Colin M Howles

ARIES Consulting SARL and The University of Edinburgh · Deanery of Biomedical Sciences, College of Medicine & Veterinary Medicine

Introduction This large multicenter study aimed to evaluate clinical outcomes using three follitropin alfa preparations within a progestin-primed ovarian stimulation (PPOS) protocol, while identifying contributing factors to cycle success. Methods A retrospective, anonymized cohort analysis was conducted on donor-recipient cycles from 12 clinics d...

Study question Is there a selection bias against embryos placed in higher-numbered wells inside a multi-well IVF culture dish. Does this selection bias alone impact implantation outcomes? Summary answer Top-quality embryos present in higher-numbered wells are statistically less likely to be selected for transfer, independent of any differences in...

Unfounded skepticism relating to biosimilars, arising from the assertion that they are not molecularly identical to their original counterpart, fails to acknowledge that no biological medicine, including Gonal-f® (from Merck Serono) is identical to itself. Molecular differences between the biosimilar and the reference medicines are irrelevant and c...

Study question Are safety and effectiveness of Ovaleap® (follitropin alfa), and Gonal-f®, comparable in one treatment cycle of ART in routine clinical practice? Summary answer Safety in terms of incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, were similar between Ovaleap® and Gonal-f®. What is known alr...

Study question Is this incidence of early stage abnormal cleavage events different between embryos created following ICSI compared with IVF? Summary answer Embryos derived from ICSI are more likely to exhibit abnormal cleavage compared with those from IVF. This difference is most marked in women ≥35 years. What is known already Time lapse imaging...

Background Ovaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice. Methods Safety...

KEY MESSAGE Salivary oestradiol testing correlates well to serum-based assessment. Saliva oestradiol and progesterone values, around the time of trigger, can vary in response to ovarian stimulation and vary from patient to patient. Saliva-based hormone tests may become the preferred method of hormone monitoring for fertility treatments in the futur...

Patient-Centered Assisted Reproduction - edited by Alice D. Domar March 2020

How to Prepare the Egg and Embryo to Maximize IVF Success - edited by Gabor Kovacs January 2019

Objective: The main objective of this user experience testing study was to evaluate the impact of human factors on the use of a disposable pen containing follitropin alfa by patients and nurses with special focus on the convenience, safety and ease of use, in different types of stimulation protocols. Methods: Infertile women trying to conceive, and...

Study question: Does an asynchronous syngamy (AS) phenotype serve as a primary selection biomarker in predicting embryo development and live birth in human embryos? Summary answer: AS is associated with higher probability of developing nucleation and cleavage errors. Implantation and live births were not affected in the absence of accompanying err...

Objective Predictors of ovarian response have been reported both for GnRH agonist and antagonist treatment cycles using established FSH stimulation agents. Various predictors have been identified in different analyses, but typically the most reported are Age, FSH, AMH, BMI. With the availability of newly registered recombinant FSH (r-FSH) preparat...

In this open-label study, women aged 36-40 years undergoing ovarian stimulation were randomized to recombinant human FSH (rhFSH) plus recombinant human luteinizing hormone (rhLH) from stimulation day 1 (group A; n = 103), or rhFSH alone (days 1-5) followed by rhFSH plus rhLH from day 6 (group B; n = 99). The primary objective was equivalence in num...

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18–34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 20...

This pilot study compared the efficacy and safety of two simple dosing algorithms, one based on anti-Müllerian Hormone (AMH) and the other on the antral follicle count (AFC), to determine the starting dose of recombinant FSH (rFSH) for ovarian stimulation in 348 women. Patients were randomized to a predefined AMH-or AFC-based algorithm. The proport...

Study question In women aged 36–40 years, how many oocytes are retrieved using two controlled ovarian stimulation (COS) treatment strategies: (Group A) recombinant follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone (r-hLH) (2:1) from Day 1 or (Group B) r-hFSH from Days 1–5, then r-hFSH plus r-hLH (2:1) from Day 6? Summary a...

The Sixth Evian Annual Reproduction (EVAR) Workshop Group Meeting was held to evaluate the impact of IVF/intracytoplasmic sperm injection on the health of assisted-conception children. Epidemiologists, reproductive endocrinologists, embryologists and geneticists presented data from published literature and ongoing research on the incidence of genet...

Introduction: There is a high medical need to identify predictors of ovarian response that will enable clinicians to individualize treatment so as to minimise excessive response to FSH but also to identify prospectively patients who may have a sub optimal or poor response to FSH and potentially provide a prospective evaluation on treatment outcomes...

Textbook of Assisted Reproductive Technologies has become a classic comprehsive reference for the whole team at the IVF clinic. The fourth edition comes more conveniently as a set of two separate volumes, one for laboratory aspects and the other for clinical applications. The text has been extensively revised, with the addition of several importan...

In a spontaneous menstrual cycle, only one follicle out of a cohort of 10–20 usually completes maturation and ovulates to release a mature oocyte. The aim of controlled ovarian stimulation (COS) in assisted reproductive technique (ART) protocols is to overcome the selection of a dominant follicle and to allow the growth of a cohort of follicles. Th...

Infertility treatment became available owing to developments in the characterization and purification of hormones. Treatment with gonadotropins and clomiphene citrate (CC) became available in 1961. The purpose of this chapter is to overview the development, structure, and mode of action of treatments for ovulation induction (OI) and controlled ovar...

Controlled ovarian stimulation (COS) with gonadotropins to produce multiple follicular development and high-quality oocytes is the cornerstone of assisted reproductive technology. Today, recombinant human follicle-stimulating hormone (r-hFSH) is widely used for COS. A long-acting r-hFSH and a combination of r-hFSH and recombinant human luteinizing...

The Fifth Evian Annual Reproduction (EVAR) Workshop Meeting discussed knowledge regarding contemporary genetics in female reproduction. Specialist reproductive medicine clinicians and geneticists delivered presentations based on published literature and current research. The content of this report is based on the expert presentations and subsequent...

Exogenous gonadotropins can be applied to treat anovulation or to stimulate multiple follicular development in women who are candidates for ART. Although both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are involved in the natural menstrual cycle, the use and benefit of exogenous LH in protocols for ovarian stimulation in ART ha...

The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplisti...

To investigate the effectiveness of treatment with transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) using GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI). Prospective randomized controlled trial. University-affiliated infertility clinic. A total of 1...

To identify baseline characteristics related to successful ovulation induction, data were analysed from oligo- or anovulatory patients undergoing their first cycle of human recombinant FSH (r-hFSH; follitropin alfa) in a chronic low-dose (75 IU starting dose), step-up protocol in two clinical trials (n=446). Patients were grouped according to respo...

PURPOSE OF REVIEW: Use of preimplantation genetic diagnosis to improve in-vitro fertilization outcomes is reviewed. RECENT FINDINGS: Many embryos produced in vitro contain chromosomal abnormalities and have little potential for forming a viable pregnancy. The most commonly used method for preimplantation genetic diagnosis involves embryo biopsy on...

Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of del...

To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In...

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34...

To compare the efficacy and safety of recombinant human FSH (r-hFSH) and hCG treatment for male hypogonadotropic hypogonadism (HH) in different populations and to identify characteristics predictive of spermatogenesis. A combined analysis of data from four clinical trials. Phase III, open-label, noncomparative studies with similar designs conducted...

Sequential exogenous oestradiol and progesterone are often used to prepare the endometrium in frozen embryo transfer (FET) cycles. This open-label, randomized study compared the efficacy and acceptability of self-administered once daily vaginal progesterone gel and vaginal micronized progesterone tablets (three times daily) for luteal support in FE...

The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stim...

IntroductionThe Structure of GonadotropinsPhysiology of GonadotropinsHypothalamic RegulationUrinary Gonadotropic Preparations with FSH ActivityGonadotropin Production Using Recombinant DNA TechnologyPhysicochemical and Pharmacological Characteristics of rhFSHClinical Applications of rhFSHReferences

Introduction: The glycoprotein hormone FSH consists of two polypeptide subunits, each subunit having 2 asparagine-linked carbohydrate side-chains attached. Micro-heterogeneity of the carbohydrate side chains gives rise to a range of FSH isoforms. Heavily sialylated, acidic FSH isoforms have longer half-lives and lower in vitro biological potency an...

Introduction: Identifying parameters that can accurately predict the response to gonadotrophins would be of great benefit to oligo-anovulatory women undergoing ovulation induction in order to individualise treatment so as to optimize treatment outcomes and avoid the risk of cancellation due to poor or excessive response and to reduce the incidence...

In women with chronic anovulation, the choice of the FSH starting dose and the modality of subsequent dose adjustments are critical in controlling the risk of overstimulation. The aim of this prospective randomized study was to assess the efficacy and safety of a decremental FSH dose regimen applied once the leading follicle was 10-13 mm in diamete...

In a spontaneous menstrual cycle, during the follicular phase, only one follicle out of a cohort of 10-20 usually completes maturation and ovulates to release a mature oocyte. The aim of ovarian stimulation in assisted reproductive technology (ART) protocols is to overcome the selection of a dominant follicle and to allow the growth of a cohort of...

In their quest for a child, infertile couples embark on a journey that is full of expectations and hopes. Over recent years, treatment procedures for assisted conception have become safer and more efficient. However, couples undergoing treatment can still experience some degree of emotional stress due to disappointment if pregnancy is not achieved,...

Identifying parameters that can accurately predict the response to controlled ovarian stimulation (COS) would be of great benefit in assisted reproductive technology (ART) procedures. An analysis was undertaken with the objective of determining whether specific factors could optimally predict a response to stimulation in ART, and to then develop a...

Since the early 1980s when gonadotrophins were first routinely used in ovarian stimulation regimens, there have been important advances in pharmaceutical product development, leading to the availability today of highly purified and consistent human gonadotrophins produced by recombinant technology, that have benefited cycle management and treatment...

Gonadotrophin-releasing hormone antagonists are effective and safe in preventing premature LH surges, a leading cause of cycle cancellation or failure during assisted conception. Two studies assessed two administration regimens for cetrorelix (as Cetrotide): the multiple-dose (MD, 0.25 mg/day, n = 1066) and single-dose (SD, 3 mg, n = 541) protocols...

The question of whether adjustment to body weight is necessary in in-vitro fertilization (IVF) cycles using GnRH antagonists is currently under discussion. Therefore, a data analysis of five prospective studies using either the single- or the multiple-dose antagonist protocol with cetrorelix (Cetrotide) was performed. The influence of stimulation p...

Gonadotrophin-releasing hormone (GnRH) antagonists have recently been introduced into clinical practice. They appear to offer a promising alternative to the long-established GnRH agonist regimens for prevention of a premature LH surge during ovarian stimulation for assisted reproductive techniques. Clinical outcomes achieved with antagonists are co...

The purpose of this study was to undertake an economic evaluation to compare the cost-effectiveness of recombinant (r)FSH with urinary (u)FSH for attaining clinical pregnancy with assisted reproduction. Mathematical modelling was utilized incorporating a Markovian decision framework and a Monte Carlo simulation. Statistical representations of recur...

A prospective randomized study was carried out in two centres to compare the number of oocytes retrieved after two different starting doses of recombinant human FSH (rhFSH) (Gonal-F) in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) cycles using the multiple dose regimen of the gonadotrophin-releasing hormone (...

Human gonadotrophin preparations have been used in the treatment of infertility for almost four decades. The earliest preparations were derived from urine from postmenopausal women and contained approximately equal amounts of follicle stimulating hormone (FSH) and luteinizing hormone (LH) activities. However, with the recognition that FSH is the pr...

This prospective, double-blind, randomized, multicentre study compared the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH; Gonal-F®) versus highly purified urinary FSH (u-hFSH HP; Metrodin® HP) in women undergoing ovarian stimulation for in-vitro fertilization, including intracytoplasmic sperm injection. A total of 27...

Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation for women with polycystic ovaries have succeeded in reducing the rate of ovarian hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple pregnancies to a minimum of 6%. This has been achieved by reaching, but not exceeding, the threshold level of FSH, st...

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following d...

The efficacy and safety of a chronic low dose (group A) and a conventional (group B) stimulation regimen of recombinant human follicle stimulating hormone (r-HFSH) were compared in 103 WHO Group II infertile women with clomiphene citrate-resistant anovulation. Mono- or bifollicular development was induced in 88.1% of patients in group A compared wi...