常早孕负压吸宫流产（手术组,n=30）绒毛及蜕膜组织中PIBF及PR的表达情况. 结果 PIBF表达于绒毛合体滋养层细胞、细胞滋养层细胞和蜕膜细胞胞质,PR表达于蜕膜组织细胞核.与手术组相比,药物流产的两组绒毛滋养层细胞中PIBF的表达差异无统计学意义,而在蜕膜细胞中,药物流产的两组PIBF、PR的表达明显下降,差异有统计学意义,且药流成功组PIBF及PR的表达低于药流失败组,差异有统计学意义. 结论 米非司酮配伍米索前列醇终止早期妊娠可能与PIBF及PR的表达降低有关,其成功率与PIBF、PR表达降低程度相关.     

Progesterone loaded thermosensitive hydrogel for vaginal application: Formulation and in vitro comparison with commercial product

Progesterone (PGT) is a natural hormone that stimulates and regulates various important functions, such as the preparation of the female body for conception and pregnancy. Due to its low water solubility, it is administered in a micronized form and/or in vehicles with specific solvents requirements. In order to improve the drug solubility, inclusion complexes of PGT and β-cyclodextrins were obtained by the freeze-drying method. Two β-cyclodextrins (native and methylated) in two solvents (water and water:ethanol) and different molar ratio of the reagents were the variables tested for the selection of the best condition for the preparation of the complexes. The PGT/randomly methylated-β-cyclodextrin complexes were incorporated into chitosan thermosensitive hydrogels, as an alternative formulation for the vaginal administration of PGT. Neither the micro and macroscopic characteristics of the gels nor the transition time from solution to gel were modified after the complexes incorporation. In addition, chitosan gels with complexes resisted better the degradation in simulated vaginal fluid in comparison to commercial gel (Crinone®). The chitosan gel with inclusion complexes and Crinone® were tested in vitro in a diffusion assay to evaluate the delivery of the hormone and its diffusion through porcine epithelial mucosa obtained from vaginal tissue. Chitosan gel presented sustained diffusion similar to the exhibited by commercial gel. The use of chitosan gels with inclusion complexes based on cyclodextrins would be a viable alternative for vaginal administration of PGT.     

Objective sleep interruption and reproductive hormone dynamics in the menstrual cycle

ObjectivesWomen report greater sleep disturbance during the premenstrual phase of the menstrual cycle and during menses. However, the putative hormonal basis of perceived menstrual cycle-related sleep disturbance has not been investigated directly. We examined associations of objective measures of sleep fragmentation with reproductive hormone levels in healthy, premenopausal women.MethodsTwenty-seven women with monthly menses had hormone levels measured at two time points during a single menstrual cycle: the follicular phase and the peri-ovulatory to mid-luteal phase. A single night of home polysomnography (PSG) was recorded on the day of the peri-ovulatory/mid-luteal-phase blood draw. Serum progesterone, estradiol, and estrone levels concurrent with PSG and rate of change in progesterone (PROGslope) from the follicular blood draw to PSG were correlated with log-transformed wake after sleep onset (lnWASO%) and number of wakes/hour of sleep (lnWake-Index) using linear regression.ResultsSleep was more fragmented in association with a steeper PROGslope (lnWASO% p = 0.016; lnWake-Index p = 0.08) and higher concurrent estrone level (lnWASO% p = 0.03; lnWake-Index p = 0.01), but the effect of estrone on WASO was lost after accounting for PROGslope. WASO% and Wake-Index were not associated with concomitant progesterone or estradiol levels.ConclusionsA steeper rate of rise in progesterone levels from the follicular phase through the mid-luteal phase was associated with significantly greater WASO, establishing a link between reproductive hormone dynamics and sleep fragmentation in the luteal phase of the menstrual cycle.     

Aging-related changes in RP3V kisspeptin neurons predate the reduced activation of GnRH neurons during the early reproductive decline in female mice

Kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) play a key role in relaying the positive feedback effects of estradiol that activate gonadotropin-releasing hormone (GnRH) neurons and drive a surge in the GnRH/luteinizing hormone (LH) level. However, the precise role of kisspeptin neurons during female reproductive senescence remains unclear. Focusing on middle-aged intact female mice with irregular estrous cycles, we found a parallel decline in c-Fos–positive kisspeptin neurons and c-Fos–positive GnRH neurons at the time of the GnRH/LH surge. Furthermore, in kisspeptin neurons, the expression of estrogen receptor α (ERα), but not progesterone receptor (PR), decreased with age. Interestingly, some kisspeptin neurons in the RP3V, but none of the GnRH neurons in the rostral preoptic area (rPOA), had a characteristic cellular senescence in middle-aged mice and old mice. These data suggest that, among the groups of neurons involved in reproductive control, the kisspeptin neurons in the RP3V are likely among the earliest to undergo aging processes and thus participate in initiating the early reproductive decline.     

Mixed-Micellar Proliposomal Systems for Enhanced Oral Delivery of Progesterone

The objective of our study was to develop a mixed-micellar proliposomal formulation of poorly water-soluble drug progesterone and evaluate the dissolution profile and membrane transport. Several formulations of proliposomes were prepared by mixing different concentrations of lipid, progesterone, polysorbate 80, and microcrystalline cellulose. The mixed-micellar formulation of drug:dimyristoyl-phosphatidycholine:polysorbate 80 (1:20:3.3) exhibited the maximum dissolution (75.27%), while pure progesterone resulted in low dissolution. The above formulation showed a 4-fold increase in transport in Caco-2 cells and a 6-fold increase in transport across the everted rat intestinal sac experiments compared with control. Proliposomal formulations enhance the extent of dissolution and membrane transport of progesterone and serve as ideal carriers for oral delivery of drugs with low water solubility.     

Polycystic ovary syndrome: Understanding the role of the brain

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and the leading cause of anovulatory infertility. Characterised by hyperandrogenism, menstrual dysfunction and polycystic ovaries, PCOS is a broad-spectrum disorder unlikely to stem from a single common origin. Although commonly considered an ovarian disease, the brain is now a prime suspect in both the ontogeny and pathology of PCOS. We discuss here the neuroendocrine impairments present in PCOS that implicate involvement of the brain and review evidence gained from pre-clinical models of the syndrome about the specific brain circuitry involved. In particular, we focus on the impact that developmental androgen excess and adult hyperandrogenemia have in programming and regulating brain circuits important in the central regulation of fertility. The studies discussed here provide compelling support for the importance of the brain in PCOS ontogeny and pathophysiology and highlight the need for a better understanding of the underlying mechanisms involved.     

Prognosis,stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour,prior endocrine treatment and radiotherapy

AimA contralateral breast cancer (CBC) is today treated as an independent primary tumour, although recent data suggest risk and prognosis of CBC to be influenced by characteristics of and treatment given for the first tumour (BC1). We hereby investigate phenotypical and prognostic features of the second tumour (BC2) in relation to prior endocrine treatment and radiotherapy.MethodsFrom a well-defined population-based cohort of CBC-patients, we have constructed a unique tissue-microarray including 600 pairs of primary tumours and CBCs. Breast cancer mortality was primary end-point for prognosis.ResultsBoth oestrogen receptor (ER) status and stage was strongly correlated between BC1 and BC2 within CBC-pairs. Although BC2 had the highest prognostic impact, BC1 continued to influence prognosis after diagnosis of CBC. Patients diagnosed with two high stage tumours within a short time-interval had a particularly bad prognosis. Prior endocrine therapy and radiotherapy both correlated to ER-negativity of BC2. An ER-negative BC2 was associated with an inferior prognosis compared to an ER-positive BC2 regardless of ER-status of BC1 or prior endocrine therapy.ConclusionsOur results suggest that both the residual prognostic impact of BC1, the possibility of contralateral metastasis, as well as prior treatment given, need to be considered when determining appropriate diagnostic work-up and treatment of CBC. In addition, radiation to the contralateral breast and risk of inducing CBC with an aggressive ER-negative phenotype should be considered when establishing new radiation treatment techniques. This study indicates loss of ER-expression as an important ‘endocrine treatment escape mechanism’, although further studies are warranted.