Richard Fleming

Successful treatment of infertile women with oligomenorrhoea using a combination of an LHRH agonist and exogenous gonadotrophins

Summary. Eight oligomenorrhoeic patients with increased luteinizing hormone (LH) and androgen levels who had failed to conceive during prolonged anti‐oestrogen therapy received a new treatment. Large doses of an LH‐releasing hormone (LHRH) analogue (HOE 766) were used to suppress circulating gonadotrophin concentrations and block the positive feedback gonadotrophin surge. Ovulation was induced during continued LHRH analogue treatment with exogenous gonadotrophins without interference from the patients own pituitary. Seven of eight patients conceived rapidly without premature luteinization and without excessive ovarian enlargement. These complications had occurred in control treatment cycles using exogenous gonadotrophins in the absence of the LHRH analogue.

Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre‐eclampsia

Objective To determine whether vascular endothelial growth factor (VEGF) concentrations are altered in pre‐eclampsia.

Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters

OBJECTIVE Women with polycystic ovary syndrome (PCOS) exhibit an abnormal lipoprotein profile, characterized by raised concentrations of plasma triglyceride, marginally elevated low density lipoprotein (LDL)‐cholesterol, and reduced high density lipoprotein (HDL)‐cholesterol. However, a normal LDL‐cholesterol level may be misleading since LDL exists as subpopulations of particles differing in size and atherogenic potential. Smaller LDL particles are more atherogenic and high concentrations often occur in association with elevated circulating triglyceride concentrations (but frequently normal total LDL‐cholesterol), increased hepatic lipase activity (HL) and insulin resistance. Information on LDL subclasses and HL activity in women with PCOS is sparse. The aim of this study was to determine the concentrations of small, dense LDL (LDL‐III) in women with PCOS relative to body mass index (BMI)‐matched controls. We also examined the association of lipoprotein subfraction concentrations with endogenous sex hormone concentrations, since existing literature suggested that androgens up‐regulate and oestrogens down‐regulate HL activity, a key determinant of LDL subfraction distribution.

Nomogram for the decline in serum antimüllerian hormone: a population study of 9,601 infertility patients

OBJECTIVE To define an optimal model for the decline in circulating antimüllerian hormone (AMH) with age and develop a validated age-related nomogram. DESIGN Cohort study with validation of linear, biphasic linear, differential, power, and quadratic equations undertaken in two additional cohorts. SETTING United Kingdom infertility clinics. PATIENT(S) Training cohort of 4,590 infertile women. Two separate validation cohorts; 4,588 infertile women, and 423 women with confirmed ovulation and normal pelvic ultrasound who have a male partner with severe oligospermia. INTERVENTION(S) Serum AMH measurement. MAIN OUTCOME MEASURE(S) Optimal fit and age-related AMH nomogram. RESULT(S) The linear model had the largest sum of absolute and squared residuals and provided a less adequate fit than the four nonlinear models. Of these, the R(2) ranged from 19.45% to 19.48% in the training dataset, from 21.30% to 21.36% in the validation dataset, and from 13.29% to 13.75% in the partners of oligospermic males. The parameters of the differential model were difficult to estimate, and the goodness-of-fit of the power model was slightly inferior to the quadratic model. CONCLUSION(S) Circulating AMH concentrations decline with increasing reproductive age in a manner optimally described by a quadratic equation. This validated age-related AMH nomogram will enable counseling of infertility patients regarding reproductive performance.

A new systematic treatment for infertile women with abnormal hormone profiles

Summary. Five infertile women, with normal menstrual rhythm who had been investigated previously by daily hormone analyses throughout at least one complete menstrual cycle and had shown poor luteal‐phase steroid‐hormone profiles were treated by a new approach. They were rendered hypogonadotrophic with large doses of a luteinizing hormone releasing‐hormone analogue (Hoe 766) and were then treated with exogenous gonadotrophins to induce follicular growth and ovulation. Progesterone production after ovulation in all cases was superior to that observed in the individual patients’ without treatment. One patient conceived in her first conception cycle and another in her fourth. This regimen offers a systematic approach to the treatment of unexplained infertility in women with deficient luteal‐phase steroid‐hormone profiles.

Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology

Polycystic ovarian syndrome is the most common form of anovulatory infertility.1 Its association with menstrual disturbance and altered hormonal parameters leads many affected women of reproductive age to attend a gynaecology or infertility clinic. The aetiology of the condition is unknown, but recent evidence suggests that the principal underlying disorder is one of insulin resistance, with the resultant hyperinsulinaemia stimulating excess ovarian androgen production. Associated with the prevalent insulin resistance, these women exhibit a characteristic dyslipidaemia and a predisposition to non-insulin dependent diabetes and cardiovascular disease in later life. Thus, polycystic ovarian syndrome seems to have many of the hallmarks of the metabolic syndrome.2–4 This article focuses on the recent change in attitudes to polycystic ovarian syndrome arising from the link with insulin resistance—a concept that not only has major implications for the health of affected women but also offers a potential for new treatments. ### Summary points This article is derived from a review of recent publications in the relevant subjects of endocrinology, reproductive medicine, and gynaecology. In addition, we conducted a Medline search of …

Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients

OBJECTIVE To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol. DESIGN Secondary analysis of data prospectively collected in a randomized, assessor-blind trial comparing two different gonadotropin preparations with respect to ongoing pregnancy rate. SETTING Twenty-five centers in seven countries. PATIENT(S) 749 women, aged 21 to 34 years, with primary diagnosis of infertility being unexplained infertility or mild male factor infertility and with serum follicle-stimulating hormone (FSH) level 1-12 IU/L and antral follicle count (AFC) ≥10. INTERVENTION(S) Controlled ovarian stimulation with highly purified human menopausal gonadotropin (hphMG) or recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer and potential subsequent 1-year cryopreserved blastocyst replacement in natural cycles. MAIN OUTCOME MEASURE(S) Relationships between AMH at start of stimulation and ovarian response and treatment outcome. RESULT(S) Serum AMH concentration was strongly correlated with oocyte yield: AMH accounted for 85%, FSH for 14%, and inhibin B and AFC for <1% each of the explained variation in oocyte yield. Also, AMH showed a high accuracy for the prediction of poor (≤3 oocytes) and high response (≥15 oocytes), which was statistically significantly better than basal FSH, AFC, or inhibin B. AMH was statistically significantly positively associated with ongoing pregnancy rate in the fresh cycle as well as with the 1-year cumulative ongoing pregnancy and live-birth rates. CONCLUSION(S) There is a positive relationship between AMH and oocyte yield in GnRH antagonist cycles, and AMH is the best predictor for identifying patients with poor and high ovarian response. The positive association between AMH and cumulative live-birth rates after fresh and cryopreserved cycles reflects the availability of more oocytes/blastocysts, not higher quality. CLINICAL TRIAL REGISTRATION NUMBER NCT00884221.

Longitudinal assessment of antimüllerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.

We examined in a prospective longitudinal pregnancy cohort the influence of advancing gestation and baseline maternal adiposity on antimüllerian hormone (AMH) and determined whether maternal hormones (insulin, leptin, adiponectin, E(2), and sex hormone-binding globulin) correlate with alterations in AMH. We demonstrate that first-trimester AMH is associated negatively with maternal adiposity, that circulating levels decline during the second and third trimesters of pregnancy, and that in univariate and multivariate models adiponectin is associated positively with AMH during this period of pregnancy-related decline.

Anti-Müllerian hormone: clairvoyance or crystal clear?

The clinical use of anti-Müllerian hormone (AMH) has increased exponentially due to its unique relationship with the ovarian reserve and ability to predict ovarian response, facilitate pretreatment counselling and individualize treatment strategies to minimize the risk of ovarian hyperstimulation syndrome. There is now a rapidly increasing literature examining additional possibilities for AMH, all of which suggest that its reach extends far beyond the assisted conception clinic. The recognition that it is a significantly more accurate and reliable measure of ovarian reserve than the antral follicle count or FSH has led to its adoption by physicians to counsel women on their reproductive lifespan, the impact of gonadotoxic chemotherapy, radiotherapy and surgery on the ovarian reserve and allow polycystic ovarian syndrome to be diagnosed by primary care physicians. We propose that there is an adequate literature base to embrace this technology while continuing to develop and refine how AMH can optimize patient care.

The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles

Moderate elevations in serum progesterone concentrations are observed following the use of gonadotrophin-releasing hormone agonists during ovarian stimulation. The clinical significance of this phenomenon has been investigated, but findings have been inconclusive. This commentary proposes that progesterone concentrations are indeed important in endometrial advancement and oocyte/embryo development, which, may lead to asynchrony between endometrial and embryo development. Based on the two-cell, two-gonadotrophin model, this commentary proposes a hypothesis to describe how progesterone concentration increases during ovarian stimulation and three factors influencing this during ovarian stimulation are identified: the number of follicles, the FSH drive and the LH activity. It also suggests how differences in gonadotrophin preparations used for ovarian stimulation may have differential effects on progesterone synthesis. It remains to be tested whether routine measurement of late follicular progesterone concentrations may prove beneficial as suitable assay methods are now available. However, strategies that reduce follicular recruitment in high-responding women and gonadotrophins that contain LH activity may reduce the degree of progesterone elevation prior to luteinization.