7.3.1.1 Pituitary Control

In the early years following its introduction, IVF was carried out using gonadotropins for controlled ovarian stimulation, but without pituitary suppression. This resulted in less flexibility with both the scheduling of IVF cycles and the timing of oocyte retrievals, which resulted in collections being performed at night and throughout weekends. This also resulted in higher cycle cancellation rates owing to the frequent occurrence of a premature endogenous LH surge prior to oocyte retrieval.

The introduction of gonadotropin-releasing hormone (GnRH) agonists for pituitary suppression in the mid-1980s to be used alongside gonadotropin ovarian stimulation enabled greater planning of controlled ovarian stimulation. Once downregulation had been achieved, oocyte retrieval could be timed to precisely 34–38 hours following administration of hCG, which serves as a surrogate for the mid-cycle LH surge and causes resumption of meiosis within an oocyte, in preparation for fertilisation.

GnRH agonists can be administered using intranasal, subcutaneous or intramuscular preparations. There are several proposed regimens when using GnRH agonist therapy for pituitary downregulation. In the long GnRH agonist protocol, the agonist is commenced in the mid-luteal phase of the preceding cycle before commencing ovarian stimulation, resulting in a 10–14-day lead-in to treatment. The objective of this is to allow time for the initial ‘flare effect’ that GnRH agonist administration will have on the pituitary gland to wear off before pituitary desensitisation is achieved 8–10 days later. Once pituitary downregulation has been achieved, stimulation with gonadotropins can begin. Downregulation can be confirmed by ultrasound (thin endometrium and quiescent ovaries), and this will be associated with low serum follicle stimulating hormone FSH, LH and oestradiol levels. The short GnRH agonist protocol involves commencing the agonist in the early follicular phase of the IVF cycle to take advantage of the initial flare effect on the pituitary gland before desensitisation is achieved. The ultrashort protocol, on the other hand, involves administering GnRH agonist for only 2–3 days in the early follicular phase using only the flare-up effect, with some studies reporting its use in poor responders.

The literature suggests comparable efficacy between the long and short GnRH agonist protocols for pituitary suppression with IVF, although there is limited evidence assessing the role of the ultrashort GnRH agonist protocol in this context. In practice, the long protocol remains the most commonly used GnRH agonist regimen.

In 1994, GnRH antagonists were introduced as an additional option to GnRH agonists in preventing premature LH surges in controlled ovarian stimulation. The GnRH antagonist acts immediately on the pituitary and prevents pituitary secretion of both FSH and LH, without the need for desensitisation. Ovarian stimulation could begin on day 2 of the menstrual cycle and daily administration of the antagonist would typically begin on day 5 or 6 of stimulation or once the leading follicle had reached 14 mm (usually by day 6–7). A fixed start (beginning on day 5 or 6 of stimulation) protocol seems to be comparable in regard to clinical outcomes when compared with a flexible start (once the leading follicle had reached 14 mm) protocol.

By eliminating the need for pituitary desensitisation, antagonist cycles are much shorter and more convenient for patients and have been shown to require lower total gonadotropin doses. Furthermore, there appears to be a reduced risk of OHSS. In antagonist cycles this risk reducing advantage is furthered by the discovery that the final maturation of oocytes can be initiated by using a single dose of GnRH agonist instead of hCG. The LH rise induced with an agonist trigger has a shorter half-life than that of hCG and this reduces the OHSS risk significantly.

A recently updated meta-analysis including all RCTs to date comparing GnRH agonist versus antagonist regimes revealed similar IVF success rates, with a lower overall consumption of gonadotropins and a reduced risk of OHSS with antagonist cycles [5].

The combined contraceptive pill (COCP) has been commonly used as pretreatment with IVF. This allows greater control with the scheduling of IVF cycles and may prevent the development of ovarian cysts which can occur with the flare effect of starting treatment with a GnRH agonist. A recent meta-analysis, however, showed a slight reduction in clinical pregnancy rates with the COCP (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.66–0.97).

7.3.1.2 Gonadotropins

Human pituitary gonadotropins were first extracted in 1958, from cadaveric human pituitaries. In 1954, it had also been discovered that FSH and LH could be extracted from the urine of post-menopausal women. Human menopausal gonadotropin (hMG) was proposed for therapy in humans in 1957. The initial products required very large volumes of urine (3.5 L required per 75 IU of FSH) and contained several other unwanted urinary proteins. In the absence of an alternative, hMG was used to induce ovulation in hypogonadotropic patients as well as anovulatory normogonadotrophic patients.

In the early 1980s hMG/hCG protocols became standard practice for assisted reproduction cycles, shifting from monofollicular development to superovulation with multiple follicles (Figure 7.1).

Figure 7.1 Ultrasound image of a stimulated ovary showing multiple follicles.

Highly purified hMG followed in 2004, which was produced through an eight-step purification process of menopausal urine. Part of this process incorporated immunological techniques and utilised specific monoclonal antibodies to FSH and LH. Following these steps, hypersensitivity was minimised and consequently it was possible to produce a subcutaneous preparation for injection.

Recombinant human FSH (rFSH) was developed to eliminate the inherent variation found with urinary FSH products as well as ensuring greater availability of a product not reliant on urinary donation. The increased purity of rFSH reduced the possibility of oxidation and led to the production of liquid gonadotropin formulations, dispensed in prefilled injection devices.

Systematic review and meta-analysis data suggested that adding recombinant human LH (rLH) to rFSH for ovarian stimulation may improve pregnancy outcomes in poor responders compared with rFSH alone. Subsequently, however, an RCT (ESPART 2016) assessed this question in poor responders and included 462 women randomised to IVF with rFSH/rLH and 477 to IVF with rFSH alone. The study found no significant difference in the number of oocytes retrieved between the two groups.

In summary, current evidence which includes an updated Cochrane review shows similar efficacy between urinary and recombinant gonadotropins including the use of FSH alone or combined FSH/LH preparations with respect to implantation rates, live births and multiple pregnancy rates.

7.3.1.3 FSH Dose

The starting dose of gonadotropins used in IVF is typically between 150 and 300 IU of FSH, with the treatment dose often based on the patient’s age and her ovarian reserve. Patients at risk of developing OHSS can be started on relatively low doses of 100–150 IU per day. Lower doses of 75 IU per day do not appear to be sufficient for most women.

An RCT (OPTIMIST) reported no clinically significant difference in cumulative live birth rates when using individualised FSH dosing regimens (100–450 IU) compared to a standard dose regimen (150 IU). The study, however, noted significantly higher cancellation rates and significantly higher rates of OHSS in the standard dose arm compared to the individualised arm. Several limitations need to be considered when interpreting the data reported in the OPTIMIST trial including that adjustments in FSH doses were allowed in the standard dose arm after the first cycle and cumulative outcomes were assessed only up to 18 months.

A Cochrane review published in 2018 concluded that tailoring the FSH dose in any particular population (low, normal, high ovarian reserve), did not appear to influence the rates of live birth/ongoing pregnancy. The review, however, concluded that individualisation of FSH doses reduced the overall incidence of moderate and severe OHSS. The authors noted that there were sample size limitations in the studies included that need to be considered when interpreting these data [6].

In summary, evidence from recent randomised studies suggests that the concept of individualised FSH dosing in IVF may not necessarily offer a significant advantage in terms of live births with IVF but does appear to reduce the risk of OHSS and lowers the risk of cycle cancellation. There are limitations to the methodology and study sample size of these reports which suggest one should exercise caution in the interpretation of these findings. More research is needed to evaluate this further.

7.3.1.4 Poor Responders

A description of poor response to fertility treatment was first defined by Garcia in 1983 as peak oestradiol levels of less than 300 pg/mL following controlled ovarian stimulation with 150 IU of hMG.

The European Society of Human Reproduction (ESHRE) provided a more recent definition of poor ovarian response (Bologna criteria 2011) as having at least two of the following three features:

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  Advanced maternal age >40 or other factors for diminished ovarian reserve

  
  
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  Previous history of poor ovarian response (fewer than three oocytes retrieved with conventional ovarian stimulation)

  
  
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  An abnormal ovarian reserve test (AFC <5–7 follicles or AMH <5.4 pmol/L)

IVF treatment for patients with diminished ovarian reserve can be challenging and is often associated with poor clinical outcomes, namely high risk of cycle cancellation and low pregnancy rates.

There is no consensus on what constitutes the optimal stimulation protocol for poor responders, although it is common practice to use high-dose FSH in such cycles. Some studies have reported on using low doses of FSH for ovarian stimulation or no FSH (natural cycle IVF) in such cases, instead of using high-dose FSH for ovarian stimulation. There is limited published evidence to guide practice and further research is required to assess the optimal treatment regimen in this context.

7.3.1.5 Monitoring During IVF

Monitoring ovarian response to superovulation is usually performed using vaginal ultrasound tracking of the follicular response to stimulation. Approximately from day 8–10 of stimulation, measurement of the number and average diameter of each follicle within the ovaries is calculated, typically on alternate days, with stimulated follicles expected to grow by 2 mm a day. Endometrial thickness is also noted during these scans. The pre-ovulatory hCG trigger can be administered once a set number of leading follicles reaches at least 17 mm (many clinical protocols aim for at least 3) and a satisfactory cohort of intermediate follicles has been achieved.

The use of biochemical indicators of follicular activity, namely serum oestradiol concentrations, may aid clinical decision-making in women at risk of OHSS although they appear of limited clinical value in women with normal or low ovarian reserve. A Cochrane review (2014) concluded that there was no evidence to suggest that combined monitoring by transvaginal pelvic ultrasound scan and serum oestradiol is more efficacious than monitoring by transvaginal pelvic ultrasound scan alone in respect of clinical pregnancy rates or the incidence of OHSS. However, the quality of the evidence assessing this was noted to be low. The authors concluded that a combined monitoring protocol including both transvaginal pelvic ultrasound scan and serum oestradiol would be precautionary good clinical practice in a subset of women considered at high risk of OHSS.