Not all patients will benefit from the standard IVF stimulation protocols. While Lupron and birth control pill (BCP) help recruit multiple follicles by preventing natural selection of a single dominant follicle, each can suppress ovarian response, especially when used together during the pre-stimulation phase.  Patients with low ovarian reserve will do better using regimens that minimize the inhibitive effects of Lupron and BCP. At ARCC we use a variety of aggressive protocols to optimize ovarian response. When choosing a protocol for patients with low egg reserve, the experience, creativity, and flexibility of the physician contribute greatly to the chance of success. Listed below are the protocols that we have used effectively over the years:

1.      Micro-Lupron Flare Protocol

Lupron binds to the pituitary to cause the release of FSH and LH to eventually exhaust the pituitary of these hormones so that the brain and pituitary can no longer regulate the function of the ovaries. Once the natural selection mechanism is removed, ovarian stimulation to recruit multiple follicles can begin.

In the classic protocol, Lupron and BCP are used for at least 10 days before stimulation. In some patients, this combination can be a potent suppressor of ovarian response. In contrast, the micro-Lupron regimen uses a very small amount of Lupron (1/20 the usual dose) just 3 days before ovarian stimulation in order to release LH and FSH from the pituitary. Thus during the first 2-3 days of micro-Lupron, the ovaries are stimulated by pituitary FSH and LH (the flare effect). On the third day of micro-Lupron, medications containing FSH and LH are added to further augment the stimulation. After a week, the pituitary finally is exhausted of its LH and FSH and can no longer interfere with the stimulation process by either selecting the dominant follicle or causing ovulation.

The micro-Lupron protocol was one of  the first aggressive protocols introduced and over the years has helped many patients with low ovarian reserve to conceive their own children without resorting to donor eggs. Its main disadvantage is that LH is also released along with FSH, which theoretically can negatively impact egg development. However, several studies have demonstrated that some early LH is necessary for optimal development of follicles. The other disadvantages are the increased risk of premature ovulation near the end of the stimulation process due to minimal pituitary suppression, and the potential inhibition of BCP on ovarian response in patients with very low egg reserve (AMH < 0.5 ng/ml).

2.      Estrogen (E2)-primed Low Lupron protocol

The E2-primed Lupron protocol was introduced to address the problem of early LH release seen in the micro-Lupron flare protocol. Unlike the classic Lupron protocol, no BCP is used in the pre-stimulation cycle. Lupron is started about a week after ovulation, its dose is halved at menses, and further halved when stimulation begins. Estrogen is added on day 3 of menses and is continued throughout the stimulation phase.

As in  in the classic Lupron protocol, this regimen uses extended Lupron pretreatment to eliminate any potential negative effect of LH during the initial phase of stimulation. The sequential decrease of Lupron dose aims to offset the suppression side effect of the medication.  Estrogen also provides a beneficial hormonal milieu for follicular development. The main disadvantage of the E2-Lupron protocol is that the prolonged pituitary inhibition with Lupron, albeit a reduced doses, can  lead to  pronounced  suppression of ovarian response in patients with AMH <0.5 ng/ml. In addition, ovarian cyst can form from  Lupron-induced release of FSH, which may necessitate longer use of Lupron and can further delay stimulation. In our experience, the stimulation duration for this protocol tends to be protracted and the medication requirement can be very high.

3.      Estrogen-primed Antagonist Protocol

In this protocol, the pretreatment cycle is a natural cycle (no BCP). About a week after ovulation, estrogen  is started to prevent premature release of FSH that can cause size discrepancy in the developing follicles. Ovarian stimulation begins on day 3 of menses in the presence of Estrogen, which provides a beneficial environment to ‘sensitize’ the follicles to  stimulation. An antagonist (Ganirelix or Cetrotide) is added later to prevent premature ovulation.

This is currently our favorite protocol for patients with very low egg reserve (AMH <0.5 ng/ml or  total antral follicle  count of 5 or less. It avoids the suppressive effect of Lupron and BCP on the ovaries. In addition, the use of estrogen during the pretreatment cycle prevents premature recruitment of follicles that can reduce the number of follicles available for stimulation.  Studies have shown that this protocol allows more gradual and coordinated growth of follicles resulting in improvement of embryo quality and quantity. The main disadvantage of this protocol is the lack of flexibility in planning the cycle since ovarian stimulation can occur on any day.

4.      Estrogen-primed Micro-Lupron Flare Protocol

We recently introduced this protocol to improve on the micro-Lupron flare protocol. We reserve this protocol for patients who do not respond well to the E2-Antagonist program.  The pretreatment phase is a natural cycle in which estrogen is given for 7 days a week after ovulation. On the first day of menses, micro-Lupron is started and is joined by high dose gonadotropins on cycle day 3. The E2-microlupron protocol avoids the use of BCP that can suppress the ovaries, while utilizing the beneficial effects of luteal phase estrogen- preventing  premature follicle recruitment and sensitizing follicles to stimulation- as well as the flare effect of micro-Lupron.  We have had several patients with AMH of 0.2-0.3 ng/ml  who conceived using this special protocol.

5.      Femara-Antagonist Protocol

And finally, a protocol for patients who had failed to respond to all previous protocols due to extremely low egg reserve (AMH of < 0.3 ng/ml but with at least 3 antral follicles). In this protocol, there is no pretreatment cycle. As soon as the baseline sonogram shows at least 3 antral follicles, ovarian stimulation begins immediately using a combination of Femara and high dose gonadotropins (FSH and HMG). Femara indirectly induces pituitary of FSH and LH by blocking the synthesis of E2. The combination of pituitary and medication LH and FSH provides very potent ovarian stimulation. After 5-6 days of stimulation, an antagonist is added to prevent ovulation until the day of HCG trigger.

The disadvantage of this protocol is the delayed endometrial growth caused by 5 days of Femara but this effect can be overcome quickly with vaginal estrogen supplementation on the last day of Femara. Another disadvantage is the lack of flexibility in cycle planning as there is no way to plan ahead the start of ovarian stimulation. However, for a patient who desires  a last chance to use her own eggs, this protocol gives her a final opportunity before closure and moving on to donor eggs. 

The above protocols have helped many of our patients with low ovarian reserve to conceive their biological children. Each regimen has its own advantages and limitations, and patients respond differently to them. The physician must be flexible, creative, and willing to change treatment whenever necessary. The patient must remember that no protocol can allow her to make more eggs than her ovaries can provide in a cycle, and that a minimum of 3 antral follicles is required before she can proceed with the process. Finally, she must also know that no protocol can reverse the negative impact of time on the quality of her eggs.

The main advantages and disadvantages of the aggressive protocols are summarized in the following table: 

In 2010 the World Health Organization (WHO) updated its reference values for the Semen Analysis.[1]  This update was long overdue as the last version was published in 1999.

There is a significant difference on how the old and new reference ranges were derived. In the past, semen data from random populations of men were analyzed and the results were plotted on a statistical distribution curve. The 5th percentile was considered to be the lower limit of normal (or reference), in another word, 95% of men tested would have sperm parameters higher than the reference ranges.

In WHO 2010, the new normal values are based on data from men with proven fertility, men who were known to help their partners conceive in the previous 12 months. Following a large analysis of semen parameters from over 4000 men in 14 countries, a new set of 5th percentile parameters was recommended. Below are the comparisons of the old and new reference values:

As can be seen above, there is a large difference between the WHO morphology references for 2010 and 1999, reflecting the subjective nature of this parameter. Thus we usually do not use morphology when recommending initial treatment. In our experience, as long as sperm concentration and motility are within normal ranges, poor morphology scores do not necessarily preclude pregnancy. Over the years we have seen many men with isolated low morphology scores (0-3%) who became biological fathers without the need for IVF or ICSI.

The new WHO criteria are unique because for the first time, a semen sample under evaluation can be compared to those of fertile men. We have found the new standards to be quite helpful in assessing the male fertility potential. If you have any questions about the new parameters, do feel free to contact us.

[1] Cooper, TG et al. WHO reference values for human semen characteristics. Hum. Reprod. Update. 2010. 16(5):559

LH (Luteinizing Hormone) is the pituitary hormone that induces ovulation in the midcycle. This hormone is released from the brain into the circulation causing release of the egg 34-36 hours later. The hormone can also be identified in the urine and ovulation usually follows 12-24 hours later, with most patients ovulating by 48 hours after LH is first detected in the urine. Consequently, the most fertile days are the day of the surge and the next 2 days. For those patients undergoing intrauterine insemination (IUI), the optimal day for the procedure is the day after the surge is first detected.

Ovulation kits do not necessarily increase the chance of pregnancy in couples having regular intercourse, but they can be helpful in ovulatory women who have infrequent intercourse or who are having an IUI.

The LH surge starts in the morning for most women, and thus LH is detectable in the urine in the late afternoon. False positives and false negatives are commonly seen. False LH positives can be seen when high constant levels of LH occurs in the circulation (as seen in patients with polycystic ovaries) or a few days after taking ovulation induction drugs (Clomid, Femara). False negatives can occur with high fluid intake (dilution effect) or when the LH surge is too transient and occurs between testing times (twice-a-day testing can help minimize this, but is unnecessary for most patients).

Menses usually occur 14 days after the LH surge, therefore, LH testing should be started approximately 17 days before a menstrual period is expected, and can be stopped once a positive surge is detected.

Most LH kits today are very accurate, but the highest accuracy is found in those that are easy to use and interpret, and those with a high level of LH sensitivity. For a conclusive positive or negative result, digital kits appear to be the easiest to interpret.

According to a study from Johns Hopkins University published in Fertility and Sterility in May of this year, the highest performing products are: ClearPlan Easy Ovulation Test Pack, First Response, and Clear Blue Easy (they also have the One Month Ovulation Test).

References: Brezina et al. F&S May 2011; Speroff et al. Clinical Gynecologic Endocrinology and Infertility, 8^th Ed.

Because fertility can be a numbers game, patients often ask if two IUIs are better than one.  Most studies so far have not demonstrated any significant difference in pregnancy rates between one versus two IUIs. In our experience, a single well timed IUI is as effective as two consecutive IUIs without the added cost of the latter.  However, if the total number of motile sperm is less than 1 million during the first IUI, we recommend a second IUI in the following day.

Julian Escobar, MD