Female fertility declines gradually with age, starting at age 30 and declining slowly until age 40, after which the decline accelerates to almost zero by age 40 to 50. ART treatment pregnancy and live birth rates are closely related to a woman’s age, with pregnancy rates declining sharply with ART treatment in patients over 35 years of age and essentially disappearing by age 46. Also the miscarriage rate increases with the age of the mother.
Advanced infertility in women is a major challenge for ART treatment. The incidence of aneuploidy increases markedly in advanced maternal age and is a major cause of decreased embryonic development. pregnancy and live birth rates decline markedly in patients after the age of 35, and successful treatment of these patients is a major challenge for ART. actively exploring strategies to improve outcomes in infertile women of advanced age is an important topic to be studied.
Ovarian hyporesponsiveness was first proposed by Garcia in 1983, mainly due to poor ovarian response to conventional Gn stimulation; peak E2 <300 pg/ml; few follicles, few egg production, few fertilized eggs; few embryos available for transfer; high Gn dosage and long duration; high cycle cancellation rate; and low pregnancy rate. Ovarian hyporesponsiveness is the primary manifestation of ovarian aging and its incidence ranges from 9% to 24% of the entire IVF treatment cycle.
Diagnosis of ovarian hyporesponsiveness
Diagnostic criteria for ovarian hyporesponsiveness: two of the following three items can be diagnosed
1, advanced age (≥40 years) or any risk factors for POF.
2, history of previous POF with ≤3 eggs obtained with conventional stimulation regimen (Gn150/day or more).
3. Abnormal ovarian reserve function test with 5-7 AFC or AMH 0.5-1.1ng/ml.
The diagnosis of ovarian hyporesponsiveness can be made by having two of the above three items. In addition, patients who are not of advanced age or with normal ovarian reserve function tests and who have two POFs after maximal stimulation can also be defined as patients with ovarian hyporesponsiveness.
Prediction of ovarian hyporesponsiveness
There is no accurate method for predicting ovarian hyporesponsiveness, but it is usually mostly predicted by the assessment of ovarian reserve.
1. Age: As we age, the number as well as the quality of eggs decreases. However, the age of the ovaries does not always correspond to the actual age.
2. ovarian characteristics assessed by ultrasound, which encompasses.
(1) Basal AFC: 2-10 mm sinus follicle number <5-7, small cycle variation, practical, sensitive, and specific.
(2) Mean ovarian diameter (MOD): mean of two mutually perpendicular planes of maximum diameter <20 mm.
(3) Ovarian volume less than 3cm.
3. According to early follicular hormone levels.
(1) Basal FSH: >10~15 IU/L. FSH/LH: >2.5~3.0, cycle may fluctuate, single elevation is meaningful.
(2) Basal E2: normal ≤ 184 pmol/L, ≥ 294 pmol/L (100 pg/ml) suggests decreased ovarian reserve. The decrease in sinus follicles secreting inhibin B, which cannot inhibit FSH, leads to early follicular phase follicle development, which may not be accompanied by elevated FSH and appears earlier than elevated FSH.
4. Inhibin B.
Sinus follicular granulosa cells secrete <45ng/L.
5, Anti-mullerian hormone AMH.
Secreted by anterior and small sinus follicles without cycle changes. Generally, age, basal FSH, basal AFC and ovarian volume are used to predict ovarian hyporesponsiveness, which is more effective, simpler and more economical, although AMH is used with higher accuracy. If necessary, a combination of multidirectional indicators can be used for prediction. When several tests are unreliable, further testing can be done using ovarian stimulation tests.
Countermeasures for ovarian hyporesponsiveness in older women
1. High dose gonadotropin (Gn)
Increasing the starting dose of Gn is a widely used routine regimen for patients with ovarian hyporesponsiveness. One is that patients with poor response to the conventional dose (150-225 IU of FSH) may produce more follicles if increased to 300-450 IU or even 600 IU per day. Further, by increasing ovarian response may increase the number of eggs obtained, the number of embryos and ultimately the pregnancy and live birth rates.
Patients with low predicted ovarian reserve or low ovarian response in previous cycles before treatment with high-dose Gn can be given an initial high dose of Gn (300-450 IU/dFSH) to maximize the production of mature oocytes. When the Gn dose increases to >450 IU/d, it is not clinically relevant.
2. GnRH agonist regimen
GnRH-a is the main method of ART ovulation promotion. Clinical studies have shown that the use of GnRH-a decreases the cycle cancellation rate, increases the number of eggs obtained, and improves clinical pregnancy per stimulation cycle and per transplantation cycle.
Ovarian cysts are a common complication of the long GnRH-a regimen, and the formation of ovarian cysts is symbolic in patients with low ovarian response and can be a reliable sign of poor ovarian response and low pregnancy in that cycle. The higher the serum progesterone level at the start of GnRH-a injection, the lower the incidence of ovarian cysts. Progesterone pretreatment is effective in reducing the formation of ovarian cysts.
3. GnRH antagonist regimen
GnRH antagonists competitively block GnRH receptors in the pituitary gland, producing an immediate dose-dependent inhibition of Gn release and a significant reduction in LH levels within 6 h of dosing.GnRH antagonists can be injected in the late follicular phase to suppress the LH peak, thus avoiding inhibition of early follicular recruitment.
GnRH antagonists avoid the initial LH excitation effect compared to GnRH agonists, shorten the total treatment time, reduce the risk of ovarian hyperstimulation (OHSS), and have fewer menopausal side effects.
4. Natural cycle and modified natural cycle regimens
The natural cycle regimen can be changed for patients who fail with poor response. When natural cycles have high cancellation rates due to premature LH peaks and early ovulation, the addition of GnRH antagonists and exogenous Gn in the late follicular phase can improve the efficacy of IVF cycles, and this regimen is called “modified natural cycle” (MNC).
Microstimulation regimens: gonadotropin stimulation regimens that are lower than conventional doses and or shorter in duration with GnRH antagonists. Oral preparations are used alone or in combination with gonadotropins and GnRH antagonists.
Advantages of microstimulation regimens: reduced Gn dosage and IVF costs; shorter treatment duration; reduced complications and improved patient compliance; reduced financial burden on patients.
5.Endocrine regulation
Supplementation with DHEA, androgens are involved in the recruitment of early follicles and increase the number of small sinus follicles. Generally, the level of androgens decreases gradually with age, and supplementation of androgens is beneficial to improve the growth of follicles.
6.Other interventions
Other interventions such as: low-dose aspirin intervention: aneuploidy screening (PGS); assisted hatching, etc., do not yet have sufficient evidence to describe their post-intervention effects.
Summary
Women entering fertility decline and requiring ART treatment represent the greatest challenge to ART. Typically, low ovarian response is common in women of advanced age, which is directly related to reduced ovarian reserve.