Allopregnanolone, The Hormone that Connects Mental Health and Menses?
By: Deepa Manda
Editor’s Note: Today, we are highlighting research published in Psychoneuroendocrinology by researchers Kimbal et al. that analyzed the allopregnanolone-to-progesterone ratio across the menstrual cycle and in menopause. Deepa Manda, a former FACTS elective participant, summarized this 2020 study, discussed how allopregnanolone might connect to mental health, and noted that this hormone might one day become a part of the hormonal assessment done in various fertility awareness-based methods.
Allopregnanolone, or 3α-5α-tetrahydroprogesterone, is a neuroactive steroid that can be synthesized from steroid hormone precursors, including progesterone or synthesized de novo from cholesterol. This hormone is made in the brain, adrenal glands, ovaries, and testes. The hormones, 5-alpha reductase, and 3-alpha hydroxysteroid dehydrogenase, convert allopregnanolone to progesterone. Low levels of allopregnanolone have been implicated in many mood disorders, including depression, anxiety, and post-traumatic stress disorder. However, it is unclear whether the level of allopregnanolone varies during the menstrual cycle or if it decreases after menopause.
“Low levels of allopregnanolone have been implicated in many mood disorders, including depression, anxiety, and post traumatic stress disorder.”
This study aimed to measure the serum levels of allopregnanolone and progesterone by gas chromatography-mass spectrometry (GC/MS) at each phase of the menstrual cycle in 10 pre-menopausal women and just once in 24 postmenopausal women. The researchers hypothesized that the allopregnanolone to progesterone ratio would decrease from the follicular to the luteal phase. They also hypothesized that post-menopausal females would have lower levels of progesterone and allopregnanolone but similar allopregnanolone to progesterone ratios when compared to premenopausal females in the follicular phase of the menstrual cycle. 
This 2020 study included 10 healthy premenopausal females and 24 postmenopausal females. Inclusion criteria required a history of regular menstrual cycles since menarche. Exclusion criteria included a patient’s history of current or lifetime psychiatric disorders, current cigarette smoking, use of psychotropic medications, and the use of estrogens or progestins. Researchers confirmed ovulatory function and menstrual phase by serum luteal progesterone of greater than 5 ng/mL in premenopausal females. The researchers measured the serum allopregnanolone and progesterone levels at three points in a single menstrual cycle: during the follicular phase (day 1-7), mid-cycle phase (day 13-16), and luteal phase (day 20-23).
Kimball et al. reported the mean age of the premenopausal females to be 34, while the mean age of the postmenopausal females was 61. All subjects were nonsmokers, and there was no significant difference in body mass index (BMI) between the groups. The researchers found that allopregnanolone and progesterone levels increased from the follicular to the luteal phase; however, the ratio of allopregnanolone to progesterone decreased 8-fold. The mean ratio was similar in pre-and postmenopausal females in the follicular phase but significantly lower at mid-cycle and in the luteal phase of premenopausal females. Kimbal et al. also found that mean allopregnanolone and progesterone levels were lower across all phases of the menstrual cycle in postmenopausal females. In addition, the levels of allopregnanolone did not increase proportionally to the level of progesterone.
“The researchers found that allopregnanolone and progesterone levels increased from the follicular to the luteal phase; however, the ratio of allopregnanolone to progesterone decreased 8-fold.”
This study is valuable as it’s the first to characterize the allopregnanolone-to-progesterone ratio throughout the menstrual cycle, but its implications for depression and mood disorders remain complicated. Existing research among women with premenstrual dysphoric disorder (PMDD) varies widely; separate studies have concluded that this population has an allopregnanolone-to-progesterone ratio that is lower, higher, and no different than healthy controls.[3-5] Although this study’s results indicate that both progesterone and allopregnanolone increase individually during the cycle, the levels do not rise proportionally and the overall allopregnanolone-to-progesterone ratio decreases.
The lower ratio of allopregnanolone to progesterone in the luteal phase suggests that this may contribute to premenstrual syndrome and luteal phase mood disorders.  However, prior research has posited that changes in allopregnanolone levels may play a greater role than lower ratios or absolute levels, . A similar study by Gilder et al. across 36 patients found that women with premenstrual dysphoric disorder (PMDD) actually had significantly greater allopregnanolone levels. Additionally, they found lower levels of allopregnanolone among less symptomatic PMDD women. Thus, the findings by Kimball et al. directly contradict the research by Gilder et al. which implicates relative allopregnanolone excess, rather than deficiency, in women with premenstrual mood disorder. This underscores the need and importance of more research among women with varying degrees of mood disorders.
Despite these contradictory findings, Kimball et al. did report lower levels of allopregnanolone and progesterone in postmenopausal females compared to premenopausal females across all phases of the menstrual cycle. This supports previous studies. Additionally, the study echoes previous research suggestive of a relationship between neuroactive steroid levels and mood disorders. 
There are several limitations of this study, including small sample size, and a procedural shortcoming. Kimball et al. estimated the timing of the mid-cycle in premenopausal females and measured serum (not central) levels of allopregnanolone. The researchers also noted that they did not collect information about participant alcohol or illicit drug use, which is important to note as acute intoxication has been shown to increase allopregnanolone levels. 
This study adds to a pool of mixed study findings and highlights the need for more research in determining the role of allopregnanolone in menstrual-related mood disorders. Although Kimball et al. found increasing allopregnanolone and progesterone levels during the menstrual cycle, there was a decrease in the allopregnanolone-to-progesterone ratio from the follicular to the luteal phase, which diverges from some of the existing research. Nonetheless, the researchers did confirm that the allopregnanolone to progesterone ratio is higher among postmenopausal women as compared to premenopausal women at mid-cycle and in the luteal phase. Overall, there is still much to learn about the role of hormones in mood disorders that affect the luteal phase of the menstrual cycle. With future research and broader sample populations, allopregnanolone may become part of the hormonal assessment done in various fertility-based awareness methods, including NaPro technology and FEMM, to lend insight into mood disorders.
“Overall, there is still much to learn about the role of hormones in mood disorders that affect the luteal phase of the menstrual cycle.”
 Kimball A et al. 2020. The allopregnanolone to progesterone ratio across the menstrual cycle and in menopause. 112, 1-13. [PubMed: 31780185]
 Direkvand-Moghadam A, S. K, Delpisheh A, Kaikhavandi S, 2014 Epidemiology of premenstrual syndrome (PMS)-a systematic review and meta-analysis study. J Clin Diagn Res. 8, 106–109. [PubMed: 24701496]
 Monteleone P, Luisi S, Tonetti A, Bernardi F, Genazzani AD, Luisi M, Petraglia F, Genazzani AR, 2000. Allopregnanolone concentrations and premenstrual syndrome. Eur J Endocrinol 142, 269–273.
 Girdler SS, Straneva PA, Light KC, Pedersen CA, Morrow AL, 2001 Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry. 49, 788–797. [PubMed: 11331087]
 Martinez PE, Rubinow DR, Nieman LK, Koziol DE, Morrow AL, Schiller CE, Cintron D, Thompson KD, Khine KK, Schmidt PJ, 2016. 5alpha-reductase inhibition prevents the luteal phase increase in plasma allopregnanolone levels and mitigates symptoms in women with premenstrual dysphoric disorder. Neuropsychopharmacology 41, 1093–1102.
 Timby E, Backstrom T, Nyberg S, Stenlund H, Wihlback AC, Bixo M, 2016 Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study. Psychopharmacology (Berl). 233, 2109–2117. [PubMed: 26960697]
ABOUT THE AUTHOR
Deepa Manda is a fourth-year medical student at University of Pikeville- Kentucky College of Osteopathic Medicine (UP-KYCOM) in Pikeville, Kentucky. She completed her undergraduate education at the University of Akron in Akron, OH, and she went on to complete her Master of Public Health with a concentration in Health Promotion and Education at the University of Cincinnati in Cincinnati, OH. She plans to do her residency in internal medicine and is extremely interested in health equity and education, along health disparities. She enrolled in the FACTS elective to gain a better understanding of how to address fertility issues and other gynecological disorders in the context of natural family planning methods. She wanted to gain knowledge about natural family planning to help empower and address fertility challenges with women and couples.