Ovulation Stimulation with Gonadotropins, 1st ed. 2015

10. Stimulation in the Ovulating Patient

Jean-Claude Emperaire1

(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)

A307741_1_En_10_Tab1_HTML.gif

This table illustrates the types of decisions that should be made with various combinations of follicular response (FD mm, top row) and plasma estradiol (E2 pg/ml, left side column)

Within each box, The Circle Number indicates the optimal number of days to continue stimulation, if triggering criteria have not yet been met after 5 days of stimulation. The Circle Color indicates the suggested percentage change for FSH dosing in relation to the previous (starting) dose. A White Circle with S indicates the cycle should be stopped or abandoned with no further stimulation. Boxes with HCG identify the follicle + estrogen criteria that permit ovulation triggering. Boxes with a number in parentheses refer to 1 of 4 footnotes listed below.

When a patient is unable to come in for assessment after the indicated number of days, it remains possible to conduct the monitor one day earlier or later, possibly including a change of the FSH dose

The number of estradiol ranges has been purposely limited in order to simplify the table’s construction, and should be considered as approximate when interpretations are made. In particular, when values are close to the indicated upper or lower value of E2 within a range, the clinical decision should consider options indicated for the adjacent hormone level

Footnotes

1. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for OHSS; additional luteal support is then mandatory

2. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for multiple pregnancy; additional luteal support is then mandatory

3. Follicular growth that progresses faster than the rise of plasma estradiol levels may be related to an insufficient LH effect; in this case it is better to repeat the stimulation with an FSH preparation that includes LH

4. Caution: Risks for OHSS appear and increase when the plasma estradiol level reaches and surpasses 800 pg/ml

·               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.

·               Duration of the hCG activity: Whereas the endogenous gonadotropin surge is some 48–54 h duration, the effect of injected hCG lasts for several days. Thus a secondary follicle may continue to grow and reach sufficient maturity to ovulate during this period of time. Its growth may indeed be stimulated by the LH-like effect of hCG at the end of the follicular phase.

hCG triggering continues to be used even in the presence of well-recognized risks for multiparous pregnancy because of a “Human Factor.” For example, when two 15 mm follicles are observed on the fourth stimulation cycle, despite the utmost care to control development, or after a cycle had to be stopped for the same type of reason, or when monofollicular cycles fail to produce a pregnancy, the patient (and her clinician as well) can grow impatient.

Plasma estradiol levels are also important, and should run 150–250 pg/ml for a single mature follicle. However, smaller follicles (<11 mm) provide some estrogen secretion as well. Nevertheless, levels should remain under 800 pg/ml with a single mature follicle on a normofollicular ovary in order to avoid the early risk of OHSS.

10.1.7 Providing Luteal Support

It has never been clearly established that supplementing the post-ovulatory phase with progesterone is useful in the spontaneously ovulatory patient. Indeed a harmonious follicular development under FSH that produces a single complete follicle, then followed by an hCG trigger, can be expected to result in an adequate luteal gland providing a normal 12–14 day luteal phase. Nevertheless, caution advises one to check on both the luteal phase duration and plasma progesterone levels, which should exceed 10 ng/ml by 7–9 days post-hCG. When these criteria are not met, it is best to sustain the luteal phase with 20 mg oral retroprogesterone, 200 mg vaginal micronized progesterone, or 90 mg of 8 % vaginal progesterone gel. Treatment should start not less than 72 h after hCG administration in order not to impair the quality of cervical mucus. Clearly a much better way is to build a more adequate corpus luteum through a more efficient stimulation of granulosa cells.

10.1.7.1 If the First Stimulation Cycle Fails

It is possible to undertake another cycle without delay, if a preliminary ultrasound evaluation establishes the absence of residual transonic structures. A persistent follicle of less than 20 mm diameter may be tolerated, but it should be located with precision so that it will not be confused as a newly mature or pre-mature follicle. If a functional cyst of >20 mm is identified, it is better to postpone an FSH administration that would potentially stimulate its further development. Allow a month to pass, or alternatively administer 5 mg oral nomegestrol acetate for 20 days if the cyst is even larger. Stimulation may then be started on the next cycle providing the structure has disappeared.

The FSH dose should certainly be reevaluated with respect to the situations that occurred during the previous treatment cycle. Careful monitoring of each cycle is always mandatory because ovarian responses may vary from one cycle to another. Different responses are possible even when the same gonadotropin dose is administered to the same patient, and even when the patient has a history of regular responses during previous cycles. Monitoring remains mandatory even when the stimulation is conducted with only a few spaced out FSH injections given during the follicular phase of a spontaneously ovulating patient; this type of stimulation, often designed for the benefit of reducing monitoring constraints, is nevertheless incapable of ensuring an adequate stimulation and at the same time of avoiding all complications.

10.1.8 Number of Trials

Ideally, an efficient treatment in an infertile patient should restore the same chances for pregnancy as in a normally fertile woman of the same age. Because these chances approximate 20–25 % in normal younger women under optimal conditions, one should allow some time to set the appropriate limits. A stimulation program of this type should yield a satisfactory result within a maximum of 6 cycles, but every program is at risk of compression because of a couples’ weariness or impatience. Realistically, for couples or patients past the age of 35, the plan may be restricted to three or four cycles, when success is most likely.

10.2 Bifollicular Stimulation

In order to increase the chances for pregnancy in a spontaneously ovulating patient, it may be appropriate to consider promotion of a second mature follicle, for various reasons:

·               To compensate for another subfertility factor in addition to impaired ovulation, such as: suboptimal sperm parameters, a patient older than age 38, or presence of a pelvic abnormality, e.g., a single patent Fallopian tube or grade I–II endometriosis

·               In certain instances of idiopathic infertility in the presence of a positive post-coital test

Growth of two follicles is managed by precise FSH administration. Bringing two follicles to maturity simultaneously requires careful management between two potential pitfalls [34]:

·               Recruiting and bringing to full maturity one additional follicle without provoking a multifollicular development

·               Avoiding a twin pregnancy; that becomes a less critical risk with advancing age

Basically, it is possible to recruit an additional follicle and bring it to maturity by stretching one or both of two cardinal rules of monofollicular stimulation, namely, the moment of the cycle when stimulation is begun, and the FSH dose.

FSH administration can be started during the follicular recruitment period, i.e., earlier than the sixth day of the cycle. Building an early rise of FSH by starting on CD 3 enables plasma levels to reach the sensitivity threshold of the two most sensitive follicles, and it then supports their additional growth by disrupting the mechanisms for selection and dominance. Dosing should remain low (50–75 IU) in order to stay below the sensitivity threshold of more than two follicles.

Alternatively, FSH administration can be started a bit later, on the sixth or seventh CD, in order to delay the rise of FSH levels and “rescue” one additional follicle that was destined for atresia. In this instance a higher FSH dose (75–125 IU) should be used to provide sufficient support for development of this additional follicle by preventing the FSH window from closing. However, the enhanced dosing must not be allowed to initiate growth of any more new follicles.

These manipulations of cardinal rules were illustrated by the work of Cedrin-Durnerin, et al. [5]. With a continuous daily dose of 112 IU rFSH beginning on CD 2–3, they observed development of three to four follicles in excess of 14 mm diameter, whereas only two such follicles were recruited when the same administration was started on CD 7. This result confirmed the value of lower dose levels when beginning administration earlier in the cycle.

10.2.1 Other Suitable Protocols for a Bifollicular Stimulation

·               Administration of double-sized doses of FSH (e.g., 150 IU) on alternate days (CD 4, 6 and 8), with the initial monitoring made on CD 9

·               A combination of oral clomiphene, 50–100 mg for 5 days starting on CD 3, followed by a single dose of 75 or 150 IU FSH on CD 9, and the first monitoring control performed on CD 11

10.2.2 Practical Considerations

For the initial stimulation cycle in a patient whose response to FSH administration is still unknown, it is best to begin with conservative dosing of 50 or 75 IU if starting on CD 3–4, or 75–125 IU when starting on CD 6–7. Both may be adjusted for the patient’s age and BMI.

At the end of the fifth day of stimulation, one of four situations is likely to appear (Table 10.2):

Table 10.2

Managing the standard step-up protocol for a bi-follicular stimulation; possible scenarios after administration of 50–125 IU FSH for 5 days (see StimXpert)

A307741_1_En_10_Tab2_HTML.gif

This table illustrates the types of decisions that should be made with various combinations of follicular response (FD mm, top row) and plasma estradiol (E2 pg/ml, left side column)

Within each box, The Circle Number indicates the optimal number of days to continue stimulation, if triggering criteria have not yet been met after 5 days of stimulation. The Circle Color indicates the suggested percentage change for FSH dosing in relation to the previous (starting) dose. A White Circle with S indicates the cycle should be stopped or abandoned with no further stimulation. Boxes with HCG identify the follicle + estrogen criteria that permit ovulation triggering. Boxes with a number in parentheses refer to 1 of 5 footnotes listed below

When a patient is unable to come in for assessment after the indicated number of days, it remains possible to conduct the monitor one day earlier or later, possibly including a change of the FSH dose

The number of estradiol ranges has been purposely limited in order to simplify the table’s construction, and should be considered as approximate when interpretations are made. In particular, when values are close to the indicated upper or lower value of E2 within a range, the clinical decision should consider options indicated for the adjacent hormone level

Footnotes

1. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for OHSS; additional luteal support is then mandatory

2. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for multiple pregnancy; additional luteal support is then mandatory

3. Follicular growth that progresses faster than the rise of plasma estradiol levels may be related to an insufficient LH effect; in this case it is better to repeat the stimulation with an FSH preparation that includes LH

4. Caution: Risks for OHSS appear and increase when the plasma estradiol level reaches and surpasses 800 pg/ml

5. In this case one may decide either to trigger ovulation, with the expectation that only one ovum will be released, or to abandon the cycle in favor of beginning a new protocol designed to produce two ova

·               Two follicles >16 mm diameter are present without secondary follicles >12 mm, and estradiol is less than 800 pg/ml. The objectives for a bifollicular cycle have been met, and the hCG trigger can be safely administered.

·               More than two follicles >16 mm diameter and/or an estradiol level >800 pg/ml. In this situation administration of hCG is liable to result in a multiple pregnancy, an ovarian hyperstimulation or both. Therefore, only a GnRH agonist should be used to trigger ovulation, with the reservations previously mentioned. Otherwise, the cycle should be aborted altogether with institution of contraceptive measures.

·               Only one follicle appears that is larger than 16 mm diameter, estradiol is <500 pg/ml and there are no secondary follicles greater than 12 mm diameter. The basic objectives for a bifollicular cycle may not be reached in this case. One may choose to terminate the cycle and start over, or to continue with FSH administration together with a GnRH antagonist, in the hope of growing a second mature follicle while ovulation of the larger one is being prevented by the antagonist.

·               A single follicle is >16 mm diameter is found, secondary follicles are 13–15 mm diameter, or the one dominant follicle does not exceed 15 mm diameter, and estradiol level is below 500 pg/ml. Stimulation must continue with the next monitoring assessment taken 2–3 days later. The dose level of FSH should be reevaluated with respect to the number of growing follicles and the levels of plasma estradiol, as described earlier (Fig. 10.1):

A307741_1_En_10_Fig1_HTML.gif

Fig. 10.1

Decision tree for a bifollicular stimulation (From P. Barri [7])

·                      FSH dose should remain unchanged when estradiol is between 250 and 500 pg/ml.

·                      The dose should be reduced when estradiol is greater than 500 pg/ml or when more than two follicles are growing, so that only the most sensitive ones resume development.

·                      The dose should be increased when E2 < 250 pg/ml.

10.2.3 Complications

Complications are definitely more prone to occur in a bifollicular stimulation than with a monofollicular treatment:

·               Risk for multiple pregnancy: This risk, most often for twins, is very real even when the number of potentially fertilizable oocytes was increased simply to offset other subfertility factors within the couple, or in case of an idiopathic infertility. Beware that the couple’s attitude may change when a twin pregnancy actually results, even though they may have previously accepted the notion of this “reasonable risk.” Whereas the overall pregnancy success rate per cycle increases 30 % when two mature follicles develop, the risk for a multiple pregnancy doubles.

·               Risk for ovarian hyperstimulation: This risk for this remains low, unless the two mature follicles are accompanied by numerous smaller ones that should be evidenced as plasma estradiol rising above 800 pg/ml. For this reason, the risk is identified with greater confidence.

Criteria for aborting the cycle should be coordinated along with other specific aspects of each patient, e.g., her age, duration of infertility, number of previously unsuccessful stimulation cycles, number and size of secondary follicles in the present cycle, and estradiol levels [6].

Use of GnRH agonists is of no value for a bifollicular stimulation. On the other hand, GnRH antagonists can be useful along with a plan to delay a single intercourse or an insemination, or to continue FSH stimulation in the presence of a single mature follicle, or if a follicle has developed in an ovary where only the contralateral Fallopian tube is patent.

If a bifollicular cycle is unsuccessful, the same decision-making process applies as is used for monofollicular stimulation protocols. Decisions regarding treatment dosing and duration apply similarly.

10.3 Paucifollicular Stimulation

There are two types of paucifollicular stimulation: unexpected paucifollicular stimulation and intentional paucifollicular stimulation.

10.3.1 Unexpected Paucifollicular Stimulation

A planned mono- or bifollicular stimulation may move out of control. The choice then becomes whether or not to continue with the ovulation trigger according to the prognosis [7].

The prognosis is good for a patient under 32 years of age, or in case of an infertility of less than 3 years’ duration: it is possible to work with three follicles, if each is greater than 10 mm diameter, so long as plasma estradiol remains less than 800 pg/ml. The prognosis becomes intermediate for patients between 32 and 38 years of age, or with an infertility of 3–5 years’ duration: it may be possible to work with three follicles >14 mm, or with up to six follicles >10 mm, if estradiol continues under 1,000 pg/ml. In a patient over 38 years of age, or with infertility of more than 5 years’ duration, the prognosis is poor: it may be possible to work with a third or even a fourth mature follicle, provided the estradiol levels remain under 1,200 pg/ ml.

It is always important to set a purpose and to define safety margins in advance because the greater the number of mature follicles, the higher the pregnancy rate and also the multiple pregnancy rate. Belaisch-Allart observed that when the rate of multiple pregnancy dropped from 14.5 to 9.5 % by applying stricter cancelation criteria, the overall pregnancy rate per cycle was also halved, from 21 to 9.5 % [8].

10.3.2 Intentional Paucifollicular Stimulation

Attempts to develop three to five mature follicles can only be justified as part of a plan to compensate with quantity in the face of a poorer quality of oocyte. This typically occurs in patients over 40 years of age. One can design this type of stimulation by combining both components of the bifollicular protocol, namely to start with higher FSH doses (75–125 IU) and at an earlier point (CD 3–5). Plasma estradiol should not be allowed to rise much above 800 pg/ml, in order to avoid risk for ovarian hyperstimulation (Table 10.3). A mature follicle number in excess of 2 increases the overall pregnancy rate only slightly, but it significantly increases the risk for a multiple pregnancy [16].

Table 10.3

Managing the standard step-up protocol for a Pauci-follicular stimulation; possible scenarios after administration of 50–75 IU FSH for 5 days (see StimXpert)

A307741_1_En_10_Tab3_HTML.gif

This table illustrates the types of decisions that should be made with various combinations of follicular response (FD mm, top row) and plasma estradiol (E2 pg/ml, left side column)

Within each box, The Circle Number indicates the optimal number of days to continue stimulation, if triggering criteria have not yet been met after 5 days of stimulation. The Circle Color indicates the suggested percentage change for FSH dosing in relation to the previous (starting) dose. A White Circle with S indicates the cycle should be stopped or abandoned with no further stimulation. Boxes with HCG identify the follicle + estrogen criteria that permit ovulation triggering. Boxes with a number in parentheses refer to 1 of 5 footnotes listed below

When a patient is unable to come in for assessment after the indicated number of days, it remains possible to conduct the monitor one day earlier or later, possibly including a change of the FSH dose

The number of estradiol ranges has been purposely limited in order to simplify the table’s construction, and should be considered as approximate when interpretations are made. In particular, when values are close to the indicated upper or lower value of E2 within a range, the clinical decision should consider options indicated for the adjacent hormone level

Footnotes

1. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for OHSS; additional luteal support is then mandatory

2. Triggering with a short-acting GnRH agonist instead of hCG can significantly reduce, but will not eliminate, the risk for multiple pregnancy; additional luteal support is then mandatory

3. Follicular growth that progresses faster than the rise of plasma estradiol levels may be related to an insufficient LH effect; in this case it is better to repeat the stimulation with an FSH preparation that includes LH

4. Caution: Risks for OHSS appear and increase when the plasma estradiol level reaches and surpasses 800 pg/ml

5. In this case one may decide either to trigger ovulation, with the expectation that fewer than three ova will be released, or to abandon the cycle in favor of beginning a new protocol designed to produce three or more ova

The risks and benefits of paucifollicular stimulation should be discussed in detail with each duly informed couple. Nevertheless, although a poorer oocyte quality rapidly decreases the risks for multiple pregnancy in patients over 38 years of age, this represents just another statistical datum that does not eliminate the potential occurrence of such an unexpected, untoward result. As a matter of fact, such risks would be quite inappropriate for an initial stimulation cycle.

References

1.

Loumaye E (1995) A phase III, open, randomized multicenter study to compare the safety and efficacy of recombinant human follicle-stimulating hormone (Gonal F) administered subcutaneously with that of urinary human follicle stimulating hormone (Metrodin) given intramuscularly, to induce ovulation in WHO group II anovulatory infertile women. ARES SERONO, Internal Report

2.

Dickey RP, Taylor SN, Lu PY et al (2001) Relationship of follicle numbers and estradiol levels to multiple implantation in 3608 intrauterine insemination cycles. Fertil Steril 75:69–78CrossRef

3.

Merviel P, Cedrin-Durnerin I, Belaisch-Allart J et al (2009) Vers la grossesse monofoetale en AMP. Gynecol Obstet Fertil Hors-serie no 1:1–11CrossRef

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5.

Cedrin Durnerin I, Massin N, Galey-Fontaine J et al (2006) Timing of FSH administration for ovarian stimulation in normo-ovulatory women: comparison of an early or a mid-follicular phase initiation of a short-term treatment. Hum Reprod 21:2941–2947CrossRef

6.

Belaisch Allart J (2009) Peut-on prévenir les grossesses multiples hors FIV? Gynecol Obstet Fertil 37:6–8CrossRef

7.

Tur R, Barri PN, Coroleu B et al (2005) Use of a prediction model for high-order multiple implantation after ovarian stimulation with gonadotropins. Fertil Steril 83:116–121CrossRef

8.

Belaisch Allart J, Mayenga JM, Grefenstette I et al (2007) Insémination intra-utérine: pourquoi continuer à stimuler l’ovulation? Gynecol Obstet Fertil 35:871–876CrossRef