Ovulation Stimulation with Gonadotropins, 1st ed. 2015

11. Stimulation in the Anovulatory Patient

Jean-Claude Emperaire1

(1)

Bordeaux, France

In contrast to the patient who already ovulates spontaneously, the anovulatory patient lacks the benefit of having a cyclic pattern of endogenous gonadotropin secretion. This situation can include a number of aspects that lead to a variety of treatment strategies.

11.1 Characterizing the Anovulation

11.1.1 Clinical Symptoms

Presenting symptoms are typically characterized as menstrual cycle disorders, either as: (1) a permanent amenorrhea, because ovulation is absent, or (2) a spaniomenorrhea, or amenorrhea interspersed with sporadic menstrual bleeding associated with ovulation, or amenorrhea that is secondary to estradiol fluctuations that lead to some endometrial shedding without ovulation having occurred. These bleedings are seldom sufficient and regular enough to mimic normal menstrual cycling.

11.1.2 Etiology

The origin of ovulatory failure is rooted in pituitary FSH secretion:

·               Hypogonadotropic anovulation, of hypothalamic-pituitary origin, due to the absence or quasi-absence of FSH and LH secretion (World Health Organization Type I, WHO I)

·               Normogonadotropic anovulation, caused either by a qualitative disorder of gonadotropin secretion (WHO IIa) or secondary to an abnormal intra-ovarian folliculogenesis (WHO IIb)

·               Hypergonadotropic anovulation corresponding to a vanishing ovarian reserve (WHO III)

A preliminary etiologic evaluation of the patient should distinguish between these three different types of anovulation, and each will point the way to a therapeutic strategy. The patient workup should encompass at least:

An ultrasound evaluation made between the third and the fifth days of a menstrual bleeding, whether spontaneous or provoked by withdrawal from oral progestins, to clarify the ovarian status and also to conduct an antral follicle count that will distinguish normofollicular from multifollicular ovaries (>25) and paucifollicular (<7) ovaries.

A hormonal evaluation conducted on the same day:

·               Dynamic response of FSH and LH, after an injection of 25 μg gonadorelin (Relfact®). Serum FSH should raise 100–150 % and LH by 150–200 %, at 60 min post-injection.

·               Measures of estradiol, prolactin, TSH, and several androgens: testosterone, Δ4-androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate, and perhaps 17α-hydroxy-progesterone, depending upon the clinical situation. AMH level will usually correlate with AFC.

Because induction of ovulation in a patient whose infertility results from a simple failure to ovulate (pure anovulation) should give her the best chances for a successful pregnancy according to her age, the goal of this procedure must be monofollicular, except in an unusual circumstance.

11.2 Hypogonadotropic Anovulation (Who Type I)

Type I anovulation is characterized by the absence of secretion of both gonadotropins FSH and LH. Because the ovaries are unstimulated they remain at rest, and do not secrete steroids. Likewise, results from a progestin withdrawal test will be negative: due to absence of estrogenic stimulation of the uterine mucosa, a ten-day treatment with oral progestin has no effect (i.e., no withdrawal bleeding).

Anovulation may be considered as primary, where menses have never spontaneously occurred (e.g., with genetic abnormalities such as Kallmann De Morsier Syndrome). It can also be “primary-secondary,” where menses did spontaneously begin but then stopped after a few cycles. A secondary anovulation may occur in a woman who apparently ovulated and menstruated normally for some time, but stopped after, for example, discontinuation of oral contraceptives, treatment for a pituitary tumor, or as a component of anorexia nervosa. Often the origin of anovulation remains idiopathic.

11.2.1 Evaluation

Ultrasound examination of these patients typically reveals resting, normofollicular ovaries and a thin quasi-virtual uterine mucosa. Serum FSH and LH are typically very low or undetectable, and a GnRH stimulation test should identify the level of the central disorder. This test distinguishes between anovulation of hypothalamic origin, with FSH-LH secretion appearing under GnRH stimulation, versus a pituitary origin that shows absent gonadotropin response to GnRH. A cranial MRI is mandatory when an organic lesion cannot be ruled out.

Estradiol levels are typically very low, and other related hormone levels will be low to normal. The AMH level is typically normal, but paradoxically may be low in the presence of a normal follicular reserve [1]. A prolactin assay is important to rule out a class of hyperprolactinemic conditions that lead to hypogonadotropic anovulation. Hyperprolactinemia should be treated with dopamine agonists when it is not secondary to an identifiable pituitary tumor, or persists after surgery, and ovarian stimulation by gonadotropins should be undertaken only when the anovulation remains despite prolonged normalization of prolactin levels.

The first line treatment of hypogonadotropic anovulation is the GnRH pump. Pulses of 10–20 μg gonadorelin acetate (Lutrelef®) every 90 min should restore normal function of the hypothalamic-pituitary-ovarian axis, without risk of ovarian hyperstimulation, and with low risk for multiple pregnancy. Resorting to direct gonadotropin stimulation should be considered only in cases of known pituitary lesions, in noncompliant patients despite availability of the latest-generation remote-controlled pumps, or in the absence of detectable ovarian response after variations of a suitable GnRH dose and administration frequency.

11.2.2 Treatment Following GnRH

Although the stimulation process in hypogonadotropic patients is fairly straightforward, the challenge remains to find the FSH threshold, and then to lead the selected follicle to full maturity by continuing with gonadotropin administration.

The Gonadotropin: In this situation, stimulation with FSH and LH together becomes necessary because the condition is characterized by the endogenous absence of both hormones. Administration of FSH alone may promote some degree of follicular development in these patients, but the necessary LH-directed estrogen secretion will be insufficient or not present. In addition, cervical mucus and endometrial growth both require adequate estrogen levels. Triggering ovulation of these apparently mature follicles is not likely to result in nidation and pregnancy.

Three mixed gonadotropin preparations are available:

·               HMG, with a fixed FSH/LH ratio of one to one

·               Pergoveris®, having a fixed 2 to 1 FSH/LH ratio that is particularly well suited for this indication. However, the product is available only in vials of 150 IU, which is rather inconvenient because this dose is higher than the FSH threshold of many patients and could result in some product wastage.

·               Concomitant administration of FSH and rLH (Luveris®). This involves two daily sc injections, but it offers the possibility of adjusting the FSH/LH ratio as needed. A dose of 75 IU rLH seems sufficient to allow for harmonious follicular development in most patients. Higher LH doses are unlikely to disturb the follicular maturation in a hypogonadotropic milieu, so long as the administered FSH/LH ratio does not fall below 1.

Administration Protocol: The step-up low-dose protocol seems in theory to be the best suited for these patients. However, there is a risk for continuing several weeks of one or two daily sc injections at insufficient doses before finding the FSH threshold, although the risk for a multifollicular response is rather low in this situation. For this reason one may initiate with a standard step-up protocol and an initial 7-day stimulation period. This should provoke a good monofollicular response and ovulation in most patients. If this does not succeed initially, the experience still provides a good estimate of ovarian sensitivity to FSH when designing the next cycle that may be shifted to a second line low-dose protocol.

As with all stimulation protocols, the starting dose should be chosen with consideration of the patient’s age and BMI: 50 IU in patients under 35 years of age with a normal or low BMI, 75 IU in other cases.

In the standard step-up protocol, stimulation is conducted according to the same principles as the monofollicular stimulation of a spontaneously ovulating patient, but with an initial 7-day treatment period.

If the low-dose step up protocol is used (Table 11.1), initiate treatment between CD2 and CD5, and with a 50–75 IU dose for 7 days. If there is no detectable ovarian response, increase the daily posology by 50 % of the initial dose for another 7 days, and so on, until a dominant follicle appears with a corresponding rise in plasma estradiol. Maintain this same dose until the moment ovulation is triggered. In case of a successful first ovulation but unsuccessful pregnancy, start the next trial with a gonadotropin dose one step lower than the observed FSH threshold.

Table 11.1

Managing the low-dose step-up protocol; possible scenarios after administration of 50–75 IU FSH for 7 days (see StimXpert)

A307741_1_En_11_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 1 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 interpreted 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 increase to the degree that plasma estradiol surpasses 800 pg/ml

Tiggering Criteria: As with all monofollicular stimulation cycles, the goal is to develop a single follicle >15 mm diameter, without any secondary follicles >12 mm, and with an estradiol level <500 pg/ml. A true hypogonadotropic hypogonadism is the only example of a classical stimulation where a luteal support is sometimes needed. In many cases but not all, the continuing action of hCG administered to trigger ovulation provides adequate support for the luteal gland in the absence of pulsatile post-ovulatory LH secretion. It is therefore prudent to monitor post-ovulatory progesterone levels and the luteal phase length during the initial stimulation cycle. When luteal inadequacy is detected, support must be provided either with a progesterone preparation, starting not less than three days after hCG, or with three additional administrations of 750–1,500 IU hCG, at 3 day intervals.

Treatment Duration: In the absence of other hypofertility factors within the couple, the chances for a successful pregnancy in this situation are similar to that of ovulatory couples, through 6–8 stimulation cycles. In case of failure after this, a protocol leading to bifollicular stimulation may be proposed to younger patients for an additional 2–3 cycles before turning to assisted conception. To be sure, this overall strategy and the reasons supporting it should be clearly explained to the couple and accepted by both partners, who often tend to grow impatient after a few ovulatory trials are completed without conception.

11.2.3 Conclusion

Monofollicular stimulation in the hypogonadotropic patient must combine LH with FSH and be administered with a standard or a low-dose step-up protocol. Chances for pregnancy are certainly among the best in all infertility situations, thus a certain amount of support for perseverance is mandatory to avoid the more burdensome process of unwarranted assisted conception.

11.3 Normogonadotropic Anovulation

In these more typical situations, a significant capacity for gonadotropin secretion is present, but it remains nevertheless unable to stimulate sufficient follicular development. Often the source of the disorder lies in the CNS, through perturbations of GnRH pulsatility or of hypothalamic-pituitary-ovarian feedback mechanisms. One of the following situations may be identified:

·               Patients with a life style that includes intense physical activity.

·               Patients who have chosen diet modification in order to lose weight.

·               Patients with pseudo- (or macro-) prolactinemia where measured excessive levels of serum prolactin are actually biologically inactive congregated molecules (“big” and “big-big” prolactin). In these cases, ovulation is not restored after treatment by dopamine agonists.

·               Patients treated with psychotropic or neuroleptic drugs that act as dopamine antagonists to disinhibit prolactin secretion.

In most patients, however, the precise origin of inadequate gonadotropin secretion will remain unknown, even when a psychological/behavioral disorder is evoked. In other instances, an ovarian origin can be suspected in the form of a defective folliculogenesis and an accumulation of antral follicles that fail to mature.

These patients typically share two characteristics: (1) A positive response in the oral progestin test because basal gonadotropin secretion has stimulated some follicular estrogenic production that promotes endometrial development capable of responding to progestin administration. (2) A first line treatment of choice by clomiphene citrate (Clomid®, Pergotime®) – this drug acts as an antagonist at the estrogen receptor level, and raises endogenous gonadotropin secretion by relieving the estrogen-mediated negative feedback at the hypothalamo-pituitary level. In these circumstances, gonadotropin administration should be considered only when clomiphene stimulation fails, either because of failure to ovulate or failure to conceive after ovulation is restored.

In ovulatory failure, a starting dose of clomiphene, 50 mg daily for 5 days, may be progressively increased up to 150 mg when there is no ovarian response. A step-wise increment may be instituted as soon as consecutive cycles in order to benefit from the remaining action of clomiphene, whose half-life can range from 10 days to more than one month, depending upon the isomer considered.

In pregnancy failures, detecting ovulation through monitoring a rise of basal body temperature may be insufficient. An ultrasound examination should be conducted to assess follicular development and rupture, and to indicate when necessary the moment for hCG administration. Consecutive ovulatory cycles without achieving a pregnancy can usually attributed to a subtle anti-estrogenic effect of clomiphene on the endometrium and/or the cervical mucus. In fact the cumulative curve of pregnancy success in patients who ovulate on clomiphene is very close to that of normally ovulating women through 6–9 treatment cycles. Thus clomiphene treatment should be continued for 6 cycles, but not more because of possible risk for long term untoward effects.

Even when ovulation is restored, the estrogen antagonist-related side effects, such as hot flashes or visual disorders, can appear with intensity proportional to the clomiphene dose.

Letrozole, an aromatase inhibitor used principally in patients with breast cancer, can also stimulate ovulation by depletion of endogenous estrogen synthesis, thus increasing gonadotropin secretion. Its potential advantages over clomiphene are the absence of peripheral anti-estrogenic effects, and also a greater success with pregnancy and live birth rates in PCOS patients [2]. However, the drug is not yet authorized for this indication, principally because the potential consequences in offspring are still unknown. There are, however, some reassuring preliminary data [3].

In a situation where gonadotropin stimulation becomes necessary, ovarian appearance at ultrasound should remain the essential assessment for deciding stimulation strategies, and more so than the patient’s history, clinical signs and symptoms or the hormonal assays.

11.3.1 Stimulation in Presence of Normofollicular Ovaries

Ultrasound evaluation of patients with hypogonadotropic anovulation and normofollicular ovaries typically show a normal ovarian volume and a total count of 24 or fewer detectable follicles in the two ovaries. Hormone testing reveals low to normal basal gonadotropin levels, a normal FSH-LH response to the GnRH test, and normal levels of prolactin, AMH, TSH and androgens. Despite having some basal secretion of FSH and LH, these patients fall somewhere between hypogonadotropic hypogonadism and normally ovulating women. Plans for ovarian stimulation should be designed along the lines of treating both situations.

Clomiphene citrate is well suited for these patients, who already have some endogenous estrogen expression. If clomiphene is unsuccessful, the GnRH pump may be able to restore normal gonadotropin dynamics, although efficacy may actually be lower than in cases of complete gonadotropin absence. Administration of gonadotropins thus becomes the last resort when both clomiphene and GnRH have failed. Any of the FSH gonadotropin preparations are equally useful, because the patient has sufficient endogenous LH secretion.

The first-line protocol for gonadotropin stimulation should be the standard step-up protocol, and it should achieve success with relatively few injections and monitoring steps. In case of failure, depending upon the observed ovarian response, one may repeat the same protocol with a different starting dose or move to a step-up low-dose protocol (Table 11.1). Triggering criteria are those used for monofollicular cycles: a single follicle with a mean diameter >15 mm and without other follicles >12 mm diameter, together with an estradiol level between 150 and 350 pg/ml. Luteal support is not necessary, unless a short luteal phase defect has been noted, and/or if serum progesterone persists below 10 ng/ml. It should be possible to repeat gonadotropin stimulations for at least 6 cycles in young patients, so long as the procedure provokes a satisfactory ovulation during each cycle.

11.3.2 Stimulation in Presence of Multifollicular Ovaries

The multifollicular situation (AFC >24) encompasses many of the principal difficulties of attempting ovarian stimulation. Because of numerous risks for a rapid excessive response, more sophisticated stimulation protocols have been designed to achieve success with this situation. The syndrome is already characterized by disturbed folliculogenesis and an overabundance of follicles capable of selection, with anti-Mullerian hormone and androgens playing a significant role. While the true origin of the disorder remains essentially obscure, two distinct types can be revealed at ultrasound:

Simple” multifollicular ovaries, which are only slightly enlarged, containing numerous follicles of various sizes distributed within the whole ovarian parenchyma, and with a normal stroma (Fig. 11.1).

A307741_1_En_11_Fig1_HTML.gif

Fig. 11.1

Ultrasound appearance of multifollicular ovaries: numerous follicles of different sizes are located throughout the ovarian parenchyma (Photo courtesy of B. Broussin)

Micropolycystic ovaries, usually enlarged, with large numbers of small to very small follicles tightly packed under the ovarian albuginea, and with a compact, echogenic stroma (Fig. 11.2).

A307741_1_En_11_Fig2_HTML.gif

Fig. 11.2

Micropolycystic ovaries: numerous small follicles are compressed under the tunica albuginea at the periphery of the ovary. Appearance at ultrasound (a) and MRI (b). (Images Courtesy P. Billet)

An intermediate or combined appearance of both is also possible, and it may be difficult to define clearly the presence of a compact stroma. This explains the tribulations endured by those attempting to establish specific ultrasound criteria for the various diagnoses. Initially absent from the First NIH Consensus Conference Proceedings (1990), the ultrasound criteria have become more refined as a result of the ESHRE Consensus Conference (Rotterdam 2003) [4]. At present, multifollicular syndromes comprise the classic polycystic ovarian syndrome (PCOS), with its spectrum of clinical, biological, and metabolic criteria, while other multifollicular ovarian presentations constitute an exclusion diagnosis. On the practical level, however, the appearance at ultrasound of a total count of more than 25 follicles in both ovaries, together with a high AMH level, should alert a clinician for a potentially excessive response to stimulation, regardless of the clinical and biological context.

PCOS was first described by Stein and Leventhal as polycystic ovaries in the presence of three principal features: anovulation, obesity and hyperandrogenism, whether or not clinically apparent [5]. In the absence of ultrasound imaging at that time, diagnosis was usually confirmed by laparoscopy that revealed markedly enlarged white nacreous ovaries, giving the impression, along with the uterus, of the three billiard balls (Fig. 11.3). Cuneiform resection of the ovaries in order to restore ovulation showed numerous small follicles packed under a very thick tunica albuginea.

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Fig. 11.3

The “billiard balls” appearance of polycystic ovaries at laparoscopy (Photo courtesy of R.B. Greenblatt)

Currently, to be considered as having PCOS, the patient should present with two of the three following features (Rotterdam consensus criteria [6]:

·               Anovulation or oligo-ovulation

·               Clinical and/or biological hyperandrogenism

·               More than a dozen follicles per ovary

The third of these criteria, while of utmost importance, is somewhat imprecise, because measures are often operator and/or equipment-dependent. Latest-generation 3-dimensional equipment can detect ever smaller follicles of less than 2 mm. A true count of 20 or even 25 follicles per ovary seems more likely the current norm for PCOS [6].

It remains possible that the diagnosis of PCOS, named essentially because of the ovarian appearance, may paradoxically be established without sonographic criteria. An apparent contradiction occurs because normofollicular ovaries may respond to ovarian stimulation like typical polycystic ovaries, yet other patients diagnosed by ultrasound with typical PCOS may occasionally respond to stimulation as one with normofollicular ovaries.

Additional clinical features of PCOS may include hyperandrogenism characterized by acne, hypertrichosis, or true hirsutism, and obesity or an elevated BMI, either as a female type or the androgynous type associated with hyperandrogenism.

Endocrine testing may show:

·               Increased plasma LH with an inversion of the FSH/LH ratio, and an excessive LH response to the dynamic GnRH test.

·               Elevated testosterone and Δ4-androstenedione – an assay of 17-hydroxy-progesterone is recommended to rule out an incomplete blockage of adrenal steroid synthesis.

·               An AMH level over 5 ng/ml is also very suggestive; measures of this hormone are indeed becoming a fourth important criterion for establishing the PCOS diagnosis [7]. Elevated AMH might indeed is one of the main causes of PCOS, instead of a simple indicator of the condition [8].

·               Hyperinsulinism that enhances the LH effect on androgen secretion along with a possible dyslipidemia and/or hypertension. PCOS is often characterized as a variant form of metabolic syndrome.

11.3.3 Treatment of PCOS

Several options may be considered, in a progressive strategy.

The GnRH pump, which may be chosen initially or after a failure with clomiphene. However, results for PCOS have not been promising to date, and it should be relegated to isolated cases.

Clomiphene citrate remains the first line therapy, after or along with metformin therapy in cases of obesity with hyperinsulinism. Letrozole seems to work as well, but its use for this indication remains a matter of debate.

Ovarian drilling, which is simply an update of the concept underlying the former wedge resection approach. This is a strategy whose mode of action has never been fully explained, yet it restores spontaneous ovulatory cycles to some 80 % of patients. With laparoscopic guidance, several small punctures are inserted into each ovary. In some series, pregnancy rates of 50 % have been observed within the first year [9]. Nonetheless, anovulation eventually returns, and new trials with clomiphene citrate, to which the ovary may have been sensitized by the drilling process, are worth considering. If this fails, a second drilling may be proposed to the patient, although with a caution of diminished expectations.

The principal value of ovarian drilling is that it can restore spontaneous ovulations and chances for a normal pregnancy without increasing the risk of ovarian hyperstimulation. Another useful and valuable outcome is that the risk of multiple pregnancy is comparable to that of spontaneously ovulating woman. On the other hand, the laparoscopy itself is a significant drawback because it is an invasive exploration of the abdomen with numerous attendant hazards from anesthesia. Modern technology has now greatly reduced complications from pelvic adhesions.

Should clomiphene trials fail, ovarian drilling may be advisable in several circumstances:

·               During a laparoscopy for another purpose, e.g. to follow up on an abnormal hysterosalpingogram or when pelvic endometriosis is suspected.

·               In PCOD patients who may not be sufficiently compliant for a protocol of repeated gonadotropin injections and monitoring steps.

·               In patients who have the best chance for success with this procedure: BMI <35, infertility duration less than 3 years, a negligible hyperandrogenism, and serum LH <10 mIU/ml [10].

·               Drilling may also be considered for a patient who continually develops multifollicular responses with gonadotropins, no matter how cautious the injection protocol.

Gonadotropin treatment remains the most difficult aspect of stimulation in PCOS patients because, by definition, their ovaries already contain a large pool of pre-antral follicles with a very close sensitivity to FSH. The margin of safety, between the threshold of FSH and the level causing an excessive response is narrow; several follicles can easily be recruited as soon as the FSH threshold is reached, or at only slightly higher doses. It is prudent to expect an excessive response and to proceed very cautiously with a progressive stimulation, even if surprisingly moderate responses should appear as well.

Choice of gonadotropin: In theory, purified FSH preparations would seem to be best suited for these patients, who already have elevated endogenous LH. Indeed, highly purified u-FSH preparations were originally designed for stimulating ovulation in the PCOS patient. Furthermore, one must also be concerned with an LH ceiling, above which an excess is deleterious to the chances for a normally developing pregnancy [11]. Nevertheless, use of regular HMG yields in fact the same rate as purified FSH for successful pregnancy as well as for miscarriage. All FSH preparations are equally effective for PCOS, as if the added LH were not able to breach the hypothetical LH ceiling.

Administration protocol: The starting dose should be 50–75 IU, depending upon the patient’s age and BMI, but a standard step-up approach is certainly not well suited for this indication. On the other hand, because many criteria for estimating ovarian response are imprecise, a fear of excessive response may lead paradoxically to insufficient stimulation over prolonged periods. A step-up low-dose protocol remains the best first line approach for PCOS. If a plurifollicular response continues after reaching the FSH threshold, other protocols are then possible:

·               The step-up chronic low-dose protocol, designed to maintain the starting dose for 7 additional days when the first 7 days failed to elicit an ovarian response. Dose increments continue for 7-day intervals (Table 11.2). If excessive follicular recruitment should appear, one can reduce the starting dose or the increment percentage from one stage to the next (e.g., a step-up chronic ultra-low dose protocol).

Table 11.2

Managing the chronic low-dose step-up protocol: possible scenarios after administration of 50–75 IU FSH for 7 days (see StimXpert)

A307741_1_En_11_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 7 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 1 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 interpreted 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 increase to the degree that plasma estradiol surpasses 800 pg/ml

·               If inadequate results persist, the next approach would be a sequential protocol, i.e., reducing the FSH dose once follicle dominance is reached, thereby to diminish the risk of recruiting secondary follicles. This approach can be tricky to manage: reducing the dose too late will end in another failure, whereas reducing it too early will simply result in a general follicular atresia (Table 11.3).

Table 11.3

Managing the sequential step-up/step-down protocol: possible scenarios after administration of 50–75 IU FSH for 7 days (see StimXpert)

A307741_1_En_11_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 7 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 1 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 interpreted 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 increase to the degree that plasma estradiol surpasses 800 pg/ml

·               If all of the progressive protocols fail, it would be possible to attempt a step-down protocol, which works along inverse principles. A higher initial dose (100–150 IU) results in a deliberate plurifollicular recruitment, and the secondary reduction in FSH leads to development of only the most sensitive follicle. Some clinicians prefer this protocol as a first line stimulation, but substantial experience is necessary to choose with confidence the very moment when FSH dosing should be reduced (Table 11.4).

Table 11.4

Managing the step-down protocol: possible scenarios after administration of 150 IU FSH for 5 days (see StimXpert)

A307741_1_En_11_Tab4_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 1 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 interpreted 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 increase to the degree that plasma estradiol surpasses 800 pg/ml

5. The daily dose of FSH should not fall below 75 IU

In patients without PCOS, estradiol production reaches a maximum at 6 h after a single FSH injection, and is maintained at this level for at least 24 h. In PCOS patients, the maximum estradiol production begins to decline sooner, by 12 h after FSH, and at 24 h post-FSH estradiol production is only 40 % of the maximal level. Unfortunately, splitting the FSH dose for a twice-daily administration does not appear to improve the clinical results [12].

Triggering criteria for a monofollicular stimulation are unchanged: one seeks a single follicle >15 mm diameter in the absence of other follicles >12 mm. Recall that PCOS ovaries contain numerous small follicles that all contribute to the total estrogen secretion, which still needs to remain below 800 pg/ml in order to obviate risk for ovarian hyperstimulation. If risk does appear, merely skipping the hCG trigger may not be sufficient to avoid multiple pregnancy for these at-risk patients. Contraceptive measures are strongly recommended for a length of time [13].

If the step-up protocols fail:

·               When a pregnancy does not follow a cycle that did result in an adequate ovulation, one may use the same FSH doses in additional cycles.

·               If different step-up protocols all fail with a persistent plurifollicular response, even in the face of slower step-up chronic low-dose protocol, it may still be possible to repeat cycles at diminished starting doses and/or with smaller dose increases for subsequent stages.

·               An insufficient response, on the other hand, may require shifting to a less progressive protocol, or to an increased starting dose and/or to a larger dose increment between each stage.

If the step-down or sequential protocols fail, the cycle may be abandoned for one of two reasons, both tied to the timing of the dose reduction. If the response is plurifollicular, the reduction of FSH dose was either insufficient or too late. On the other hand, follicular atresia usually follows an FSH dose reduction that was too early or too great. Noting the details of inadequate responses will guide management of the next stimulation cycle. If difficulties continue despite corrections of timing and dosing, it is better to change the protocol altogether.

Finally, the appearance of polycystic ovaries on ultrasound, with or without other signs of PCOS, should lead one to expect a possible plurifollicular response, and to adjust the administration protocol and FSH dosing appropriately. Even at the cost of a few initial failures, the ability to select from a variety of available protocols should lead to an effective monofollicular ovulatory response in every patient. When the stimulation failures continue for some reason, one should then reconsider the possibility of ovarian drilling, if not previously performed, or alternatively to consider in vitro fertilization as a last resort. Indeed, the excessive ovarian response may be used to some advantage in this situation.

11.3.4 (Apparently) Simple Multifollicular Ovaries

Ovarian reactions may shift between normal and multifollicular responses, due to the variety of beginning forms, transition forms and mixed forms with PCOS. For some authors, these asymptomatic patients, that range from 10 to 30 %, depending upon the discrimination power of the ultrasound equipment, should be considered as moderate or silent forms of PCOS [2]. A standard step-up protocol is best suited to evaluate the patient’s response quickly, involving only a few injections with few monitoring controls. Even if it results an initial ovulatory failure, observations of the initial ovarian reaction aids the planning of future cycles.

11.3.5 Paucifollicular Ovaries

A paucifollicular condition is defined as the appearance at ultrasound of a follicular total count equal to or less than six within both ovaries, during the initial stimulation cycle. This is seen more frequently in patients over 38 years of age, or at any age when accompanied by other irregularities of ovarian reserve.

For these situations, classic stimulation protocols are not at all unsuitable. A standard step-up protocol, at the usual or a slightly increased starting dose (e.g., 100–150 IU FSH), will provoke a mono- or paucifollicular response in most cases. Should the ovarian reaction prove to be insufficient, it is acceptable to increase the dose, without fear of an excessive response. In this condition, the problem is less with the ovarian response than with quality of the oocytes themselves, which remains unresponsive to any type of stimulation. Prior to beginning any stimulation it is critically important to decide with the patient about acceptable limits of treatment, and with the understanding that a pleasant surprise always remains possible.

11.4 Hypergonadotropic Anovulations

Hypergonadotropic anovulation is a distinct contraindication for gonadotropin treatment. The combination of continually elevated FSH levels, together with an AMH <0.5 ng/ml, and the appearance of an occasional follicle at ultrasound, are all associated with a premature pre-menopause. High FSH levels are the consequence of diminished feedback due to diminished ovarian responsiveness, and this cannot be relieved by administration of more FSH.

Many treatment schedules have been proposed in an attempt to manage this most frustrating situation in younger women, often using high doses of administered FSH following a return to normal endogenous FSH levels through treatment with estradiol or a GnRH agonist preparation. However, the proclaimed rates of success do not exceed the number of spontaneous pregnancies that follow a simple estrogen-progestin therapy that is recommended in any case for prevention of osteoporosis. While oocyte donation may be the only realistic option for these patients, two additional points should be emphasized:

·               Moderately elevated FSH levels (<15 IU/l) may simply be the result of an FSH receptor mutation, which in this case could justify an attempt with additional gonadotropins. Either a normal ovulation will occur with higher than usual FSH doses over several cycles, because the oocyte quality itself is most likely normal, or no response will occur, and the treatment should then be abandoned.

·               The diagnosis of premature menopause should lead to a thorough exploration in search of its origin, particularly if genetic or immunologic aspects could be involved. Although a precise diagnosis will not change the reproductive outcome, some possible etiologies may have other medical consequences.

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