By: Grace Le
Editor’s Note: As March is Endometriosis Awareness Month, this week we highlight a study that explores the relationship between prolactin and infertility in the setting of endometriosis. The study was published in 2009 by Wang et al and is titled, “The Role of Prolactin- and Endometriosis-associated Infertility.” Grace Le summarized the article while on the FACTS online elective. Having learned about charting the female cycle and its role in both endometriosis and infertility, she noted potential benefits of charting with fertility awareness-based methods (FABMs) for future research in this area. Learn more about the practical applications of FABMs in one of our thirteen FACTS CME courses!
Introduction
Within the realm of women’s health, the complex relationship between endometriosis and infertility is understood, though not fully appreciated. Evidence of endometriosis has been found in 25-50% of patients who experience infertility and undergo laparoscopy. [1] However, endometriosis can have a diagnostic delay as long as 12 years due to its variable clinical manifestations and/or treatment approach. [2] For the patient, this means more time with suboptimal cycles and less time for reproductive potential. Thus, it is important to investigate this complex association between infertility and endometriosis to better care for such patients.
“Evidence of endometriosis has been found in 25-50% of patients who experience infertility and undergo laparoscopy. However, endometriosis can have a diagnostic delay as long as 12 years due to its variable clinical manifestations and/or treatment approach.”
In the study by Wang et al [3] summarized below, the authors conducted a literature review of prior research to understand the role of prolactin (PRL) in endometriosis-associated infertility (EAI). The study assessed serum PRL levels, PRL receptors in endometriosis implants, PRL hyperstimulation, peritoneal fluid PRL, nocturnal PRL, and luteal phase PRL among patients with endometriosis. As PRL has far-reaching effects on a woman’s reproductive and overall health and can be targeted in therapies for EAI, this study aimed to address potential opportunities to prevent and manage EAI.
Baseline PRL levels in endometriosis-associated infertility
Most studies report that patients with EAI tend to have elevated serum PRL levels at baseline. [4] Some studies show a correlation between hyperprolactinemia and severity of endometriosis. However, other research contradicts this finding, and no consistent relationship has been confirmed.
PRL levels after thyrotropin-releasing hormone (TRH)
As PRL is involved in numerous biological processes, many factors influence its secretion. Thyrotropin-releasing hormone (TRH) is a hypothalamic hormone that stimulates the release of PRL from the pituitary gland. It has been thought that even if baseline PRL levels are normal, if they rise after TRH administration, occult hyperprolactinemia could be present. This could be one mechanism by which EAI and PRL interact. Studies of patients with EAI have found that PRL levels after TRH were significantly higher among patients who did not eventually conceive compared to those who did. The researchers concluded that occult hyperprolactinemia could cause EAI, but there was no further evidence as to where the excess PRL originates from (implants, pituitary, or other sources) or if PRL correlates with endometriosis staging.
“Studies of patients with endometriosis-associated infertility have found that prolactin levels after thyrotropin-releasing hormone (TRH) were significantly higher among patients who did not eventually conceive compared to those who did.”
PRL levels in luteal phase
Endometriosis has long been presumed to be associated with ovulatory cycles, as many patients report improved symptoms during pregnancy and menopause when ovulation does not occur. Yet, increasing evidence over time reveals that endometriosis can exhibit a wide range of ovulatory dysfunction, particularly luteal phase defects (LPD). In physiologically normal cycles, the endometrium secretes PRL during the luteal phase, and it is thought that endometriotic implants may also do this. However, this was controversial as of the time of publication based on conflicting research results.
Studies have not always found significantly different PRL levels in the luteal phase between women with EAI and those with unexplained infertility. One study found significantly lower progesterone levels on days 3, 7, and 10 of the luteal phase in women with EAI. There has been no evidence that PRL secretion in the luteal phase is a clear cause of EAI, nor that there is any relationship between PRL levels and endometriosis severity.
Peritoneal fluid PRL levels
It is known that endometriosis can affect any location within the pelvic and peritoneal cavity, with implants on the diaphragm, liver, bowel, and/or bladder. PRL in peritoneal fluid has been proposed as a marker of endometriosis, as secretory implants would likely be the only source of PRL within the abdomen. Women with endometriosis tend to have larger volumes of peritoneal fluid compared to women without the condition, and the fluid has an inflammatory profile (increased macrophages, lymphocytes, prostaglandins). Some studies found elevated luteal phase PRL and LH in peritoneal fluid in women with EAI compared to controls; follicular phase concentrations were normal. Still, other research has not reached similar conclusions and there remains a lack of consensus.
Nocturnal PRL levels
In healthy women, PRL typically rises during sleep, possibly due to its roles in neurodevelopment and learning. [5] One theory of PRL’s role in EAI involves an alteration in nocturnal PRL levels. One study found more pronounced and prolonged PRL peaks at night in women with EAI; unfortunately, there was no control for other causes of higher PRL, including stress. As of the time of publication, no other studies addressed this potential relationship between PRL and EAI.
Discussion
The study by Wang et al attempted to shed light regarding causes of EAI and the potential role of increased PRL secretion in its pathophysiology. Endometriosis remains a common women’s health condition, with a prevalence of 6-10% of the population. It not only causes pain and reduced quality of life but also often coincides with reduced fertility potential for these women. This study is an important step to understand the mechanism of infertility in endometriosis and the role PRL may play. Even though much of the referenced research had conflicting results, it seems possible that hyperprolactinemia, whether overt or latent, is present and could lead to infertility. Since PRL is such an influential hormone and often a target in other causes of infertility, additional studies must address the question with more robust, updated, and controlled studies.
“This study is an important step to understand the mechanism of infertility in endometriosis and the role PRL may play … it seems possible that hyperprolactinemia, whether overt or latent, is present and could lead to infertility.”
Much of the research referenced in this study is over three decades old, and improved laboratory testing and methods could yield more accurate results. Each study had discrepancies of PRL level thresholds, timing of lab draws, and confounding factors such as other etiologies of PRL secretion. Often these studies performed lab draws at day 21 or some other “standard” cycle day without regard to the likely wide range in timing of ovulation in the study subjects. None of the studies used fertility awareness-based methods (FABMs) to ascertain a patient’s fertile window, and PRL is known to be more elevated in the ovulatory or luteal phase, or after recent nipple stimulation. Inappropriately timed lab draws could have confused the results.
Future research could benefit from utilizing FABMs and a restorative reproductive medicine (RRM) approach to better define the various phases of the female cycle. Though the question of prolactin’s role in EAI is complicated and likely multifactorial, addressing this through the lens of FABMs and RRM could optimize women’s reproductive and overall health.
Editor’s Note: Ongoing research into this topic continues to find an association between higher PRL levels and EAI. A study published in the Iranian Journal of Reproductive Medicine in 2015 revealed statistically significant associations between PRL levels and staging of endometriosis. In 2019, a study published in JBRA Assisted Reproduction observed higher PRL levels in women with infertility with more severe endometriosis (stages III/IV) when compared to women with infertility and no endometriosis. The researchers concluded PRL levels may be helpful to detect endometriosis in these patients.
References
[1] Giudice LC, Kao LC. Endometriosis. 2004;364(9447):789–799. doi: 10.1016/S0140-6736(04)17403-5
[2] Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod. 1996 Apr;11(4):878-80. doi: 10.1093/oxfordjournals.humrep.a019270. PMID: 8671344
[3] Wang, H. , Gorpudolo, N. & Behr, B. (2009). The Role of Prolactin– and Endometriosis-Associated Infertility. Obstetrical & Gynecological Survey, 64 (8), 542-547. doi: 10.1097/OGX.0b013e3181ab5479
[4] Mirabi P, Alamolhoda SH, Golsorkhtabaramiri M, Namdari M, Esmaeilzadeh S. Prolactin concentration in various stages of endometriosis in infertile women. JBRA Assist Reprod. 2019 Aug 22;23(3):225-229. doi: 10.5935/1518-0557.20190020. PMID: 30969738; PMCID: PMC6724390
[5] Mogavero MP, Cosentino FII, Lanuzza B, Tripodi M, Lanza G, Aricò D, DelRosso LM, Pizza F, Plazzi G, Ferri R. Increased Serum Prolactin and Excessive Daytime Sleepiness: An Attempt of Proof-of-Concept Study. Brain Sci. 2021 Nov 28;11(12):1574. doi: 10.3390/brainsci11121574. PMID: 34942875; PMCID: PMC8699448
ABOUT THE AUTHOR
Grace Le
Grace Le is a fourth-year medical student at Virginia Commonwealth University School of Medicine in Richmond, VA. She completed her undergraduate education at Virginia Commonwealth University in Richmond, VA. She will soon start family medicine residency training and is interested in lifestyle medicine, FABMs, and caring for underserved populations. She enrolled in the FACTS elective to better understand FABMs and how to share this knowledge with women, empowering them to know their bodies and improve their overall health no matter their age or circumstances.
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