Infertility and in vitro fertilisation medicines

Introduction

Infertility treatments — including in vitro fertilisation (IVF) — provide individuals and couples experiencing infertility with the opportunity to become parents by addressing underlying reproductive problems and creating embryos through assisted fertilisation outside of the body^​1​. This is heavily orchestrated by medicines and their effects on hormones to methodically manipulate the body’s natural reproductive processes, allowing clinicians to coordinate each stage of the IVF cycle^​1–4​. This may encompass treatment scheduling, follicular stimulation for egg development, prevention of premature ovulation, induction of final oocyte maturation before egg collection, and support of embryo implantation and early pregnancy^​1–4​. The article — ‘In vitro fertilisation: eligibility, processes and technologies’^​4​ — discusses IVF processes and modifiable lifestyle factors for optimising fertility.

Other medicines may be used to address specific causes of infertility, such as inducing ovulation in women with anovulatory infertility^​1​, treating selected causes of male-factor infertility^​1​ or providing luteal support in early pregnancy following successful embryo transfer^​2​.

Fertility treatment involves both licensed medicines and off-label prescribing^​1​. While fertility clinics operate within national guidance on fertility treatment and the regulatory framework of the Human Fertilisation and Embryology Authority (HFEA)^​5​, the National Institute for Health and Care Excellence (NICE) directs clinicians to the European Society of Human Reproduction and Embryology (ESHRE) guideline for several aspects of IVF treatment^​1​, including pituitary suppression and controlled ovarian stimulation^​2​. However, no single UK-based national formulary or evidence-based guideline brings together detailed prescribing recommendations for medicines used in infertility and IVF, including medicine selection, dosing and treatment duration. Consequently, prescribing practices vary between clinics based on clinical experience and historical, clinic-specific data on treatment outcomes.

In a bid to maximise outcomes, it is not unusual for some clinics to offer a range of IVF add-ons or adjuvants alongside conventional, evidence-based infertility medicines^​6,7​. These optional medications, treatments and supplements vary considerably in their proposed mechanisms, evidence of clinical benefit and safety profiles^​6–8​. NICE advises against using unproven treatments to help patients have a baby^​1​, while the HFEA highlights the limited evidence supporting many treatment add-ons^​6​. ESHRE similarly advocates evidence-based use of add-ons and ensuring patients understand uncertain benefits^​9​.

This variation in evidence and practice presents an important role for pharmacists in supporting informed patient choice, ensuring that the potential benefits, uncertainties and risks of medicines and adjuvants are clearly communicated. Medication regimens can also be complex, requiring pharmacists to know the medicines used in fertility treatment alongside a strong understanding of reproductive physiology and the processes involved in assisted reproductive technology^​10​. This article will discuss medicines used across fertility treatment and assisted reproduction, including, but not limited to, IVF.

Fertility cycle and IVF process

Natural fertility is regulated by the hypothalamic–pituitary–gonadal axis, with gonadotrophin-releasing hormone (GnRH) stimulating the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH)^​11​. In women, a coordinated rise and fall in FSH, LH, oestrogen, and progesterone levels regulate follicular development, ovulation, and preparation of endometrial tissue and blood supply for implantation within an average 28-day menstrual cycle^​11,12​. In men, the same hormones hold specific roles in testosterone production for normal sexual function, spermatogenesis and sperm function, including motility and the ability to fertilise an egg^​11​.

Figure 1 illustrates the main hormones involved in female and male fertility, as well as their roles throughout the reproductive cycle^​11,12​. IVF medicines act on these same hormonal pathways to control and manipulate different stages of fertility treatment. A more detailed explanation of the hormonal regulation of natural fertility is provided in ‘In vitro fertilisation: eligibility, processes and technologies‘^​4​.

Figure 1: Role of key fertility hormones in females and males

IVF treatment sequence

IVF uses medicines to control and manipulate the natural reproductive cycle^​1–3​ within various protocols^​2​, allowing several eggs to develop and be collected for fertilisation in one IVF cycle^​1–3​ (see Figure 2). Ovarian stimulation using FSH — with or without LH — stimulates the development of multiple ovarian follicles. GnRH agonists or antagonists may then be used to prevent a premature LH surge and ovulation. Once the follicles have developed sufficiently, a trigger injection induces final oocyte maturation, followed by egg collection approximately 34–36 hours later^​1,2​. The collected eggs are fertilised with sperm using conventional IVF or intracytoplasmic sperm injection (ICSI), while the resulting embryos are cultured in the laboratory^​1–3​. A high-grade embryo is then transferred into the womb, with suitable remaining embryos potentially frozen for future use^​1–3​. Progesterone is given following embryo transfer to support the endometrium in early pregnancy^​1–3​, with the duration of treatment often determined by clinic protocol.

Figure 2: IVF process

Medicines information

Pharmacological treatment is an integral part of IVF, utilising a range of medicines at different stages of the IVF cycle^​1,2​. These drugs are used across different assisted reproductive techniques, such as IVF, intrauterine insemination (IUI) and frozen embryo transfer (FET)^​13​. However, these techniques do not necessarily involve all stages of a complete IVF cycle — each involves a different combination of treatment stages, and, consequently, different medication requirements. Furthermore, different treatment protocols may be used within each assisted reproductive technique, including variations in ovarian stimulation, pituitary suppression and hormonal pre-treatment^​2​.

Treatment regimens are individualised according to the clinical presentation of infertility, reflecting factors such as male or female infertility, patient preference, the female patient’s ovarian reserve, age, BMI, previous IVF outcomes, previous and current response to stimulation, and modifiable lifestyle factors^​1,2​. In practice, many medicines used in fertility treatment are prescribed outside the terms of their marketing authorisation (i.e. off-label)^​14,15​, meaning that dosing information for these uses may not be available in resources such as the British National Formulary^​16​ and the Electronic Medicines Compendium^​17​. Pharmacists therefore need to consult relevant guidelines, clinical studies, other evidence sources and clinic-specific protocols.

Fertility drugs for women

Figure 3 contains information on the comprehensive range of medicines used in infertility and IVF techniques for women^{​2,18–33​}. Click or tap on each class of medicine to see details on indication, mechanism, dose, side effects and red flags.

Figure 3: Medicines used in infertility and IVF techniques

Fertility drugs for men

Figure 4 contains information on the comprehensive range of medicines used in infertility and IVF techniques for men^{​24,30,34–36​}. Click or tap on each class of medicine to see details on indication, mechanism, dose, side effects and red flags.

Figure 4: fertility drugs: men

Pharmacological adjuvants and treatment add-ons

Clinics offer pharmacological adjuvants or add-ons on an empirical or rationale basis to support evidence-based treatments, meaning some have been adopted into clinical practice before sufficient evidence of efficacy has been established^​7,9​. However, many lack robust evidence showing improved IVF success^​6–8​. Consequently, HFEA ratings for treatment add-ons range from insufficient or conflicting evidence to evidence of no benefit, with some receiving red ratings because of potential safety concerns or evidence suggesting they may reduce treatment effectiveness^​6​.  

Additionally, NICE warns that further research is required to determine their efficacy^​1​. Patients should therefore receive clear information about the quality and limitations of available evidence, potential side effects and risks^​6,9​. The rationale for pharmacological adjuvants often rests on proposed mechanisms of action; however, this theoretical rationale alone does not establish clinical efficacy^​9​.

The rationale for pharmacological adjuvants is often based on their proposed mechanisms of action. (see Figure 5^{​6–9,37–72​}).

Figure 5: Fertility and IVF pharmacological adjuvants

Gamete protection

Indications: improve egg and sperm quality.

Promotion of optimum blood supply

Indications: implantation failure and recurrent early miscarriage (off-label).

Improve ovarian response

Indication: history of poor egg reserve or egg quality; poor embryo quality; poor ovarian response to ovulation induction or stimulation; implantation failure. In-clinic regimens: commonly reserved for advanced maternal age (> 40 years).

Immune modulation

Indication: recurrent miscarriage or recurrent implantation failure owing to suspected abnormalities in the immune system that create hostile womb environments. Immune modulation proposes to control the inflammation and immune activation responsible. In practice: many are expensive, pose risks, and are not recommended by the HFEA. NICE also advises against immunological agents, including intralipids, IVIG or steroids, as part of fertility treatment.

Improving health of the uterus or ovaries

Indication: intrauterine adhesions (Asherman’s syndrome), recurrent implantation failure, recurrent miscarriage, thin endometrial lining, diminished ovarian reserve.

Metabolic management

Indication: Polyendocrine Metabolic Ovarian Syndrome (PMOS- formally Polycystic Ovary Syndrome); high BMI