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Defining and Addressing an Abnormal Luteal Phase

by Dr. Geoffrey Sher on October 10, 2016

Following ovulation, what remains of the ruptured follicle transforms itself into a structure called the Corpus Luteum (CL) which produces progesterone. The purpose of progesterone is to prepare the uterus to accept and support an early pregnancy until it is able to sustain itself at around 8-10 weeks of gestation.

The life span of the CL is predetermined to be 12-13 days, unless rescued by a signal from the early pregnancy. If no pregnancy occurs, the CL stops making progesterone and menses ensues 1-2 days later. For most women the length of the second half of the menstrual cycle (the luteal phase) is constant at 14 days. A small percentage of infertile women (3-4%) have a shortened luteal phase. This may result in the loss of pregnancy support before the budding pregnancy has a chance to signal the ovary that it is there.

The lining of the uterus (the endometrium) has a specific appearance that changes throughout the menstrual cycle, such that a biopsy of the lining a few days prior to expected menstruation, can accurately date endometrial development. A 3 or more day difference between endometrial dating by biopsy and cycle day as determined by the start of the next menstrual period is indicative of a luteal phase defect (LPD). Sequential mid luteal progesterone levels < 10 ng/dl can also be used to diagnose a LPD. Luteal phase defect can be treated with Clomiphene Citrate, Progesterone supplementation or hCG injection

PROGESTERONE LEVELS

Normal Progesterone (P) levels rise sharply after ovulation, peaking a week after ovulation. Because P secretion occurs in a pulsatile fashion (around every 90 minutes), single low levels are often found in the course of a normal luteal phase and cannot be used as a predictor of luteal defect or poor fertility potential.

In pregnancy, P is secreted by the corpus luteum (of pregnancy) until about 10 weeks of gestation. Because of the large variation in individual P levels, the predictive value of single P measurement in early pregnancy is limited. Usually levels above 20 ng/ml indicate a normal pregnancy while levels below 5 ng/ml suggest a potential problem. It is also important to point that persistent low P levels are usually the result, rather than the cause, of poor outcome and that unfortunately, as a result, P supplementation does not prevent the inevitable.

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  • Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 13, 2016 reply

    My questions:
    1) Embryos from my fourth cycle were slow growing. On third day morning all three embryos were just 4 cells. In afternoon two made to six cells and were frozen.What causes slow growth of embryo? Can they still implant and make healthy baby?

    A: THE OVARIAN STIMULATION PROTOCOLS YOU SHOULD CONSIDER:
    • Long GnRH Agonist Protocols: The most commonly prescribed protocol for agonist/gonadotropin administration is the so-called “long protocol”. An agonist (usually, Lupron) is given either in a natural cycle, starting a 5-7 days prior to menstruation or is overlapped with the BCP for two days whereupon the latter is stopped and the Lupron, continued until menstruation ensues. The agonist precipitates a rapid rise in FSH and LH level, which is rapidly followed by a precipitous decline in the blood level of both, to near zero. This is followed by uterine withdrawal bleeding (menstruation) within 5-7 days of starting the agonist treatment, whereupon gonadotropin treatment is initiated (preferably within 7-10 days of the onset of menses) while daily Lupron injections continue, to ensure a relatively “low LH- environment”. Gonadotropin administration continues until the hCG trigger.
    o Long-agonist/antagonist conversion protocol (A/ACP): With a few (notable) exceptions I preferentially advocate this protocol for many of my patients. With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts, she supplants the agonist with a half dosage (125mg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide).Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman’s own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation, a large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of testosterone can also have an adverse effect on endometrial growth. Also, since agonists might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.
    o Agonist/antagonist conversion protocol with estrogen priming: Women who have a significant degree of diminished ovarian reserve are first given GnRH agonist for a number of days to effect pituitary down-regulation. Upon post-BCP/agonist-induced menstruation, the dosage of GnRH agonist is drastically lowered (or commonly is supplanted by 125mg daily of an antagonist) and the woman is given twice-weekly injections of 2-4mg of estradiol valerate (E2V) for a period of 7-10 days. Ovarian stimulation is then initiated using a relatively high dosage of an FSH-dominant gonadotropins such as Follistim, Puregon or Gonal F for a few days, whereupon the dosage is reduced and a small amount of DNA-recombinant LH (Luveris) is added daily. Both the FSH and the LH are then continued along with daily administration of GnRH agonist (or antagonist) until the “hCG trigger”. The reason for the “estrogen priming” is because it enhances follicle response to FSH and also helps optimize the uterine lining.
    There is one potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress. Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-threatening Severe Ovarian Hyperstimulation Syndrome (OHSS). The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly we currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-protocol” approach.
    • The “Trigger Shot”- A Critical Decision: The egg goes through maturational division (meiosis) during the 36 hour period that precedes ovulation or retrieval. The efficiency of this process will determine the outcome of reproduction. It follows that when it comes to ovulation induction, aside from selecting a suitable protocol for COS one of the most important decisions the clinician has to make involves choosing and implementing with logic and precision, the “trigger shot” by which to facilitate meiosis.
    o “Selecting the Ideal Trigger shot”
     Urinary versus recombinant hCG: Until quite recently, the standard method used to initiate the “trigger shot” was through the administration of 10,000 units of hCGu. More recently, a recombinant form of hCGr (Ovidrel) was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably at best only has 60%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should be doubled to 500 mcg.

    2) My doctor is recommending to thaw all four embryoes, grow them for two days and then transfer them. If I do what doctor says, then how can growth of all four embryoes can be synchronized if they have different number of cells?

    A: I agree. Any embryo that does not reach blastocyst within 3 days of further culture is almost certainly chromosomally abnormal and should not be transferred.

    3) How would you recommend transferring them? Day 3 or grow and transfer at day 5.

    A: As blastocysts at day 5-6.

    Geoff Sher

  • Rachel - October 12, 2016 reply

    Hi Dr. Sher!

    My husband have been confirming ovulation with OPK’s and temping and timing intercourse right for 7 months and have not conceived. I have a slow rising temp after ovulation and I also spot new and old blood for 5 days before CD1. I had my progesterone tested 7 DPO and it was 10.4. Should I be concerned or continue trying until we hit the 1 year mark before intervening?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 12, 2016 reply

    Unless you are aware of a clear underlying cause of infertility, and depending on your age being <35y, I would give it a full year of timed intercourse, before submitting to a comprehensive infertility evaluation.

    Geoff Sher

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