Colin Howles

University of Edinburgh, School of Biomedical Sciences, Honorary Fellow

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Colin has worked for 44 years in the field of Reproductive Endocrinology. He started his IVF career in 1984, when he went to work at the first human IVF clinic in the world, Bourn Hall Clinic, Cambridge, directly with the pioneers of human IVF, Professor R G Edwards (Nobel Prize Winner 2010 in Physiology or Medicine), Mr. Patrick Steptoe and Ms Jean Purdy. He then moved to work in biotech Pharma from the late 1980’s and then in the ‘90’s was involved in the development and worldwide clinical introduction of the first highly purified urinary derived gonadotropin and subsequently, recombinant h-FSH, h-LH, hCG and the first on the market GnRH antagonist, cetrorelix. Colin is now based in Geneva, where in 2013, he founded a fertility consulting company, ARIES Consulting Sàrl. ARIES Consulting provides services to Biotech/Pharma companies, lab device manufacturers, biotech start-up companies, private equity groups as well as working directly with IVF clinics in Europe, Australia, Asia and Japan. He is also an Honorary Fellow in the Dept. Biomedical Sciences, University of Edinburgh, where he lectures and supervises research projects with the aim of enthusing a new generation of students on the wonders of reproductive medicine.

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The influence of the pharmaceutical industry on the development of gonadotrophins and ovarian stimulation protocols in assisted reproductive technologies

Front Endocrinol (Lausanne), 2025

Introduction: This review examines the evolution of gonadotrophins in ovarian stimulation (OS) pr... more Introduction: This review examines the evolution of gonadotrophins in ovarian stimulation (OS) protocols for assisted reproductive techniques (ART). Since the advent of in vitro fertilisation (IVF) in the late 1970s, the pharmaceutical industry has played a pivotal role in advancing gonadotrophin production, improving drug purity and optimising delivery methods. Despite significant progress, questions remain about the robustness of the evidence supporting the use of different gonadotrophins and the impact of industry-driven research on clinical practice. The review critically examines the evolution, evidence and future directions of gonadotrophin use in ART.

Methods: A comprehensive literature search was carried out in multiple databases to select articles/reviews on historical developments, manufacturing and analytical techniques, regulatory frameworks and clinical trials undertaken to assess gonadotrophin production, formulation processes and their integration into clinical practice. The analysis included mainly evidence from pharmaceutical sponsored randomised controlled trials (RCTs) as well as single arm, registration or post approval studies. Studies on new molecular entities were reviewed. Systematic reviews and meta-analyses, national registries were consulted. Laboratory developments, regulatory challenges, economic constraints, were considered.

Results: Over the past four decades, ART has seen remarkable improvements, including increased live birth rates in women of advanced ovarian age, reduced multiple births, and the advent of patient-friendly pen devices. Innovations such as recombinant FSH (rFSH) and biosimilars have expanded treatment options. However, the high cost of drug development as well as the complexity of the ART process have contributed to underpowered trials and reliance on meta-analyses, which often fail to account for confounding factors.

Discussion: While gonadotrophins have been shown to be effective for OS, unresolved issues, such as the role of supplementing LH activity in OS protocols, highlight the need for more robust trials. Collaboration between stakeholders is essential to standardise trial designs, define key outcomes and minimise bias. Emerging technologies, including AI and genetic testing, offer opportunities to refine embryo assessment and implantation outcomes, thus improving trial design. A renewed focus on rigorous, transparent trials and interdisciplinary collaboration is essential to advance patient care and address unmet challenges in ART treatment. Beyond gonadotrophins, alternative therapeutic avenues to improve oocyte competence and implantation success warrant exploration.

Child T, Bassett R, Howles CM. The influence of the pharmaceutical industry on the development of gonadotrophins and ovarian stimulation protocols in assisted reproductive technologies. Front Endocrinol (Lausanne). 2025 Apr 4;16:1536844. doi: 10.3389/fendo.2025.1536844. PMID: 40255498; PMCID: PMC12006903.

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Does HCG and LH supplementation during ovarian stimulation improve clinical outcome? A evaluation of 30 years of clinical research BIOGRAPHY

Reprod Biomed Online, 2025

This review evaluates the effect of HCG and LH supplementation during ovarian stimulation. Contro... more This review evaluates the effect of HCG and LH supplementation during ovarian stimulation. Controlled trials were divided into four groups comparing the treatment effect of recombinant FSH (r-FSH) with urinary FSH (u-FSH), with human menopausal gonadotrophin (HMG), with r-FSH + recombinant LH (r-LH) and with rFSH + recombinant HCG (r-HCG). First r-FSH seemed to be more potent than u-FSH in downregulated women, which translated into more follicles and oocytes. In line, numerous trials comparing HMG (containing u-FSH + u-HCG) with r-FSH demonstrated that HMG recruited fewer follicles, thus providing fewer oocytes but resulted in slightly higher pregnancy rates after a first fresh embryo transfer. The latter may be explained by the higher potency of r-FSH resulting in more and higher premature progesterone rises. Prospective trials addressing r-FSH + r-LH compared with r-FSH could not demonstrate any difference in pregnancy rates in normal or poor responders. A placebo-controlled trial of r-HCG added to a fixed daily r-FSH dose revealed that r-HCG inhibited the growth of intermediate follicles, resulting in fewer oocytes, fewer embryos and lower pregnancy rates. In conclusion, the beneficial effect of HCG and LH supplementation on clinical outcome has never been definitely proven for any of the combined gonadotrophin products.

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Textbook of Assisted Reproductive Techniques

CRC Press eBooks, Jun 27, 2012

Textbook of Assisted Reproductive Techniques

CRC Press eBooks, Jun 27, 2012

The Gonadotropins in IVF

Recombinant human follicle stimulating hormone (r-hFSH; Gonal-F) versus highly purified urinary FSH (Metrodin HP): results of a randomized comparative study in women undergoing assisted reproductive techniques

Human Reproduction, Oct 1, 1997

A prospective, randomized, comparative, assessor-blind study was carried out in two centres to co... more A prospective, randomized, comparative, assessor-blind study was carried out in two centres to compare the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH; Gonal-F ®) versus highly purified urinary FSH (u-hFSH HP; Metrodin HP ®), both administered s.c. in women undergoing ovarian stimulation for in-vitro fertilization including intracytoplasmic sperm injection (ICSI). A total of 235 patients started a long gonadotrophinreleasing hormone agonist protocol: 119 received r-hFSH and 114 received u-hFSH HP (150 IU/day) for the first 6 days. Two patients were excluded from the study because they mistakenly received the incorrect treatment combination. Human chorionic gonadotrophin (HCG; 10 000 IU, s.c.) was administered once there was at least one follicle 18 mm in diameter and two others ജ16 mm. In all, 119 (100%) and 102 (89%) of the patients respectively in the r-hFSH and u-hFSH HP groups achieved the criteria for HCG. The mean numbers (⍨SD) of oocytes recovered (the primary endpoint) were 12.2 ⍨ 5.5 and 7.6 ⍨ 4.4 in the r-hFSH and u-hFSH HP groups respectively (P < 0.0001). However, the number of FSH treatment days (11.0 ⍨ 1.6 versus 13.5 ⍨ 3.7) and the number of 75 IU ampoules (21.9 ⍨ 5.1 versus 31.9 ⍨ 13.4) used were significantly less (P < 0.0001) in the r-hFSH group than in the u-hFSH HP group. In patients treated using ICSI (63 patients in each group), no difference in oocyte maturation was observed. The mean numbers of embryos obtained were 8.1 ⍨ 4.2 and 4.7 ⍨ 3.5 (P < 0.0001), in favour of the r-hFSH group. In the majority of patients (96 and 99% respectively) only one or two embryos were replaced (mean 2.0 ⍨ 0.2 and 1.9 ⍨ 0.1 respectively) in the r-hFSH and u-hFSH HP groups. The clinical pregnancy rates per started cycle and per embryo transfer were 45 and 36%, and 48 and 47%, respectively in the r-hFSH and u-hFSH HP groups (not significant). There were six (5.1%) and two (1.7%) cases of ovarian hyperstimulation syndrome respectively. In conclusion, it was found that r-hFSH was more effective than u-hFSH at inducing multiple follicular development. However, the high rate of low ovarian © European Society for Human Reproduction and Embryology 2133 response in the u-hFSH group compared with our general experience was unexpected. The availability of a gonadotrophin with less inter-batch variation would be beneficial for clinicians. r-hFSH seems to fulfil such a requirement.

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Human Recombinant Follicle Stimulating Hormone (Follitropin‐α)

Treatment strategies in assisted reproduction for women of advanced maternal age

PubMed, Apr 18, 2007

In a spontaneous menstrual cycle, during the follicular phase, only one follicle out of a cohort ... more 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 follicles. This strategy leads to an increase in the number of oocytes and hence embryos available for transfer, thereby increasing the chance of transferring up to three viable embryos. However, the chance of pregnancy and also live birth begins to dramatically decline after the age of 35, and successful treatment for these patients continues to be a major challenge in ART programs. Preimplantation genetic screening studies over the last decade have identified a dramatic increase in the rate of aneuploidy as a major contributor to the reduction in embryo viability in older patients. It has also been demonstrated that women of advanced maternal age may have oocytes that are compromised by a significant reduction in the amount of mitochondrial DNA in their cytoplasm. The strategies outlined in this review may provide a means of augmenting follicular recruitment and cytoplasmic integrity by utilizing pharmacogenomics and manipulating endocrinology to improve the prognosis for these women. Recent studies indicate that androgen supplementation may be one area to explore further. The availability of recombinant human leutinizing hormone (rhLH) has made it possible to investigate the role of LH in the endocrinology of follicular recruitment: it appears that a defect in the balance of LH/ follicle-stimulating hormone (FSH) might be involved in the subtle age-related decline in follicular recruitment, and patients of older reproductive age undergoing ART might benefit from the addition of LH and/or hGH. Further studies are required to investigate the physiological mechanisms behind this observation and to assess the possible effect of LH and/or hGH supplementation on the age-related decline in pregnancy rate.

Progesterone supplementation in the late follicular phase of an in-vitro fertilization cycle: a ‘natural’ way to time oocyte recovery?

Human Reproduction, May 1, 1988

Twenty-eight patients superovulated with clomiphene citrate (CC) and human menopausal gonadotroph... more Twenty-eight patients superovulated with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) were given a single injection of 25 mg progesterone (P group) 4 h prior to the ovulation-inducing injection of human chorionic gonadotrophin (HCG). Plasma and urinary LH levels were significantly higher (P less than 0.05) in the P group immediately prior to HCG compared to controls. Plasma progesterone concentrations were also elevated (P less than 0.01) in the P group from the time of injection to oocyte recovery. The number of mature oocytes recovered was also higher (P less than 0.001; 59% versus 40% in controls) and the time interval between oocyte recovery and insemination was also shorter (P less than 0.01) in the P group. The pregnancy rate/replacement 15 days after oocyte recovery was 39% versus 23% in the P and control groups respectively. It was concluded that as more mature oocytes were recovered in the P group, progesterone supplementation in the late follicular phase may be beneficial for patients undergoing GIFT. This was borne out when the first two GIFT patients pretreated in this way became pregnant.

Can "patient-friendly" salivary hormone measurements replace serum monitoring of IVF patients? An European multi-center assessment

Session title: Female infertility Session type: Poster viewing session Presentation number: P-383... more

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Drug used for controlled ovarian stimulation: clomiphene citrate and gonadotropins

Evaluation and treatment of the low responder patient

Endogenous opioid peptide modulation of LH secretion in the ewe lamb: possible involvement of 5-hydroxytryptamine

Journal of Endocrinology, Mar 1, 1988

Evidence from several species suggests that the endogenous opioid peptides participate in the reg... more Evidence from several species suggests that the endogenous opioid peptides participate in the regulation of gonadotrophin and prolactin secretion. The aim of the present study involving intact and ovariectomized prepubertal ewe lambs was to compare the effects in vivo of an opioid peptide agonist d-Ala2,N-Phe4,Met(0)ol5]-enkephalin (FK 33\p=n-\824) and antagonist, naloxone, on concentrations of LH and prolactin in plasma, and levels of neurotransmitter metabolites in cerebrospinal fluid (CSF), with their effects in vitro on the release of gonadotrophin-releasing hormone (GnRH) and neurotransmitters from isolated median eminences. K+/l in tissue obtained from both intact and ovariectomized ewe lambs. Since neurotransmitter levels in superfusate samples were below the limit of detection of the high-performance liquid chromatography assay, it remains to be ascertained whether FK 33\p=n-\824 concomitantly affected neurotransmitter release. These results lead us to conclude that FK 33\p=n-\824 inhibits the secretion of LH, but not prolactin, in intact and ovariectomized prepubertal ewe lambs. The action of FK 33\p=n-\824is mediated, at the level of the median eminence, through a reduction of GnRH release. It is tentatively suggested that FK 33\p=n-\824may exert this inhibitory effect by stimulating the release of 5-hydroxytryptamine.

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Randomized controlled trials do not always fit the purpose: A science-based response to Venetis and Mol’s editorial on biosimilars of follitropin alfa

Drug Discovery Today

Overlapping biosimilar and originator follitropin alfa preparations: How much closer can they get?

Drug Discovery Today

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Frontiers in Endocrinology

BackgroundOvaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a bio... more BackgroundOvaleap® (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.MethodsSafety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confou...

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The Development of Ovarian Stimulation for In-Vitro Fertilization

Optimisation of ovarian stimulation protocols for assisted reproduction

A comparative prospective study of a chronic low dose versus a conventional ovulation stimulation regimen using recombinant human follicle stimulating hormone in anovulatory infertile women

Human Reproduction, 1998

The efficacy and safety of a chronic low dose (group A) and a conventional (group B) stimulation ... more 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 with 76.1% in group B. Ovulation and pregnancy rates were higher in group A (71.4% and 33.3%, respectively) than in group B (63.0% and 20%), but these differences were not statistically significant. Additionally, the total number of follicles that were >10 mm diameter was lower in group A than group B (3.0 ⍨ 2.6 versus 6.3 ⍨ 6.5; P < 0.0001), as was the oestradiol concentration (504 ⍨ 477 pg/ml versus 988 Ϯ 740 pg/ml; P < 0.03). The median dose of FSH (75 IU ampoules) used per cycle was 11 ampoules in group A and 12.5 in group B. In terms of the incidence of ovarian hyperstimulation syndrome, no differences were recorded between the two groups. The results demonstrated that r-HFSH is effective and safe in both these treatment protocols. The chronic low dose regimen was associated with a trend towards a higher rate of mono-or bifollicular development, without jeopardizing the incidence of pregnancy.

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Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation

Human Reproduction, 2007

BACKGROUND: The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for ... more BACKGROUND: 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 stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n 5 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration. RESULTS: The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P 5 0.007), and an increased yield of normally fertilized (2 PN) embryos (P 5 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P 5 0.002). CONCLUSIONS: This sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.

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Colin Howles

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