[Several techniques can help men with testicular azoospermia to become biological fathers]. / Möjligheterna för infertila män att få biologiska barn är många.

Men with testicular azoospermia (NOA) have impaired spermatogenesis, and surgical testicular procedures are required to retrieve sperm. If testicular sperm can be retrieved, men with NOA can become biological fathers via intracytoplasmic sperm injection (ICSI). Several techniques are available today, such as needle aspiration (TESA), percutaneous biopsies and open biopsies (conventional TESE/micro-TESE). The most recent technique is micro-TESE, a non-blind technique, where seminiferous tubules with the highest probability of containing sperm are selected using an operative microscope. Though clinical routines differ between fertility centres where micro-TESE is available, sperm recovery rates are high. Similar risk for adverse outcomes have been observed in offspring compared with standard IVF. New non-blind sperm recovery techniques, such as micro-TESE, are encouraging and may improve sperm retrieval outcome in men with NOA. However, they require surgical and embryologist skills as well as investment in an operative microscope.

Vaginal progesterone as luteal phase support in natural cycle frozen-thawed embryo transfer (ProFET): protocol for a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Vaginal progesterone supplementation is frequently given to patients receiving frozen embryo transfer (FET) in the natural cycle aiming to increase the chance of pregnancy and live birth. To date, only a few studies have investigated if progesterone supplementation is beneficial in these cycles and the level of evidence for progesterone supplementation is very low. METHODS AND ANALYSIS: The ProFET trial is a multicentre, open-label, randomised controlled trial powered for this investigation, including 1800 women with regular menstrual cycles (24-35 days), aged 18-43 years planned for natural cycle-FET receiving a single blastocyst for transfer. Participants are randomised (1:1:1) to either luteal phase progesterone for 3 weeks, luteal phase progesterone for 7 weeks or no luteal phase progesterone. The participating study centres consist of 12 in vitro fertilisation-clinics in Sweden and 1 in Iceland. The primary outcome is to investigate if luteal phase support (LPS) by vaginal progesterone increases the chance of a live birth per randomised patient in a natural FET cycle compared with no LPS. ETHICS AND DISSEMINATION: The trial was approved by the Swedish Ethical Review Authority (ID 2020-06774, 2021-02822 and 2022-01502-02) and the Swedish Medical Products Agency (ID nr 5.1-2020-102613). All participants are required to provide written informed consent. The outcome of this study will be disseminated to the public through broadcasts, newspapers and presentations at scientific congresses as well as publications in international scientific journals. TRIAL REGISTRATION NUMBER: NCT04725864.

A double-blind randomized controlled trial investigating a time-lapse algorithm for selecting Day 5 blastocysts for transfer.

STUDY QUESTION: Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone? SUMMARY ANSWER: The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone. WHAT IS KNOWN ALREADY: Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection. STUDY DESIGN, SIZE, DURATION: A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics. LIMITATIONS, REASONS FOR CAUTION: During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registration number NCT03445923. TRIAL REGISTRATION DATE: 26 February 2018. DATE OF FIRST PATIENT'S ENROLMENT: 11 June 2018.

Utility of micro-TESE in the most severe cases of non-obstructive azoospermia.

The use of intracytoplasmic sperm injection (ICSI) has been a major breakthrough in the treatment of male infertility. Even patients with non-obstructive azoospermia (NOA) may benefit from the ICSI technique to father a child as long as spermatogenesis is present. There are several techniques to recover testicular sperm in patients with NOA. However, retrieval of spermatozoa is unfortunately still only successful in a subset of patients with NOA, and the most superior sperm retrieval method is still under debate. A more recent technique, microdissection testicular sperm extraction (MD-TESE) with an operative microscope collecting larger and more opaque seminiferous tubules, is a non-blind sperm retrieval technique with theoretical benefits. The MD-TESE procedure seems to be feasible, effective, and safe in NOA patients but also more technically demanding and time-consuming compared with conventional blind techniques. In the present report, we describe our clinical experience and results from our first 159 MD-TESE procedures. The probability to retrieve sperm with the MD-TESE technique is high in NOA cases where earlier sperm retrieval with blind methods such as needle aspiration, percutaneous needle biopsy, or conventional TESE has failed.

[Microdissection testicular sperm extraction (MD-TESE) - a new sperm recovery technique helping men with non-obstructive azoospermia]. / Ny operationsmetod hjälper infertila män bli biologiska fäder - Mikro-TESE kan vara ett sista hopp för män med icke-obstruktiv azoospermi.

The most severe form of male infertility is non obstructive azoospermia (NOA), where spermatogenesis is impaired or absent. If testicular sperm can be retrieved, men with NOA can become biological fathers with IVF/ ICSI. In Sweden, testicular sperm aspiration (TESA) is the most common method used to retrieve sperm but is only successful in up to 34% of procedures. In 2013, our fertility center introduced MD-TESE, where an operating microscope is used to target the biopsies. We have performed more than 134 MD-TESE procedures, mainly in cases where TESA sperm recovery failed previously. Sperm sufficient for ICSI were recovered in 52 % and in these cases 75 % resulted in embryo transfer, resulting in a 34 % ongoing pregnancy rate/deliveries per transfer. Results are encouraging and hopefully more Swedish IVF centers will introduce this technique.

Neonatal and maternal outcome after blastocyst transfer: a population-based registry study.

BACKGROUND: Previous studies have shown a higher risk of birth defects and preterm birth (PTB) in singletons born after blastocyst transfer as compared to singletons born after cleavage-stage transfer. Few studies have investigated the maternal outcomes. OBJECTIVE: We sought to analyze the neonatal and maternal outcome after blastocyst transfer (day 5-6) compared to transfer of cleavage-stage embryos (day 2-3) and spontaneous conception. STUDY DESIGN: This was a population-based retrospective registry study including all singleton deliveries after blastocyst transfer in Sweden from 2002 through 2013. The in vitro fertilization register was cross-linked with the Swedish Medical Birth Register, the Register of Birth Defects, and the National Patient Register. Deliveries after blastocyst transfer were compared with deliveries after cleavage-stage transfer and deliveries after spontaneous conception. Outcome measures included birth defects, PTB, low birthweight, small for gestational age, large for gestational age, perinatal mortality, placenta previa, placental abruption, and preeclampsia. Crude and adjusted odds ratios (AOR) with 95% confidence interval (CI) were calculated. Adjustment was made for year of birth of child, maternal age, parity, smoking, body mass index, years of involuntary childlessness, and child's sex and, for cleavage stage, also for number of oocytes retrieved, number of embryos transferred, and fresh/frozen embryo transfer. RESULTS: There were 4819 singletons born after blastocyst transfer, 25,747 after cleavage-stage transfer, and 1,196,394 after spontaneous conception. Singletons born after blastocyst transfer had no increased risk of birth defects compared to singletons born after cleavage-stage transfer (AOR, 0.94; 95% CI, 0.79-1.13) or spontaneous conception (AOR, 1.09; 95% CI, 0.92-1.28). Perinatal mortality was higher in the blastocyst vs the cleavage-stage group (AOR, 1.61; 95% CI, 1.14-2.29). When comparing singletons born after blastocyst transfer to singletons born after spontaneous conception, a higher risk of PTB (<37 weeks) was seen (AOR, 1.17; 95% CI, 1.05-1.31). Singletons born after blastocyst transfer had a lower rate of low birthweight (AOR, 0.83; 95% CI, 0.71-0.97) as compared to cleavage-stage transfer. The rate of being small for gestational age was lower in singletons born after blastocyst transfer as compared to both cleavage-stage and spontaneous conception (AOR, 0.71; 95% CI, 0.56-0.88 and AOR, 0.70; 95% CI, 0.57-0.87, respectively). The risk of placenta previa and placental abruption was higher in pregnancies after blastocyst transfer as compared to pregnancies after cleavage-stage (AOR, 2.08; 95% CI, 1.70-2.55 and AOR, 1.62; 95% CI, 1.15-2.29, respectively) and spontaneous conception (AOR, 6.38; 95% CI, 5.31-7.66 and AOR, 2.31; 95% CI, 1.70-3.13, respectively). CONCLUSION: No increased risk of birth defects was found in singletons born after blastocyst transfer. Perinatal mortality and risk of placental complications were higher in the blastocyst group as compared to the cleavage-stage group, observations that need further investigations.

Pre-ovarian block versus paracervical block for oocyte retrieval.

BACKGROUND: A pre-ovarian block (POB) technique can be used for pain relief during oocyte retrieval in IVF. The local anaesthetic is deposited in the vaginal wall and between the vaginal wall and the peritoneal surface near the ovary using ultrasound guidance. The aim of this study was to test whether analgesia with POB resulted in improved pain relief compared to paracervical block (PCB). METHODS: A prospective, randomized, multicentre study of POB versus PCB (10 ml of 1% lidocaine each) with 183 patients randomized to POB (n = 96) or PCB (n = 87) was performed. Randomization (via a computer-generated list) was balanced for age, previously completed IVF cycles, degree of anxiety, estimated number of follicles, BMI, premedication and centre. Pain was measured using a visual analogue scale (VAS, 0-100 mm) and given as median values. The primary end-point of this study was overall VAS pain score for both sides during the oocyte retrieval procedure. RESULTS: Overall pain during the entire oocyte retrieval was 22 (POB) and 16 (PCB) (P = 0.42). No differences were found in degree of anxiety, premedication, dose of alfentanil, fertilization rate, number of good-quality embryos or clinical pregnancy rate. CONCLUSIONS: No differences were found in overall pain experienced during the entire oocyte retrieval procedure with POB compared to PCB.

Effect of a synthetic progestin on the exercise status of sedentary young women.

CONTEXT: The impact of progestins on exercise performance in women has not been previously studied. OBJECTIVE: The objective of this study was to examine the effect of a synthetic progestin on aspects of exercise status in young women. DESIGN, PATIENTS, SETTING: Twenty-three young, healthy, habitually sedentary women participated in a single-blind, randomized, counterbalanced, cross-over study in a university-based laboratory setting. INTERVENTION: Two monophasic oral contraceptive pills (OCPs) were administered in which the dose of the synthetic progestin, norethisterone, was 2-fold different but the dose of the synthetic estrogen, ethinyl estradiol, was constant. During each month of OCP aspects of exercise status were assessed during incremental exercise to exhaustion and steady-state submaximal exercise and with a performance test. MAIN OUTCOME MEASURES: The main outcome measures were peak oxygen uptake (VO(2peak)), respiratory exchange ratio (RER), time to exhaustion, lactate concentrations, and total work done. RESULTS: Peak heart rates were approximately 95% of age-predicted values with both OCP preparations, whereas VO(2peak) was approximately 30% above age-predicted values. Peak postincremental exercise plasma lactate concentrations exceeded those reported for males and females, whereas the RER was below expected values throughout both incremental and steady-state exercise. The effects on VO(2peak) and RER were increased with the higher dose progestin OCP, as were exercise time to exhaustion and total work done. CONCLUSION: Synthetic progestins in OCP formulations can have a significant effect on the exercise status of young, sedentary women, possibly through an effect on stroke volume and a shift in the principal energy substrate used during exercise from carbohydrate to lipid.

Testicular sonography in men with Klinefelter syndrome shows irregular echogenicity and blood flow of high resistance.

PURPOSE: Klinefelter syndrome is the most common chromosomal aberration among azoospermic men. We wanted to compare testicular echogenicity and intratesticular arterial blood in men with this syndrome versus men with normal sperm parameters. METHODS: Testicular sonography including Doppler imaging, was performed as part of the infertility workup in 26 men with Klinefelter syndrome as well as in 26 men with normal sperm parameters. RESULTS: In men with Klinefelter syndrome, sonography of the testicular parenchyma revealed a heterogeneous irregular pattern with spread hyper- and hypoechoic foci. Doppler sonography resulted in waveforms of high impedance patterns, reflecting intratesticular blood flow of a high resistance. In men with normal sperm parameters testicular echogenicity was of an almost homogeneous regular pattern. In these men, intratesticular blood flow typically exhibited a pattern of low vascular resistance. CONCLUSIONS: The study demonstrates that testicular echogenicity as well as intratesticular blood flow are different in men with Klinefelter syndrome versus men with normal sperm parameters.