Monitoring of Treatment
Ovulation induction is based on the administration of gonadotropins in order to enhance fertility. Daily administration of the drug causes a supra-physiological increase in serum follicle-stimulating hormone (FSH) that leads to the recruitment of a larger cohort of follicles, further causes their growth and development, and ultimately, triggers the final stage of ovulation. Occasionally, the stimulation process is rather aggressive, leading to the development of a large number of assorted-sized follicles in order to achieve as many mature oocytes as possible in one stimulated cycle. This type of treatment has certain detrimental consequences, like: Severe Ovarian Hyperstimulation Syndrome (OHSS), and torsion of the ovary, which may transpire mainly if the patient is pregnant.
The monitoring process is intended to enable the physician to:
1. Choose the most suitable protocol, obtain the best possible outcome, and endeavor to avoid complications
2. Add information to the common pool, which increases our knowledge and understanding of human reproduction
3. Complete therapy
These objectives raise the question of how frequent monitoring should be, and which tools are required to provide a safe treatment cycle.
Basic monitoring procedures are performed by repetitive vaginal ultrasound scans to measure the number of follicles and follicular diameters, as well as to observe endometrial thickness. It is generally agreed that a mature follicle reaches approximately 18 mm in diameter, and endometrial thickness between 7 and 14 mm, by measuring the two lines of the endometrium in a sagittal dimension of the uterus. With regard to serum estrogen concentration, the value should correlate with the size and number of follicles. There are no absolute values for a monitoring stage. It is acceptable that when pituitary down-regulation is examined, the estrogen levels are usually <70 pg/ml or 200 pmol/l.
When we consider the most suitable monitoring process for the individual, we should do so by abiding by the following points:
1. Increase patient comfort by simplifying treatment protocols (i.e., reducing time commitments)
2. Evaluate whether the dose of gonadotropin administered is optimal
3. Optimize the time of human chorionic gonadotropin (hCG) administration
4. Avoid development of OHSS
5. Take advantage of significant improvements that have been achieved in embryology and laboratory practice
7. Address economic considerations.
The purpose of this short chapter is to observe the monitoring system, and endeavor to define a way in which it will lead to safe, cost-effective and well-tolerated procedures.
Monitoring as a whole cannot prevent complications, but it can direct us to the required point. In ART cycles, the goal is to retrieve mature oocytes, and this goal can not be reached by measuring estrogen only, since the maturity of the oocyte is closely associated to the size of the follicle, a parameter which can accurately be measured by ultrasound. In addition to the size of the follicles, it has been shown that the best bioassay for serum estrogen concentration, and also a major factor in the implantation process is endometrial thickness and its ultrasonographic texture, a parameter which, again, can adequately be measured by ultrasound.
There are two major approaches to monitoring. The use of hormonal blood levels, mainly measuring estradiol (E2) and vaginal ultrasound, or using mainly vaginal ultrasound, and only in some cases where there is a strong suspicion of the development of OHSS, extra serum E2 concentration is added.
Based on the above, the question is whether by performing repeated ultrasound scans, safe monitoring can be executed. In response, Wiessman and colleagues, and Shoham and colleagues were able to demonstrate that ultrasound can adequately monitor the process of down-regulation, follicular and endometrial development, and timely administration of hCG, with no decrease in overall pregnancy rates, and no increase in the OHSS rate. This was supported by Barash and colleagues, who concluded their study with the statement that “pituitary down-regulation can be predicted with a high degree of accuracy by ultrasonographic measurement of endometrial thickness”. Thus, routine testing for serum E2 concentration may be safely omitted.
One of the important issues in the monitoring process is whether hCG can safely be administered. and hence will not cause the patient to be at a higher risk for OHSS. In order to provide a solution for this question, we should first ask ourselves whether there is an upper limit to serum estrogen concentration above which we would withhold hCG administration, and cancel the cycle. In an extensive search of the literature it was found that only a minimal number of physicians would cancel a cycle due to a high level of estrogen ( >25,000 pmol/l). Among the selected preventive measures, coasting is the most popular choice, followed by the use of i.v. albumin or hydroxyethyl starch solution and cryopreservation of all embryos. Basically, these safety measures are being taken following the ultrasonographic observation of high-density, multifollicular ovaries in patients with polycystic ovarian disease (PCOD), or if more than 30 eggs are retrieved. In such extreme cases, where coasting would probably be the preferable method for prevention of OHSS, a clear justification exists for adding serum estrogen measurements to the monitoring process.
The other significant issue is the time of hCG administration. Should it depend on serum E2 concentrations? Is it important to schedule the time of administration in a very precise manner in relation to estrogen secretion? In an elegant study, Tan and colleagues sought to address this issue. They found that there were no significant differences in the fertilization and cleavage rates, number of embryos frozen, or in pregnancy rates per initiated cycle and per embryo transfer (ET) when the hCG was given on the day that the mean diameter of the leading follicle reached 18 mm, or 1 or 2 days after this specific day. Therefore, it was concluded that there is no significant advantage in the precise timing of hCG administration after pituitary desensitization with a gonadotropin-releasing hormone (GnRH)-agonist.