(1)
Bordeaux, France
In a spontaneously ovulating patient, the classic stimulation protocol can be used for several purposes:
A monofollicular stimulation that is intended to mimic closely the normal physiologic cycle. It is mandatory to begin with this protocol in ovulating younger patients under age 35, those with a low BMI, in patients who have been infertile for less than 3 years, and also in preparation for an intrauterine insemination (IUI) in cases of infertility of cervical origin or when using donor sperm.
A bifollicular stimulation of course includes the risk for multiple pregnancy. While the possibility of a twin pregnancy may usually be acceptable in a couple that has been infertile for several years, any multiple pregnancy can become a hazardous situation with an uncertain prognosis. This sort of risk should only be undertaken when one anticipates a clear benefit from having an extra oocyte, whether for intercourse or insemination, and to compensate for certain fertility challenges such as an altered ovarian reserve, in a patient of advanced age or with a structural pelvic abnormality (e.g., a single fallopian tube, or mild endometriosis), or in case of a suboptimal sperm quality, or with an idiopathic infertility.
A paucifollicular stimulation. Ovulation in the presence or three or more mature follicles is too great a risk to be undertaken, except possibly in a very select population of patients over 40 years of age, who have been fully informed of potential risks, and only after several unsuccessful bifollicular stimulation cycles.
10.1 Monofollicular Stimulation
10.1.1 Indications in a Spontaneously Ovulating Woman
Mild ovulatory disorders (dysovulation), which typically involve a premature or delayed follicular maturation (dysmaturation), cervical mucus insufficiency, luteal phase deficiencies secondary to an ovulatory dysfunction, or an inadequate endogenous gonadotropin surge. Stimulation may also be indicated for a patient who appears to be ovulating normally but simply does not conceive. Adding FSH increases estradiol secretion and in turn optimizes the cervical mucus and endometrial development. hCG administration then ensures adequate luteinization and supports the early luteal phase.
With programmed intercourse, in the case of spontaneous inadequate cervical mucus but with a good post-coital test on estradiol treatment.
In preparation for an intrauterine insemination, in one of several situations:
When using donor insemination in young patients, without other recognized factors, and who failed to conceive after 2 or 3 attempts with spontaneous ovulation
In cases of infertility suspected to be due to cervical factors, or having a negative post-coital test, either as first line treatment or in patients without other recognized subfertility factors who have failed to conceive after 2 or 3 attempts with classic stimulation
In situations of oligo-astheno-teratospermia with a recovery of at least 1 million motile spermatozoa
After 4–6 failed classic stimulation cycles with programmed intercourse, prior to moving toward trials of IVF
In spontaneously ovulating women, even those ovulating inadequately, the aim of the stimulation is to correct a pre-existing ovulatory process. These patients do have pulsatile gonadotropin secretion and an intact feedback interaction between the follicle and the hypothalamic-pituitary axis. The addition of exogenous gonadotropins merely adjusts or stabilizes an already functioning process to a more satisfactory manner. This is the simplest type of stimulation.
10.1.2 Choosing a Gonadotropin
In a patient who spontaneously ovulates, endogenous LH secretion is presumably sufficient, thus the stimulation can be conducted with FSH only. Addition of LH does not provide any specific benefit unless plasma sampling does reveal a possible insufficiency. Any of the preparations of FSH or FSH + LH may be administered, with the caution that reconstituted lyophilized urinary extracts are more difficult to divide with accuracy and much may be wasted.
10.1.3 Choosing a Protocol
Because the treatment objective is to sustain development of a follicle that has already been selected, the stimulation should not begin earlier than the sixth or seventh cycle day, when this selection has just occurred. It is important to administer gonadotropin after the FSH window has closed, to support growth of the sole dominant follicle and not others. In case of an early follicular dysmaturation, treatment should begin earlier, on cycle day 5. The step-up standard protocol is perfectly designed for this purpose, and should be the first-line strategy for adequate stimulation in most patients. Incremental increases of gonadotropin dosage may be adjusted up to less than 100 % of the initial dose. Presence of multifollicular ovaries may lead to decreasing the starting dose, or to choosing a step-up low-dose protocol that should be considered anyway if the standard step-up treatment has resulted in an excessive response.
10.1.4 Doses of FSH
The starting dose should remain low, e.g., 50–75 IU daily. This may prove insufficient in patients with a higher BMI or in those older than their late 30s. But one cannot be certain. It is easier to increase an insufficient dose than to manage an excessive dose. Furthermore, higher doses might support growth of secondary follicles during the recruitment phase, and result in a pauci- or multifollicular cycle. Careful observation of the ovarian response during the first stimulation cycle will of course help manage a subsequent cycle.
10.1.5 Duration of Stimulation
The initial period of stimulation lasts 5–7 days. Five days should be sufficient to balance exogenously administered gonadotropins with endogenous pituitary secretion that should together provoke a detectable effect on follicular growth. Seven days’ administration could delay the initial monitoring to cycle day 13–14, which may be too late. The first monitoring evaluation should ideally be conducted on the 11th or 12th cycle day. A second evaluation might be indicated after 2–4 additional days of treatment, depending upon results from ultrasound and hormone measures.
10.1.6 Expected Outcomes
The initial monitoring will most likely show one of the following (Table 10.1):
Table 10.1
Managing the standard step-up protocol for a mono-follicular stimulation; possible scenarios after administration of 50–75 IU FSH for 5 days (see StimXpert)
A single mature follicle with a mean diameter >16 mm, plasma estradiol <350 pg/ml, and the absence of other follicles >12 mm in diameter. In this situation, hCG may be administered, with an insignificant risk for multiple pregnancy. If the mature follicle’s mean diameter is borderline (15–16 mm), ovulation may be postponed until after one more day of FSH administration, without need for another monitoring visit.
One follicle with a mean diameter >16 mm, together with secondary 13–15 mm follicles, and an estradiol level under 800 pg/ml. In this case the stimulation cycle has become paucifollicular. Administration of hCG may result in a multiple pregnancy, and this possibility should be discussed with the patient. The risk may be significantly reduced, although not totally eliminated, by triggering ovulation with a GnRH agonist. If it is decided to stop the stimulation cycle without triggering ovulation, contraceptive measures should be undertaken because spontaneous ovulation may nevertheless occur.
Several follicles >16 mm diameter. Administration of hCG brings a high risk for multiple pregnancy in this situation. It may also provoke an early ovarian hyperstimulation when numerous secondary follicles are present and/or plasma estradiol exceeds 800 pg/ml. hCG must not be administered in this situation, and contraceptive measures are strongly indicated. Triggering ovulation with a GnRH agonist in order to reduce the risk of hyperstimulation and multiple pregnancy may be considered, but it still may not prevent a late hyperstimulation.
The dominant follicle is <14 mm diameter. FSH administration must continue with another evaluation made 2 or 3 days later, depending on the size of the follicle, which may grow 1.5–3 mm a day. The continued dose level of FSH should be reevaluated according to the number of growing follicles and the observed estradiol level:
Maintain the same dosage when 150 < E2 < 250 pg/ml
Reduce the dosage when E2 > 250 pg/ml or when several other follicles are growing, so that only the most sensitive one continues to develop
Increase the FSH dose when E2 <100 pg/ml
The optimal time for a single intercourse would be the day after hCG or GnRH agonist administration (shortly before ovulation) so that the spermatozoa have already reached the fecundation site. Intercourse on the same day of hCG, or 2 days later, may also be effective.
In this population of spontaneously ovulating patients, a single monitoring control is sufficient in about half of the cycles; a second evaluation becomes necessary in an additional 35 %. Three or more evaluations will be required in the remaining 15 % of patients, before the moment of triggering.
The criterion of triggering ovulation in the presence of a single follicle ≥16 mm and no other ones >12 mm would seem not to be entirely adequate because, even when strictly adhered to, a twin pregnancy results 5–10 % of the time. Except in situations when only one ovary is clearly visualized with ultrasound, there are two complementary explanations for this paradox:
Secondary follicles: 15–25 % of multiple pregnancies result when there is more than one follicle between 11 and 15 mm diameter at the time hCG is administered [1]. It is thus mandatory to take all of the smaller follicles into careful account. A single follicle of only 12 mm diameter may produce a 7.1 % pregnancy rate [2]. On the other hand, the pregnancy has every chance to remain single when no follicle aside from the mature one is >11 mm.
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