14.2 Avoidance of Pre-cycle Oral Contraceptives

While most of our minimal stimulation in vitro fertilization (IVF) patients have diminished ovarian reserve and would not be expected to have hypogonadotropic hypogonadism, we take this lesson from nature to help us apply the importance of LH presence during our treatment protocols and to help us avoid iatrogenic low LH. One of the most common practices we see that can cause LH suppression is the use of pretreatment oral contraceptive pills.

For traditional IVF, oral contraceptive pills prior to stimulation may have many advantages. First, they help prevent ovarian cysts prior to stimulation start, reduce the risk for ovarian hyperstimulation syndrome, and may even result in better cycle outcomes in certain high-responder patients [7–9]. Second, they allow for follicular synchronization, which ultimately increases the chances that the follicles will grow at an even pace throughout stimulation. Third, the use of oral contraceptive pills allows fertility clinics to schedule IVF cycles according to facility and embryologist availability and thus adds to convenience for both the clinic and the patient. All of these reasons make the use of oral contraceptive pills leading up to IVF stimulation very reasonable for patients who are expected to be normal or high responders.

However, the use of long-term oral contraceptive pills for patients with diminished ovarian reserve needs to be avoided. Oral contraceptive use has been shown to decrease ovarian volume, antral follicle count, and anti-Mullerian hormone (AMH) levels [10]. Since patients with diminished ovarian reserve are already low on all of these factors, the implementation of oral contraceptives can have a large detrimental effect. In addition, oral contraceptives reduce endogenous DHEA-S, testosterone, and serum insulin-like growth factor (IGF-1) levels [11–13]. At a time when many patients are eager to take fertility supplements such as DHEA, testosterone, and growth hormone, we feel that a better strategy is to avoid suppression of those important cofactors. Oral contraceptives and, more specifically, the progestin component of oral contraceptives are known to suppress endogenous LH [14, 15]. The length of suppression after cessation of oral contraceptives can vary, but since IVF stimulation is usually started approximately 3–4 days after oral contraceptives have been stopped, it is logical to expect some ongoing effects during the early portion of the stimulation. Since the early part of the stimulation is critical for optimizing the number of follicles that can be recruited for the cycle, we recommend complete avoidance of oral contraceptives altogether just before starting the stimulation. Alternatively, we recommend the use of estrogen priming. As discussed in the minimal stimulation chapter, the short-term use of oral contraceptives for a few days may be needed in some clinical scenarios. However, any such use is always after estrogen priming and followed by estrogen priming again before starting stimulation.

14.3 Estrogen Priming as an Alternative to Pre-cycle Oral Contraceptives

Estrogen suppresses endogenous FSH, which allows for the same follicular synchronization that oral contraceptives provide. But, unlike progestin use, estrogen use does not cause profound LH suppression. Hence, its use prior to minimal stimulation IVF is beneficial. Our estrogen priming protocol consists of initiating estradiol 4 mg orally starting approximately 3–4 days after ovulation as confirmed by a rise in the serum progesterone level [16]. The oral estradiol is discontinued at the time of menses in preparation for IVF stimulation start on cycle day 2 or 3.

14.4 The Importance of LH Monitoring

When we initially began implementing minimal stimulation IVF for patients with diminished ovarian reserve, we did not monitor LH levels. Unfortunately, at that time (2012–2014), we had a premature ovulation rate of 12% (unpublished data). We have learned that women with diminished ovarian reserve and/or advanced reproductive age tend to have a higher risk for premature ovulation when compared to normal or high responders [17]. At the same time, the standard fixed or flexible GnRH antagonist protocols that are commonly used for the average patient are not applicable to our special patient population as mentioned in minimal stimulation IVF section.

Starting in 2015, we incorporated close LH monitoring during our minimal stimulation IVF cycles, which is started as early as day 4 of treatment with clomiphene citrate. Our premature ovulation rate dropped drastically from 12% in the years 2012–2014 to 0% in the years 2015–2016 (p = 0.0017, unpublished data, Fig. 14.2a). Our data shows that monitoring serum LH levels during the stimulation resulted in an overall earlier average initiation of GnRH antagonist when compared to previous years. The 2012–2014 group (which did not monitor LH) initiated GnRH antagonist on an average of stimulation day 8 versus an average of stimulation day 5.6 in the 2015–2016 group (which underwent LH monitoring, p < 0.0001, unpublished data, Fig. 14.2b). In addition, the group that underwent frequent LH monitoring used less GnRH antagonist overall (416 mcg versus 670 mcg, p < 0.0001, Fig. 14.2c).

14.5 When to Initiate GnRH Antagonist Treatment

To initiate monitoring of serum LH, we bring patients in immediately after their third day of stimulation for their first LH level. It is important to concurrently draw an estradiol serum level as this gives context on how to interpret the LH level (Fig. 14.3). If the LH level is low (≤5 IU/L), GnRH antagonist treatment is not yet begun. If the LH is >5 IU/L, the LH level is further interpreted according to the patient’s serum estradiol level. In general, a follicle would need to have an estradiol exposure of >150 pg/mL for at least 36–40 hours to have the potential for premature ovulation. Therefore, if the estradiol is <150 pg/mL, the GnRH antagonist is withheld. If the estradiol level is above 150 pg/mL and the LH level is >5 IU/L, a half dose of a GnRH antagonist (125 mcg) is given immediately, and the patient is scheduled for a sonogram and repeat labs the next day. The sonogram can give further guidance on whether the GnRH antagonist needs to be continued at that time of the cycle. For example, if a sonogram shows several follicles measuring 16 mm, continuation with the GnRH antagonist is necessary since those follicles are likely capable of premature ovulation. However, if the sonogram demonstrates that all follicles are less than 12 mm, the GnRH antagonist can be safely held that day since smaller follicles are not likely to undergo premature luteinization and/or ovulation. At times, one can encounter LH levels at or above 10 IU/L, while the estradiol level is still less than 100 pg/mL. Rather than considering GnRH antagonist administration, we recognize that this could be an indicator of more severe diminished ovarian reserve and that we may need to consider what the FSH level is in such patients. If the LH level continues to be higher than 10 IU/L with low estradiol levels at another measurement, we assess FSH level. If the FSH level is above 20 IU/L, it is illogical to continue with that cycle as discussed in the minimal stimulation section.

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