Perimenopause & Menopause Awareness Month
Oral Progesterone for Perimenopausal Symptoms: A Review of Research
By: Kathryn Messelt, DO
Director’s Note: During Perimenopause & Menopause Awareness Month, we are featuring research published in 2020. The Canadian study by Prior et al [1]addresses the use of oral micronized progesterone for perimenopausal night sweats and hot flashes. Dr. Kathryn Messelt, a former FACTS elective participant, summarized findings that highlight the shortcomings of hormone therapy in the traditional management of perimenopause. The research sparks questions about treatment options for women in the perimenopausal period and focuses on the need to improve vasomotor symptom management. To learn more about this important topic, please sample our CME webinar, Perimenopause: Common Issues of the Transition to Ovarian Quiescence from Part C of our online CME course.
Introduction
Vasomotor symptoms (VMS) including hot flashes and night sweats are common in the perimenopausal and postmenopausal stages of the female reproductive cycle. Previous studies in postmenopausal women confirm the effectiveness of traditional menopause hormone therapy (MHT) with combined estrogen and progesterone (including synthetic progestins) to treat these symptoms. [2][3]However, these randomized control trials (RCTs) have also shown MHT is insufficient to treat similar VMS in perimenopausal women. Several RCTs evaluated the use of estrogen-only therapy versus placebo in perimenopausal women with VMS and failed to show a significant difference between the treatment groups.
According to Prior et al, research has demonstrated several benefits of progesterone; it decreases central nervous system inflammation, improves sleep, and reduces anxiety. [4][5] Along with well-established research showing that combined progesterone and estrogen play a part in decreasing VMS, these researchers hypothesized progesterone may be beneficial to treat VMS in perimenopausal women.
“Research has demonstrated several benefits of progesterone; it decreases central nervous system inflammation, improves sleep, and reduces anxiety.”
Methodology
Women were recruited initially from Vancouver but later from all of Canada to participate in this four-month study. Eligible participants included women aged 35-58 years who had menstruated at least once within the prior twelve months. Applicants underwent a 1-month baseline monitoring period during which they noted vasomotor symptoms as well as their frequency, quality, and severity, and were required to meet a standardized baseline in order to be randomized. Progesterone treatment groups received 300 mg of oral micronized progesterone daily while placebo groups received an identical placebo pill which they took daily. Over 3 months, participants kept a daily record of VMS on a standardized scoring form. They also completed a perceived change questionnaire and an overall interference in perimenopause questionnaire. Analysis was by intention-to-treat and utilized a log of the average daily baseline VMS score. Treatment efficacy was assessed by ratio of the mean VMS score between groups.
Results
A total of 189 women were randomized into placebo and progesterone groups and included a majority of women who were white, educated, and employed. At the end of the 3-month treatment period, VMS scores, frequency, and severity of symptoms were not significantly different between groups.
Although VMS scores did not vary between therapy groups, the perception of participants on the overall effectiveness of therapy was significantly different between groups. Women receiving oral progesterone perceived a greater subjective improvement in night sweat severity and frequency as well as quality of sleep compared to placebo group participants. Moreover, women in the progesterone therapy group felt that perimenopausal symptoms were less disruptive in daily life and less bothersome compared to those in the placebo group.
“Women receiving oral progesterone perceived a greater subjective improvement in night sweat severity and frequency as well as quality of sleep … (and) felt that perimenopausal symptoms were less disruptive in daily life and less bothersome compared to those in the placebo group.”
Discussion
The purpose of this study was to assess, over the course of 3 months, whether oral progesterone had a significant effect on vasomotor symptoms in perimenopausal women who had experienced VMS and who had menstruated within the last 12 months. This is an important distinction, given the different symptoms women experience before and after menopause that require more refined treatment options. Previous RCTs have demonstrated MHT is less effective when prescribed in perimenopause than when used after menopause.
This topic was investigated further by Prior et al in 2023 via a double-blind RCT in which two groups of perimenopausal women received oral progesterone or placebo. Although the size of the randomized population fell below the number needed to achieve the desired study power, their findings provided insight into the role of progesterone to manage VMS in perimenopausal women.
The study results revealed no significant difference between the mean VMS scores of both study populations. Thus, no direct correlation could be drawn between oral progesterone therapy and VMS management in perimenopausal women. However, study participants who were taking progesterone therapy perceived an overall decrease in the frequency and severity of night sweats. Additionally, when asked about the impact of VMS and perimenopausal symptoms on daily life, participants perceived less interference when taking progesterone versus placebo.
This unique study differentiates between perimenopausal and postmenopausal women who experience VMS and identifies a need to define therapeutic interventions for these distinct populations. Ideally, the study would have enrolled 228 women to achieve maximum statistical power. Despite the limited study size and the lack of statistically significant differences between the placebo and intervention groups, the presence of perceived differences in symptom improvement among participants warrants larger studies to determine the role of progesterone in managing perimenopausal VMS.
“This unique study differentiates between perimenopausal and postmenopausal women who experience vasomotor symptoms and identifies a need to define therapeutic interventions for these distinct populations.”
Most study participants were white, educated, employed women, and the study was limited to the population of Canada, lacking generalizability to the general female population. A more diverse pool of potential participants may lend strength to the application of future study data.
This study elicits curiosity regarding treatment options for women in the perimenopausal period and highlights a lack of effective treatments for vasomotor symptoms in particular. It also brings to light the fact that MHT has proven to be suboptimal in alleviating VMS in perimenopause due to the unique hormonal profile between peri- and postmenopausal women. A unique question posed by this study is whether there may be a significant difference between the use of progesterone alone for VMS compared to combined estrogen and progesterone in MHT. Determining whether progesterone therapy alone versus MHT or placebo may provide relief from vasomotor symptoms and their interference in daily life in perimenopause would benefit patients in this stage of their reproductive life.
Editorial Note: The 2023 article by Prior et al included errors in Table 2 that were subsequently corrected. The author correction was added in editing as reference #5.
References
[1] Prior J, Cameron A, Fung M, et al. Oral micronized progesterone for perimenopausal night sweats and hot flushes: A 12-week randomized phase III Canada-wide clinical trial. SSRN Electronic Journal. Published online 2020. doi:10.2139/ssrn.3517407
[2] Genazzani AR, Monteleone P, Giannini A, Simoncini T. Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice. Hum Reprod Update. 2021;27(6):1115-1150. doi:10.1093/humupd/dmab026
[3] Fait T. Menopause hormone therapy: latest developments and clinical practice. Drugs Context. 2019;8:212551. Published 2019 Jan 2. doi:10.7573/dic.212551
[4] Prior JC, Cameron A, Fung M, et al. Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial [published correction appears in Sci Rep. 2024 Jul 27;14(1):17229. doi: 10.1038/s41598-024-68283-0]. Sci Rep. 2023;13(1):9082. Published 2023 Jun 5. doi:10.1038/s41598-023-35826-w
[5] Prior JC, Cameron A, Fung M, et al. Author Correction: Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial. Sci Rep. 2024;14(1):17229. Published 2024 Jul 27. doi:10.1038/s41598-024-68283-0
ABOUT THE AUTHOR
Kathryn Messelt, DO
Kathryn Messelt, DO is a first-year family medicine resident at UMN St. John’s Hospital. She earned her medical degree from Kansas City University in Joplin, Missouri. Dr. Messelt completed undergraduate training at the University of St. Thomas in St. Paul, Minnesota with a degree in biology. She has a special interest in preventive medicine and women’s health.
Learn more about perimenopause with Teresa Kenney in Part C!
