Characterization of ovarian tissue oocytes from transgender men reveals poor calcium release and embryo development, which might be overcome by spindle transfer.

STUDY QUESTION: Can spindle transfer (ST) overcome inferior embryonic development of in vitro matured ovarian tissue oocytes (OTO-IVM) originating from testosterone-treated transgender men? SUMMARY ANSWER: ST shows some potential to overcome the embryo developmental arrest observed in OTO-IVM oocytes from transgender men. WHAT IS KNOWN ALREADY: OTO-IVM is being applied as a complementary approach to increase the number of oocytes/embryos available for fertility preservation during ovarian tissue cryopreservation in cancer patients. OTO-IVM has also been proposed for transgender men, although the potential of their oocytes remains poorly investigated. Currently, only one study has examined the ability of OTO-IVM oocytes originating from transgender men to support embryo development, and that study has shown that they exhibit poor potential. STUDY DESIGN, SIZE, DURATION: Both ovaries from 18 transgender men undergoing oophorectomy were collected for the purposes of this study, from November 2020 to September 2022. The patients did not wish to cryopreserve their tissue for fertility preservation and donated their ovaries for research. All patients were having testosterone treatment at the time of oophorectomy and some of them were also having menses inhibition treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sibling ovaries were collected in either cold or warm medium, to identify the most optimal collection temperature. Cumulus oocyte complexes (COCs) from each condition were isolated from the ovarian tissue and matured in vitro for 48 h. The quality of OTO-IVM oocytes was assessed by calcium pattern releasing ability, embryo developmental competence following ICSI, and staining for mitochondrial membrane potential. In vitro matured metaphase I (MI) oocytes, germinal vesicle (GV) oocytes, and in vivo matured oocytes with aggregates of smooth endoplasmic reticulum (SERa) were donated from ovarian stimulated women undergoing infertility treatment and these served as Control oocytes for the study groups. ST was applied to overcome poor oocyte quality. Specifically, enucleated mature Control oocytes served as cytoplasmic recipients of the OTO-IVM spindles from the transgender men. Embryos derived from the different groups were scored and analysed by shallow whole genome sequencing for copy number variations (CNVs). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 331 COCs were collected in the cold condition (OTO-Cold) and 282 were collected in the warm condition (OTO-Warm) from transgender men. The maturation rate was close to 54% for OTO-Cold and 57% for OTO-Warm oocytes. Control oocytes showed a calcium releasing ability of 2.30 AU (n = 39), significantly higher than OTO-Cold (1.47 AU, P = 0.046) oocytes (n = 33) and OTO-Warm (1.03 AU, P = 0.036) oocytes (n = 31); both values of calcium release were similar between the two collection temperatures. Mitochondrial membrane potential did not reveal major differences between Control, OTO-Warm, and OTO-Cold oocytes (P = 0.417). Following ICSI, 59/70 (84.2%) of Control oocytes were fertilized, which was significantly higher compared to 19/47 (40.4%) of OTO-Cold (P < 0.01) and 24/48 (50%) of OTO-Warm oocytes (P < 0.01). In total, 15/59 (25.4%) blastocysts were formed on Day 5 in the Control group, significantly higher than 0/19 (0%) from the OTO-Cold (P = 0.014) and 1/24 (4.1%) in OTO-Warm oocytes (P = 0.026). Application of ST rescued the poor embryo development, by increasing the Day 5 blastocyst rate from 0% (0/19) to 20.6% (6/29) (P = 0.034), similar to that in the ICSI-Control group (25.4%, 15/59). A normal genetic profile was observed in 72.7% (8/11) of OTO-Cold, 72.7% (8/11) of OTO-Warm and 64.7% (11/17) of Control Day 3-Day 5 embryos. After ST was applied for OTO-IVM oocytes, 41.1% (7/17) of the embryos displayed normal genetic patterns, compared to 57.1% (4/7) among ST-Control Day 3-Day 5 embryos. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Due to the limited access to human oocytes and ovarian tissue, our results should be interpreted with some caution, as only a limited number of human oocytes and embryos could be investigated. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study, clearly indicate that OTO-IVM oocytes originating from transgender patients are of inferior quality, which questions their use for fertility preservation. The poor quality is likely to be related to cytoplasmic factors, supported by the increased blastocyst numbers following application of ST. Future research on OTO-IVM from transgender men should focus on the cytoplasmic content of oocytes or supplementation of media with factors that promote cytoplasmic maturation. A more detailed study on the effect of the length of testosterone treatment is also currently missing for more concrete guidelines and guidance on the fertility options of transgender men. Furthermore, our study suggests a potentially beneficial role of experimental ST in overcoming poor embryo development related to cytoplasmic quality. STUDY FUNDING/COMPETING INTEREST(S): A.C. is a holder of FWO grants (1S80220N and 1S80222N). A.B. is a holder of an FWO grant (1298722N). B.H. and A.V.S. have been awarded with a special BOF (Bijzonder Onderzoeksfonds), GOA (Geconcerteerde onderzoeksacties) and 2018000504 (GOA030-18 BOF) funding. B.H. has additional grants from FWO-Vlaanderen (Flemish Fund for Scientific Research, G051516N and G1507816N) and Ghent University Special Research Fund (Bijzonder Onderzoeksfonds, BOF funding (BOF/STA/202109/005)), and has been receiving unrestricted educational funding from Ferring Pharmaceuticals (Aalst, Belgium). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Early-life residential green spaces and traffic exposure in association with young adult body composition: a longitudinal birth cohort study of twins.

BACKGROUND: Globally, the rapid increase of obesity is reaching alarming proportions. A new approach to reduce obesity and its comorbidities involves tackling the built environment. Environmental influences seem to play an important role, but the environmental influences in early life on adult body composition have not been thoroughly investigated. This study seeks to fill the research gap by examining early-life exposure to residential green spaces and traffic exposure in association with body composition among a population of young adult twins. METHODS: As part of the East Flanders Prospective Twin Survey (EFPTS) cohort, this study included 332 twins. Residential addresses of the mothers at time of birth of the twins were geocoded to determine residential green spaces and traffic exposure. To capture body composition, body mass index, waist-to-hip ratio (WHR), waist circumference, skinfold thickness, leptin levels, and fat percentage were measured at adult age. Linear mixed modelling analyses were conducted to investigate early-life environmental exposures in association with body composition, while accounting for potential confounders. In addition, moderator effects of zygosity/chorionicity, sex and socio-economic status were tested. RESULTS: Each interquartile range (IQR) increase in distance to highway was found associated with an increase of 1.2% in WHR (95%CI 0.2-2.2%). For landcover of green spaces, each IQR increase was associated with 0.8% increase in WHR (95%CI 0.4-1.3%), 1.4% increase in waist circumference (95%CI 0.5-2.2%), and 2.3% increase in body fat (95%CI 0.2-4.4%). Stratified analyses by zygosity/chorionicity type indicated that in monozygotic monochorionic twins, each IQR increase in land cover of green spaces was associated with 1.3% increase in WHR (95%CI 0.5-2.1%). In monozygotic dichorionic twins, each IQR increase in land cover of green spaces was associated with 1.4% increase in waist-circumference (95%CI 0.6-2.2%). CONCLUSIONS: The built environment in which mothers reside during pregnancy might play a role on body composition among young adult twins. Our study revealed that based on zygosity/chorionicity type differential effects of prenatal exposure to green spaces on body composition at adult age might exist.

Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.

OBJECTIVES: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. DESIGN: Multicenter, open-label, phase 3 trial. SETTING: Sixty-nine sites in Europe and Russia. POPULATION: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 . METHODS: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. MAIN OUTCOME MEASURES: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. RESULTS: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. CONCLUSION: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. TWEETABLE ABSTRACT: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Improved Limits for Violations of Local Position Invariance from Atomic Clock Comparisons.

We compare two optical clocks based on the ^{2}S_{1/2}(F=0)→^{2}D_{3/2}(F=2) electric quadrupole (E2) and the ^{2}S_{1/2}(F=0)→^{2}F_{7/2}(F=3) electric octupole (E3) transition of ^{171}Yb^{+} and measure the frequency ratio ν_{E3}/ν_{E2}=0.932829404530965376(32), improving upon previous measurements by an order of magnitude. Using two caesium fountain clocks, we find ν_{E3}=642121496772645.10(8) Hz, the most accurate determination of an optical transition frequency to date. Repeated measurements of both quantities over several years are analyzed for potential violations of local position invariance. We improve by factors of about 20 and 2 the limits for fractional temporal variations of the fine structure constant α to 1.0(1.1)×10^{-18}/yr and of the proton-to-electron mass ratio µ to -8(36)×10^{-18}/yr. Using the annual variation of the Sun's gravitational potential at Earth Φ, we improve limits for a potential coupling of both constants to gravity, (c^{2}/α)(dα/dΦ)=14(11)×10^{-9} and (c^{2}/µ)(dµ/dΦ)=7(45)×10^{-8}.

Cervical cancer prevention in transgender men: a review.

There is increased awareness of transgender physical and mental health widely and in academic research. A significant proportion of transgender men will retain their cervix with an increased risk of cervical cancer. In this review of cervical cancer screening among transgender men, we try to estimate how many transgender men still have a cervix, understand to identify challenges and barriers to cervical screening and propose possible solutions. Organised cervical screening programmes need to consider the needs of this population, in particular the provision of HPV self-sampling. TWEETABLE ABSTRACT: Transgender men need access to cervical screening.

Adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery versus laparoscopy: results of a first randomised controlled trial (NOTABLE trial).

OBJECTIVE: To compare adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) versus laparoscopy. DESIGN: Parallel group, 1:1 single-centre single-blinded randomised trial, designed as non-inferiority study with a margin of 15%. SETTING: Belgian teaching hospital. POPULATION: Non-pregnant non-virgin women with an intact uterus and without obliteration of the pouch of Douglas scheduled to undergo removal of an adnexal mass assessed to be benign on ultrasound by IOTA criteria. METHODS: Randomisation to laparoscopy (control group) or vNOTES (experimental group). Stratification according to adnexal size. Blinding of participants and outcome assessors by sham incisions. MAIN OUTCOME MEASURES: The primary outcome measure was adnexectomy by the allocated technique. Secondary outcomes included duration of surgery, pain scores and analgesics used, quality of life and adverse events. RESULTS: We randomly assigned 67 participants (34 to the vNOTES group and 33 to the laparoscopy group). The primary end point was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the laparoscopy group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 13%, which is below the predefined non-inferiority margin of 15%. The secondary outcomes demonstrated a shorter duration of surgery, lower pain scores, lower total dose of analgesics and a trend for more adverse events in the vNOTES group. CONCLUSIONS: vNOTES is non-inferior to laparoscopy for a successful adnexectomy without conversion. vNOTES allowed shorter operating times and less postoperative pain but there was a trend for more adverse events.

Delivery mode for prolonged, obstructed labour resulting in obstetric fistula: a retrospective review of 4396 women in East and Central Africa.

OBJECTIVE: To evaluate the mode of delivery and stillbirth rates over time among women with obstetric fistula. DESIGN: Retrospective record review. SETTING: Tanzania, Uganda, Kenya, Malawi, Rwanda, Somalia, South Sudan, Zambia and Ethiopia. POPULATION: A total of 4396 women presenting with obstetric fistulas for repair who delivered previously in facilities between 1990 and 2014. METHODS: Retrospective review of trends and associations between mode of delivery and stillbirth, focusing on caesarean section (CS), assisted vaginal deliveries and spontaneous vaginal deliveries. MAIN OUTCOME MEASURES: Mode of delivery, stillbirth. RESULTS: Out of 4396 women with fistula, 3695 (84.1%) delivered a stillborn baby. Among mothers with fistula giving birth to a stillborn baby, the CS rate (overall 54.8%, 2027/3695) rose from 45% (162/361) in 1990-94 to 64% (331/514) in 2010-14. This increase occurred at the expense of assisted vaginal delivery (overall 18.3%, 676/3695), which declined from 32% (115/361) to 6% (31/514). CONCLUSIONS: In Eastern and Central Africa, CS is increasingly performed on women with obstructed labour whose babies have already died in utero. Contrary to international recommendations, alternatives such as vacuum extraction, forceps and destructive delivery are decreasingly used. Unless uterine rupture is suspected, CS should be avoided in obstructed labour with intrauterine fetal death to avoid complications related to CS scars in subsequent pregnancies. Increasingly, women with obstetric fistula add a history of unnecessary CS to their already grim experiences of prolonged, obstructed labour and stillbirth. TWEETABLE ABSTRACT: Caesarean section is increasingly performed in African women with stillbirth treated for obstetric fistula.

Hysterectomy by transvaginal natural orifice transluminal endoscopic surgery versus laparoscopy as a day-care procedure: a randomised controlled trial.

OBJECTIVE: To compare hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (vNOTES) versus total laparoscopic hysterectomy (TLH) as a day-care procedure. DESIGN: Parallel group, 1:1 randomised single-centre single-blinded trial, designed as a non-inferiority study with a margin of 15%. SETTING: Belgian teaching hospital. POPULATION: Women aged 18-70 years scheduled to undergo hysterectomy for benign indications. METHODS: Randomisation to TLH (control group) or vNOTES (experimental group). Stratification according to uterine volume. Blinding of participants and outcome assessors. MAIN OUTCOME MEASURES: The primary outcome was hysterectomy by the allocated technique. We measured the proportion of women leaving within 12 hours after hysterectomy and the length of hospital stay as secondary outcomes. RESULTS: We randomly assigned 70 women to vNOTES (n = 35) or TLH (n = 35). The primary endpoint was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the TLH group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 7.5%, which is below the predefined non-inferiority margin. More women left the hospital within 12 hours after surgery after vNOTES: 77 versus 43%, difference 34% (95% CI 13-56%), P = 0.007. The hospital stay was shorter after vNOTES: 0.8 versus 1.3 days, mean difference -0.5 days, (95% CI -0.98 to -0.02), P = 0.004. CONCLUSIONS: vNOTES is non-inferior to TLH for successfully performing hysterectomy without conversion. Compared with TLH, vNOTES may allow more women to be treated in a day-care setting. TWEETABLE ABSTRACT: RCT: vNOTES is just as good as laparoscopy for successful hysterectomy without conversion but allows more day-care surgery.

Texture profile analysis reveals a stiffer ovarian cortex after testosterone therapy: a pilot study.

PURPOSE: The importance of the surrounding ovarian stromal cells and extracellular matrix in the development and maturation of follicles has recently gained attention. An aberrant extracellular matrix has been described in ovaries of patients with polycystic ovary syndrome where a more rigid structural environment, possibly induced by endogenous testosterone, impairs normal folliculogenesis. In this context, we describe the textural parameters of the ovarian cortex of transgender men after prolonged testosterone administration compared to the textural parameters of the non-exposed ovarian cortex originating from female oncological patients. METHODS: Texture profile analysis (TPA) was performed on ovarian cortex (5 × 5 mm) of oncological and transgender patients in order to measure stiffness, hardness, cohesiveness, and springiness of the ovarian cortex (LRXplus universal testing system). Statistical analysis was performed using repeated measurements mixed models and the Spearman rank order correlation test (IBM SPSS Statistics 23). RESULTS: A total of 36 frozen-thawed cortical strips (5 × 5 mm) were subjected to TPA. The superficial part of cortex fragments originating from transgender persons (fragments < 1.4 mm; N = 10) appeared to be significantly stiffer compared to cortex derived from oncology patients (fragments < 1.4 mm; N = 7) (6.78 ± 1.38 N/mm versus 5.41 ± 0.9 N/mm respectively, p = 0.036). CONCLUSIONS: This is the first application of TPA in ovarian cortex to study the physical properties. Comparing the physical properties, we objectively describe an increased cortical stiffness in the most outer part of the ovarian cortex following prolonged testosterone administration in transgender men compared to the ovarian cortex of oncological patients. This preliminary and novel approach could be the start of future research to understand the physical properties of ovarian tissue.

Association of dietary patterns with five-year degree and progression of coronary artery calcification in the Heinz Nixdorf Recall study.

BACKGROUND AND AIMS: As a modifiable lifestyle factor, diet is hypothesized to play an important role in the progression of atherosclerosis. The aim of this study was to explore associations of comprehensive dietary patterns derived by cluster analysis with degree and progression of coronary artery calcification (CAC) over five years of follow-up. METHODS AND RESULTS: In the population-based Heinz Nixdorf Recall study, 3718 participants (45-75 years; 47.6% men) without coronary heart disease completed a food frequency questionnaire at baseline. Five distinct dietary patterns were identified using cluster analysis: "Health-conscious", "Traditional German/Less alcohol", "Mediterranean-like", "Western" and "Animal fat/Alcohol" (used as reference). CAC was measured using electron-beam computed tomography at baseline and five years later. CAC after five years was predicted based on sex- and age-specific baseline percentiles. After comparing observed and predicted CAC Scores, CAC progression was classified as slow, expected, or rapid. Compared to "Animal fat/Alcohol" diet, a "Mediterranean-like" diet was associated with a relative risk (RR) for a rapid CAC progression in both sexes (men: 0.61; 95%-confidence interval [95%-CI]: 0.41; 0.90; women: 0.59; 95%-CI: 0.45; 0.78). Furthermore, reduced RRs were observed in women with a "Health-conscious" and a "Traditional German/Less alcohol" diet (0.63; 95%-CI: 0.47; 0.84, respectively 0.69; 95%-CI: 0.52; 0.90). No association was observed for a "Western" diet for both sexes. Similar results were revealed for degree of CAC. CONCLUSION: The study results support the hypothesis that a "Mediterranean-like" diet is associated with a lower CAC-progression and lower degree of CAC in men and women.

Fertility preservation for trans men: frozen-thawed in vitro matured oocytes collected at the time of ovarian tissue processing exhibit normal meiotic spindles.

PURPOSES: At the moment of sex reassignment surgery (SRS), the ovarian tissue is sometimes cryopreserved as fertility preservation option for female-to-male trans men, also called trans men. During this preparation, cumulus-oocyte-complexes (COCs) can be found and in vitro matured. It is not known if these oocytes are developmentally competent. In order to use these oocytes for fertility preservation and subsequent fertilization, a normal spindle structure before and after vitrification is necessary. METHODS: A total of 680 COCs were collected from trans men (n = 16) at the time of SRS and after testosterone treatment. The COCs were subjected to in vitro maturation and those that reached the metaphase II stage (MII) were collected and split into two groups; group 1 was immediately fixed for spindle staining and group 2 was first vitrified and warmed followed by spindle staining. Statistical analysis was performed by Fisher's exact test. RESULTS: After 48 h in vitro maturation, 38.1% of COCs were at MII stage. Those oocytes were split in two groups: (1) 126 MII oocytes in the noncryopreservation group and (2) 133 MII oocytes underwent cryopreservation through vitrification. The oocyte survival rate, after 2 h warming, was 67.7%. Both the noncryopreserved and the vitrified group showed comparable results concerning normal spindle structure and chromosomes alignment, 85.7% vs. 92.2% (P = 0.27). CONCLUSIONS: Spindle structure analysis and chromosomal alignment after vitrification seem normal in in vitro matured COCs collected during the tissue processing of ovaries in trans men at the time of SRS. The MII oocytes do not seem to be morphologically affected by prolonged testosterone treatment.

Improved limit on a temporal variation of mp/me from comparisons of Yb+ and Cs atomic clocks.

Accurate measurements of different transition frequencies between atomic levels of the electronic and hyperfine structure over time are used to investigate temporal variations of the fine structure constant α and the proton-to-electron mass ratio µ. We measure the frequency of the (2)S1/2→(2)F7/2 electric octupole (E3) transition in (171)Yb(+) against two caesium fountain clocks as f(E3)=642,121,496,772,645.36 Hz with an improved fractional uncertainty of 3.9×10(-16). This transition frequency shows a strong sensitivity to changes of α. Together with a number of previous and recent measurements of the (2)S1/2→(2)D3/2 electric quadrupole transition in (171)Yb(+) and with data from other elements, a least-squares analysis yields (1/α)(dα/dt)=-0.20(20)×10(-16)/yr and (1/µ)(dµ/dt)=-0.5(1.6)×10(-16)/yr, confirming a previous limit on dα/dt and providing the most stringent limit on dµ/dt from laboratory experiments.

Leiomyomatosis peritonealis disseminata associated with ascites and endometriosis: a case report and review of the literature.

We present a case of leiomyomatosis peritonealis disseminata (LPD) and review the literature. LPD is a rare, benign disorder that is characterized by multiple subperitoneal or peritoneal nodules of varying sizes on the omentum and peritoneal surfaces, grossly resembling disseminated carcinoma. It should be differentiated from other peritoneal tumors. It is mostly asymptomatic and diagnosis is often incidental during surgery. One should be aware of the iatrogenic component of this entity. LPD is being documented with increasing frequency. We report the case of a 39-year-old woman with chronic abdominal pain and heavy dysmenorrhea due to endometriosis associated with LPD. She underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy. LPD and endometriosis is a known association. LPD with ascites and endometriosis however has not yet been reported.

High-accuracy optical clock based on the octupole transition in 171Yb+.

We experimentally investigate an optical frequency standard based on the 467 nm (642 THz) electric-octupole reference transition (2)S(1/2)(F=0)→(2)F(7/2)(F=3) in a single trapped (171)Yb(+) ion. The extraordinary features of this transition result from the long natural lifetime and from the 4f(13)6s(2) configuration of the upper state. The electric-quadrupole moment of the (2)F(7/2) state is measured as -0.041(5)ea(0)(2), where e is the elementary charge and a(0) the Bohr radius. We also obtain information on the differential scalar and tensorial components of the static polarizability and of the probe-light-induced ac Stark shift of the octupole transition. With a real-time extrapolation scheme that eliminates this shift, the unperturbed transition frequency is realized with a fractional uncertainty of 7.1×10(-17). The frequency is measured as 642 121 496 772 645.15(52) Hz.

A case of disseminated tuberculosis during a twin pregnancy following in vitro fertilization.

A woman presented with cough, fever, and dyspnea during a twin pregnancy following a 13th in vitro fertilization procedure. Ultimately, she was diagnosed with miliary tuberculosis and tuberculostatic treatment was initiated, complicated by drug-induced hepatotoxicity. In retrospect, previous pelvic tuberculosis had likely been overlooked. This case report highlights the need to recognize tuberculosis as a cause of infertility even in low-incidence countries and emphasizes that the peripartum period is a major risk factor for drug-induced liver injury.

Anti-adhesion Gel versus No gel following Operative Hysteroscopy prior to Subsequent fertility Treatment or timed InterCourse (AGNOHSTIC), a randomised controlled trial: protocol.

STUDY QUESTIONS: Does the application of anti-adhesion gel, compared to no gel, following operative hysteroscopy to treat intrauterine pathology in women wishing to conceive increase the chance of conception leading to live birth? WHAT IS KNOWN ALREADY: Intrauterine adhesions (IUAs) following operative hysteroscopy may impair reproductive success in women of reproductive age. Anti-adhesion barrier gels may decrease the occurrence of IUAs, but the evidence on their effectiveness to improve reproductive outcomes is sparse and of low quality. STUDY DESIGN SIZE DURATION: This multicentre, parallel group, superiority, blinded and pragmatic randomised controlled trial is being carried out in seven participating centres in Belgium. Recruitment started in April 2019. Women will be randomly allocated to treatment with anti-adhesion gel (intervention group) or no gel (control group). Sterile ultrasound gel will be applied into the vagina as a mock-procedure in both treatment arms. The patient, fertility physician and gynaecologist performing the second-look hysteroscopy are unaware of the allocated treatment. Power analysis, based on a target improvement of 15% in conception leading to live birth using anti-adhesion gel, a power of 85%, a significance level of 5%, and a drop-out rate of 10%, yielded a number of 444 patients to be randomised. The baseline rate of conception leading to live birth in the control group is expected to be 45%. PARTICIPANTS/MATERIALS SETTING METHODS: Women of reproductive age (18-47 years), wishing to conceive (spontaneously or by fertility treatment) and scheduled for operative hysteroscopy to treat intrauterine pathology (endometrial polyps, myomas with uterine cavity deformation, uterine septa, IUAs or retained products of conception) are eligible for recruitment. Women may try to conceive from 3 to 6 weeks after receiving allocated treatment with follow-up ending at 30 weeks after treatment. If the woman fails to conceive within this timeframe, a second-look hysteroscopy will be scheduled within 2-6 weeks to check for IUAs. The primary endpoint is conception leading to live birth, measured at 30 weeks after randomisation. The secondary endpoints are time to conception, clinical pregnancy, miscarriage and ectopic pregnancy rates, measured at 30 weeks after receiving allocated treatment. The long-term follow-up starts when the patient is pregnant and she will be contacted every trimester. STUDY FUNDING/COMPETING INTERESTS: This work is funded by the Belgian Healthcare Knowledge Centre (KCE). The anti-adhesion gel is supplied at no cost by Nordic Pharma and without conditions. Dr. Tomassetti reports grants and non-financial support from Merck SA, non-financial support from Ferring SA, personal fees and non-financial support from Gedeon-Richter, outside the submitted work. None of the other authors have a conflict of interest.

Contribution of androgen receptor sensitivity to the relation between testosterone and sexual desire: An exploration in male-to-female transsexuals.

BACKGROUND: Low sexual desire is present in 1/3 of male-to-female transsexuals (post-operative male-to-female transsexual persons on estrogen replacement). Several studies report lower endogenous testosterone (T) levels in this group compared to community dwelling women. However, no relationship between T and sexual desire has been found in male-to-female transsexuals. Considering its role in androgen sensitivity, cytosine-adenine-guanine (CAG) trinucleotide repeat sequence in the androgen receptor (AR) might modify the relationship between T levels and sexual desire in male-to-female transsexuals. AIM: This study aims to assess the potential contribution of the number of CAG repeats in the association between T and sexual desire in male-to-female transsexuals. MATERIAL, SUBJECTS, AND METHODS: Thirty-four post-operative male-to-female transsexuals participated in a cross-sectional study. The Sexual Desire Inventory, a questionnaire measuring sexual desire, was completed. Serum levels of total (TT) and free T (FT), DHEA-S, SHBG, and LH were measured in morning blood samples. AR gene CAG repeat length was determined by automated DNA fragment analysis of exon 1 of the AR gene. RESULTS: The CAG repeat length ranged from 14 to 28 with a median of 21. CAG polymorphism was correlated with FT (r=0.389; p=0.023) but not with TT (r=0.191; p=0.280). The observed interaction between TT and CAG was significant only for solitary sexual desire (p=0.002). The interaction of CAG repeats and FT on sexual desire failed to reach significance. CONCLUSIONS: We could not establish that CAG repeat length is a consistent modulating factor in the relationship between TT or FT and sexual desire in male-to-female transsexuals.

Cytology of the 'penile' neovagina in transsexual women.

OBJECTIVE: The primary objective was to describe the neovaginal cytology in transsexual patients (n = 50) treated with the inverted penile skin technique. Secondary objectives were to compare our cytological findings with patient characteristics including use of oestrogens, sexual orientation and penetrative intercourse. METHODS: The medical and surgical history, sexual orientation and whether there was a current relationship were ascertained. A speculum examination was followed by microscopy of a Pap smear of the neovaginal vault. RESULTS: Well-preserved nucleated squamous cells were found in 72%. The correlation between their presence and sexual orientation was highly significant (P = 0.016), with those not sexually interested and homosexually oriented all having nucleated cells on the Pap smear. However, the correlation between these cells and penetrative intercourse failed to reach significance. Four samples showed atypical squamous cells of undetermined significance, all were negative for high-risk human papillomavirus (HR-HPV) types. One patient showed a low-grade squamous intraepithelial lesion that was HR-HPV positive. There was a significant correlation between the presence of cytological lesions and sexual orientation (P = 0.006). Four percentage of the specimens showed Döderlein bacilli. Inflammation was found in 30.6% of samples with squamous cells. CONCLUSIONS: The penile skin-lined neovagina of transsexual women can reflect the cytological findings present in biological women. However 'normal' cervical cytology, with superficial, intermediate and parabasal cells as well as Döderlein bacilli, was found in only 4% of transsexual women. Although one patient's Pap test showed koilocytes and was HR-HPV positive, no high-grade squamous intraepithelial lesions were identified.