Controlled Ovarian Hyperstimulation for Unexplained Infertility

What is controlled ovarian hyperstimulation?

It involves the use of the same medications used for induction of ovulation in women that have anovulation. These drugs are used to stimulate development of multiple mature follicles and eggs in order to increase pregnancy rates with various infertility treatments.

Who should be treated with controlled ovarian hyperstimulation?

This therapy is commonly used as infertility treatment for infertile couples. It is usually done in conjunction with intrauterine insemination, which increases success rates.

This treatment does not really correct any specific cause of infertility. Instead it is a “shotgun” approach to get multiple eggs and sperm together at the time of ovulation. This type of treatment has been shown to increase the monthly chances for a pregnancy as compared to timed intercourse alone in patients with unexplained infertility.

Ovarian stimulation with insemination should not be used with very low sperm concentration or very poor sperm motility, blocked fallopian tubes, or if the age of the female partner is over 41. This treatment is very unlikely to be effective in those situations.

Controlled ovarian hyperstimulation is also used to develop multiple mature follicles for in vitro fertilization cycles.

General protocol for an ovarian stimulation treatment cycle:

  • A baseline blood and ultrasound is usually done on day 2-4 of the menstrual cycle
  • The medication is started soon after that
  • Ultrasound and blood testing is done to monitor the response to the meds and follicle sizes
  • An HCG trigger shot is given when the follicles are mature
  • Sex or insemination are timed for about 36 hours after the trigger shot

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 folliclesthere 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 (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 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.
  • Body mass index
  • Previous hyperstimulation experiences
  • Length of menstrual cycles, with shorter cycles being associated with poorer response.
  • Previous ovarian surgery.[5]

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 than using daily FSH when using low dosages (60 to 120 µg of corifollitropin alfa).

Recombinant FSH (rFSH) 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 10 days of injections will be necessary.

Alternatives and complements to FSH

Administering recombinant hCG in addition to an FSH-preparation has no significant beneficial effect.

A small number of underpowered randomized trials came to the result that use of clomifene in addition to gonadotropins results in similar live birth rate but with a reduction in the incidence 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.

Luteinizing hormone (LH) in addition to FSH has evidence of increased pregnancy rate, but not of live birth rate.Using low dose human chorionic gonadotropin (hCG) to replace FSH during the late follicular phase in women undergoing hyperstimulation as part of IVF does not seem to reduce the chances of ongoing and clinical pregnancy, and likely results in an equivalent number of oocytes retrieved, but with less expenditure of FSH. Administration of progestogen before hyperstimulation has evidence of improved pregnancy outcomes, while that of combined oral contraceptive pills before hyperstimulation has poorer pregnancy outcomes.

 

Suppression of spontaneous ovulation

When used in conjunction with in vitro fertilization (IVF), 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.

Controlled Ovarian Hyperstimulation

Monitoring

There is a concomitant monitoring, including frequently checking the estradiol level and, by means of gynecologic ultrasonography, follicular growth. Cycle monitoring by ultrasound plus serum estradiol compared to monitoring by ultrasound only does not increase live birth or pregnancy rates, but may be useful in preventing ovarian hyperstimulation syndrome (OHSS), and may therefore be a used in a subset of women to identify those at high risk of OHSS.

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.

Pregnancy success rates for controlled ovarian hyperstimulation

Success rates for controlled ovarian hyperstimulation with intrauterine insemination vary considerably and depend on the age of the woman, the total motile sperm count, the quality of the sperm, how long the couple has been trying to get pregnant, what the infertility factors are in the couple, etc. It is used most often in couples with unexplained infertility and in those with slight reductions in sperm counts (“mild” male factor).

Ovarian stimulation with gonadotropins (injectable FSH products like Pergonal or Follistim) plus intrauterine insemination gives pregnancy rates of about 5-15% per cycle (women 36 and younger) for unexplained infertility, as demonstrated in several published studies.

Success rates are lower if the woman is over age 36 or if there is a sperm problem – male factor infertility.

For women 40 and older, success rates with this form of infertility treatment are very low, and IVF should be considered relatively soon.

In general, this type of treatment is considered reasonable for about 3 cycles (in women under about 38), after which IVF is usually considered as the next step.