Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency.

RESEARCH QUESTION: Does a genetic condition underlie the diagnosis of primary ovarian insufficiency (POI) in a 21-year-old woman with primary amenorrhoea? DESIGN: A karyotype and genetic testing for Fragile X syndrome was undertaken. A next-generation sequencing panel of 24 genes associated with syndromal and non-syndromal POI was conducted. RESULTS: A nonsense variant c.1336G>T, p.(Glu446Ter) and whole gene deletion in STAG3 were identified. CONCLUSIONS: Biallelic loss of function variants in STAG3 are associated with primary ovarian failure type 8 and are a rare cause of POI.

Growth hormone for in vitro fertilisation (IVF).

BACKGROUND: In an effort to improve outcomes of in vitro fertilisation (IVF) cycles, the use of growth hormone (GH) has been considered as adjuvant treatment in ovarian stimulation. Improving the outcomes of IVF is especially important for women with infertility who are considered 'poor responders'. We have compared the outcomes of IVF with adjuvant GH versus no adjuvant treatment in routine use, and specifically in poor responders. OBJECTIVES: To assess the effectiveness and safety of growth hormone as an adjunct to IVF compared to standard IVF for women with infertility SEARCH METHODS: We searched the following databases (to November 2020): Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, CINAHL, Epistemonikos database and trial registers together with reference checking and contact with study authors and experts in the field to identify additional trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of adjuvant GH treatment in IVF compared with no adjuvant treatment for women with infertility. We excluded trials where additional adjuvant treatments were used with GH. We also excluded trials comparing different IVF protocols. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Two review authors independently performed assessment of trial risk of bias and extraction of relevant data. The primary review outcome was live birth rate. The secondary outcomes were clinical pregnancy rate, oocytes retrieved, embryo transfer, units of gonadotropin used and adverse events, i.e. ectopic pregnancy, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), congenital anomalies, oedema. MAIN RESULTS: We included 16 RCTs (1352 women). Two RCTs (80 women) studied GH in routine use, and 14 RCTs (1272 women) studied GH in poor responders. The evidence was low to very low certainty, the main limitations being risk of bias, imprecision and heterogeneity. Adjuvant growth hormone compared to no adjuvant: routine use for in vitro fertilisation (IVF) The evidence is very uncertain about the effect of GH on live birth rate per woman randomised for routine use in IVF (odds ratio (OR) 1.32, 95% confidence interval (CI) 0.40 to 4.43; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). If the chance of live birth without adjuvant GH is assumed to be 15%, the chance of live birth with GH would be between 6% and 43%. There was insufficient evidence to reach a conclusion regarding clinical pregnancy rates per woman randomised, number of women with at least one oocyte retrieved per woman randomised and embryo transfer achieved per woman randomised; reported data were unsuitable for analysis. The evidence is very uncertain about the effect of GH on mean number of oocytes retrieved in normal responders (mean difference (MD) -0.02, 95% CI -0.79 to 0.74; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). The evidence is very uncertain about the effect of GH on mean units of gonadotropin used in normal responders (MD 13.57, 95% CI -112.88 to 140.01; I2 = 0%; 2 trials, 80 participants; very low-certainty evidence). We are uncertain of the effect of GH on adverse events in normal responders. Adjuvant growth hormone compared to no adjuvant: use in poor responders for in vitro fertilisation (IVF) The evidence is very uncertain about the effect of GH on live birth rate per woman randomised for poor responders (OR 1.77, 95% CI 1.17 to 2.70; I2 = 0%; 8 trials, 737 participants; very low-certainty evidence). If the chance of live birth without adjuvant GH is assumed to be 11%, the chance of live birth with GH would be between 13% and 25%. Adjuvant GH results in a slight increase in pregnancy rates in poor responders (OR 1.85, 95% CI 1.35 to 2.53; I2 = 15%; 11 trials, 1033 participants; low-certainty evidence). The results suggest, if the pregnancy rate without adjuvant GH is assumed to be 15%, with GH the pregnancy rate in poor responders would be between 19% and 31%. The evidence suggests that GH results in little to no difference in number of women with at least one oocyte retrieved (OR 5.67, 95% CI 1.54 to 20.83; I2 = 0%; 2 trials, 148 participants; low-certainty evidence). If the chance of retrieving at least one oocyte in poor responders was 81%, with GH the chance is between 87% and 99%. There is a slight increase in mean number of oocytes retrieved with the use of GH for poor responders (MD 1.40, 95% CI 1.16 to 1.64; I2 = 87%; 12 trials, 1153 participants; low-certainty evidence). The evidence is very uncertain about the effect of GH on embryo transfer achieved (OR 2.32, 95% CI 1.08 to 4.96; I2 = 25%; 4 trials, 214 participants; very low-certainty evidence). If the chance of achieving embryo transfer is assumed to be 77%, the chance with GH will be 78% to 94%. Use of GH results in reduction of mean units of gonadotropins used for stimulation in poor responders (MD -1088.19, 95% CI -1203.20 to -973.18; I2 = 91%; 8 trials, 685 participants; low-certainty evidence). High heterogeneity in the analyses for mean number of oocytes retrieved and units of GH used suggests quite different effects according to differences including in trial protocols (populations, GH dose and schedule), so these results should be interpreted with caution. We are uncertain of the effect of GH on adverse events in poor responders as six of the 14 included trials failed to report this outcome. AUTHORS' CONCLUSIONS: The use of adjuvant GH in IVF treatment protocols has uncertain effect on live birth rates and mean number of oocytes retrieved in normal responders. However, it slightly increases the number of oocytes retrieved and pregnancy rates in poor responders, while there is an uncertain effect on live birth rates in this group. The results however, need to be interpreted with caution, as the included trials were small and few in number, with significant bias and imprecision. Also, the dose and regimen of GH used in trials was variable. Therefore, further research is necessary to fully define the role of GH as adjuvant therapy in IVF.

Tubal flushing for subfertility.

BACKGROUND: Establishing the subgroup analysis of the fallopian tubes (tubes) is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and visualising patency on radiographs, ultrasonography or laparoscopy. Many women were noted to conceive in the first three to six months after tubal flushing, raising the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. An important adverse event during tubal flushing is intravasation (backflow of contrast medium into the blood or lymphatic vessels),which could lead to embolism although it is asymptomatic in most cases. OBJECTIVES: To evaluate the effectiveness and safety of tubal flushing with oil-soluble contrast media (OSCM) and water-soluble contrast media (WSCM) on subsequent fertility outcomes in women with subfertility. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, MEDLINE, Embase, CENTRAL, PsycINFO, reference lists of identified articles and trial registries. The most recent search was conducted in April 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing tubal flushing with OSCM, WSCM with each other or with no treatment, in women with subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Fifteen trials involving 3864 women were included in this systematic review. Overall, the quality of evidence varied from very low to moderate: the main limitations were risk of bias, heterogeneity and imprecision. OSCM versus no treatment Four studies (506 women) were included in this comparison. Tubal flushing with OSCM may increase the odds of live birth (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.57 to 6.85, 3 RCTs, 204 women, I2 = 0, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 11%, the chance following tubal flushing with OSCM would be between 16% and 46%. Tubal flushing with OSCM may increase in the odds of clinical pregnancy (OR 3.54, 95% CI 2.08 to 6.02, 4 RCTs, 506 women, I2 = 18%, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 9%, the chance following tubal flushing with OSCM would be between 17% and 37%. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. WSCM versus no treatment Only one study (334 women) was included in this comparison. We are uncertain whether tubal flushing with WSCM increase live birth compared to no treatment (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 21%, the chance following tubal flushing with WSCM would be between 15% and 33%. We are uncertain whether tubal flushing with WSCM increases clinical pregnancy compared to no treatment (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 27%, the chance following tubal flushing with WSCM would be between 29% and 40%. One case with pelvic infection was reported in the WSCM group and no case with infection in the no treatment group in a one study (334 women). Meta-analysis was not performed due to the rare events. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. OSCM versus WSCM Six studies (2598 women) were included in this comparison. Three studies reported live birth, including two with higher live birth in the OSCM group (OR 1.64, 95% CI 1.27 to 2.11, 1119 women; OR 3.45, 95% CI 1.97 to 6.03, 398 women); and one with insufficient evidence of a difference between groups (OR 0.92, 95% CI 0.60 to 1.40, 533 women). Given the substantial heterogeneity observed (I2 = 86%), meta-analysis was not performed. Tubal flushing with OSCM probably increased in the odds of intravasation (asymptomatic) compared to tubal flushing with WSCM (OR 5.00, 95% CI 2.25 to 11.12, 4 RCTs, 1912 women, I2 = 0, moderate-quality evidence). This suggests that if the chance of intravasation following tubal flushing with WSCM is assumed to be 1%, the chance following tubal flushing with OSCM would be between 2% and 9%. Tubal flushing with OSCM may increase the odds of clinical pregnancy (OR 1.42, 95% CI 1.10 to 1.85, 6 RCTs, 2598 women, I2 = 41%, low-quality evidence). This suggests that if the chance of clinical pregnancy following tubal flushing with WSCM is assumed to be 26%, the chance following tubal flushing with OSCM would be between 28% and 39%. We are uncertain whether tubal flushing with OSCM decreases the odds of infection (OR 0.22, 95% CI 0.04 to 1.22, 2 RCTs, 662 women, I2 = 0, very low-quality evidence) or haemorrhage (OR 0.65, 95% CI 0.40 to 1.06, 2 RCTs, 662 women, I2 = 0, very low-quality evidence). Three neonates with congenital abnormalities were reported in the OSCM group while no congenital abnormality was reported in the WSCM group in one study (1119 women). No meta-analysis was performed due to the rare events. AUTHORS' CONCLUSIONS: The evidence suggests that compared to no treatment, tubal flushing with OSCM may increase the chance of live birth and clinical pregnancy, while it is uncertain whether tubal flushing with WSCM improves those outcomes. Compared to tubal flushing with WSCM, OSCM may improve clinical pregnancy while meta-analysis was impossible for live birth due to heterogeneity. Evidence also suggests that OSCM is associated with an increased risk of asymptomatic intravasation. Overall, adverse events, especially long-term adverse events, are poorly reported across studies.

The impact of IVF on birthweight from 1991 to 2015: a cross-sectional study.

STUDY QUESTION: Has birthweight (BW) changed over time among IVF-conceived singletons? SUMMARY ANSWER: Singleton BW has increased markedly over the past 25 years. WHAT IS KNOWN ALREADY: IVF conceived singletons have had a higher incidence of low BW compared to spontaneously conceived singletons, and this has raised concerns over long-term increased risks of cardio-metabolic disease. However, few causal links between IVF procedures and BW have been robustly established, and few studies have examined whether BW has changed over time as IVF techniques have developed. STUDY DESIGN, SIZE, DURATION: A total of 2780 live born singletons conceived via IVF or ICSI treated in the reproductive medicine department of a single publicly funded tertiary care centre between 1991 and 2015 were included in this retrospective study. The primary outcome measure was singleton BW adjusted for gestational age, maternal parity and child gender. Multivariable linear regression models were used to estimate the associations between patient prognostic factors and IVF treatment procedures with adjusted BW. PARTICIPANTS/MATERIALS, SETTING, METHODS: All singletons conceived at the centre following IVF/ICSI using the mother's own oocytes, and non-donated fresh or frozen/thawed embryos with complete electronic data records, were investigated. Available electronic records were retrieved from the Human Fertilization and Embryology Authority for dataset collation. Multiple linear regression analysis was used to evaluate associations between IVF treatment parameters and BW, after adjusting for the year of treatment and patient characteristics and pregnancy factors. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary multivariable model, singleton BW increased by 7.4 g per year (95% CI: 3.2-11.6 g, P = 0.001), an increase of close to 180 g throughout the 25-year period after accounting for gestational age, maternal parity, child gender, IVF treatment parameters, patient prognostic characteristics and pregnancy factors. Fresh and frozen embryo transfer-conceived singletons showed a similar increase in BW. Frozen/thawed embryo transfer conceived singletons were on average 53 g heavier than their fresh embryo conceived counterparts (95% CI: 3.7-103.3 g, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The independent variables included in the study were limited to those that have been consistently recorded and stored electronically over the past two decades. WIDER IMPLICATIONS OF THE FINDINGS: There has been a progressive BW increase in IVF singletons over time in one large centre with consistent treatment eligibility criteria. Such a change is not seen in the general population of live born singletons in the UK or other developed countries, and seems to be specific to this IVF population. This may be a reflection of changes in practice such as undisturbed extended embryo culture to the blastocyst stage, optimized commercial culture media composition, single embryo transfer and ICSI. Moreover, singletons conceived from frozen/thawed embryos had higher birth weights when compared to their fresh embryo transfer counterparts. The causal pathway is unknown; however, it could be due to the impact on embryos of the freeze/thaw process, self-selection of embryos from couples who produce a surplus of embryos, and/or embryo replacement into a more receptive maternal environment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the EU FP7 project grant, EpiHealthNet (FP7-PEOPLE-2012-ITN-317146). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Ovarian response to controlled ovarian stimulation for fertility preservation before oncology treatment: A retrospective cohort of 157 patients.

This is a retrospective cohort study aiming to examine the response of oncology patients undergoing controlled ovarian stimulation (COS) for fertility preservation and to review the incidence of short-term complications. The study group consisted by all oncology patients undergoing ovarian stimulation for fertility preservation (n = 157) between April 2009 and April 2016. Patients undergoing COS for IVF/ICSI for male factor only infertility in the same time period (n = 2,128) provided a comparator group. Oncology patients underwent COS to retrieve eggs for storage and future use. The cancer patients had a very similar distribution of oocyte yield to the comparator group. Those with ovarian cancer did have significantly lower oocyte recovery than those with other cancers (age-adjusted difference 7, 95% CI: 2-12). None of the patients in the study group were admitted with ovarian hyperstimulation syndrome or any other complication of COS or oocyte retrieval. This is one of the largest reported cohorts of patients treated for fertility preservation before oncology treatment. Our data have demonstrated a good response to stimulation, offering a reasonable chance of pregnancy in the future. In contrast to previous studies, we have demonstrated a similar number of oocytes retrieved to that of women undergoing IVF/ICSI treatment for male factor infertility.

Tubal flushing for subfertility.

BACKGROUND: Establishing the patency of the fallopian tubes is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and taking radiographs. However, it has been noted that many women conceive in the first three to six months after the tubal flushing, which has raised the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. OBJECTIVES: To evaluate the effect of flushing fallopian tubes with oil- or water-soluble contrast media on live birth and pregnancy rates in women with subfertility. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials, MEDLINE, EMBASE, Biological Abstracts, trial registers and reference lists of identified articles. The most recent search was conducted in June 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing tubal flushing with oil-soluble or water-soluble contrast media, or with no treatment, in women with subfertility. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Thirteen trials involving 2914 women were included, of whom 2494 were included in the analysis. Oil-soluble contrast media (OSCM) versus no interventionThe OSCM group had a higher rate of live birth (odds ratio (OR) 3.09, 95% CI 1.39 to 6.91, 1 RCT, 158 women, low quality evidence) and ongoing pregnancy (OR 3.59, 95% CI 2.06 to 6.26, 3 RCTs, 382 women, I(2) = 0%, low quality evidence) than women who had no intervention. Our findings suggest that among subfertile women with a 17% chance of an ongoing pregnancy if they have no intervention, the rate will increase to between 29% and 55% if they have tubal flushing with OSCM. Water-soluble contrast media (WSCM) versus no interventionThere was no evidence of a difference between the groups in rates of live birth (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, very low quality evidence) or ongoing pregnancy (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, very low quality evidence). OSCM versus WSCMTwo RCTs reported live birth: one found a higher live birth rate in the oil-soluble group and the other found no evidence of a difference between the groups. These studies were not pooled due to very high heterogeneity (I(2) = 93%). There was no evidence of a difference between the groups in rates of ongoing pregnancy, however there was high heterogeneity (OR 1.44, 95% CI 0.84 to 2.47, 5 RCTs, 1454 women, I(2) = 76%, random-effects model, very low quality evidence). OSCM plus WSCM versus WSCM aloneThere was no evidence of a difference between the groups in rates of live birth (OR 1.06, 95% CI 0.64 to 1.77, 1 RCT, 393 women, very low quality evidence) or ongoing pregnancy (OR 1.23, 95% CI 0.87 to 1.72, 4 RCTs, 633 women, I(2) = 0%, low quality evidence).There was no evidence of a difference between any of the interventions in rates of adverse events, but such events were poorly reported in most studies. AUTHORS' CONCLUSIONS: The evidence suggests that tubal flushing with oil-soluble contrast media may increase the chance of pregnancy and live birth compared to no intervention. Findings for other comparisons were inconclusive due to inconsistency and lack of statistical power. There was insufficient evidence on adverse events to reach firm conclusions. Further robust randomised controlled trials are needed.

Management of congenital hypogonadotropic hypogonadism in females.

This review explores the challenges in the diagnosis of hypogonadotropic hypogonadism, the transition of care from paediatric to adult care and the considerable health implications of this condition. The role gynaecologists and general practitioners have in managing hormone replacement therapy and reproductive potential is also highlighted. The fertility treatment options, which include ovulation induction with gonadotrophins and in-vitro fertilisation, are discussed in detail along with highlighting the fact that anovulation and markers of low ovarian reserve prior to priming treatment may not be reflective of poor reproductive potential. The holistic management of women with hypogonadotropic hypogonadism is still not standardised and evidence for subfertility management is scarce. This review aims to highlight this concern and provide guidance by evaluating current evidence.

DuoStim protocol- a novel fertility preservation strategy for female oncology patients.

Fertility loss is one of the primary concerns among female oncology patients of childbearing age about to undergo gonadotoxic therapy. Currently, controlled ovarian stimulation (COS) followed by oocyte or embryo cryopreservation is the only technique of fertility preservation (FP) endorsed by the American Society of Clinical Oncology. This retrospective cohort study aims to evaluate the effectiveness of a modified 'DuoStim' COS protocol in 36 female oncology patients at an FP clinic at St Mary's Hospital Reproductive Medicine Unit (Manchester, UK). Patients underwent two consecutive cycles of COS and outcomes assessed included total oocyte yield, mature oocytes of metaphase stage II, side effects of ovarian stimulation such as ovarian hyperstimulation syndrome (OHSS) and delays to planned cancer therapy. Details of patient outcomes were determined by the review of patient medical records. Results of the study showed that this novel protocol increased oocyte yield by two-fold without delaying oncology treatment. Medical records confirmed that none of the 36 patients developed OHSS or experienced any delays in their cancer therapy. We conclude that the results of this study are encouraging and support DuoStim protocol as an effective strategy for FP in female FP patients.

Anti-Mullerian hormone: poor assay reproducibility in a large cohort of subjects suggests sample instability.

STUDY QUESTION: What is the variability of anti-Müllerian hormone (AMH) concentration in repeat samples from the same individual when using the Gen II assay and how do values compare to Gen I [Diagnostic Systems Ltd (DSL)] assay results? SUMMARY ANSWER: The Gen II AMH assay displayed appreciable variability, which can be explained by sample instability. WHAT IS KNOWN ALREADY: AMH is the primary predictor of ovarian performance and is used to tailor gonadatrophin dosage in cycles of IVF/ICSI and in other routine clinical settings. Thus, a robust, reproducible and sensitive method for AMH analysis is of paramount importance. The Beckman Coulter Gen II ELISA for AMH was introduced to replace earlier DSL and Immunotech assays. The performance of the Gen II assay has not previously been studied in a clinical setting. STUDY DESIGN, SIZE AND DURATION: We studied an unselected group of 5007 women referred for fertility problems between 1 September 2008 and 25 October 2011; AMH was measured initially using the DSL AMH ELISA and subsequently using the Gen II assay. AMH values in the two assays were compared using a regression model in log(AMH) with a quadratic adjustment for age. Additionally, women (n = 330) in whom AMH had been determined in different samples using both the DSL and Gen II assays (paired samples) identified and the difference in AMH levels between the DSL and Gen II assays was estimated using the age-adjusted regression analysis. A subset of 313 women had repeated AMH determinations (n = 646 samples) using the DSL assay and 87 women had repeated AMH determinations using the Gen II assay (n = 177 samples) were identified. A mixed effects model in log(AMH) was utilized to estimate the sample-to-sample (within-subject) coefficients of variation of AMH, adjusting for age. Laboratory experiments including sample stability at room temperature, linearity of dilution and storage conditions used anonymized samples. MAIN RESULTS AND THE ROLE OF CHANCE: In clinical practice, Gen II AMH values were ∼20% lower than those generated using the DSL assay instead of the 40% increase predicted by the kit manufacturer. Both assays displayed high within-subject variability (Gen II assay CV = 59%, DSL assay CV = 32%). In the laboratory, AMH levels in serum from 48 subjects incubated at RT for up to 7 days increased progressively in the majority of samples (58% increase overall). Pre-dilution of serum prior to assay, gave AMH levels up to twice that found in the corresponding neat sample. Pre-mixing of serum with assay buffer prior to addition to the microtitre plate gave higher readings (72% overall) compared with sequential addition. Storage at -20°C for 5 days increased AMH levels by 23% compared with fresh samples. The statistical significance of results was assessed where appropriate. LIMITATIONS, REASONS FOR CAUTION: The analysis of AMH levels is a retrospective study and therefore we cannot entirely rule out the existence of differences in referral practices or changes in the two populations. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggests that AMH may not be stable under some storage or assay conditions and this may be more pronounced with the Gen II assay. The published conversion factors between the Gen II and DSL assays appear to be inappropriate for routine clinical practice. Further studies are urgently required to confirm our observations and to determine the cause of the apparent instability. In the meantime, caution should be exercised in the interpretation of AMH levels in the clinical setting. CONFLICT OF INTEREST/STUDY FUNDING: S. Roberts is supported by the NIHR Manchester Biomedical Research Centre.

Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium.

Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a prospective nonrandomized study of women with obesity and atypical hyperplasia or low-grade stage 1a endometrial cancer undergoing progestin treatment. Women with a body mass index (BMI) ≥ 35 kg/m2 were offered bariatric surgery; those who declined and those with a BMI of 30 to 34.9 kg/m2 were encouraged to lose weight by low-calorie diet. We assessed uptake of bariatric surgery; weight lost during progestin treatment; and the impact of more than 10% total body weight loss on progestin treatment response at 12 months. 71 women [median age 58 years (interquartile range; IQR 35-65); mean BMI 48 kg/m2 (SD 9.3)] completed the study. Twenty-three women (32%) had bariatric surgery, on average 5 months (IQR 3-8) after progestin treatment commenced. Weight change during progestin treatment was -33.4 kg [95% confidence interval (CI) -42.1, -24.7] and -4.6 kg (95% CI -7.8, -1.4) in women receiving bariatric surgery and low-calorie diet, respectively (P < 0.001). Forty-three women (61%) responded to progestin, while 23 (32%) showed stabilized and 5 (7%) progressive disease. Response at 12 months was not predicted by age or baseline BMI, but women who lost more than 10% of their total body weight were more likely to respond to progestin than those who did not (adjusted odds ratio 3.95; 95% CI 1.3, 12.5; P = 0.02). Thus weight loss may improve oncological outcomes in women with obesity-associated endometrial neoplastic abnormalities treated with progestin. PREVENTION RELEVANCE: This study found that weight loss improves response rates in women with obesity and atypical hyperplasia or low-risk endometrial cancer undergoing conservative management with intrauterine progestin. Given the additional benefits of weight loss for fertility, cardiovascular health and quality of life, future research should focus on how best to accomplish it.

Adjuvant immunotherapy: the sting in the tail.

Adjuvant therapy with PD-1 inhibitors for resected Stage III/IV melanoma reduces the risk of recurrence by 40-50% and is now a standard of care. Immune-related adverse events occurred in approximately 37% of patients in the pivotal trials, 10-15% were severe (grade III-IV). Endocrine toxicities were common and mostly irreversible. Thyroid toxicity occurred in 15-20% of patients, hypophysitis (2.2%), insulin-dependent diabetes mellitus (1%) and adrenalitis (1%). Revision of the American Joint Committee on Cancer staging system (version 8) has resulted in a significant improvement in prognosis for patients with Stage III disease. As a result, clinicians may now offer adjuvant immunotherapy to patients with a lower risk of recurrence than those in the pivotal trials. There is a need to balance the relatively small reduction of absolute risk of recurrence against the risk and impact of toxicity. Five-ten percent of biochemically euthyroid patients on levothyroxine report symptoms of depression. Hypogonadism can result from toxicity to the hypothalamic-pituitary axis, and can lead to sexual dysfunction and subfertility. Secondary hypogonadism can be treated by the administration of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) which induce spermatogenesis/ovulation in a functioning gonad but is not always successful. Insulin-dependent diabetes mellitus often presents with rapid onset of hyperglycemia and potentially life-threatening diabetic ketoacidosis. Long-term adverse outcomes are likely to mimic Type 1 DM with a 6-fold increase in cardiovascular disease related mortality and 3-fold in all-cause mortality. These survivorship issues are relevant to all melanoma patients but are particularly pertinent where the absolute benefit is modest.

Modelling the impact of single embryo transfer in a national health service IVF programme.

BACKGROUND: Greater use of single embryo transfer (SET) to reduce twin rates associated with IVF requires good information on prognostic factors and appropriate models of treatment outcomes. METHODS: Using data from a cohort of 1198 IVF cycles, we have developed a statistical model of live birth and twin outcomes in terms of routinely measured clinical parameters. From this model, we predict potential outcomes if those who had two embryos transferred had actually received SET. RESULTS: Embryo quality, age, FSH level, idiopathic diagnosis, sperm count, smoking and alcohol consumption are all significant factors predicting outcome. Couples with good embryos and good prognosis have a much greater risk of producing twins. In this cohort, to achieve a 10% twin rate would require 55% SET which, without selection of appropriate cycles, would lead to a reduction in success rate from ca. 21% to 17%. Selecting on the basis of twin risk can partially mitigate this reduction to give a success rate of 18.5%. CONCLUSIONS: The use of SET to reduce twin rates will lead to a significant reduction in treatment success. Around half this reduction could be mitigated with careful selection of patients and cycles, including embryo quality.

A nationwide UK survey of female fertility preservation prior to cancer treatment.

This survey examined the provision of fertility preservation for female oncology patients prior to cancer treatments, given their well-established gonadotoxic effects. Questionnaires were sent to all assisted conception units in the UK enquiring about the provision of oocyte or embryo cryopreservation, as well as funding for female oncology patients. In addition, data were obtained from the Human Fertilisation and Embryology Authority (HFEA) on the number of cryopreservation cycles in 2013-2014. Of the 60 responding units, 53 (88%) offered fertility preservation. However, only 6 (11%) units performed more than 25 oocyte or embryo cryopreservation cycles per year, with 33 units (62%) treating fewer than 10 women per year. A total of 44 (90%) reported some National Health Service (NHS) funding, but only 12 (23%) had funding granted automatically and only 26 (49%) could offer NHS funded treatment exempt from their local eligibility criteria for in vitro fertilisation (IVF). The HFEA data reported 154 NHS funded oocyte cryopreservation cycles in 2014. We conclude that the provision of fertility preservation is lacking and improvements can be made in the number of referrals from oncology, the provision of cryopreservation and the provision of NHS funding. Developing a national fertility preservation network and close liaison with oncology and Clinical Commissioning Groups are recommended.

Anti-Müllerian hormone levels and antral follicle count in women enrolled in in vitro fertilization cycles: relationship to lifestyle factors, chronological age and reproductive history.

The aims of this prospective study were to investigate the relationship between anti-Müllerian hormone (AMH) and antral follicle count (AFC), and to determine whether these markers of ovarian reserve correlate with lifestyle factors, ethnicity, chronological age and reproductive history. Participants were 136 normo-ovulatory women undergoing infertility work-up within 3 months of their first ovarian stimulation cycle for in vitro fertilization. On day 3 of a spontaneous menstrual cycle, a blood sample for measurement of plasma AMH levels was taken and a transvaginal ultrasound scan to determine the AFC (follicles measuring 2-5 mm in diameter) was performed. Information about smoking, body mass index, alcohol consumption, ethnic origin, chronological age, age at menarche, years since menarche and gravidity were recorded using a case report form. The main outcome measures were plasma AMH concentrations and total number of small antral follicles (AFC). Median plasma levels of AMH were 2.0 ng/ml (interquartile range 1.1-3.6) and AFC was 10 (interquartile range 7-15). A positive correlation between AMH and AFC (r = 0.54, p < 0.0001) was found. AMH and AFC correlated negatively with age (r = -0.30, p < 0.001 and r = -0.27, p = 0.001 respectively) and number of years since menarche (r = -0.23, p = 0.007 and r = -0.21, p = 0.015 respectively), but not with any of the other measures. Circulating AMH levels and AFC correlated with each other and declined significantly with age. There were only weak, non-significant, correlations with lifestyle factors and reproductive history. These putative markers could be used individually or together to assess the age-related decline of ovarian function in normo-ovulatory candidates for IVF.

Double ovarian stimulation (DuoStim) protocol for fertility preservation in female oncology patients.

This article describes a revised ovarian stimulation protocol (DuoStim) for fertility preservation in female oncology patients which aims to maximise the number of gametes obtained with subsequent improvement in cumulative birth rate, without delaying cancer treatment. Ten patients diagnosed with malignancy between September 2014 and October 2015 were included. The patients were treated with the DuoStim protocol, undergoing two consecutive ovarian stimulation cycles and two oocyte retrievals. The primary outcome was the number of oocytes collected and vitrified during each oocyte retrieval and in total. The protocol was evaluated regarding medical risk and patients' feedback. During the first oocyte collection 81 oocytes (61 metaphase II) were retrieved (mean = 8.1; range = 1-13) and during the second oocyte collection 82 oocytes (67 metaphase II) were retrieved (mean= 8.2; range = 1-19). A total of 163 oocytes (128 metaphase II) were collected (mean = 16.3; range = 6-32) and cancer treatment was not delayed for any of these patients. There were no cases of ovarian hyperstimulation syndrome recorded. More patients and long-term follow-up is needed to assess the efficacy and safety of the DuoStim protocol. However, these early results are encouraging, demonstrating an increase in number of mature oocytes retrieved during ovarian stimulation for oncology patients, without delaying cancer treatment.

How much variation in oocyte yield after controlled ovarian stimulation can be explained? A multilevel modelling study.

STUDY QUESTION: How much variation in oocyte yield after controlled ovarian stimulation (COS) can be accounted for by known patient and treatment characteristics? SUMMARY ANSWER: There is substantial variation in the COS responses of similar women and in repeated COS episodes undertaken by the same woman, which cannot be accounted for at present. WHAT IS ALREADY KNOWN: The goal of individualized COS is to safely collect enough oocytes to maximize the chance of success in an ART cycle. Personalization of treatment rests on the ability to reduce variation in response through modifiable factors. STUDY DESIGN SIZE DURATION: Multilevel modelling of a routine ART database covering the period 1 October 2008-8 August 2012 was employed to estimate the amount of variation in COS response and the extent to which this could be explained by immutable patient characteristics and by manipulable treatment variables. A total of 1851 treatment cycles undertaken by 1430 patients were included. The study was not subject to attrition, as cancelled cycles were included in the analysis. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 21-43 years undergoing ovarian stimulation for IVF (possibly with ICSI) using their own eggs at a tertiary care centre. MAIN RESULTS AND THE ROLE OF CHANCE: Substantial unexplained variation in COS response (oocyte yield): was observed (3.4-fold (95% CI: 3.12 to 3.61)). Only a relatively small amount of this variation (around 19%) can be explained by modifiable factors. A significant, previously undescribed predictor of response was the practitioner performing oocyte retrieval, with 1.5-fold variation between surgeons with the highest and lowest yields. LIMITATIONS REASONS FOR CAUTION: Although a large number of covariables were adjusted for in the analysis, including those that were used for dosing and determination of the stimulation regimen, this study is subject to confounding due to unmeasured variables and measurement error. WIDER IMPLICATIONS OF THE FINDINGS: The present study suggests that there are limits to the extent that COS response can be predicted on the basis of known factors, or controlled by manipulation of treatment factors. Moreover, modifiable variation in response appears to be partially attributable to differences between surgeons performing oocyte retrieval. Consequently, consistent prevention of ineffective or unsafe responses to COS is not likely to be possible at present. Our results highlight the importance of blinding surgeons in RCTs. The data also suggest that there is likely to be limited scope for personalized treatment unless additional predictors of ovarian response can be identified. STUDY FUNDING/COMPETING INTERESTS: J.W. is funded by a Doctoral Research Fellowship from the National Institute for Health Research (DRF-2014-07-050) supervised by S.A.R. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. J.W. is a statistical editor of the Cochrane Gynaecology and Fertility Group. S.A.R. is a statistical editor for Human Reproduction. J.W. also declares that publishing peer-reviewed articles benefits his career. A.L.M. has received consultation fees from MSD, Merck Serono, Ferring, TEVA, Roche, Beckman Coulter.

The optimal length of 'coasting protocol' in women at risk of ovarian hyperstimulation syndrome undergoing in vitro fertilization.

Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening complication following ovarian stimulation for in vitro fertilization (IVF). Coasting is the practice whereby the gonadotrophins are withheld and the administration of human chorionic gonadotrophin (hCG) is delayed until serum oestradiol (E2) has decreased to what is considered to be a safe level, to prevent the onset of OHSS. This study aimed to assess the length of coasting on the reproductive outcome in women at risk of developing OHSS. Coasting was undertaken when the serum E2 concentrations were > or = 17000 pmol/L but < 21000 pmol/L. Daily E2 measurements were performed and hCG was administered when hormone levels decreased to < 17000 pmol/L. Eighty-one women who had their stimulation cycles coasted were grouped according to the number of coasting days. Severe OHSS occurred in one case, which represented 1.2% of patients who underwent coasting because of an increased risk of developing the syndrome. No difference was found between cycles coasted for 1 - 3 days and cycles coasted for > or = 4 days in terms of oocyte maturity, fertilization and embryo cleavage rates. Women in whom coasting lasted for > or = 4 days had significantly fewer oocytes retrieved (P < 0.05) and decreased implantation rate (P < 0.05) compared to those coasted for 1 - 3 days. Pregnancy rate/embryo transfer and live birth rate did not differ between groups. In conclusion, coasting appears to decrease the risk of OHSS without compromising the IVF cycle pregnancy outcome. Prolonged coasting is, however, associated with reduced implantation rates, perhaps due to the deleterious effects on the endometrium rather than the oocytes.

Sperm concentration and forward motility are not correlated with age in adolescents with an idiopathic varicocele and symmetrical testicular volumes.

AIM: Idiopathic varicocele is a common condition that may impair fertility. Its treatment in children and adolescents is reserved for those patients who develop symptoms or testicular growth arrest. We evaluated the trends in sperm parameters among adolescent varicocele patients with symmetrical testicular volumes who have not undergone varicocelectomy. METHOD: Data were prospectively collected from a single institution (2009 to 2014). Post-pubertal patients aged 12 to 17years produced semen samples by masturbation. Outcomes measured were semen volume, sperm concentration, and forward motility. Additional variables recorded included: a) testicular volume (ultrasound measurement), b) clinical varicocele grade, c) venous Doppler grading. Linear regression analysis was performed using Fisher's transformation. P<0.05 was considered significant, and data are presented as median (IQ range). RESULTS: Forty-one patients with a median age of 15.4 (15.0-15.9) years each provided a sperm sample during the study period. Thirty-five had grade 3 (visible) varicocele, and 6 had grade 2 (palpable) varicocele. All patients had spontaneous venous reflux on Doppler ultrasound, and none had undergone varicocelectomy prior to producing the sperm sample. Table 1 summarizes the sperm parameters according to patient age. The overall median sperm concentration was 37 (16-64) millions/ml and was not correlated with age. The overall median forward motility was 55% (44-64) and was not correlated with age. Thirty-four patients had normal sperm parameters, which remained within the WHO range of normality. CONCLUSIONS: Following the European Association of Urology guidelines does not cause progressive deterioration of sperm parameters between the age of 12 and 17years.

Effect of salpingectomy, ovarian cystectomy and unilateral salpingo-oopherectomy on ovarian reserve.

Pelvic surgery can affect ovarian reserve, but estimates of the potential effect of different surgical procedures are lacking. This study examines the markers of ovarian reserve after different procedures in order to help the provision of informed consent before surgery. Anti-Müllerian hormone (AMH), antral follicle count (AFC) and follicle-stimulating hormone (FSH) of women with a history of salpingectomy, ovarian cystectomy or unilateral salpingo-oophorectomy were compared to those without history of surgery using cross-sectional data adjusting for patient and clinical factors in multivariable regression model. There were 138 women who had had salpingectomy, 36 unilateral salpingo-oopherectomy, 41 cystectomy for ovarian cysts that are other than endometrioma and 40 women had had excision of endometrioma. There was no significant difference in AMH (9 %; p = 0.33), AFC (-2 %; p = 0.59) or FSH (-14 %; p = 0.21) in women with a history of salpingectomy compared to women without surgery. Women with a history of unilateral salpingo-oophorectomy were found to have significantly lower AMH (-54 %; p = 0.001). These women also had lower AFC (-28 %; p = 0.34) and higher FSH (14 %; p = 0.06), the effect of which did not reach statistical significance. The study did not find any significant associations between a history of cystectomy, for disease other than endometrioma and AMH (7 %; p = 0.62), AFC (13 %; p = 0.18) or FSH. (11 %; p = 0.16). Women with a history of cystectomy for ovarian endometrioma had 66 % lower AMH (p = 0.002). Surgery for endometrioma did not significantly affect AFC (14 %; p = 0.22) or FSH (10 %; p = 0.28). Salpingo-oopherectomy and cystectomy for endometrioma cause a significant reduction in AMH levels. Neither salpingectomy nor cystectomy for cysts other than endometrioma has appreciable effects on ovarian reserve.