Skive Hospital

Diminished ovarian reserve (DOR) is common in women with infertility and is associated with poorer in vitro fertilization (IVF) outcomes. Testosterone is widely used off-label in this patient group, although evidence for its efficacy and safety is limited. To address this, we conducted a triple-blind, placebo-controlled, randomized clinical trial evaluating whether transdermal testosterone gel prior to IVF improves clinical pregnancy rates in women with DOR. Females aged 18-43 with infertility and DOR according to the Bologna criteria were recruited at 10 fertility clinics in Europe between April 2015 and November 2022. Of 316 assessed for eligibility, 290 were enrolled and randomized. Two were excluded from the primary analysis as their treatment coincided with the onset of the COVID-19 pandemic, and they did not start ovarian stimulation, leaving 288 participants. Participants were randomized to 5.5 mg of transdermal testosterone or matching placebo once daily for ~9 weeks prior to ovarian stimulation. All participants received ovarian stimulation in a long GnRH-agonist cycle with 300IU/day of highly purified human menopausal gonadotropin; fresh embryo transfer was performed if an embryo was available. The primary outcome was clinical pregnancy rate following fresh embryo transfer, defined as an intrauterine gestational sac with an embryo demonstrating cardiac activity at ≥7 weeks' gestation. Of the 288 participants, 134 were randomized to testosterone and 154 to placebo. Clinical pregnancy rates did not differ significantly, occurring in 21 women (15.7%) in the testosterone group and 23 (14.9%) in the placebo group (risk ratio (RR), 1.05; 95% confidence interval (CI) 0.61 to 1.81, p = 0.86). The study was terminated for futility at the prespecified interim analysis based on a conditional power calculation once 70% of the target sample size were randomized. In this study, transdermal testosterone did not improve clinical pregnancy rates compared with placebo in patients with infertility and DOR. Trial Registration: ClinicalTrials.gov: NCT02418572, EudraCT: 2014-001835-35.

PurposeAlongside being contraceptives, progestins have been investigated as potential anti-inflammatory and analgesic therapies for use in painful gynaecological conditions. This review aims to synthesise evidence pertaining to the efficacy of progestins as analgesics for use in endometriosis, fibroids and pre-menstrual syndrome (PMS).MethodsWe conducted a systematic review of the extant literature investigating the analgesic efficacy of progestins compared to any comparator interventions for individuals with the three specified gynaecological conditions. The search was carried out across the PubMed and CENTRAL databases on 7 April 2024 for randomised control trials (RCTs) published in the peer-reviewed literature from 2000 onwards. Data pertaining to analgesic efficacy, assessed by changes in pain indices/scores before and after treatment, were synthesised narratively. Data pertaining to adverse effect frequency and changes in bone mineral density (BMD) were also synthesised narratively. Risk of bias was assessed using the Cochrane risk of bias 2 tool.ResultsThe primary search identified 1220 potentially eligible RCTs of which 21 were ultimately included; 19 RCTs related to endometriosis, two related to fibroids and zero related to PMS. Quality assessment identified nine studies to be at a low risk of bias, nine studies with some concerns surrounding bias and three studies to be at a high risk of bias. The included studies represented a total of 2745 participants of whom 1317 were treated with a progestin and 1428 received a comparator intervention. In 18 of the 19 studies concerning endometriosis, progestins produced a statistically significant reduction in pain, further, in five instances progestins were more efficacious in reducing pain than comparator interventions. In both studies on fibroids, progestins produced significant reductions in pain, however, statistically significant differences compared to comparator interventions were not demonstrated. The most frequently cited adverse effect of progestins was spotting/irregular bleeding whilst those receiving comparator interventions most often reported hot flushes; cited in 12 and seven studies respectively. Five studies assessed the impact of progestins and comparators on BMD. Three studies found progestins significantly reduced BMD, however, in these instances reductions were significantly lower than those produced by comparator interventions and in two studies were not statistically significant after 12 months of follow-up.ConclusionOur review demonstrates the potential scope for the use of progestins as analgesics in the management of pain associated with endometriosis. Further research will need to be conducted to identify their efficacy in the management of pain associated with fibroids and PMS.

To explore whether a 25mg subcutaneous progesterone daily rescue daily improves the reproductive outcomes in patients with low serum progesterone (P4) levels (7-10ng/mL), measured one day before true natural cycle (t-NC) frozen embryo transfer (FET). A cohort study of 192 women undergoing t-NC warmed blastocyst transfer. Patients were stratified into three different groups based on serum P4 levels on the FET-1day: patients who had serum P4 levels of 7-10ng/mL and underwent rescue progesterone administration (rescue group), patients with serum P4 levels of 7-10ng/mL without progesterone administration (non-rescue group), and patients with serum P4 > 10ng/mL on FET-1day (control group). The primary outcome was possible differences in live birth rate (LBR) between groups. The LBRs for the serum P4 7-10ng/mL without rescue, 7-10ng/mL with rescue, and > 10ng/mL (control) groups were 41%, 46%, and 52%, respectively (p = 0.61). The estimated adjusted probability of live birth for serum P4 7-10ng/mL without rescue, 7-10ng/mL with rescue, and > 10ng/mL (control) groups were also comparable: 43.5% (95% CI, 20.0-70.4%), 49.8% (95% CI, 28.1-71.6%), and 57.4% (95% CI, 44.0-69.8%), respectively. Serum P4 levels higher than 7ng/mL seem to secure LBRs in patients undergoing t-NC FET. A rescue policy consisting of a daily subcutaneous 25mg progesterone dose in patients with serum P4 levels 7-10ng/mL does not further enhance LBRs when compared to those patients with similar serum P4 levels without rescue.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this consensus provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes.

Abstract Purpose: Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying molecular mechanisms. Methods: In this study, aqueous humor samples from eyes with treatment-naïve clinically significant DME (n = 13) and age-matched controls (n = 11) were compared with label-free liquid chromatography–tandem mass spectrometry. Additional aqueous humor samples from eyes with treatment-naïve DME (n = 15) and controls (n = 8) were obtained for validation by enzyme-linked immunosorbent assay (ELISA). Best-corrected visual acuity (BCVA) was evaluated, and the severity of DME was measured as central subfield thickness (CST) employing optical coherence tomography. Control samples were obtained before cataract surgery. Significantly changed proteins were identified using a permutation-based calculation, with a false discovery rate of 0.05. A human donor eye with DME and a control eye were used for immunofluorescence. Results: A total of 101 proteins were differentially expressed in the DME. Regulated proteins were involved in complement activation, glycolysis, extracellular matrix interaction, and cholesterol metabolism. The highest-fold change was observed for the fibrinogen alpha chain (fold change = 17.8). Complement components C2, C5, and C8, fibronectin, and hepatocyte growth factor-like protein were increased in DME and correlated with best-corrected visual acuity (BCVA). Ceruloplasmin and complement component C8 correlated with central subfield thickness (CST). Hemopexin, plasma kallikrein, monocyte differentiation antigen CD14 (CD14), and lipopolysaccharide-binding protein (LBP) were upregulated in the DME. LBP was correlated with vascular endothelial growth factor. The increased level of LBP in DME was confirmed using ELISA. The proteins involved in desmosomal integrity, including desmocollin-1 and desmoglein-1, were downregulated in DME and correlated negatively with CST. Immunofluorescence confirmed the extravasation of fibrinogen at the retinal level in the DME. Conclusion: Elevated levels of pro-inflammatory proteins, including the complement components LBP and CD14, were observed in DME. DME was associated with the loss of basal membrane proteins, compromised desmosomal integrity, and perturbation of glycolysis.

Research questionCan a novel classification system of the infertile male – ‘APHRODITE’ (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) – stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception? DesignA collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing. ResultsFive patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility. ConclusionThe APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility.

Abstract Study question Should blastocysts cryopreserved D6 be transferred on the 5th or 6th day of progesterone administration in HRT-FET cycles? Summary answer No significant differences in outcome parameters were found when D6 vitrified blastocysts were transferred on either day 5 or day 6 of progesterone in HRT-FET. What is known already Several studies have shown that D6 blastocyst transfer should be avoided in fresh transfer IVF cycles; consequently, these more slowly developing embryos are transferred in a HRT-FET cycle on the 6th day of progesterone administration in line with day 5 (D5) blastocysts. For successful implantation, a receptive endometrium and optimal synchronization between the endometrium and embryo are important. However, no definitive evidence exists regarding the optimal timing of transferring D6 blastocysts. Interestingly, a few studies have reported better reproductive outcomes if D6 blastocysts are transferred on the 5th day of progesterone administration instead of the 6th day of progesterone administration. Study design, size, duration This cohort study included a total of 718 vitrified D6 single blastocyst HRT-FET cycles performed between 2013 and 2022. 576 blastocysts were transferred on the 6th day of progesterone administration (2013-2021), and 142 blastocysts transferred on the 5th day of progesterone administration (2021-2022). Main outcomes were biochemical pregnancy rate (PR), implantation rate (IR), clinical pregnancy rate (CPR), and early pregnancy loss rate (EPLR). Participants/materials, setting, methods Patients undergoing HRT-FET in a public Fertility Clinic. Endometrial preparation included oral oestradiol (6mg/24hours), followed by vaginal micronized progesterone. As mentioned above, single blastocyst transfer was performed on either the 5th or 6th day of progesterone administration. Serum β-hCG level was measured 9-11 days after embryo transfer and biochemical pregnancy was defined as an hCG level >10 IU/L. Clinical pregnancy was defined as visualization of a gestational sac and fetal heartbeat in gestational week 7. Main results and the role of chance In this cohort of a total of 718 HRT-FET cycles transferred on either the 5th or 6th day of progesterone administration the mean age of the patients at embryo transfer was 34.5±4.5 years vs. 33.0±4.9 years, respectively, p = 0.30. There was no significant difference between numbers of top-quality blastocyst transfers within the two groups 63% (89/142) vs. 64% (369/576), p = 0.76. The overall, biochemical pregnancy rate (PR), implantation rate (IR), clinical pregnancy rate (CPR) and early pregnancy loss (EPLR) in the group of patients transferred on the 5th day of progesterone administration were 38% (54/142), 29% (41/142), 25% (36/142) and 33% (18/54). In the group of patients transferred on the 6th day of progesterone administration 41% (235/576), 33% (191/576), 30% (170/576) and 28% (65/235). There were no significant differences between PR, IR, CPR and EPLR when transferring D6 vitrified blastocysts on either the 5th or the 6th day of progesterone administration (38% vs. 41%, p = 0.53, 29% vs. 33%, p = 0.33, 25% vs. 30%, p = 0.33 and 33% vs. 28%, p = 0.41). Limitations, reasons for caution Limitations of the study are the retrospective design and the limited number of D6 vitrified blastocysts transferred on the 5th day of progesterone administration. Furthermore, the two groups represented two different time periods. Wider implications of the findings Growing evidence shows that D5 vitrified blastocysts have better reproductive outcomes than slower developing embryos which are vitrified on day 6. Whether this is caused by intrinsic embryonic factors or poor timing of transfer in a subsequent FET cycle still needs to be unraveled. Trial registration number not applicable