Research Blog
October 23, 2023
Optimal Takeaways
Progesterone, a vital hormone derived from cholesterol, plays a pivotal role in reproduction, pregnancy, bone health, and several physiological functions. Low levels may be associated with hot flashes, night sweats, and interrupted sleep in postmenopausal women. Progesterone therapy may help alleviate these symptoms, possibly due to its interactions with stress hormones, neurotransmitters, and temperature regulation. Progesterone may also support antioxidant status and reduce oxidative stress in postmenopausal women.
However, higher levels of progesterone in postmenopausal women have been linked to prediabetes, type 2 diabetes, and certain types of ovarian tumors. While progesterone has shown positive effects on memory and cognition in certain phases of menopause, its overall impact remains inconclusive. For postmenopausal hormone therapy, natural progesterone is preferred over synthetic versions, and it's typically applied transdermally.
Standard Range:
Quest
- Immunoassay: Below 0.5 ng/mL (1.59 nmol/L)
- LC/MS: 0.2 ng/mL (0.64 nmol/L) or below
Low progesterone in menopause may be associated with hot flashes, night sweats, and poor sleep (Hitchcock 2012).
High progesterone in menopause may be associated with prediabetes and type 2 diabetes (Jiang 2019). Higher progesterone was associated with reduced alcohol craving during abstinence in postmenopausal women (Weinland 2021).
Overview
Progesterone is a cholesterol-based steroid hormone essential to reproduction, pregnancy, bone health, the nervous system, and cardiovascular health (Taraborrelli 2015). It may help control symptoms of menopause, including hot flashes, night sweats, and poor sleep, possibly by lessening stress hormones, interacting with neurotransmitters, and regulating body temperature (Hitchcock 2012).
Higher serum progesterone was associated with prediabetes and type 2 diabetes in a study that included 1,303 postmenopausal women: 446 controls, 427 with prediabetes, and 430 with type 2 diabetes. Median serum progesterone was 0.8 ng/mL (2.54 nmol/L) in controls, 1.1 ng/mL (3.5 nmol/L) in those with prediabetes, and 1.4 ng/mL (4.45 nmol/L) in those with type 2 diabetes. Although the mechanism of action was not clear, researchers note it may be associated with a potential inhibitory effect of progesterone on insulin release and beta-cell proliferation (Jiang 2019).
Progesterone in the postmenopausal period doesn’t appear to be associated with breast cancer risk the way estrogens and androgens are and may even be somewhat protective (Missmer 2004). Progesterone counteracts the proliferative effects of estradiol throughout the menstrual cycle. It is often incorporated into postmenopausal hormone therapy to protect the uterus (Gompel 2018) and reduce the risk of atrial fibrillation (Wong 2017) associated with estrogen-only treatment.
Progesterone also reduces menopause symptoms without negatively affecting carbohydrate and lipid metabolism, blood pressure, thrombogenicity, or body weight (Regidor 2014). Higher progesterone levels in menopause are also associated with higher levels of the antioxidant enzyme CuXnSOD and lower protein carbonyl oxidative stress markers (Unfer 2015).
Research suggests that progesterone helps reduce hot flashes via its effects on the hypothalamus, a different mechanism than estrogen, which reduces hot flashes by decreasing brain levels of serotonin and norepinephrine. Progesterone is known to have sedative effects and may even reduce brain inflammation (Pe’er 2021). However, the direct impact of progesterone on postmenopausal cognition is unclear. One 12-week double-blind placebo-controlled randomized crossover pilot study suggests that progesterone therapy positively affected visual and verbal working memory. Serum progesterone levels were not documented in the study (Berent-Spillson 2015).
The Leisure World cohort study found that higher serum progesterone was associated with decreased performance on cognitive tasks, while other research found no association. Additional research on 643 healthy postmenopausal women who were not on hormone therapy found that higher serum progesterone was associated with better verbal memory and global cognition but only early in menopause, i.e., those within six years of menopause with a mean age of 55.4 versus within 10 years of menopause with a mean age of 65.4 (Henderson 2013, Henderson 2018).
Higher serum progesterone levels in postmenopausal women with alcohol use disorder were associated with reduced craving for alcohol during abstinence than those with lower serum progesterone (Weinland 2021).
Progesterone is often incorporated into menopausal hormone replacement therapy. Researchers note that natural progesterone is preferred over synthetic progestin, and the transdermal route is recommended (Genazzani 2021). However, topically applied progesterone can increase saliva levels by 10-fold and capillary blood levels by 100-fold, and serum monitoring of progesterone levels may not identify an overdose (Du 2013).
Oral micronized progesterone, which is “bioidentical” to human progesterone, may be considered an option for hormone therapy. A randomized placebo-controlled trial of 133 healthy menopausal women found that the bioidentical progesterone Prometrium significantly reduced vasomotor symptoms. Those on Prometrium reported significant improvements in the frequency and severity of daytime and nighttime hot flashes and night sweats and significant improvements in sleep. Those on progesterone had a mean serum level of 26.98 ng/mL (85.81 nmol/L), while those taking the placebo had 0.28 ng/mL (0.89 nmol/L). Women who had been randomized to progesterone but had stopped taking it had progesterone levels below 0.63 ng/mL (2 nmol/L) (Hitchcock 2012). Oral micronized progesterone appears to relieve vasomotor symptoms and improve the ratio of progesterone to estradiol as well (Prior 2011).
However, additional research suggests that higher progesterone after menopause may be contraindicated in some individuals. One study of postmenopausal women with ovarian tumors found that higher serum progesterone was significantly and independently associated with mucinous versus other ovarian tumors. A cut-off of 0.41 ng/mL (1.3 nmol/L) or above helped differentiate those with mucinous tumors (Matsuoka 2016).
References
Berent-Spillson, Alison et al. “Distinct cognitive effects of estrogen and progesterone in menopausal women.” Psychoneuroendocrinology vol. 59 (2015): 25-36. doi:10.1016/j.psyneuen.2015.04.020
Du, Joanna Y et al. “Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood.” Menopause (New York, N.Y.) vol. 20,11 (2013): 1169-75. doi:10.1097/GME.0b013e31828d39a2
Genazzani, Andrea R et al. “Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.” Human reproduction update vol. 27,6 (2021): 1115-1150. doi:10.1093/humupd/dmab026
Gompel, A. “Progesterone, progestins and the endometrium in perimenopause and in menopausal hormone therapy.” Climacteric : the journal of the International Menopause Society vol. 21,4 (2018): 321-325. doi:10.1080/13697137.2018.1446932
Henderson, Victor W et al. “Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause.” Proceedings of the National Academy of Sciences of the United States of America vol. 110,50 (2013): 20290-5. doi:10.1073/pnas.1312353110
Henderson, V W. “Progesterone and human cognition.” Climacteric : the journal of the International Menopause Society vol. 21,4 (2018): 333-340. doi:10.1080/13697137.2018.1476484
Hitchcock, Christine L, and Jerilynn C Prior. “Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women.” Menopause (New York, N.Y.) vol. 19,8 (2012): 886-93. doi:10.1097/gme.0b013e318247f07a
Jiang, Jingjing et al. “The effect of progesterone and pregnenolone on diabetes status in Chinese rural population: a dose-response analysis from Henan Rural Cohort.” European journal of endocrinology vol. 181,6 (2019): 603-614. doi:10.1530/EJE-19-0352
Matsuoka, Ayumu et al. “Elevated serum progesterone levels in postmenopausal women with mucinous ovarian tumors.” Menopause (New York, N.Y.) vol. 23,5 (2016): 544-9. doi:10.1097/GME.0000000000000587
Missmer, Stacey A et al. “Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women.” Journal of the National Cancer Institute vol. 96,24 (2004): 1856-65. doi:10.1093/jnci/djh336
Pe’er, Eitan. "Progestogens and the Menopause." Progestogens in Obstetrics and Gynecology (2021): 193-202.
Prior, J C. “Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause.” Facts, views & vision in ObGyn vol. 3,2 (2011): 109-20.
Regidor, P-A. “Progesterone in Peri- and Postmenopause: A Review.” Geburtshilfe und Frauenheilkunde vol. 74,11 (2014): 995-1002. doi:10.1055/s-0034-1383297
Taraborrelli, Stefania. “Physiology, production and action of progesterone.” Acta obstetricia et gynecologica Scandinavica vol. 94 Suppl 161 (2015): 8-16. doi:10.1111/aogs.12771
Unfer, T C et al. “Estrogen plus progestin increase superoxide dismutase and total antioxidant capacity in postmenopausal women.” Climacteric : the journal of the International Menopause Society vol. 18,3 (2015): 379-88. doi:10.3109/13697137.2014.964669
Weinland, Christian et al. “Progesterone serum levels correlate negatively with craving in female postmenopausal in-patients with alcohol use disorder: A sex- and menopausal status-separated study.” Progress in neuro-psychopharmacology & biological psychiatry vol. 110 (2021): 110278. doi:10.1016/j.pnpbp.2021.110278
Wong, Jorge A et al. “Menopausal age, postmenopausal hormone therapy and incident atrial fibrillation.” Heart (British Cardiac Society) vol. 103,24 (2017): 1954-1961. doi:10.1136/heartjnl-2016-311002
