Thomas Tang

Metabolism and karyotype analysis of oocytes from patients with polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is associated with metabolic disturbances which include impaired insulin signalling and glucose metabolism in ovarian follicles. The oocyte is metabolically dependent upon its follicle environment during development, but it is unclear whether PCOS or polycystic ovarian (PCO) morphology alone affect oocyte metabolism and energy-demanding processes such as meiosis. METHODS Immature human oocytes were donated by PCOS (n = 14), PCO (n = 14) and control (n = 46) patients attending the assisted conception programme at Leeds Teaching Hospitals NHS Trust. Oocytes were cultured individually and carbohydrate metabolism was assessed during overnight in vitro maturation (IVM). Meiotic status was assessed and oocyte intracellular nicotinamide adenine dinucleotide phosphate (NAD(P)H) content and mitochondria activity were measured prior to karyotype analysis by multifluor in situ hybridization. RESULTS Patient aetiology had no significant effect on oocyte maturation potential or incidence of numerical chromosome abnormalities (44%), although PCOS and PCO oocytes were more likely to suffer predivision. Group G chromosomes were most likely to be involved in non-disjunction and predivision. PCOS was associated with increased glucose consumption (2.06 +/- 0.43 and 0.54 +/- 0.12 pmol/h for PCOS and control oocytes, respectively) and increased pyruvate consumption (18.4 +/- 1.2 and 13.9 +/- 0.9 pmol/h for PCOS and control oocytes, respectively) during IVM. Prior prescription of metformin significantly attenuated pyruvate consumption by maturing oocytes (8.5 +/- 1.8 pmol/h) from PCOS patients. Oocytes from PCO patients had intermediate metabolism profiles. Higher pyruvate turnover was associated with abnormal oocyte karyotypes (13.4 +/- 1.9 and 19.9 +/- 2.1 pmol/h for normal versus abnormal oocytes, respectively). Similarly, oocyte NAD(P)H content was 1.35-fold higher in abnormal oocytes. CONCLUSIONS The chromosomal constitution of in vitro matured oocytes from PCOS is similar to that of controls, but aspects of oocyte metabolism are perturbed by PCOS. Elevated pyruvate consumption was associated with abnormal oocyte karyotype.

Use of metformin for women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects up to 15% of women of reproductive age and is characterized by hyperandrogenism, menstrual disturbance, anovulatory infertility and obesity. A large body of evidence has indicated that increased insulin resistance and compensatory hyperinsulinaemia play a key role in the pathogenesis of PCOS. At least 40% of women with PCOS are obese and are more insulin resistant than weight-matched individuals with normal ovaries. Obesity, and particularly abdominal obesity as indicated by an increased waist:hip ratio, is correlated with reduced fecundity, menstrual disorders and hyperinsulinaemia. Metformin, an oral anti-diabetic, reduces serum insulin concentrations and improve the symptoms of PCOS. The aim of this systematic review (Tang et al., 2012) is to ascertain the effectiveness of metformin in improving reproductive outcomes in women with PCOS.

Retinoids and pregnancy: an update

The use and pharmacokinetics of retinoids. The main known teratogenic effects of retinoids are face, skull, cardiovascular, nervous system and thymic abnormalities. The pregnancy prevention programme must be adhered to when initiating retinoid treatment. Effective contraception should be continued for at least one month after cessation of retinoid treatment. Management options of pregnant women with recent retinoid use or exposure in early pregnancy; including involvement of the specialist multidisciplinary team.

Preventing recurrent miscarriage of unknown aetiology

One to three per cent of couples are affected by recurrent miscarriage (defined as more than three consecutive pregnancy losses). Current interventions are centred on known causes of aetiology. Recent research on miscarriage of unknown cause has investigated the requirements for successful embryo implantation. Treatment of immunological risk factors with immunotherapy does not have a strong evidence base. The overall evidence supporting the use of human chorionic gonadotrophin supplementation during pregnancy is inconclusive. The efficacy of progesterone as an intervention remains empirical, with further trials under way.

Spotlight on … fertility and assisted reproduction

Nearly 1 in 6 couples in the UK experience delayed conception. The number of in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles performed in the UK has increased steadily (65 000 cycles in 2013). The average age of women undergoing IVF treatment was 35 years with an average length of time trying to conceive of 4.5 years. The average live birth rate per treatment cycle started was 25% in 2012, accounting for nearly 2% of all babies born in the UK (data obtained from www.hfea.gov.uk). It is hardly a surprise that subfertility is one of the most common referrals from GPs for the reproductive age group. In the last 5 years, TOG has published a large number of review articles covering this clinically, scientifically and emotionally challenging specialty. Common causes of subfertility have not changed much in the last 20 years, although we are seeing a gradual increase in male factor subfertility with a continuous rise of ICSI cycles as well as assisted conception procedures using donor sperm. Karavolos et al. (TOG 2013;15:1–9) summarise the common causes and the management of this condition. Despite the demand for donor sperm, Allan Pacey (TOG 2010;12:43–48) highlighted the current shortfall and ethical issues in recruiting sperm donors in the UK. Polycystic ovary syndrome (PCOS) is themost common cause of anovulatory disorders. Adam Balen (TOG 2000;2:17–20) reviewed the current evidence on surgicalmanagement of PCOS, whilst Meek et al. (TOG 2013;15:171–6) focused on the differential diagnoses of hyperandrogenism including PCOS. Gorthi et al. (TOG 2012;14:188–96) also provided an update on the current issues in ovulation induction treatment. Other common endocrine disorders that have an impact on reproductive health are hyperprolactinaemia (TOG 2012;14:81–86) and thyroid dysfunction (TOG 2015;17:39–45). Jefferys et al. (2015;17:39–45) also discussed the controversies in treating women with subclinical hypothyroidism. Endometriosis affects 5–10% of women. These women usually present with a range of symptoms at various degrees of severity that are causing significant impact on their physical wellbeing and quality of life, as well as experiencing subfertility. Both Mary Wingfield (TOG 2000;2:21–24) and Raj Mathur (TOG 2011;13:1–6) addressed the difficulties in managing endometriosis-related subfertility. Tubal factors remain a common cause of subfertility, and mostly result from previous sexually transmitted disease. Despite the popularity of offering IVF treatment for women with tubal factor subfertility, Suresh and Barvekar (TOG 2014;16:37–45) discussed the role of tubal surgery in improving natural conception, considering current limited NHS funding for IVF in the UK. The authors also described the role of surgery in optimising the success of IVF treatments (TOG 2013;15:91–8). With changes in sociocultural factors, women are more inclined todelay childbearing. Sincebothquantity andquality of eggs declines with time, age poses a significant negative impact on the success of assisted reproductive treatments (ART). As a result, even IVF treatment cannot compensate for the natural loss of fertility. Cooke and Nelson (TOG 2011;13:161–168) provide an in-depth account on the physiology of reproductive ageing, while Bhide and Homburg (TOG 2012;14:161–66) summarise the current evidence on the usefulness and limitations of measuring serum anti-müllerian hormone on assessing ovarian reserve/function. With advancing technology inART, success in egg freezing techniques (TOG 2011;14:45–49) has improved the viability of preserving female fertility. Radon et al. (TOG 2015;17:116–24) described the advances in female fertility preservation, mainly in women newly diagnosed with cancer. This technique can also be used in ‘social’ fertility preservation in women who wish to defer their childbearing for personal reasons. Fertility treatment often generates a lot of ethical dilemmas. Burrell and O’Connor (TOG 2013;15:113–9) highlighted the ethical and medico-legal issues in management of surrogate pregnancy in the UK. Couples embarking on surrogacy treatment or fertility treatment using donated gametes/ embryos are required to see an infertility counsellor. Furthermore, being infertile provokes many emotional and stressful issues to the couples who desperately need support and guidance. Joy and McCrystal (TOG 2015;17:83-9) gave a detailed account on the role of counselling in the management of couples with infertility and related treatments. Finally, one of the most serious iatrogenic complications of IVF treatment is ovarian hyperstimulation syndrome (OHSS). Prakash andMathur (TOG 2013;15:31–5) gave an update on the pathophysiology and management on OHSS. In severe cases, women should be looked after in a tertiary care centre where there is amulti-disciplinary teamwith experienceofdealingwith this complicated and potentially lethal condition. A virtual issue of all TOG articles on fertility and assisted reproduction is available at http://onlinetog.org.

Website reviews@TOG

The GMC website is a familiar interface for most doctors, the layout is logical and easy to navigate. Information on revalidation is under the tab ‘registration and licensing’. As expected, the GMC is an authority on revalidation and under this subsection it provides a single point of reference on the subject, providing links to relevant literature. Information is helpfully divided into sections for; licensed doctors, doctors in training, responsible officers and employers, and the patients and public. To the right are quick links to all the GMC published guidance. The section for licensed doctors reads a little like a ‘how to’ guide and is less extensive and personalised than the section for doctors in training but it is well organised and the subsections are logical. FAQs are hidden in the ‘help and guidance’ section. For trainees there is extensive information on the key areas likely to cause confusion, for example: changing of completion of training (CCT) dates and time out of programme. There is a good section on FAQs and the opportunity to email theGMC if your specific question remains unanswered. Information specifically for SAS doctors or those in locum posts is lacking. The section for patients and the public helpfully outlines their role in the use of structured feedback and the importance of complaints and compliments. In conclusion, this subsection of the GMC website is useful, well thought out and fairly exhaustive when used in conjunction with specialty literature. It should be continually updated as the revalidation process continues and problems are encountered. Anna Fabre-Gray

Current issues in ovulation induction

Key content Anovulation contributes to infertility in up to one-quarter of couples attending infertility clinics. Polycystic ovary syndrome accounts for almost 90% of cases of anovulatory infertility. Careful monitoring is needed to minimise the complications of ovulation induction treatment such as multiple pregnancy and ovarian hyperstimulation syndrome. Lifestyle has a very significant impact on ovarian function. Learning objectives To be able to identify causes of anovulation. To understand appropriate patient selection and to be able to address lifestyle issues and individualise treatment. To recognise the significance of ovulation and cumulative conception rates. Ethical issues Should fertility treatment be offered to overweight and obese women? Counselling should be made available for couples undergoing fertility treatments, including ovulation induction.Anovulation contributes to infertility in up to one‐quarter of couples attending infertility clinics. Polycystic ovary syndrome accounts for almost 90% of cases of anovulatory infertility. Careful monitoring is needed to minimise the complications of ovulation induction treatment such as multiple pregnancy and ovarian hyperstimulation syndrome. Lifestyle has a very significant impact on ovarian function.