Mechanisms The luteal phase is normally characterized by progesterone secretion by the corpus luteum and appropriate endometrial secretory transformation that allow for embryonic implantation in the endometrium and support of early pregnancy for the first 7 to 8 weeks of gestation (258,259). Luteal phase defect (LPD) is a failure to develop a fully mature secretory endometrium during the implantation window and is thought to account for 4% of infertility (260,261). Proposed mechanisms for LPD include inadequate production of progesterone following ovulation, improper GnRH pulsatility causing insufficient gonadotropin production during the LH surge, and inadequate endometrial responsivity to progesterone (260– 262). ART or gonadotropin ovulation induction medications may induce iatrogenic LPD via disruption of granulosa cells from follicular aspiration and suppression of endogenous LH secretion through a combination of supraphysiologic estradiol levels and GnRH agonist or antagonist therapy (259,262).
Diagnosis Diagnostic criteria for LPD have been varyingly defined, but have included a low mid-luteal phase serum progesterone levels of less than 5 to 10 ng/mL, a delay of 2 days or more in endometrial histology when compared to chronologic cycle day in two or more cycles, a BBT rise lasting less than 11 days, and a shortened luteal phase of less than 14 days (259–261). Unfortunately, the characteristic pulsatile secretion of progesterone during the luteal phase of the menstrual cycle combines with wide temporal variations (even within a 60-to 90-minute time span) to make interpretation of midlueal progesterone levels difficult (258). Similar rates of shortened luteal phase are found in fertile and infertile women, and there is significant variability of luteal phase length from cycle to cycle in an individual woman (261). Finally, there is significant interobserver variability in pathologic interpretation of endometrial biopsies from infertile women, and out-of-phase biopsy results poorly discriminate between fertile and infertile women (263,264).
Treatment Progesterone therapy is considered standard practice during ART cycles, but is more controversial during non-ART fertility treatments (258,259,262). When used, progesterone supplementation can be administered via oral, vaginal, or intramuscular routes. Intramuscular progesterone is dosed at 25 to 50 mg daily. Most products are delivered in oil, and caution should be used to ascertain the presence of sesame or peanut allergies. Oral micronized progesterone is associated with erratic absorption and decreased bioavailability, so it is typically administered via an off-label delivery route—vaginally 200 to 600 mg daily, and often in divided doses. The side effects of this delivery route, however, can include vaginal discharge and irritation. Other vaginal preparations include a once-daily gel and a 100 mg insert that is given two to three times daily. There remains no consensus regarding the superiority of vaginal versus intramuscular administration. Progesterone therapy typically begins 3 to 4 days following the hCG trigger or LH surge and, if pregnancy occurs, continues for at least 8 to 9 weeks of gestation (258,259,262). Although some progestins can stimulate the androgen receptor, there is no evidence of teratogenicity with the progesterone supplementation described herein (258).