(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)
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].
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