Controlled ovarian hyperstimulation

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation, or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.
In this article, unless otherwise specified, hyperstimulation will refer to hyperstimulation as part of IVF. In contrast, ovulation induction is ovarian stimulation without subsequent IVF, with the aim of developing one or two ovulatory follicles.

Procedure

Response prediction

Response predictors determine the protocol for ovulation suppression as well as dosage of medication used for hyperstimulation. Response prediction based on ovarian reserve confers substantially higher live birth rates, lower total costs and more safety.
It is commonly agreed not to exclude anyone from their first IVF attempt only on the basis of poor results on response predictors, as the accuracy of these tests can be poor for the prediction of pregnancy.

Antral follicle count

The response to gonadotropins may be roughly approximated by antral follicle count, estimated by vaginal ultrasound, which in turn reflects how many primordial follicles there are in reserve in the ovary.
The definition of "poor ovarian response" is the retrieval of less than 4 oocytes following a standard
hyperstimulation protocol, that is, following maximal stimulation. On the other hand, the term "hyper response" refers to the retrieval of more than 15 or 20 oocytes following a standard hyperstimulation protocol. The cut-offs used to predict poor responders versus normal versus hyper-responders upon vaginal ultrasonography vary in the literature, with that of likely poor response varying between an AFC under 3 and under 12, largely resulting from various definitions of the size follicles to be called antral ones.
The following table defines antral follicles as those about 2–8 mm in diameter:

Antral follicle count	Classification	Approximate expected response	Risks	Pregnancy rates	Recommendation
Less than 4	Extremely low	Very poor or none	Cancelled cycle expected	0–7% with 1 oocyte	Not attempt IVF
4-7	Low	Possibly/probably poor response	Higher than average rate of IVF cycle cancellation	15%	High doses of gonadotropin likely
8-10	Reduced	Lower than average	Higher than average rate of IVF cycle cancellation	Slightly reduced
11-14	Normal	Sometimes low, but usually adequate	Slight increased risk for IVF cycle cancellation	Slightly reduced compared to the "best" group
15-30	Normal	Excellent	Very low risk for IVF cycle cancellation. Some risk for ovarian overstimulation	Best overall as a group with approx. 35%	Low doses of gonadotropins
More than 30	High	Likely high	Overstimulation and ovarian hyperstimulation syndrome	Very good overall as a group, but potential egg quality issues	Low doses of gonadotropins

The incidence of poor ovarian response in IVF ranges from 10 to 20%. Older poor responders have a lower range of pregnancy rates compared with younger ones. Also, the other way around, there is a lower prevalence of poor responders among young women compared to those of advancing age, with 50% of women aged 43–44 years being poor responders.

Other response predictors

Circulating anti-Müllerian hormone can predict excessive and poor response to ovarian stimulation. According to NICE guidelines of in vitro fertilization, an anti-Müllerian hormone level of less than or equal to 5.4 pmol/L predicts a low response to ovarian hyperstimulation, while a level greater than or equal to 25.0 pmol/L predicts a high response. For predicting an excessive response, AMH has a sensitivity and specificity of 82% and 76%, respectively. Overall it may be superior to AFC and basal FSH. Tailoring the dosage of gonadotrophin administration to AMH level has been shown to reduce the incidence of excessive response and cancelled cycles.
Elevated basal follicle stimulating hormone levels imply a need of more ampoules of gonadotropins for stimulation, and have a higher cancellation rate because of poor response. However, one study came to the result that this method by itself is worse than only AMH by itself, with live birth rate with AMH being 24%, compared with 18% with FSH.
Advanced maternal age causes decreased success rates in ovarian hyperstimulation. In ovarian hyperstimulation combined with IUI, women aged 38–39 years appear to have reasonable success during the first two cycles, with an overall live birth rate of 6.1% per cycle. However, for women aged ≥40 years, the overall live birth rate is 2.0% per cycle, and there appears to be no benefit after a single cycle of COH/IUI. It is therefore recommended to consider in vitro fertilization after one failed COH/IUI cycle for women aged ≥40 years.
Body mass index
Previous hyperstimulation experiences
Length of menstrual cycles, with shorter cycles being associated with poorer response.
Previous ovarian surgery.
Hyperstimulation medications

FSH preparations

In most patients, injectable gonadotropin preparations are used, usually FSH preparations. The clinical choice of gonadotrophin should depend on availability, convenience and costs. The optimal dosage is mainly a trade-off between the pregnancy rate and risk of ovarian hyperstimulation syndrome. A meta-analysis came to the result that the optimal daily recombinant FSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy rates and embryo cryopreservation rates. For women predicted to have a poor response, there may not be any benefit to start at a higher FSH dosage than 150 IU per day.
When used in medium dosage, a long-acting FSH preparation has the same outcome in regard to live birth rate and risk of ovarian hyperstimulation syndrome as compared to daily FSH. A long-acting FSH preparation may cause decreased live birth rates compared to daily FSH when using low dosages.
Recombinant FSH appears to be equally effective in terms of live birth rate compared to any of the other types of gonadotropin preparations irrespective of the protocol used for ovulation suppression.
Typically, approximately 8–12 days of injections are necessary.

Alternatives and complements to FSH

Administering recombinant hCG in addition to an FSH-preparation has no significant beneficial effect. The hCG is the FSH extracted from the urine in menopausical women.
Clomifene, in addition to gonadotropins, may make little or no difference to the live birth rate but may lower the probability of ovarian hyperstimulation syndrome. A systematic review showed that using clomifene citrate in addition to low dose gonadotropin resulted in a trend towards better pregnancy rates and a greater number of oocytes retrieved when compared with a standard high-dose FSH regime. Such a protocol avails for using lower dosages of FSH-preparations, conferring lower costs per cycle, being particularly useful in cases where cost is a major limiting factor.
Recombinant luteinizing hormone in addition to FSH probably increases pregnancy rates, but it is not certain if the live birth rate is also increased. Using low dose human chorionic gonadotropin to replace FSH during the late follicular phase in women undergoing hyperstimulation as part of IVF may make little or no difference to pregnancy rates, and possibly leads to in an equivalent number of oocytes retrieved, but with less expenditure of FSH. Before ovarian stimulation with antagonist protocols, pretreatment with combined oral contraceptive pills probably reduces the rate of live birth or ongoing pregnancy, while it is uncertain whether pretreatment with progesterone only has any effect on live birth or ongoing pregnancy rates. For other stimulation protocols, the evidence around pretreatment with combined oral contraceptives and progesterone only is uncertain.
Findings are conflicting, but metformin treatment as a complement in IVF cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates.

Suppression of spontaneous ovulation

When used in conjunction with in vitro fertilization, controlled ovarian hyperstimulation confers a need to avoid spontaneous ovulation, since oocyte retrieval of the mature egg from the fallopian tube or uterus is much harder than from the ovarian follicle. The main regimens to achieve ovulation suppression are:

GnRH agonist administration given continuously before starting the gonadotropin hyperstimulation regimen. Physiologically, GnRH agonists are normally released in a cyclical fashion in the body to increase normal gonadotropin release, including luteinizing hormone that triggers ovulation, but continuous exogenous administration of GnRH agonists has the opposite effect of causing cessation of physiological gonadotropin production in the body.
GnRH antagonist administration, which is typically administered in the mid-follicular phase in stimulated cycles after administration of gonadotropins and prior to triggering final maturation of oocytes. The GnRH antagonists that are currently licensed for use in fertility treatment are cetrorelix and ganirelix. In GnRH antagonist cycles, hyperstimulation medication is typically started on the second or third day of a previous natural menstruation.