Ovarian hyperstimulation (also called controlled ovarian hyperstimulation) is where a regimen of fertility medications are used to stimulate the development of multiple follicles of the ovaries in one single cycle, resulting in superovulation (release of a larger-than-normal number of eggs). Unless otherwise specified, hyperstimulation in this article refers to hyperstimulation as part of in vitro fertilisation (IVF), although it can theoretically be used in conjunction with in vivo fertilisation (conferring a very high risk of multiple gestation).
Response predictors determine the protocol for ovulation suppression as well as dosage of medication used for hyperstimulation.
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 (AFC), 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.[note 1] 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 (but intermediate)||Sometimes low, but usually adequate||Slight increased risk for IVF cycle cancellation||Slightly reduced compared to the "best" group|
|15-30||Normal (good)||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 (1.5–12.7 versus 13.0–35%, respectively). Also, the other way around, there is a 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 (AMH) 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 (0.8 ng/mL) predicts a low response to ovarian hyperstimulation, while a level greater than or equal to 25.0 pmol/l (3.6 ng/mL) 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 (FSH) 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.
- Previous hyperstimulation experiences
- Previous ovarian surgery.
Hyperstimulation medications used
Hyperstimulation medication is typically started on the third day of menstruation.
In most patients injectable gonadotropins are used, usually FSH analogues. 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. Individual dosage depends on response predictors such as detailed in section below.
There is a concomitant monitoring, including frequently checking the estradiol level and, by means of gynecologic ultrasonography, follicular growth. Typically approximately 10 days of injections will be necessary. Concomitantly administering recombinant hCG has no significant beneficial effect. Spontaneous ovulation during the cycle is typically prevented by the use of GnRH agonists or GnRH receptor antagonists, which block the natural surge of luteinising hormone (LH).
For women predicted to have a poor response, there doesn't seem to be of any benefit to start at a higher FSH dosage than 150 IU per day.
Suppression of spontaneous ovulation
When used in conjunction with in vitro fertilization (IVF), there is 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.
- Practically, the timing of the hyperstimulation and the day of oocyte retrieval in a GnRH antagonist protocol needs to be timed after the spontaneous initiation of the previous menstrual cycle, while the schedule can be started at a time to meet practical needs in a GnRH antagonist protocol.
- Regarding time per cycle, on the other hand, the cycle duration using GnRH antagonist protocol is typically substantially shorter than one using a standard long GnRH agonist protocol, potentially resulting in a higher amount of cycles in any given time period, which is beneficial for women with more limited time to become pregnant.
- Regarding antral follicle count, with the GnRH antagonist protocol initial follicular recruitment and selection is undertaken by endogenous endocrine factors prior to starting the exogenous hyperstimulation. This results in a smaller number of growing follicles when compared with the standard long GnRH agonist protocol. This is an advantage in women expected to be high responders, thereby decreasing the risk of ovarian hyperstimulation syndrome.
- Regarding subsequent final maturation of oocytes, usage of GnRH agonist protocol necessitates subsequent usage of human chorionic gonadotropin (HCG or hCG) for this purpose, while usage of GnRH antagonist protocol also avails for subsequently using a GnRH agonist for final oocyte maturation. Using a GnRH agonist for final oocyte maturation rather than hCG results in an elimination of the risk of ovarian hyperstimulation syndrome, while having a delivery rate after IVF of approximately 6% less.
Thus, in short, a GnRH antagonist protocol may be harder to schedule timewise but has shorter cycle lengths and less (or even eliminated) risk of ovarian hyperstimulation syndrome.
GnRH agonist protocol has overall better results for expected poor and hyper-responders; A study of these protocols in women undergoing their first IVF and having a poor predicted response (by an AMH level below 5 pmol/l by DSL assay), using the GnRH antagonist protocol was associated with a substantial drop in cycle cancellation (odds ratio 0.20) and required fewer days of gonadotrophin stimulation (10 days versus 14 days) compared to GnRH agonist protocol. Using GnRH antagonist protocol in high responders has been associated with significantly higher clinical pregnancy rates (62 versus 32%).
Tracking or supervising the maturation of follicles is performed in order to timely schedule oocyte retrieval. Two-dimensional ultrasound is conventionally used. Automated follicle tracking does not appear to improve the clinical outcome of assisted reproduction treatment.
When used in conjunction with IVF, ovarian hyperstimulation may be followed by final maturation of oocytes using human chorionic gonadotropin (hCG), or a GnRH agonist if a GnRH antagonist protocol is used for ovulation suppression. A transvaginal oocyte retrieval is then performed just prior to when the follicles would rupture. Alternatively, coasting may be performed, which is ovarian hyperstimulation in IVF without induction of final maturation. Coasting radically decreases the risk of ovarian hyperstimulation syndrome (OHSS), with a study of high risk patients showing no incidence of OHSS in 21 patients, versus ~20% in the control group. On the other hand, live birth rate may be slightly decreased, with the same study resulting in 38% in coasting vs. 45% among controls, as well as decreased cumulative live birth rate (52% vs. 59%), presumably because of more difficulty in timing oocyte retrieval with full maturation. However, there appears to be no significantly decreased birth rate among high responder patients, in the associated study defined as those having at least 20 follicles, each measuring ≥10 mm in diameter with ≥20% of them of diameter ≥15 mm.
Ovarian hyperstimulation does not seem to be associated with an elevated risk of cervical cancer, nor with ovarian cancer or endometrial cancer when neutralizing the confounder of infertility itself.
In vitro maturation is letting ovarian follicles mature in vitro, and with this technique ovarian hyperstimulation isn't essential. Rather, oocytes can mature outside the body prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body. However, there still isn't enough evidence to prove the effectiveness and security of the technique.
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