The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions.

BACKGROUND: Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions. METHODS: This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8-12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey's multiple comparisons test. RESULTS: Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions. CONCLUSIONS: Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies.

BACKGROUND: A Cochrane review in 2006 concluded that further knowledge is required before recommendation can be made with regard to progesterone in the prevention of preterm birth. OBJECTIVE: To provide an update on the preventive effect of progesterone on preterm birth in singleton pregnancies. SEARCH STRATEGY: A search in the PubMed, Embase, and Cochrane database was performed using the keywords: pregnancy, progesterone, preterm birth/preterm delivery, preterm labor, controlled trial, and randomized controlled trial. SELECTION CRITERIA: Studies on singleton pregnancies. DATA COLLECTION AND ANALYSIS: A meta-analysis was performed on randomized trials including singleton pregnancies with previous preterm birth. MAIN RESULTS: Two new randomized controlled trials of women with previous preterm birth were added to the four analyzed in the Cochrane review, and the meta-analysis of all six studies now showed that progesterone supplementation was associated with a significant reduction of delivery before 32 weeks and of perinatal mortality. Furthermore, a third trial showed a positive effect on women with a short cervix at 23 weeks, and a fourth study showed that progesterone reduces the risk of preterm delivery in women with preterm labor. CONCLUSIONS: In women with a singleton pregnancy and previous preterm delivery, progesterone reduces the rates of preterm delivery before 32 weeks, perinatal death, as well as respiratory distress syndrome and necrotizing enterocolitis in the newborn. Women with a short cervix or preterm labor may also benefit from progesterone, but further evidence is needed to support such a recommendation. Follow-up studies should focus on possible metabolic complications in the mother or the offspring.

[Quality monitoring based on data from the Danish National Patient Registry]. / Kvalitetsmonitorering ud fra data i Landspatientregisteret.

The Danish National Patient Registry (DNRP) was established in Denmark in 1976, and since then in accordance with current law, it has been collecting discharge diagnoses, surgical codes and recently also different diagnostic and treatment codes from all Danish hospitals. Besides being an administrative tool and a tool for epidemiological research through recent years, the DNPR has also supported national clinical quality databases. We report the experiences from a national quality control in Danish reproductive gynaecology based on data from the DNPR. We conclude that the NRP is a suitable tool for continuous clinical quality control, and discuss ways of improving the validity of DNPR data.

[The National Patient Registry as a tool for continuous production and quality control]. / Landspatientregisteret som redskab i løbende produktions-og kvalitetskontrol.

INTRODUCTION: In Denmark, the National Register of Patients has, by law since 1977, received discharge diagnoses, surgical codes, and, in recent years, also codes for specific medical treatments for all hospitalised patients. It is an important source of administrative data and for epidemiological research. This paper summarises the results of an evaluation of the register as a tool for assessing quality in gynaecological departments in Denmark. MATERIAL AND METHODS: We obtained data describing production and quality of abortions, ectopic pregnancies, hysterectomies, endometrial ablations, ovarian cysts, ovarian, cervical, and endometrial cancer, in vitro fertilisation, insemination, and urine incontinence. A search was also made for possible miscodings in order to evaluate the extent of such miscoding and to obtain more valid quality estimates. RESULTS: The validity and completeness of the diagnosis codes were generally poorer than that of the surgical codes, especially that of the newer medical treatment codes. We found a rather different clinical practice and quality at the 38 gynaecological departments studied. In order to reduce this stochastic noise, we analysed all small departments as a single unit. Generally, the quality was the same in both the larger and the smaller units. CONCLUSION: The register seems well suited for routine production and quality control.