Stephen D. Keay

Metformin Decreases the Adipokine Vaspin in Overweight Women With Polycystic Ovary Syndrome Concomitant With Improvement in Insulin Sensitivity and a Decrease in Insulin Resistance

OBJECTIVE—Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Vaspin (visceral adipose tissue–derived serine protease inhibitor) levels increase with hyperinsulinemia and obesity. Currently, no data exists on vaspin in PCOS women. We therefore assessed mRNA and protein levels of vaspin, including circulating vaspin, from subcutaneous and omental adipose tissue of PCOS women and matched control subjects. Ex vivo regulation of adipose tissue vaspin and the effects of metformin treatment on circulating vaspin levels in PCOS subjects were also studied. RESEARCH DESIGN AND METHODS—Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of vaspin. Serum vaspin was quantified by enzyme-linked immunosorbent assay. The effects of d-glucose, insulin, and gonadal and adrenal steroids on adipose tissue vaspin were analyzed ex vivo. RESULTS—There were significantly higher levels of circulating vaspin (P < 0.05), vaspin mRNA (P < 0.05), and protein (P < 0.05) in omental adipose tissue of PCOS women. Interestingly, in omental adipose tissue explants, glucose significantly increased vaspin protein levels and secretion into conditioned media (P < 0.001). Also, after 6 months of metformin treatment, there was a significant decrease in serum vaspin levels in PCOS women (P < 0.001). Furthermore, multivariate regression analysis revealed that following metformin therapy, changes in circulating glucose levels were predictive of changes in serum vaspin levels (P = 0.014). CONCLUSIONS—We report, for the first time, elevated serum and omental adipose tissue levels of vaspin in overweight PCOS women and ex vivo regulation of vaspin, predominantly by glucose. More importantly, metformin treatment decreases serum vaspin levels, a novel observation.

Investigation and current management of recurrent IVF treatment failure in the UK

Objective  To determine current practice in the management of recurrent in vitro fertilisation (IVF) treatment failure in licensed UK infertility centres.

Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome

Aims/hypothesisPolycystic ovary syndrome (PCOS) is a multifaceted metabolic disease linked with insulin resistance (IR) and obesity. Adiponectin, which is lower in IR states, exerts its glucose-lowering and anti-inflammatory effects by activating two receptors, ADIPOR1 and ADIPOR2. There are no data on the relative expression of these receptors in adipose tissue of PCOS women.MethodsWe investigated the expression of adiponectin receptors from corresponding s.c. and omental (o.m.) adipose tissue in women with PCOS compared with matched non-PCOS women. As there is a disturbance in the steroid milieu in PCOS women, we also assessed the effects of testosterone and oestradiol on adiponectin receptors using adipocytes and adipocyte explants. Real-time RT-PCR and western blotting were used to assess the relative adiponectin receptor mRNA expression and protein production, respectively. Biochemical measurements were performed in our hospital’s laboratory.ResultsWe are the first to describe adiponectin receptor expression and production, in corresponding s.c. and o.m. human adipose tissues at the mRNA and protein level. We demonstrate the upregulation of mRNA expression and protein production of adiponectin receptors in women with PCOS, in s.c. and o.m. adipose tissue. Treatment of adipose tissue explants and adipocytes with testosterone and oestradiol induced the expression of adiponectin receptor mRNA and protein. There was a significant positive association between ADIPOR1/R2 expression and homeostasis model assessment, testosterone, oestradiol and triglycerides and a negative relationship with sex hormone-binding globulin.Conclusions/interpretationThe precise reason for the upregulation of adiponectin receptors seen in PCOS women, a pro-diabetic state, is unknown, but it appears that sex steroids may play a role in their regulation in adipose tissue.

The role of hCG in reproductive medicine.

Human chorionic gonadotrophin (hCG) has an essential role in early pregnancy and is of fundamental importance in obstetrics and gynaecology. hCG measurement is used for early pregnancy testing and monitoring, biochemical prenatal screening and the assessment of gestational trophoblastic disease. hCG is used therapeutically to induce final oocyte maturation prior to oocyte retrieval for IVF/ ICSI and recombinant hCG has recently been developed (Table 1). This review will relate to early pregnancy complications and reproductive medicine practice and will not deal in detail with its measurement in prenatal trisomy screening. Before considering the pathophysiological conditions that may lead to abnormalities of hCG synthesis and secretion, the expression and structure of both hCG and the hCG/LH receptor will be described. hCG is a member of the glycoprotein hormone family also comprising the pituitary derived follicle stimulating hormone (FSH), luteinising hormone (LH) and thyroid stimulating hormone (TSH). Each hormone consists of a non-covalently bound aand h-subunits where within a species the a-subunit is identical and hormone specificity is determined by the unique h-subunit.

REVIEW: The role of hCG in reproductive medicine

Human chorionic gonadotrophin (hCG) has an essential role in early pregnancy and is of fundamental importance in obstetrics and gynaecology. hCG measurement is used for early pregnancy testing and monitoring, biochemical prenatal screening and the assessment of gestational trophoblastic disease. hCG is used therapeutically to induce final oocyte maturation prior to oocyte retrieval for IVF/ ICSI and recombinant hCG has recently been developed (Table 1). This review will relate to early pregnancy complications and reproductive medicine practice and will not deal in detail with its measurement in prenatal trisomy screening. Before considering the pathophysiological conditions that may lead to abnormalities of hCG synthesis and secretion, the expression and structure of both hCG and the hCG/LH receptor will be described. hCG is a member of the glycoprotein hormone family also comprising the pituitary derived follicle stimulating hormone (FSH), luteinising hormone (LH) and thyroid stimulating hormone (TSH). Each hormone consists of a non-covalently bound aand h-subunits where within a species the a-subunit is identical and hormone specificity is determined by the unique h-subunit.

The Practical Implications of a Raised Serum FSH and Age on the Risk of IVF Treatment Cancellation Due to a Poor Ovarian Response

AbstractPurpose: Chronological age, or biological age as indicated by elevated FSH levels, are related to ovarian reserve. This study addresses the likelihood of cancellation of IVF treatment due to a poor ovarian response utilising both basal serum FSH and womans age. Methods: A prospective cohort of 536 infertile but ovulating women were studied in their first cycle of IVF treatment. Standardised methods of pituitary desensitisation and ovarian stimulation prior to IVF treatment were employed. Treatment cycles cancelled due to a poor ovarian response to gonadotrophins were studied. A series of logistic regression models were used to explore the probabilities of cancellation in relation to age and FSH. Results: Both age and basal serum FSH levels were independently associated with the risk of treatment cancellation. A low risk of treatment cancellation was observed in women under the age of 35 irrespective of serum FSH, however in older women the risk of treatment cancellation was most likely in women with a high FSH. Conclusions: In combination both age and FSH may serve as a valuable indicator of poor ovarian response leading to treatment cancellation. However, among older women FSH has particular importance, while less so in younger women with regular menstrual cycles.

Acquired factor VIII inhibitors as a cause of primary post-partum haemorrhage

Acquired haemophilia was diagnosed following detailed investigation of a post-partum haemorrhage unresponsive to standard management. Circulating factor VIII inhibitors and low factor VIII levels were detected and intravenous DDAVP treatment lead to a resolution of symptoms. This case highlights the importance of haematological investigations in persisting post-partum haemorrhage.

The anti-atherogenic aspect of metformin treatment in insulin resistant women with the polycystic ovary syndrome: Role of the newly established pro-inflammatory adipokine Acute-phase Serum Amyloid A; evidence of an adipose tissue-monocyte axis

OBJECTIVE Acute-phase Serum Amyloid A (ASAA) is a novel pro-inflammatory adipokine, increased in obese, insulin resistant subjects. Polycystic ovary syndrome (PCOS) is associated with inflammation and atherosclerosis. We assessed sera, adipose tissue (AT) mRNA and protein levels of ASAA of PCOS women and matched controls. Ex vivo regulation of AT ASAA by d-glucose, effects of metformin treatment on circulating ASAA in PCOS subjects and effects of sera from normal and PCOS subjects (before and after metformin) on ASAA production (THP-1 macrophages) were also studied. METHODS AND RESULTS Circulating ASAA (ELISA), subcutaneous and omental AT ASAA mRNA (RT-PCR) and protein (western blotting) were significantly higher in PCOS women (P<0.05). In AT explants, glucose significantly increased ASAA production and secretion (P<0.05, P<0.01). Furthermore, ASAA production (THP-1 macrophages) was significantly greater by sera from PCOS women compared to controls (P<0.01). ASAA protein production was significantly decreased by sera from PCOS women following 6 months of metformin treatment (P<0.05). After 6 months of metformin treatment, there was a significant decrease in circulating ASAA (P<0.05). Importantly, changes in intima media thickness were predictive of changes in circulating ASAA (P=0.034). CONCLUSION Serum and AT ASAA are increased in PCOS women and are elevated by glucose. Metformin treatment decreases serum ASAA in these women. An adipose tissue-monocyte axis may be pivotal in the pathogenesis of inflammation and atherosclerosis. ASAA may be a valuable diagnostic marker in the management of dysmetabolic states including PCOS.

Should cryopreserved epididymal or testicular sperm be recovered from obstructive azoospermic men for ICSI

Objective  To determine the effect of the anatomical site of sperm recovery on intracytoplasmic sperm injection (ICSI) embryo implantation, pregnancy and live birth rates in couples with isolated obstructive azoospermia as the sole cause of infertility.

Poor ovarian response to gonadotrophin stimulation - the role of adjuvant treatments

Poor ovarian response to gonadotrophin stimulation represents a clinical problem in in vitro fertilization practice. Women showing poor ovarian response are a heterogeneous group, many of whom have a reduced ovarian reserve and consequently a lower pregnancy potential. Various management strategies have been proposed to improve ovarian response to gonadotrophins, but these have met with limited success. Adjuvant treatments aim to potentiate the effect of exogenous follicle-stimulating hormone. In separate, randomized, placebo-controlled trials low-dose dexamethasone and aspirin have been shown to reduce the incidence of poor response in an initial stimulation cycle. Preliminary studies using pyridostigmine and l-arginine in established poor responders are encouraging but require confirmation in adequately powered studies. Evidence from randomized controlled trials does not support the use of adjuvant growth hormone or growth hormone-releasing hormone in poor responders without overt growth hormone deficiency. The mechanisms of action of adjuvant treatments require further investigation.