The Poor Ovarian Responders – Causes and Treatment Strategies
Despite the advances made in reproductive technology, the poor ovarian responders remain a challenge to treat to clinicians worldwide. With increasing number of women falling into this group of patients, it is imperative that treatment strategies aimed at improving pregnancy rates in these women are devised and implemented.
The aim of IVF treatment is to stimulate the ovaries for multi-follicular development in contrast to the spontaneous menstrual cycle where a single dominant follicle develops out of a cohort of 10-20 follicles which were recruited for that particular cycle. This leads to an increased number of fertilizable oocytes that are available which translates into increased number of embryos available for transfer.
Women Undergoing Gonadotropin stimulation fall under three categories based on their ovarian response to the drugs:
- high responders;
- intermediate responders and
- poor responders
Poor responders a have a significant impact on IVF success rates and require a different approach to get the desired results.
Why Is Poor Ovarian Responders a cause for concern?
Poor Ovarian responders are women who fail to develop an adequate response to IVF stimulation, have a lower yield of embryos leading to reduced success of IVF due to a fall in the Cumulative Pregnancy Rate (CPR). This usually means
- Cycle cancellations due to inadequate folliculogenesis.
- Multiple failed cycles
- More number of attempts to start a family
- Increased treatment costs
- Increased aneuploidy causing poor embryo quality and failure to implant
- significantly diminished probability of pregnancy
The poor ovarian responder
Due to the importance of oocyte yield in the success of IVF it became necessary to define the group of women who respond less than adequately. These are the poor ovarian responders - women who fail to produce adequate, good quality fertilizable oocytes. Over the years, many criteria were used to define these women. Screening tests like ovarian reserve, CC challenge, GnRH, GnRH agonist, measurement of Anti-Mullerian hormone (AMH) and antral follicular count (AFC), FSH and E2 levels, cycle cancellation rate, gonadotropin dose have been used as criteria for gauging the ovarian response to ovulation induction.
The definition of poor responder differed widely but mostly included the following:
- advanced age (=?37 years),
- History of previous cycle cancellation,
- Poor response in a previous cycle
- Abnormal Basal FSH parameter
- low ovarian volume and or
- a reduced AFC
Low responders were also previously identified as patients with one or more of the following characteristics:
- advanced age (=?37 years),
- high basal cycle day 3 FSH (=?10?mIU/mL) or high basal E2 levels (=?90 pg/mL),
- high FSH:LH ratio and low LH levels in basal cycle day 3 (Scott et al., 1989; Evers et al., 1998; Barroso et al., 2001),
- and/or low ovarian volume
- And/or a reduced AFC.
Due to the wide variability in criteria and definition of this group, ESHRE( European society for human reproduction and embryology) in 2011, reached a consensus where the exact terms of Poor ovarian responder were defined. This is called the Bologna criteria and it defines Poor Ovarian responder in the following terms-
At least two of the following three features must be present:
- Advanced maternal age or any other risk factor for Poor Ovarian Reserve;
- A previous Poor ovarian Response- defined as 3 or less oocytes following standard IVF stimulation; and
- An abnormal ovarian reserve test (ORT).
Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ovarian reserve test.
Patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. These patients are defined as 'expected poor responder'.
RISK FACTORS FOR POOR OVARIAN RESPONSE
POR in younger women:
In addition to advanced age and reduced ovarian reserve, there have been found to be other risk factors that may predict a poor response to ovarian stimulation in younger women. The reasons for encountering POR in younger women include:
- Single ovary
- previous ovarian cystectomy
- chronic smoking
- unexplained infertility
- Previous chemotherapy and/or radiotherapy treatment.
- Auto-immune response
- Genetic risk factors such as family history of premature menopause, X chromosome derangements and fragile X mental retardation 1 (FMR1) pre-mutation.
Incidence of POR
A study conducted by the Jones Institute from 1995 through 2010 involving a total of 5,289 transferred cycles revealed that the low responders constitute a very large proportion of our patient population. In fact, the study speculates about 47% of cycles performed during the last decade were low responders.
- Poor responders represent more than a third of women undergoing assisted reproduction.
- The incidence of poor ovarian response (POR) following ovarian stimulation varies worldwide between 5.6 and 35.1%
- 40% of women above the age of 35 are Poor Ovarian Responders
- 10% of women undergoing gonadotropin stimulations are Poor Ovarian Responders
CHALLENGES OF POOR RESPONDERS
Women with poor response to IVF stimulation frequently run the risk of cycle cancellation. This is frequently frustrating to patients as there is considerable physical, mental and financial strain associated with IVF.
It has been reported that treatment cancelation owing to poor ovarian response is a significant problem seen in 12-30% of all stimulated cycles (Al-Azemi et al., 2011).
Due to few oocytes being recovered, overall pregnancy rates in these women are far lower than normal responders.
Another problem frequently encountered is the higher rates of miscarriage even if pregnancy were to occur.
Decline in primordial follicle number with ageing has been linked to an equivalent decline in oocyte number and quality which is a major reason for poor ovarian response. Poor Quality oocytes translates to poor embryo quality which impacts the treatment outcome
All of the above contribute to a very low Live Birth RATE in this population.
Treatment strategies in the poor responder
Since IVF success is dependent on the oocyte yield, treatment aims at improving the pool of the follicles that can be recruited in the IVF cycle. This means that treatment frequently begins about 2 months prior to start of IVF, since this group of follicles will be available at the pre-antral stage. Once the follicles reach the antral follicle stage, they are less likely to respond. These pre-treatment strategies include use of androgens like testosterone and DHEA supplements.
Poor responders can also benefit from high dose gonadotropins. However, very high doses of >300 IU are unlikely to be beneficial and should be avoided.
The long protocol remains one of the treatments of choice for the poor responder. Reducing the dose of the agonist at the start of the gonadotropin can improve the overall success.
The antagonist protocol is also one of the treatments of choice as there is lower gonadotropin consumption and shorter duration of stimulation with comparable results.
The short or microdose flare protocol can also be applied for the poor responder. Preteatment with OCP’s is advisable when using this protocol.
The double stimulation protocol involves running two IVF stimulations in one menstrual cycle. This leads to recruitment of follicles from the follicular and luteal phase both.
Egg accumulation and embryo pooling is another method by which women may improve their pregnancy rates after running multiple IVF cycle with subsequent bab=nking of embryos and transfer of an adequate number of good quality embryos.
Last, but not least, one critical component of treatment includes history-taking and investigations. One a woman is diagnosed as a poor responder, it is imperative to find the cause. Several times, a wrong diagnosis, improper drug administration, selection of the wrong protocol, suboptimal drug storage and obesity can all contribute to an inadequate response to IVF. These should always be considered and managed accordingly.
Conclusion
Women with poor response to IVF are an increasing group of patients who need IVF. They are a challenge to treat but with the correct assessment and right protocol can have good success with IVF especially those who are younger. They should be thoroughly counselled and risks and success explained. Newer research will help us in optimising the treatment options for this group of women.
References
- Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L, et al. ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria.
- Johnny s younis,moshe ben ami, izhar ben-sholmo. The Bologna criteria for poor ovarian response: a contemporary critical appraisal
- van hoof mh, alberda at, huisman gj, zeilmaker gh, leerentveld ra. Doubling the HMG dose in course of IVF in the low responder
- olivennes f, rhighini c, fanchin r, torissi c, hazout a, glissant m, Fernandez h, frydman f. A protocol using low dose of gonadotropin-releasing hormone agonist might be the best protocol for patients with high FSH
- kim ch, howles cm, lee ha. The effect of transdermal testosterone gel preteatment on COS and IVF outcome in low responders.
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