Evaluating transition in Turner syndrome in the West of Scotland.

BACKGROUND: A Turner Syndrome (TS) Transition clinic, Royal Hospital for Children Glasgow (RHCG), with paediatric and adult endocrinology/gynaecology teams was established in 1998 with an aim of improving health outcomes in TS throughout the lifespan. OBJECTIVE: To evaluate the success of our TS transition service, focussing on evaluating established follow-up after transfer to adult services. METHODS: Girls attending the TS Transition clinic at Royal Hospital for Children Glasgow, 1998-2017, were identified. Attendance data were obtained from patient records and an electronic appointment system. We assessed good and late early attendance in our cohort of TS patients as well as established endocrine follow-up, defined as those still attending adult endocrine services 3 years after transfer. Success of TS transition was determined by the proportion of girls in established endocrine follow-up. RESULTS: Forty-six girls (median age 18.3 yrs) were identified. Thirty-six, 36/46 girls transferred prior to 2015 and 26 of those (72%) were in established follow-up at 3 years, 22/36 girls had met with an Adult specialist prior to transfer and 14/36 had not met with an adult specialist prior to transfer. Twenty-one (80.7%) were good early attenders (p = 0.10). In the early attenders' cohort, there was no significant difference between those that had and had not met an adult specialist prior to transfer. CONCLUSION: A significant proportion of girls with TS are currently lost to endocrine follow-up following transfer to adult clinics. Early attendance at an adult clinic appears to predict established long-term follow-up. Strategies to improve early attendance and long-term endocrine follow-up are needed to ensure lifelong health needs are addressed.

Time-lapse imaging of inner cell mass splitting with monochorionic triamniotic triplets after elective single embryo transfer: a case report.

RESEARCH QUESTION: Can detailed scrutiny of time-lapse imaging (TLI) of inner cell mass (ICM) splitting help to reduce the frequency of multiple pregnancies following elective single embryo transfer (eSET)? DESIGN: Retrospective analysis of time-lapse images of an embryo in vitro, which resulted in a monochorionic triamniotic pregnancy following eSET on Day 5 of development. RESULTS: A 37-year-old female patient underwent a frozen embryo transfer cycle whereby a single vitrified/warmed embryo was transferred at the hatching blastocyst stage. The subsequent pregnancy scan revealed a monochorionic triamniotic pregnancy. Because the blastocyst was cultured in an incubator incorporating TLI, retrospective scrutiny of the digital recordings demonstrated two distinct ICM structures splitting apart, which formed during the '8-shaped hatching'. CONCLUSIONS: Assisted reproductive techniques and in-vitro culture have been associated with an increased frequency of embryo splitting. This has been postulated to be linked to the in-vitro hatching method observed at the blastocyst stage of development. This case report highlights the need to objectively assess any splitting of the ICM, beyond standard grading of the quality of the ICM and the trophectoderm. Such assessments of ICM splitting should be routine practice in clinical embryology when selecting embryos for transfer.

Pre-conception maternal erythrocyte saturated to unsaturated fatty acid ratio predicts pregnancy after natural cycle frozen embryo transfer.

The environment for embryo implantation and fetal growth and development is affected by maternal nutritional, metabolic and health status. The aim of this prospective, cohort study was to test whether plasma metabolic and inflammatory biomarkers can predict pregnancy resulting from in vitro fertilisation (IVF). Women with a natural menstrual cycle undergoing frozen embryo transfer (FET) were recruited and fasting baseline blood samples were collected a mean of 3.4 days prior to the luteinising hormone (LH) surge and a non-fasting blood sample was taken on the day of FET. Ongoing pregnancy was defined by positive fetal heartbeat on ultrasound scan at day 45 post LH surge. Thirty-six pregnancies resulted from FET in 143 women. In an overall stepwise multivariable analysis, erythrocyte saturated to unsaturated fatty acid ratio was positively associated with ongoing pregnancy. A similar model incorporating day of FET covariates found that erythrocyte saturated to unsaturated fatty acid ratio, erythrocyte fatty acid average chain length and plasma log-triglycerides predicted ongoing pregnancy. In conclusion, a higher peri-conceptional saturated to unsaturated fatty acid ratio predicted ongoing pregnancy after natural cycle frozen embryo transfer and may reflect a maternal nutritional status that facilitates pregnancy success in this assisted conception scenario.

Maternal Plasma DHA Levels Increase Prior to 29 Days Post-LH Surge in Women Undergoing Frozen Embryo Transfer: A Prospective, Observational Study of Human Pregnancy.

CONTEXT: Docosahexaenoic acid (DHA) is an important fatty acid required for neurological development but its importance during early fetal neurological organogenesis is unknown. OBJECTIVE: This study aimed to assess plasma fatty acid changes in early pregnancy in women undergoing natural cycle-frozen embryo transfer as a means of achieving accurately timed periconceptual sampling. DESIGN: Women undergoing frozen embryo transfer were recruited and serial fasting blood samples were taken pre-luteinizing hormone (LH) surge, and at 18, 29, and 45 d post-LH surge and fatty acids were analyzed using gas chromatography. SETTING: This study took place at the Assisted Conception Unit, Glasgow Royal Infirmary, Scotland. MAIN OUTCOME MEASURES: Plasma fatty acid concentrations and influence of twin pregnancies on DHA plasma concentration were measured. RESULTS: In pregnant women, there was a rapid, early increase in the maternal rate of change of plasma DHA concentration observed by 29 d post-LH surge (mean ± SD, from 0.1 ± 1.3 to 1.6 ± 2.9 nmol DHA per mL plasma per day). This early pressure to increase plasma DHA concentration was further emphasized in twin pregnancies where the increase in DHA concentration over 45 d was 2-fold higher than in singleton pregnancies (mean ± SD increase, 74 ± 39 nmol/mL vs 36 ± 40 nmol/mL). An index of delta-6 desaturase activity increased 30% and positively correlated with the rate of change of DHA concentration between 18 and 29 d post-LH surge (R2 adjusted = 41%; P = .0002). DHA was the only fatty acid with a continual accelerated increase in plasma concentration and a positive incremental area under the curve (mean ± SD, 632 ± 911 nmol/mL × d) during the first 45 d of gestation. CONCLUSIONS: An increase in maternal plasma DHA concentration is initiated in human pregnancy prior to neural tube closure which occurs at 28 d gestation.

Turner syndrome--issues to consider for transition to adulthood.

BACKGROUND: Turner syndrome (TS) is associated with a spectrum of health problems across the age span, which requires particular attention during the transition period in these adolescents. AREAS OF AGREEMENT: The majority of girls with TS require oestrogen replacement from puberty onwards, which is important for adequate feminization, uterine development and maintenance of bone health. There is a lifetime increased risk from autoimmune conditions like hypothyroidism, coeliac disease, hearing loss and aortic dilatation with the potential to lead to aortic dissection. A systematic and holistic approach to provision of health care in TS is needed. AREAS OF CONTROVERSY: Several unanswered questions remain, including the choice of hormone replacement therapy in the young person with TS and in adulthood; the optimal mode of cardiovascular assessment; the best management and assessment prior to and during pregnancy. AREAS TIMELY FOR DEVELOPING RESEARCH: The optimal model of care and transition to adult services in TS requires attention. Further research is needed in relation to cardiovascular risk assessment, pregnancy management and hormone replacement therapy in TS.

Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception.

BACKGROUND: Individualization of controlled ovarian stimulation (COS) for assisted conception is complicated by variable ovarian response to follicle stimulating hormone. We hypothesized that anti-Müllerian hormone (AMH), a predictor of oocyte yield, may facilitate treatment strategies for women undergoing COS, to optimize safety and clinical pregnancy rates. METHODS: Prospective cohort study of 538 patients in two centres with differential COS strategies based on a centralized AMH measurement. RESULTS: AMH was associated with oocyte yield after ovarian stimulation in both centres, and a 'reduced' AMH (1 to <5 pmol/l) was associated with a reduced clinical pregnancy rate. Women with a 'normal' AMH (5 to <15 pmol/l) treated with a long GnRH-agonist protocol (both centres) showed a low incidence of excess response (0%) and poor response (0%). In women with 'high' AMH (>15 pmol/l), the antagonist protocol eliminated the need for complete cryopreservation of embryos due to excess response (P < 0.001) and showed a higher fresh cycle clinical pregnancy rate than agonist cycles [OR 4.40 (95% CI 1.95-9.93), P < 0.001]. CONCLUSIONS: The use of circulating AMH to individualize treatment strategies for COS may result in reduced clinical risk, optimized treatment burden and maintained pregnancy rates, and is worthy of prospective randomized examination.

Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome.

Hirsutism is a common and distressing symptom frequently encountered in women with polycystic ovary syndrome (PCOS), who also show relative insulin resistance. The aim of this trial, in which hirsutism was the primary end point, was to compare the efficacy of the oral antihyperglycemic medication metformin with that of an established treatment, combined ethinyl estradiol and cyproterone acetate. Patients (n = 52) were randomized to receive either metformin (500 mg, three times daily) or Dianette (ethinyl estradiol, 35 micro g; cyproterone acetate, 2 mg) treatment for 12 months, with assessments before treatment, at 6 months, and at 12 months. Both objective and subjective methods of evaluating hirsutism were used, and in addition, patient perceptions were examined. The results show that metformin is potentially an effective treatment for moderate to severe hirsutism in women with PCOS. They also suggest that in some respects (Ferriman-Gallwey score and patient self-assessment), it is more efficacious than the standard treatment (Dianette). The objective evaluation of hair diameter reduction showed that both treatments were moderately effective at multiple anatomical sites. Dianette treatment was responsible for profound suppression of androgen activity, in contrast to metformin, which induced negligible change. However, metformin did reduce markers of insulin resistance. The data suggest that hirsutism may be effectively treated by reducing hyperinsulinemia.

Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome.

Use of metformin in polycystic ovary syndrome (PCOS) is becoming increasingly accepted and widespread, but clinical practice is ahead of the evidence. Although a wide range of benefits in metabolic, reproductive, and clinical measures have been reported from non-randomised trials with metformin, close inspection of results from the adequately controlled studies shows that the benefits are modest. Our aim in this descriptive review is not to define practice guidelines but to improve clinicians' knowledge of the available published clinical evidence, concentrating on the few randomised controlled trials. We also highlight other issues, including hirsutism, acne, pregnancy, and neonatal outcome, that require more attention before clinical recommendations for the use of metformin in PCOS can be formalised. The potentially greater benefits achievable by lifestyle changes alone are also emphasised. We hope that the review will lead to more judicious use of metformin in PCOS and a more structured approach to research.

A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome.

There is increasing evidence that elevated plasma levels of hemostatic factors [fibrinogen, factor VII, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator (t-PA) antigen] are independently linked to risk for coronary heart disease (CHD). Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for CHD and type 2 diabetes, but there are few data on hemostatic markers in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index (BMI) were recruited. Insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique. Factor VIIc was determined by a clotting assay; fibrinogen was determined by nephelometry; and t-PA, D-dimer, and von Willebrand factor antigens were measured by ELISA techniques. Of these hemostatic markers, only t-PA concentration was significantly (P = 0.013) elevated in women with PCOS relative to controls. t-PA correlated with BMI in both PCOS and controls (r = 0.428, P < 0.1; and r = 0.686, P < 0.01) and inversely with the insulin sensitivity index (r = -0.590, P < 0.05; and r = -0.620, P < 0.05, respectively). After further adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA between cases and controls (P = 0.017). Together, age and insulin sensitivity explained 39% of the variance in t-PA in women with PCOS (P < 0.05). Total testosterone did not correlate significantly with t-PA in either group. We conclude that women with PCOS have significantly increased t-PA concentrations relative to women with normal menstrual rhythm and normal androgens. We suggest that elevated t-PA and dysfibrinolysis may be a factor in the increased cardiovascular morbidity seen in PCOS.

Altered vascular function in young women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinemic insulin resistance, a metabolic disorder that in other circumstances is associated with increased cardiovascular risk. We compared macrovascular and microvascular function in 19 women with PCOS with 12 control subjects matched as a group for body mass index. Macrovascular function was assessed by recording pulse wave velocity (PWV) across the aorta and brachial artery. Microvascular function was studied by wire myography, by measuring the concentration response curve to norepinephrine (NE) before and after incubation with insulin (100 and 1,000 pM). PWV at the level of the brachial artery was found to be significantly elevated in the PCOS group [9.08 (range, 8.34-11.15) m/sec(-1) vs. 8.27 (range, 7.5-9.01) m/sec(-1); P = 0.03]. In contrast, PWV measured in the aorta did not differ between the two groups [7.49 +/- 1.21 vs. 7.84 +/- 1.44 m/sec(-1); P = 0.8]. In vessels from control subjects, insulin reduced the contraction response to NE. At an insulin concentration of 100 pM, NE negative log EC50 (pD(2)) was 6.2 +/- 0.24 vs. 6.7 +/- 0.15 (P = 0.02). At a concentration of 1,000 pM, NE pD(2) was 6.4 +/- 0.14 vs. 6.9 +/- 0.19 (P = 0.0006). Both concentrations also caused attenuation in maximal tension developed in response to NE (insulin 100 pM, 12 +/- 3%, P = 0.002; insulin 1,000 pM, 17 +/- 5%, P = 0.009). In contrast, there was no change in the PCOS group with insulin at 100 pM for either pD(2) (6.7 +/- 0.24 vs. 6.8 +/- 0.27; P = 0.3) or maximum contraction (-0.4 +/- 2%; P = 0.8). At 1,000 pM, there was a change in pD(2) (6.4 +/- 0.2 vs. 6.8 +/- 0.2; P = 0.003) but not maximum contraction (4 +/- 3%; P = 0.2). In conclusion, this study is the first to demonstrate increased vascular stiffness and a functional defect in the vascular action of insulin ex vivo in patients with PCOS. We suggest that these findings are indicative of insulin resistance at a vascular level in women without overt cardiovascular disease.