A Review of Research on Luteal Phase Deficiency

By: Alexandra Piselli, MD, MS

Director’s Note: Last week, we featured research on the various markers of ovulation. Given the importance of ovulation as a key indicator of health, it is critical for future physicians to learn how to read the female cycle chart and evaluate each phase, including the luteal phase, to assess a woman’s hormonal health. While on the FACTS elective, Alexandra Piselli summarized research by Schliep et al [2] that addresses luteal phase deficiency in regularly menstruating women. Of note, as part of my research fellowship, I (Dr. Duane) published a similar research paper with Dr. Schliep that addressed the link between luteal phase length and risk of miscarriage.

Are you ready to learn more or share the gift of knowledge? Sign up for a FACTS webinar, such as The Female Cycle as the Fifth Vital Sign, gift a webinar to a friend or make a donation to support student learning. For a deep dive into luteal phase defects with Dr. Gabriel James, enroll in Part H (RRM and Medical Applications) of our growing CME course!

Introduction

Luteal phase deficiency (LPD) is associated with abnormal production of estradiol (E2) and progesterone, shortening of the menstrual cycle, irregular menstrual bleeding, infertility, and early pregnancy loss. Given that 28% of recurrent pregnancy loss is thought to be due to LPD, further understanding of LPD could direct management. [1]

Being able to identify ovulation is crucial for timing the blood draws required to identify LPD. To predict the day of ovulation and determine the length of the luteal phase, it is more accurate to rely on urine LH measurements rather than basal body temperature (BBT). [2]

“Being able to identify ovulation is crucial for timing the blood draws required to identify luteal phase deficiency.”

Schliep et al sought to (1) evaluate whether LPD occurs in healthy women with regular menses and no known gynecological disorders, (2) determine the prevalence of LPD, and (3) investigate any overlap of short luteal phase duration with suboptimal luteal progesterone concentration. Secondarily, they explored the overlap of established LPD diagnostic criteria for clinical LPD and biochemical LPD, and their relationship with the cycle phase specific reproductive hormones E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

Methodology

The prospective study took place in Western New York (2005-2007) and followed 259 healthy premenopausal women, aged 18-44 years, for up to two menstrual cycles. Participants provided serum samples to measure E2, progesterone, LH, and FSH levels at up to 8 clinic visits per cycle, with mid-cycle visits determined with the assistance of the Clearblue Easy fertility monitor. The goal was for clinic visits to correspond with menstruation, mid- and late-follicular phase, LH/FSH surge, ovulation, and early-, mid-, and late-luteal phase.

Although a progesterone level > 3 ng/mL indicates ovulation, concentrations below that have been found in normally ovulating women; thus, ovulatory cycles were defined as a progesterone level > 1 ng/mL with a urine or serum LH surge prior to the mid-luteal visit. Day of ovulation was assigned using the day of urine LH surge on the monitor or the day of serum LH maximum plus one day when monitor data was unavailable.

Diagnostic criteria for LPD included short luteal phase duration of < 10 days (clinical LPD) and low luteal progesterone < 5 ng/mL (biochemical LPD). An additional, more liberal assessment of low luteal progesterone (≤ 10 ng/mL) and luteal phase duration (< 9 or < 11 days) was also done.

“Diagnostic criteria for LPD included short luteal phase duration of < 10 days (clinical LPD) and low luteal progesterone < 5 ng/mL (biochemical LPD).”

Covariates included percentage body fat, age, self-reported race, smoking status, reproductive history, and daily minutes of vigorous exercise. Final models were adjusted for age, race, and percentage of body fat.

Results

Thirteen anovulatory cycles (luteal progesterone < 1 ng/mL) were excluded. The remaining 463 cycles had 41 clinical LPD cycles (8.9%), 39 biochemical LPD cycles (8.4%), and 20 cycles meeting both criteria (4.3%). Most experienced LPD for only one cycle, though 8 experienced two clinical cycles (3.4%) and 5 experienced two biochemical cycles (2.1%). Of note, nearly all women with clinical LPD had a peak luteal progesterone of ≤ 10 ng/mL, but of 422 cycles without clinical LPD, many also had progesterone levels of ≤ 10 ng/mL.

Following covariate adjustment, clinical LPD had lower E2, FSH, and LH concentrations during the follicular and luteal phases, and lower luteal progesterone levels compared with women without clinical LPD. With integrated hormone levels, clinical LPD had lower E2, progesterone, LH, and FSH across the cycle.

Women with biochemical LPD had significantly lower E2 during the follicular and luteal phases and lower luteal progesterone levels, but no significant differences in LH or FSH. Integrated hormone levels showed lower E2 and progesterone, but higher LH against controls.

Discussion

This study suggests that regularly menstruating women exhibit evidence of LPD based on luteal length or level of progesterone secretion, potentially through different mechanisms. Short luteal phase duration (< 10 d) or suboptimal luteal progesterone (< 5 ng/mL) affected 8.9% and 8.4% of ovulatory cycles, respectively.

Short luteal phase duration is a poor predictor of luteal integrated progesterone levels, with some studies reporting that half of cycles with a short luteal phase (<11 d) had adequate luteal progesterone. [3] This study found over half the cycles with short luteal phase duration had a luteal progesterone level > 5 ng/mL. There was greater overlap with clinical LPD when the criterion for maximum serum luteal progesterone was extended to < 10 ng/mL, but this would incur a higher false positive rate diagnostically.

The study reports both types of LPD are highly associated with hormonal differences in the follicular and luteal phases. Both follicular and luteal E2 concentrations were significantly lower in biochemical and clinical LPD. Clinical LPD had significantly lower LH and FSH across the cycle compared to those without clinical LPD, supporting the hypothesis that alterations of the hypothalamic-pituitary-ovarian axis impair both folliculogenesis and corpus luteum function, which may ultimately compromise endometrial stability. The higher integrated LH found only in biochemical LPD supports the idea that clinical and biochemical LPD may differ in etiology.

“Clinical LPD had significantly lower LH and FSH across the cycle compared to those without clinical LPD, supporting the hypothesis that alterations of the hypothalamic-pituitary-ovarian axis impair both folliculogenesis and corpus luteum function, which may ultimately compromise endometrial stability.”

While the data showed both types of LPD were associated with decreased blood flow at menses, results regarding LPD criteria and cycle length varied. Though a shorter luteal duration was associated with reduced cycle length, biochemical LPD had longer cycle lengths. It is unclear if this is due to differing pathologic mechanisms in LPD — biochemical LPD pathophysiology being more similar to PCOS — or missed progesterone assessments in the study from variability in days to sera collection after ovulation.

Given that a short luteal phase duration of < 10 days along with maximum luteal progesterone of ≤ 10 ng/mL reveals the best overlap between clinical and biochemical LPD, LPD assessment with a validated ovulation prediction kit and a well-timed serum progesterone sample is cost-effective, reasonably accurate, and minimally invasive. A serum progesterone level of < 10 ng/mL approximately 6-8 days after ovulation may indicate an LPD cycle has occurred.

“A serum progesterone level of < 10 ng/mL approximately 6-8 days after ovulation may indicate an LPD cycle has occurred.”

Study strengths include thorough monitoring of a large cohort with no known gynecological disorders for two menstrual cycles, and use of a validated monitor to time clinic visits to biologically relevant windows. Limitations include the inability to obtain daily biospecimen measurements or to assess ovulation via ultrasound. This could lead to incorrect classification of some luteal progesterone levels as suboptimal, or inaccurate assessment of some luteal phases as short.

The lack of consistency of menstrual cycle characteristics and reproductive hormone concentrations between biochemical and clinical LPD suggests their differing mechanisms. Although any luteal phase progesterone concentration > 3 ng/mL provides reliable evidence of ovulation, no consistent threshold has been established to identify abnormal corpus luteum function, supporting that serum progesterone alone lacks specificity to diagnose LPD. Future research could examine whether well-diagnosed LPD is associated with implantation delay, as implantation occurs in the mid-luteal phase, and delayed implantation predisposes to infertility and/or pregnancy loss. Additional research is also needed to assess the clinical implications of both types of luteal phase deficiency.

References

[1] Smith ML, Schust DJ. Endocrinology and recurrent early pregnancy loss. Semin Reprod Med. 2011;29(6):482-490. doi:10.1055/s-0031-1293202
[2] Schliep KC, Mumford SL, Hammoud AO, et al. Luteal phase deficiency in regularly menstruating women: prevalence and overlap in identification based on clinical and biochemical diagnostic criteria. J Clin Endocrinol Metab. 2014;99(6):E1007-E1014. doi:10.1210/jc.2013-3534
[3] Smith SK, Lenton EA, Landgren BM, Cooke ID. Is the short luteal phase a defective luteal phase? Ann N Y Acad Sci. 1985;442:387-90. doi: 10.1111/j.1749-6632.1985.tb37544.x. PMID: 3860044

ABOUT THE AUTHOR

Alexandra Piselli, MD, MS

Alexandra Piselli, MD, MS is a recent graduate of Georgetown University School of Medicine in Washington, DC. She earned her master’s degree in biophysics and physiology from Georgetown University, and completed a bachelor of science in biology at the University of North Carolina at Chapel Hill in Chapel Hill, NC. Dr. Piselli plans to pursue residency in obstetrics and gynecology and is interested in infertility and fertility preservation. She enrolled in the FACTS elective to be able to offer as many options as possible for those struggling with infertility in her future practice.