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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Ovarian response to gonadotropins after laparoscopic salpingectomy or the division of fallopian tubes for hydrosalpinges.

OBJECTIVE: To compare the effect of prophylactic laparoscopic salpingectomy versus division of the fallopian tubes on ovarian response to gonadotropins in women undergoing IVF. DESIGN: Retrospective study. SETTING: National Health Service-based tertiary referral center for reproductive medicine. PATIENT(S): One hundred sixty-eight women with tubal factor infertility. Sixty-five women with hydrosalpinges had either salpingectomy (n = 40, group A) or proximal tubal division (n = 25, group B), while the remaining women with tubal disease but without hydrosalpinges acted as the control group (n = 103, group C). INTERVENTION(S): Prophylactic laparoscopic salpingectomy or proximal division of the fallopian tubes and ovarian stimulation with gonadotropins for IVF. MAIN OUTCOME MEASURE(S): Day 2 serum FSH levels before surgery and 3 months after surgery but before ovarian stimulation, ovarian response assessed as total dose of hMG administered, serum E2 concentrations on day 3 and day 8 of stimulation and on the day of hCG injection, number of follicles, and number of oocytes retrieved and fertilized. RESULT(S): In group A, baseline FSH levels were significantly raised after surgery compared with before surgery. Postsurgery FSH concentrations were significantly higher in group A compared with group B. The number of follicles (15-20 mm) was significantly lower in group A compared with group B and group C. The serum E2 levels on day 8 of stimulation were lower in group A compared with group B, and on the day of hCG injection it was significantly reduced in group A compared with groups B and C. The number of oocytes retrieved per cycle was significantly lower in group A compared with group B. There were no significant differences in pregnancy rates and miscarriage rates among the three groups. CONCLUSION(S): These findings suggest that prophylactic salpingectomy in women with hydrosalpinx may compromise ovarian response to stimulation without affecting pregnancy rates. A randomized control trial is recommended to determine the most appropriate laparoscopic procedure in the management of hydrosalpinx before IVF.

Cryopreserved-thawed embryo transfer in natural or down-regulated hormonally controlled cycles: a retrospective study.

OBJECTIVE: To assess the implantation, pregnancy, and live birth rates after the transfer of frozen-thawed embryos (FET) in a natural or hormonal control cycle. DESIGN: Retrospective study. SETTING: National Health Service tertiary referral center for reproductive medicine in Manchester, United Kingdom. PATIENT(S): Two comparable groups of women with regular menstrual cycles: Group A (n = 212) had FET in a natural cycle after spontaneous ovulation; group B (n = 205) had FET in a pituitary-desensitized hormonally controlled cycle. INTERVENTION(S): In group B, GnRH agonist was commenced in the midluteal phase of the previous cycle and discontinued 3 days before embryo transfer. Oral estradiol valerate and vaginal progesterone pessary were used to prepare the endometrium. Embryo transfer was carried out 3 days after detection of the endogenous LH surge in group A and on day 3 of progesterone administration in group B. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and live birth rates per cycle and per embryo transfer (ET). RESULT(S): In the 212 women who had natural-cycle FET, 172 ETs were performed and 247 embryos replaced. The implantation rate was 14.1% (35/247). Twenty clinical pregnancies (20/172, 11.6%) were achieved. In the 205 women who had down-regulated hormone replacement-cycle FET, 173 embryo transfers were performed and 243 embryos replaced. The implantation rate was 13.5% (33/243). Eighteen clinical pregnancies (18/173, 10.2%) were achieved. There were no significant differences between the two groups with regard to the implantation, clinical pregnancy, or live birth rates per cycle or per ET. CONCLUSION(S): These findings suggest that both FET protocols are equally effective in terms of implantation rate and pregnancy outcome in women with regular menstrual cycles.