According to the latest statistics in 2011, ovarian hyporesponsiveness occurs in approximately 9%-24% of people during assisted reproduction ovulation promotion. This group of patients has a low number of growing follicles, insufficient number of eggs obtained, few embryos available for transfer, low clinical pregnancy rate, and the criteria for diagnosis and treatment are currently a difficult area of concern in the field of reproduction.
In 2011, the European Society of Human Embryology and Reproduction published the Bologna Consensus on POR, which is currently accepted by the majority of international studies on ovarian hyporesponsiveness.
The new version of the Consensus summarizes the three aspects of diagnostic criteria, etiology, and treatment strategies, and seeks to reflect the latest and most important advances in POR diagnosis and treatment research in recent years, by standardizing treatment criteria in order to facilitate academic exchange and summarization. Therefore, the following is the author’s personal opinion on the core recommendations reached in this latest POR Consensus, which is organized and interpreted as follows.
1.Diagnosis of POR
According to the Bologna Consensus, POR can be diagnosed by meeting at least 2 of the following 3 criteria.
(1) Advanced age (≥40 years) or the presence of other risk factors for poor ovarian response.
(2) Low ovarian response in the previous IVF cycle, with ≤3 eggs obtained with the conventional protocol.
(3) Decreased ovarian reserve (sinus follicle count AFC <5-7 or basal anti-Müllerian hormone AMH <0.5-1.1 ng/ml). POR can also be diagnosed if age or ovarian reserve tests are normal and the patient still presents with POR despite the application of a maximized ovarian stimulation regimen for two consecutive cycles. The new version of the Consensus also makes the additional statement that in patients aged ≥40 years with abnormal ovarian reserve function tests, i.e., abnormal AFC or/and AMH, POR should be diagnosed as expected (suspected) before an IVF cycle is performed.
Diagnostic criteria commonly used internationally before 2010.
(1) Use of a standard ovarian stimulation protocol in the previous assisted conception: <3-5 mature follicles (≥16 mm in diameter) on the day of HCG injection or <3-5 eggs obtained on the day of egg retrieval; or <500 pg/ml of blood estradiol (e:) prior to concomitant ovulation;< span="">
(2) Average daily gonadotropin (Gn) dosage >300 IU during ovarian stimulation cycle; or standard dose of FSH for ≥12 d
(3) History of failure of standard ovarian stimulation regimen or history of cancelled ovarian stimulation cycles.
The diagnosis of ovarian hyporesponsiveness can be made in those who present with the above. The previous diagnostic criteria focused on the number of eggs obtained or Gn dosage during a routine IVF ovulation cycle. If POR is diagnosed due to high Gn dosage for a long duration, but this group of patients can still obtain the desired number of eggs obtained, the number of available embryos, and the desired pregnancy rate, the Gn dosage and duration alone do not affect their clinical pregnancy outcome, so this group of patients should no longer be considered POR patients. The new Consensus adopts the 2011 Bologna criteria and removes the influence of Gn dosage and medication duration on the diagnosis, which is scientifically significant. The new version of the Consensus also considers that the most important assessment of the Bologna criteria is the low ovarian response during the stimulation cycle, and that in patients aged ≥40 years with abnormal ovarian reserve function tests, i.e., abnormal AFC or/and AMH, before an IVF cycle, the diagnosis should be expected (suspected) POR.
Low ovarian reserve function is also an important indicator for the diagnosis and prediction of POR occurrence. The following indicators are currently meaningful for measuring ORT: basal FSH, AFC, inhibin B, AMH, ovarian volume, and ovarian stimulation test. The new version of the Consensus recommends the value of AMH (<0.5-1.1ng>10U/L).
2. Etiology of ovarian hyporesponsiveness
The new version of the Consensus states that the current etiology of POR is as follows.
(1) Age: It is the most important factor influencing reactivity, and the incidence of POR in women older than 40 years of age undergoing IVF assisted conception exceeds 50%.
(2) Genetic and immunological factors: (i) chromosomal aberrations; (ii) cellular gonadotropin receptor defects and gene mutations; (iii) the presence of anti-hyaline antibodies in some patients; (iv) susceptibility gene polymorphisms; (v) congenital enzyme deficiencies.
(3) Acquired factors: ovarian surgery, autoimmune diseases, pelvic infections, chemotherapy and pelvic radiotherapy.
(4) Body mass index (BMI): presumably decreasing fertility with increasing weight mass.
(5) Inappropriate use of previous ovulation promotion drugs.
(6) Environmental factors: (i) long-term exposure to harmful substances; (ii) radiation; (iii) poor living habits.
(7) Unknown causes. Some patients with normal basal FSH level and E2 level, and normal ovarian reserve function, but with ovarian hyporesponsiveness during ovulation promotion, also known as unanticipated ovarian hyporesponsiveness.
3. Treatment strategies
3.1 Conventional ovulation promotion protocol for IVF
The new Consensus states that the conventional IVF regimen has no significant effect on the treatment of POR, but it is worthwhile to adjust the regimen for each individual. In patients with POR who have a history of IVF ovulation, the medical history and previous cycle’s ovulation regimen should be reviewed, taking care to exclude pseudo-POR, such as slow response or low starting Gn (high BMI). The new consensus recommends that adding LH in the early stage of follicular recruitment can improve egg maturation and fertilization rate, thus increasing the rate of available embryos; adding exogenous LH in the late stage of follicular growth is beneficial to follicular development; and increasing the Gn dose from the standard 150-300 IU/day to 450-600 IU/day can be tried as a way to improve ovarian response and increase the number of eggs gained, but its clinical However, the clinical efficacy of this treatment needs to be further analyzed.
3.2 Non-traditional ovulation protocols
The new Consensus recommends that non-traditional ovulation regimens, such as microstimulation, natural cycling, and luteal phase ovulation, be considered for POR patients with a history of IVF ovulation. Because hyperovulation may not be effective in these patients and even lead to a significant decrease in ovarian function, increasing the chance of aneuploidy embryos and worse final outcome, these regimens should be applied with monitoring of follicular development and keeping an eye on the changes of sex hormones LH, E2 and P (especially E2) to decide whether and when to inject GnRHa or HCG trigger and timing of egg retrieval. In case of thin endometrium due to microstimulation protocol or other causes of thin endometrium and missed “transfer window”, embryos should be frozen as much as possible (by vitrification) and later thawed for transfer after taking measures to adjust the endometrium for better results.
3.3 Common pretreatment methods for POR patients
The new Consensus suggests that the current growth hormone and androgen pretreatment may improve ovarian responsiveness and embryo quality and increase pregnancy and birth rates.
(1) Growth hormone: 4-24 IU every other day 1-2 months or 12-14 days before Gn initiation until Gn day; after Gn initiation change to 1-5 IU daily and stop after 5-7 days. Addition of GH synergistically with Gn in POR patients increases LH receptor levels on granulosa cells and stimulates ovarian aromatase activity, thereby improving ovarian responsiveness to Gn, promoting follicular recruitment in POR patients, and increasing endometrial tolerance in POR, which facilitates embryo implantation.
(2) Androgens: The moderate accumulation of androgens in the follicular microenvironment promotes the proliferation of granulosa cells, increases the number of pre-sinus and sinus follicles, and stimulates the growth of early follicles. Elevated intraovarian androgen concentrations promote granulosa cell FSH receptor expression. Treatment includes DHEA, transdermal administration of testosterone, addition of aromatase inhibitors, addition of LH, addition of hCG, etc.
(3) Estrogen: oral supplementation with Glaxo 2 mg, bid, starting 10 d after the LH peak or on day 21 of the previous cycle until day 3 of menstruation, or until the day of hCG injection. Oral estrogen in the luteal phase of the previous cycle suppresses prematurely elevated ascending FSH, inhibits premature follicle recruitment in the luteal phase, and promotes synchronized follicle growth, while exogenous estrogen therapy inhibits circulating FSH, upregulates granulosa cell FSH receptors, and increases granulosa cell sensitivity to FSH.
(4) Oral contraceptives: contraceptives improve the synchronization of follicle development in the early follicular phase. Also studies have shown that patients with POR pretreated with OC using an inhibitor regimen have better ovarian responsiveness than those without OC. but OC pretreatment does not improve pregnancy rates.
4. Traditional Chinese medicine treatment for POR
”Ovarian hyporesponsiveness” is a modern medical name for a disease that is not recorded in ancient Chinese medical texts. According to its clinical symptoms, it is classified as “infertility”, “irregular menstruation”, “symptoms before and after menstruation”, “amenorrhea”, and “blood loss” in TCM. “amenorrhea”, and “blood withering”.
4.1 Chinese medicine
The treatment principle is to tonify the kidney and nourish the blood, invigorate blood circulation and remove blood stasis as well as de-stasis the liver and regulate qi.
Kidney tonifying herbs with superovulation protocol can significantly reduce Gn dosage, improve ovarian responsiveness, increase oocyte quantity, improve egg quality and increase pregnancy rate. The effector mechanism of the intervention of the Kidney tonifying and blood activation method on low ovarian reserve function is to regulate reproductive hormones, inhibit ovarian granulosa cell apoptosis and promote ovarian angiogenesis.
4.2 Acupuncture
There were three main groups of selected acupuncture points. Group 1, bilateral uterine points and Sanyinjiao points; Group 2, bilateral Tianshu points, Guangyuan points and Zhongji points; Group 3, bilateral kidney acupoints, Life Gate points and Waist Yangguan points. The three groups of acupoints were done three times a day, except during menstruation, in the morning, midday and evening, with a frequency of 2HZ selected and an electrical stimulation intensity of 20-30mA, and the treatment cycle was 1-3 menstrual cycles. Clinical data proved that the number of sinus follicles can be increased by giving transcutaneous acupoint electrical stimulation before the cycle, which can significantly improve the quality of embryos, fertilization rate and the rate of high quality embryos. Chinese herbal medicine with acupuncture can complement each other and provide better therapeutic effects.
4.3 External Chinese medicine treatment
The main treatments are umbilical moxibustion, doujian moxibustion and acupuncture and bloodletting therapy.
5. Summary
In recent years, a large number of multicenter studies on POR have shown that the clinical diagnosis and treatment of POR has made great progress, especially the release of a consensus that follows high-level evidence-based medicine, which plays an important role in standardizing the clinical treatment of POR and unifying the evaluation of clinical studies. However, the clinical outcome of POR patients is still unsatisfactory, and it is recommended that patients with risk factors for POR and those with a definite diagnosis of POR should be accurately assessed for ovarian reserve function and then pre-treated with ovulation in order to improve the clinical pregnancy outcome of POR patients. The publication of the 2015 edition of the Expert Consensus on Ovarian Hyporesponsiveness of the Chinese Society of Reproductive Medicine is believed to play a good role in improving the treatment of POR patients in China.