November 8, 2021
By Estefan Michael P. Beltran, M.S.
Hormone Profiles and the Luteal Phase: A Review of Research
Editor’s Note: The luteal phase is the consistent, post-ovulatory phase of a woman’s menstrual cycle. A normal luteal phase reflects proper functioning of internal hormones, which can be measured through serum and urinary testing. A study[i] by Alliende et al published in Frontiers in Public Health in 2018 studied the luteal phase in healthy fertile women. Their research and findings were summarized below by Estefan Michael Beltrán while on the FACTS elective.
Introduction
Luteal phase defects are associated with infertility and pregnancy loss. Presently, clinicians typically use serum progesterone levels to evaluate the quality of the luteal phase. However, due to the pulsatile release of progesterone from the corpus luteum, it can be difficult for both patients and clinicians to get an accurate reading of their progesterone level at the desired time. Additionally, patients are often inconvenienced by the need to anticipate which day to come into a lab to get their blood drawn. This is especially difficult for women whose peak days vary from cycle to cycle.
This studyi by Alliende et al aims to evaluate the urinary hormone profile of women during their post-ovulatory phase to provide a preliminary reference range for the urinary reproductive hormones.
Methods
Early morning urine was collected daily from 25 white, healthy, fertile-proven women ranging from 24 to 37 years of age. These samples were stored in a freezer until collected for evaluation, which occurred every 2 weeks. Urinary hormone profiles were tested for estrone-3-glucuronide (EG), pregnanediol-3 alpha-glucuronide (PG), and luteinizing hormone (LH) levels using World Health Organization (WHO) monitored radioimmunoassay measurements. Both EG and PG have been accepted as surrogates for serum estrogen and serum progesterone, respectively. Non-competitive radioimmunoassays were used to measure hormone levels, which were adjusted for urine excretion rate. Luteal phase hormonal profiles were broken down into three percentile groups (≤10th percentile, 50th percentile, and ≥90th percentile).
In total, 78 cycles were assessed, with each woman completing at least 3 cycles. The participants had regular cycles (25-35d) prior to this study, asevidenced by vulvovaginal mucus and basal body temperatures (BBT). Exclusion criteria included current/prior use of hormonal contraception in the last six cycles, breastfeeding within the last six months, participation in vigorous exercise, abnormal body mass, liver or kidney dysfunction, and use of chronic drug therapy. Throughout the study, cycles were monitored via mucus, BBT, and LH to identify the luteal phase and presumed ovulation. The luteal phase was divided into initial, medial, and final zones.
Results
All evaluated cycles followed a normal ovulatory mucus pattern with biphasic basal body temperatures and normal cycle length (mean cycle length = 28d). The identification of luteal phase by vulvovaginal mucus versus LH was similar. Overall, a perception of “very poor” mucus during the follicular phase was significantly related (p<0.001) to luteal EG levels ≤ 10th percentile. Additionally, five out of six women with low luteal PG reported having newborns <5.5lbs.
The median PG (10-90th percentile group) level rose from 1.7µg/mol and peaked at luteal phase day 8 to 9.0µg/mol before eventually falling back to 2.0µg/mol. PG levels were recorded as low as 1.2µg/mol (≤10th percentile group) and as high as 39.8µg/mol (≥90th percentile group). EG profiles were also established into three groups, with the median range starting at 66.6µg/mol (high: 191µg/mol in ≥90th percentile group) and dropping to 30.1µg/mol (low: 22.6µg/mol in ≤10th percentile group). It should be noted that only some women (n=3) had both PG and EG levels concurrently in the ≤10th percentile group for at least one cycle. Only one woman demonstrated recurrent low PG and EG levels.
LH levels were also measured but not reported in the published version of this study, since a more comprehensive article using ultrasound to monitor ovulation in relation to LH was published during the publication process.
Discussion
The results of this study provide a tangible preliminary classification system of urinary luteal phase hormones. Abnormalities in progesterone are often associated with luteal phase defects and poor pregnancy outcomes (e.g., preterm birth, IUGR, miscarriage).
As a result of this study, home urinary progesterone tests can be developed with more specificity and quantitative value. This is also true for estrogen levels during the luteal phase, which may provide further insight into luteal phase defects and infertility, especially given the strong correlation between a perception of “very poor” mucus quality and low luteal estrogen found in this study.
Some individuals in this study exhibited recurrent PG levels in the ≤10th percentile despite having normal length luteal phases and a history of successful fertility. The participants in this study, however, demonstrate generally higher PG and EG luteal phase levels compared to previous publications.[ii] The authors attribute this difference to their healthy, fertile patient population compared to a mixed population in prior studies. Additionally, they note a difference in the hormonal assays used (WHO radioimmunoassays in the present study vs. Ovarian Monitor enzyme immunoassays in prior work) as well as the decision in previous studies to adjust values for creatinine as opposed to excretion rates used in this study.
Some fertile-proven women showed isolated incidences of low PG or EG during their luteal phase. Therefore, evaluating at least two cycles would be best. Also, this study provides potential reference ranges for PG outside of the mid-luteal phase, which is most often monitored in clinical practice. Urine tests are easier to obtain than serum tests, and can paint the entire picture of a woman’s luteal phase. Additionally, urine testing may help discover luteal phase defects that may be unrecognized due to a normal length cycle.
This study prompts the need for further investigation to see how these values hold up against women who have ovulatory dysfunction. Furthermore, their work should be compared to other hormonal assays and methods that adjust for creatinine to determine which is more useful in clinical settings.
References
[1] Alliende ME, Arraztoa JA, Guajardo U, Mellado F. Towards the Clinical Evaluation of the Luteal Phase in Fertile Women: A Preliminary Study of Normative Urinary Hormone Profiles. Front Public Health. 2018;6:147. Published 2018 May 31. doi:10.3389/fpubh.2018.00147.
[1] Johnson S, Weddell S, Godbert S, Freundl G, Roos J, Gnoth C. Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day. Clin Chem Lab Med. (2015) 53:1099–108. 10.1515/cclm-2014-1087.
About the Author
Estefan Beltran
Estefan Beltran wrote this review as a fourth-year medical student at Chicago Medical School-Rosalind Franklin University. Upon graduation from the University of Maryland, he taught high school biology and gained a deeper understanding of how social determinants of health manifest in the lives of students and their families. After medical school, he plans to complete residency training in family medicine to serve as an advocate for individuals like his former students. He is excited to interact with the community via all aspects of health: acute care, prevention, education, mentorship, and family planning! He would like to learn more about FABMs and how these methods can be used to help low-income couples conceive (or not!) before resorting to more expensive treatments.
