Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.

STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2017.

Single-cell reconstruction of follicular remodeling in the human adult ovary.

The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.

Outcome and Prognostic Impact of Surgical Staging in Serous Tubal Intraepithelial Carcinoma: A Cohort Study and Systematic Review.

The optimal management of breast cancer susceptibility gene (BRCA)1/2 carriers with isolated serous tubal intraepithelial carcinoma (STIC) found at risk-reducing salpingo-oophorectomy (RRSO) is unclear. The prevalence of occult carcinoma and STIC in a consecutive series of BRCA1/2 carriers undergoing RRSO is reported. The outcome of staging procedures in BRCA1/2 carriers with isolated STIC at RRSO as well as the relationship between staging, chemotherapy treatment and risk of recurrence was assessed via a systematic review of the literature. Our series included 235 BRCA1/2 carriers who underwent RRSO. Federation of Gynaecology and Obstetrics stage IA carcinoma or STIC was found at RRSO in three (1.3%) and two (0.9%) patients, respectively. A systematic review of the literature included 82 BRCA1/2 carriers with isolated STIC found at RRSO. In 13/82 (16%) cases with STIC, staging was reported. In none of these cases staging revealed more advanced disease. Recurrent disease was found in four of 36 patients with reported follow-up. The estimated risk of recurrence in patients with isolated STIC at RRSO was about 11% (95% confidence interval 3-26%) after a median follow-up of 42 months (range 7-138). No recurrences were reported in those patients with STIC at RRSO who underwent staging or received chemotherapy. We found 1.3% occult carcinoma and 0.9% STIC at RRSO in our cohort of BRCA1/2 carriers. A systematic review of the literature suggests that additional treatment after RRSO, i.e. staging and/or chemotherapy, is associated with a lower risk of recurrence. However, data on staging and follow-up are limited.

Factors associated with frequency of discussion of or referral for counselling about fertility issues in female cancer patients.

Current practices in counselling of female cancer patients with respect to fertility issues need considerable improvement, particularly given the general underuse of fertility preservation options and the negative impact that infertility can have on quality of life. We investigated the relationship between physicians' and physician-related factors and the frequency of physicians discussing fertility issues and referring to a reproductive specialist. We invited 1,832 physicians in the Netherlands who had treated at least five reproductive-age female cancer patients within the past year to complete a questionnaire. Of the 748 respondents, 406 met our inclusion criteria, and 280 participated. Analysis revealed that 79% of the participants usually or always discuss fertility issues. Specialty, confidence in knowledge regarding fertility issues and a lack of reproductive specialists in their region contributed independently to the variance in the frequency of discussing fertility issues. Moreover, 54% either regularly or always refer. Specialty and frequency of discussion contributed independently to the variance in referral. In conclusion, although high, frequency of discussion of fertility issues is not optimal, and referral seems limited. Patients would benefit from more knowledge among physicians regarding fertility issues and referral options, both in terms of informed choice, and more importantly, quality of life.

Stimulation of the ovaries in women with breast cancer undergoing fertility preservation: Alternative versus standard stimulation protocols; the study protocol of the STIM-trial.

BACKGROUND: Chemotherapy for breast cancer may have a negative impact on reproductive function due to gonadotoxicity. Fertility preservation via banking of oocytes or embryos after ovarian stimulation with FSH can increase the likelihood of a future live birth. It has been hypothesized that elevated serum estrogen levels during ovarian stimulation may induce breast tumour growth. This has led to the use of alternative stimulation protocols with addition of tamoxifen or letrozole. The effectiveness of these stimulation protocols in terms of oocyte yield is unknown. METHODS/DESIGN: Randomized open-label trial comparing ovarian stimulation plus tamoxifen and ovarian stimulation plus letrozole with standard ovarian stimulation in the course of fertility preservation. The study population consists of women with breast cancer who opt for banking of oocytes or embryos, aged 18-43years at randomisation. Primary outcome is the number of oocytes retrieved at follicle aspiration. Secondary outcomes are number of mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during ovarian stimulation. DISCUSSION: Concerning the lack of evidence on which stimulation protocol should be used in women with breast cancer and the growing demand for fertility preservation, there is an urgent need to undertake this study. By performing this study, we will be able to closely monitor the effects of various stimulation protocols in women with breast cancer and pave the way for long term follow up on the safety of this procedure in terms of breast cancer prognosis. TRIAL REGISTRATION: NTR4108.

[Can I still get pregnant? Options for fertility preservation in young women diagnosed with cancer]. / Kan ik nog zwanger worden?

- In 2015 around 2300 women under the age of 40 years were diagnosed with cancer in the Netherlands.- Cancer treatment can have a negative effect on fertility.- Due to improving survival rates, discussing this effect and the options for fertility preservation has become an important part of counselling these patients.- Cryopreservation of oocytes and embryos is standard procedure in fertility preservation in the Netherlands.- Cryopreservation of ovarian tissue is a new, rapidly-developing technique. Recently, the first child following autotransplantation of thawed ovarian tissue was born in the Netherlands.- If gonadotoxic treatment has to be given, it is important to talk well in advance with the patient about fertility preservation.

Practice, attitude and knowledge of Dutch paediatric oncologists regarding female fertility.

BACKGROUND: Chemotherapy and radiotherapy for childhood cancer can result in a decreased reproductive function. It is therefore important that paediatric oncologists discuss the possible impact of treatment on female fertility and available fertility preservation options with their patients. However, it is unknown what Dutch paediatric oncologists know about of the effect of cancer treatment on female fertility, whether or not they address this issue in clinical practice, what their attitudes are towards addressing fertility after cancer treatment and fertility preservation options, and to what extent they require additional information resources. METHODS: In this nationwide quantitative cross-sectional study a survey was sent to all registered paediatric oncologists in the Netherlands (n=64). RESULTS: Thirty-seven paediatric oncologists participated (participation rate 58%). Fertility issues were discussed with patients and/or parents by 97%. Of the paediatric oncologists, 54-76% were aware of possibilities for fertility preservation; however only <25% reported a moderate or high confidence in their knowledge of these techniques. Paediatric oncologists stated that they had little resources to counsel their patients and 92% found educational resources not completely sufficient. CONCLUSION: Paediatric oncologists are well aware of the effect that cancer treatment may have on female fertility and their responsibility to counsel their patients and/or the parents on this issue. They do not (yet) possess the knowledge to sufficiently counsel these patients and, if needed, do not frequently refer them to a fertility specialist.

[Fertility preservation in female oncology patients]. / Fertiliteitspreservatie bij vrouwen met kanker.

Four women were referred to the department ofGynaecology for fertility preservation. A 33-year-old nulliparous woman with breast cancer stage pT1cN0M0 underwent an IVF-ICSI cycle; five embryos were frozen. Pre-implantation genetic diagnosis (PGD) because of BRCA2 gene mutation carriage was not carried out and more recently follow-up oocyte donation options are being considered. A second, 32-year-old nulliparous woman with breast cancer stage pT2N1M0 underwent an IVF cycle; seven embryos were frozen. The third patient was a 14-year-old girl with osteosarcoma of the distal femur, who underwent a laparoscopic unilateral ovariectomy, one day after referral, and cortical tissue was frozen. The fourth patient was a 33-year-old nulliparous woman without partner, with non-Hodgkin lymphoma stage IIA. She underwent laparoscopic ovariectomy and cortical tissue was frozen. Infertility due to cancer treatment and fertility preservation options should be discussed early in treatment planning. Patients' expectations and fertility preservation limitations are important to consider. Fertility preservation options can be conducted in specialised hospitals under institutional review board approval. It still has an experimental status.

A randomised comparison of vaginoscopic office hysteroscopy and saline infusion sonography: a patient compliance study.

OBJECTIVE: The purpose of this study was to compare patient discomfort during saline infusion sonography (SIS) and office hysteroscopy performed according to a vaginoscopic approach. DESIGN: Randomised controlled trial. SETTING: University hospital. POPULATION: Women with an indication for further investigation of the uterine cavity. METHODS: A total of 100 women randomly allocated to either SIS or vaginoscopic office hysteroscopy in an outpatient clinic. MAIN OUTCOME MEASURES: Scores on a visual analogue scale (VAS) for pain and a present pain intensity (PPI) scale, conclusiveness and success rate. RESULTS: The patients' pain scores on both the VAS and the PPI were lower for SIS when compared with office hysteroscopy (P < 0.05). However, in cases of severe pain (VAS > 7 or PPI > 2), there was no statistically significant difference between both groups. The success rate, defined as adequate inspection of the cervical canal and uterine cavity, was 94% for SIS compared with 92% for office hysteroscopy (P = 0.633). SIS, multiparity, shorter procedure time and position of the uterus in anteversion decreased pain scores among women studied. CONCLUSIONS: Both SIS and office hysteroscopy are successful procedures and well tolerated by women. SIS induces significantly less discomfort than office hysteroscopy and should therefore be considered the method of choice.

Anonymous or identity-registered sperm donors? A study of Dutch recipients' choices.

BACKGROUND: The aim of the present study was to gain insight into parents' own donor preferences within a system offering the choice between an anonymous and identity-registered donor. A comparison was made between recipients choosing for an anonymous donor (AD choosers) and those choosing for an identifiable donor (ID choosers) with regard to their sexual orientation, demographic characteristics, disclosure issues and infertility distress. METHODS: Data from 105 couples (61% heterosexual, 39% lesbian) were registered on a standardized form during implication counselling sessions previous to treatment. RESULTS: Sixty-three per cent of the heterosexual couples and 98% of the lesbian couples had chosen an ID donor. Major differences between ID and AD choosers were identified. Among the ID choosers secrecy towards the child was no option, whereas 83% of the AD choosers did not intend to inform their child. Compared with heterosexual ID choosers, AD choosers were more distressed about their infertility and had a lower educational level. CONCLUSION: Legislation imposing ID donors appears to be acceptable for the majority of this study population. For a vulnerable group of heterosexual couples, who remained secretive about the use of a donor, adaptation to the new system is not self-evident.

Endometrial cancer in four sisters: report of a kindred with presumed cancer family syndrome.

Hereditary nonpolyposis colorectal cancer (HNPCC, synonyms: cancer family syndrome, Lynch syndrome) is characterized by the occurrence of colorectal cancer and other primary tumors in susceptible family members. Inheritance is autosomal dominant with high penetrance. Endometrial cancer is the most frequent extracolonic malignancy in gene carriers. The criteria for the diagnosis HNPCC include the occurrence of colorectal cancer in three close relatives. However, not only colorectal cancer but also endometrial cancer may indicate HNPCC. We present a family diagnosed as a probable HNPCC kindred after endometrial cancer was observed in four sisters. One of these patients and the father of the four sisters had had colorectal cancer. This kindred illustrates the importance of recording the family history in patients with endometrial cancer.

Study of the distribution of circumsporozoite antigen in Anopheles gambiae infected with Plasmodium falciparum, using the enzyme-linked immunosorbent assay.

Anopheles gambiae, experimentally infected with Plasmodium falciparum, were dissected 14 days later for microscopical detection of sporozoites and oocysts. The head, salivary glands, thorax, midgut, legs, ovaries, Malpighian tubules, the remainder of the abdominal tissues and the dissection fluid of each mosquito were examined by a two-site enzyme-linked immunosorbent assay (ELISA) for the detection and quantification of circumsporozoite antigen (CS ag). 19 mosquitoes had CS ag in at least one of the specimens examined. Very large individual variability was observed in the presence and/or quantity of CS ag in the various parts. 7 mosquitoes were ELISA-positive in all 9 specimens; the salivary glands and thorax contained most CS ag, whereas the Malpighian tubules and ovaries contained the least; all the thoraces contained CS ag, even that of one mosquito of which the salivary glands lacked both sporozoites and CS ag; of 17 ELISA-positive salivary glands, 15 were found to contain sporozoites. The existence of free antigen associated with sporozoites, and the limitations of the ELISA technique in demonstrating the infectivity of a malaria vector, are discussed.