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Bordeaux, France
The ovary is hardly an isolated organ. It is not only unique to each patient; it is subject to numerous intrinsic and extrinsic factors of the patient’s health and disease, as well as to personal and psychosocial environments.
4.1 Searching for Other Hypofertility Factors
Ovulatory stimulation using gonadotropins is a powerful treatment, to be initiated only with sage advice. A complete and thorough preliminary assessment is mandatory to identify and eliminate other factors that may be impeding a couple’s fertility or the efficacy of a treatment plan.
A proper evaluation must include:
A clear hysterosalpingogram, to appraise utero-adnexal integrity. If patency of one or both tubes remains doubtful, a selective salpingogram should be performed. Should the procedure be technically impossible, or if a tubal obstruction is confirmed. Direct visualization also affords the opportunity to search for abnormalities such as adhesions or parietal endometriosis that may be missed by ultrasound scanning. When the integrity of the uterine cavity is doubtful, hysterosonography will confirm or eliminate the need for a hysteroscopy.
An evaluation of the male partner’s fertility based upon a spermiogram and, when possible, supplemented by a post-coital test with spontaneous or estrogen-treated cervical mucus.
It bears noting that discovery of some abnormal findings during these initial explorations does not necessarily obviate ovulation stimulation, but it nevertheless suggests that some additional issues should be considered when developing a therapeutic strategy. Correction of a secondary problem may improve chances for clinical success.
4.2 Evaluation of the Patient
A patient’s age and body mass index (BMI) are certainly two of the more obvious characteristics relevant to success of ovulation induction. However, one must take into account a variety of related malfunctions or ongoing medical treatments.
4.2.1 Patient Age
A relatively advanced age should not automatically eliminate every candidate for ovarian stimulation, provided that FSH levels are not continually elevated. To be sure, numerous experimental studies of donor insemination and IVF have documented the progressive decline of pregnancy rates past the age of 38, even with a satisfactory process of ovulation induction, so age must always be a consideration. There are no reported studies of variations of the FSH threshold in relation to age, but a diminished ovarian response does appear more frequently in the late 30s and beyond, and higher FSH doses are typically needed with older patients. In addition, a substantial variation of individual responses to dosage may be encountered among older patients.
Advancing age does not necessarily alter the prognosis for a successful pregnancy in many types of anovulation. Indeed, time may actually become an ally in the patient of polycystic ovary syndrome. Pregnancy success rates with gonadotropin treatment actually increase in PCOS patients past the age of 36, possibly because of an age-related decrease in the size of the pre-antral follicular cohort.
4.2.2 Patient Weight
Ovulation stimulation should ideally be undertaken in patients within a normal BMI range of 20–25. Deviation from normal brings a variety of problems for a successful stimulation.
4.2.2.1 Insufficient Weight
Weight insufficiency usually occurs in a context of eating disorders that are associated with psychosocial problems. Decisions for stimulating ovulation in these cases should be taken judiciously, inasmuch as achieving a normal weight does not always restore spontaneous menstrual cycling. Ovarian stimulation can be a perplexing task in these low-weight patients because safety margins are narrower. Ovarian responses are somewhat more difficult to anticipate and stimulation should be attempted only when weight and psychological status are believed to have stabilized. Concurrence of a mental health professional should be obtained.
4.2.2.2 Excess Weight
A high proportion of anovulatory women present with weight excess. It is well established that the ovarian response to administered gonadotropins is blunted even when obesity is moderate (BMI < 28), perhaps due to a “depot” effect at the injection site in fat-infiltrated tissues combined with an increased volume of distribution. This would explain why increased dosing of gonadotropins, and/or prolonged duration of stimulation, is often necessary in the more obese patient, even when using the IM route: Bioavailability of injected FSH has been shown to be lower in these patients after SC administration than after IM injection [1]. For the same reasons, gonadotropins should be administered just above the knee when the SC route is chosen.
Spontaneous fertility is also lower in the more obese patient, and the risks for miscarriage and perinatal morbidity are higher. There is emerging evidence that leptin, a protein secreted by adipocytes, plays a key role in fertility, and elevated plasma levels are thought to disrupt folliculogenesis, steroid hormone secretion, and endometrial receptivity [2]. Although the overall success rates of obese patients are similar to those of normal weight women, at least in IVF trials, it remains important to attempt significant weight reduction prior to stimulation, using dietary or behavioral modification [3]. Indeed a weight loss of only 2–5 % has been reported sufficient for restoration of spontaneous ovulation within a few months in nearly half of anovulatory overweight patients [4].
All that said, it may be illusionary to hope for significant and stable weight loss in patients with a prolonged history of repeated weight losses and gains. Such a pattern frequently correlates with shifting phases of active to absent motivation about weight reduction, even when reinforced by an increased desire to become pregnant. Bariatric surgery may be cautiously considered in some instances. Because declining to help a patient with persistent obesity may represent for her yet another failure, it would be well advised to negotiate a “contract” of weight stability. By recording and discussing body weight during each monitoring appointment, one may pose the prospect of interrupting the stimulation protocol until the patient is able to return to a previously agreed weight. It is also important to refute the notion in the mind of heavy patients that “hormones put weight on.”
In patients with polycystic ovarian syndrome (PCOS), a peripheral insulin resistance is often encountered that leads to a hyperinsulinemia and an independent risk factor for obesity. Because weight loss, however difficult to achieve, may be necessary before embarking on ovarian stimulation, it may be advantageous to add metformin together with the stimulation itself [5]. Even if an obese patient succeeds in becoming pregnant, her excess weight adds additional risk to the pregnancy that is usually correlated with the degree of weight excess. Hypertension, diabetes, and perinatal complications can turn this apparent success into a very dismal outcome. Ovulation stimulation must be careful to avoid unreasonable and risky procedures.
4.2.2.3 Associated Pathologies
The prospect of ovarian stimulation and pregnancy provides a very appropriate time to heighten a patient’s awareness of the deleterious effects of alcohol, tobacco, and numerous other toxic substances on oocyte reserve and quality. It is also important to take into account a number of other associated risk factors before beginning the treatment:
Chronic diseases: If one can establish that a given patient’s underlying chronic conditions such as a demyelinating syndrome, colorectal hemorrhage, epilepsy, or cardiovascular complications will likely be compatible with the prospect of a pregnancy, then the syndrome can be anticipated to be similarly compatible with protocols of ovarian stimulation. However, it is important to contact the patient’s specialist before beginning therapy in order to uncover potential hazards. For example, it is crucial to avoid all risk, however small it may be, for an ovarian hyperstimulation situation in a patient with an established coagulation disorder. Another example for caution would occur in a patient being treated for systemic lupus erythematosus, because her ovarian reserve may have been compromised even in the absence of alkylating treatment [6].
Previous history of (extra-ovarian) cancer: It is difficult to comprehend why an oncologist would recommend against ovarian stimulation while still consenting to a pregnancy in a patient with a history of cancer. The levels of plasma estradiol resulting from a monofollicular stimulation protocol remain very close to those of the physiologic menstrual cycle. Even with a multifollicular protocol that might be used for IVF, the relatively high estradiol levels found during mid- to late follicular phase of a stimulated cycle are minimal compared to those which will flood a patient during the 9 months of pregnancy. This example of a “precaution principle” needs to be discussed each time with the patient’s oncologist in order to agree on the strategy best suited to the patient’s condition.
Medications. Each patient’s therapies must be carefully evaluated, even if they do not appear as directly detrimental to ovarian stimulation, because it is also highly important to anticipate continued management of therapies once a pregnancy begins. This would be especially true for cytotoxic or psychoactive medications.
4.3 Evaluation of Ovarian Status
A thorough evaluation of the ovarian condition is a fundamental step. One must evaluate the complement of follicles, and thus the potential sensitivity to FSH and prognosis for stimulation. A woman’s oocyte reserve decreases steadily from intra-uterine life until menopause: from a mean of 100,000 at age 20–30,000 at age 30, and only 8,000 remaining at 40 years of age [7]. Although stem germ cells that appear capable of division and differentiation may be found in the adult female ovary, the reserve of primordial follicles must be considered as finite [8]. The ovarian endowment of oocytes should be assessed around the third day of the cycle (CD 2–5) using both ultrasound and hormonal measures.
4.3.1 Hormonal Parameters
4.3.1.1 FSH
Determination of plasma FSH remains a principal index, because levels increase as the follicular supply decreases. However the correlation between these two variables is far from tight, because FSH levels can fluctuate widely in blood. While a continuously elevated FSH level (>15 IU/l) is probably an early sign of ovarian insufficiency, moderately elevated FSH levels below 15 IU/l indicate only a need for a very cautious interpretation.
FSH secretion is pulsatile with peaks about every 90 min during the follicular phase. Thus a best evaluation of FSH should be performed on three pooled blood samples taken at 20 min intervals, a practice that is not routinely conducted. In addition, the normal range of plasma FSH varies between laboratories and also between hormone assay systems. Upper levels of normal can vary from 9.5 to 12 IU/l in individual laboratories.
While abnormally high FSH levels are usually confirmed by repeated observations in successive cycles, a pattern of normal FSH mixed interspersed with elevated readings should be taken as a warning for a declining ovarian reserve: in these cases, however, overall results from stimulations are not better when started on a cycle with a subnormal FSH value. Some patients with moderately elevated FSH (10–13 IU/l) demonstrate nevertheless a normal ability to achieve pregnancy on stimulation; this could reflect a physiological variation such as an FSH receptor polymorphism. Such a possibility must be kept in mind when working with young patients before considering oocyte donation. An attempt to stimulate follicular growth can still be carried out in these cases, although it may well require higher FSH doses in order to be successful.
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