Women in Balance

Progesterone & General Health

Dalton K. Prenatal progesterone and educational attainments. British Journal of Psychiatry 1976; 126:438-42.

This study compares educational attainments of 34 children whose mothers received prenatal progesterone with 37 normal and 12 toxemic controls. Results at ages 17-24 showed that progesterone children were more likely to continue schooling after 16 years, a higher number left school with ‘O’ and ‘A’ level grades and more obtained entrance to university. The best academic results were found for children whose mothers had received over 5 grams of progesterone for a minimum of eight weeks, with treatment beginning before week sixteen.
Mahesh VB, Brann DW, and Hendry LB. Diverse modes of action of progesterone and its metabolites. J Steroid Biochem Molec Biol 1996;56(1-6):209-219.

A review of the actions of progesterone and its metabolites demonstrates physiological significance in such biological activities as may have importance in the regulation of stress, post-partum depression, memory, cognition, PMS, and depression, to name a few.
Nappi C, Affinito P. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endocrin Invest 1994;15(11):801-6.

Eighty regularly menstruating women with mastodynia were studied to evaluate the clinical effectiveness of vaginally administered micronized progesterone. Subjects were randomly assigned to one of two groups, with all participating in a control cycle prior to treatment. One group received 4 grams of vaginal cream containing 2.5% natural progesterone for six cycles from day 19 to day 25 of the cycle. The other group was similarly treated with placebo. Both subjective reporting on a daily basis and clinical examination revealed a significant reduction in breast pain, defined as 50% reduction, in 64.9% of subjects receiving progesterone and 22.2% of subjects receiving placebo. Effects of breast nodularity were not significant. No side effects were detected.
itruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. Contraception 1987 Oct; 36(4): 373-402.

This paper reviews the effects and benefits of oral micronized progesterone. Progesterone exhibits anti-estrogenic effects, anti-androgenic effects, and anti-mineralcorticoid effects in addition to its progestational effects. No side effects have been reported for micronized progesterone with respect to lipid profile, coagulation, or blood pressure, leading the authors to recommend micronized progesterone as suitable for treatment of PMS, menopause, irregular cycles, and pregnancy maintenance. Sofuoglu M, Babb DA, Hatsukami DK. Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav 2001 May-Jun;69(1-2):299-304. In this unique randomized controlled study, administration of progesterone (200 mg oral) demonstrated a decrease in craving for and subjective effects of cigarette smoking in female smokers. With progesterone treatment, there was a noted trend to decrease smoking.

Progesterone Safety

Historically and unfortunately, progesterone and synthetic progestins have been lumped together with respect to their safety profiles, although the two hormones vastly different in their molecular structure and effects. Further complicating the understanding of individual safety, early reports of concerns for progestins were not often separated from those of the combination hormone therapies they were a part of. In the last decade, and increasingly since the pivotal Women’s Health Initiative (WHI) study results of 2002, there has been heightened interest by researchers for elucidating the safety of progesterone – alone, in combination, and in contrast to synthetic progestins. This research suggests a good safety profile for progesterone with respect to the cardiovascular system, breasts, brain, and other target tissues. Numerous human studies evaluating progesterone reported the treatments were well tolerated, with few side effects.

Ovaries:
Hu Z, Deng X. [The effect of progesterone on proliferation and apoptosis in ovarian cancer cell] Zhonghua Fu Chan Ke Za Zhi 2000 Jul;35(7):423-6. [Article in Chinese]

In this in vitro study, researchers demonstrated that administered progesterone had a dose-dependent effect causing inhibition of growth of epithelial ovarian cancer cells, suggesting an anti-cancer effect.
Yu S, Lee M, Shin S, Park J. Apoptosis induced by progesterone in human ovarian cancer cell line SNU-840. J Cell Biochem 2001;82(3):445-51.

Although the mechanism is not fully understood, progesterone has been used as an anticancer therapy for the treatment of ovarian cancer. This study evaluates the effects of progesterone on ovarian cancer cells (SNU-840). Following incubation with 100 microM progesterone, viability of the cancer cells was evaluated by MTT assay, resulting in 45% of the cells being viable after 48 h. Additionally, [(3)H] thymidine incorporation assay showed that progesterone completely inhibited the proliferation of the cells at the same duration and concentration. Cell death was by apoptosis as seen by fragmentation of the chromosomal DNA via colorimetric TUNEL assay. The level of the p53 mRNA reached its maximum at 12 h, then decreased following incubation with progesterone as determined by northern blotting assay. This is consistent with the fact that many apoptosis processes are mediated by up-regulation of the p53 expression. The authors conclude that progesterone inhibits the proliferation of and elicits apoptosis of the SNU-840 line of ovarian cancer cells and up-regulates p53 expression.

General Safety:
Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988 Nov; 159(5): 1203-9.

This small pilot study evaluated progesterone and its metabolites following administration of oral micronized progesterone in eight postmenopausal women. Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-massspectrometry. Evaluation of serial blood samples showed elevated levels of serum progesterone and its metabolites from baseline, reaching a peak between 2 and 6 hours after oral administration. The following compounds: progesterone, 5 beta-pregnan-3 alpha, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione, were identified. These compounds have reported anesthetic qualities, which may contribute to the sedative and hypnotic effects seen with oral administration of progesterone. The authors reported that, in one subject, 400 mg of oral micronized progesterone induced a hypnotic state lasting approximately 2 hours.
Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999 Jun;180(6 Pt 1):1504-11.

This pilot study demonstrated a significant increase in serum progesterone levels in 6 women receiving topical progesterone cream (Pro-Gest Ò ; 30-60 mg P4/day) and 17beta estradiol (0.05mg patch). The absorption of progesterone via a topical cream correlated well with estrogen absorption (p< 0.001). They concluded that progesterone cream appeared to be a safe and effective route of application.
Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause 2002 Jul-Aug;9(4):253-63.

Twenty-three early postmenopausal women were randomized to either medroxyprogesterone acetate (MPA) or oral micronized progesterone combined with conjugated equine estrogens (CEE) and followed for 91 days in a sequence of treatments. None of the hormone treatments had any noticeable effect on mood. Participants using MPA experienced more breast tenderness and bleeding than those using progesterone. This study debunks the belief that progesterone depresses mood in healthy individuals.
de Wit H, Schmitt L, Purdy R, Hauger R. Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. Psychoneuroendocrinology 2001 Oct;26(7):697-710.

This randomized controlled study investigated the effects of acute progesterone administration (25, 50, 100 mg, intramuscularly, 1 dose/wk) on mood. Contrary to the investigators’ expectations, very few unwanted behavioral effects were noted, and only in the highest dose (100 mg) did women slightly increase their self-rating of “sluggishness”.
Darj E, Axelsson O, et al. Liver Metabolism During Treatment with Estradiol and Natural Progesterone. Gynecological Endocrinology June 1993; 7(2):111-4.

Thirty postmenopausal women were treated daily for four months with 2 mg micronized 17 beta-estradiol and micronized progesterone orally in doses of 50, 100 and 200 mg daily. Serum concentrations of sex hormone-binding globulin (SHBG), corticosteroid binding globulin (CBG), ceruloplasmin, lipoprotein A and liver enzymes were measured. Serum SHBG and CBG increased during treatment with a weak association shown between progesterone and serum CBG. Levels of lipoprotein A and liver enzymes did not change, concluding that natural progesterone supplementation in postmenopausal women does not appear to cause any side effects to the liver.
de Ziegler D, Fanchin R. Progesterone and progestins: applications in gynecology. Steroids 2000 Oct-Nov;65(10-11):671-9.

This paper reviews the use of a transvaginal progesterone gel as a viable option to other routes of application of natural progesterone (intramuscular, oral micronized), and offered it as a viable option to synthetic progestins given the low incidence of side effects noted in existing studies.
Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999 Sep;72(3):389-97.

The literature reviewed in this tutorial indicates a potential use for oral micronized progesterone for the treatment of secondary amenorrhea, dysfunctional uterine bleeding, luteal phase disorders, premenopausal bleeding disorders, and as a component of hormone replacement therapy that may provide a better safety profile than commonly utilized synthetic progestins.
Horita K, Inase N, Miyake S, Formby B, Toyoda H, Yoshizawa Y. Progesterone induces apoptosis in malignant mesothelioma cells. Anticancer Res 2001 Nov-Dec;21(6A):3871-4.

In this study, researchers demonstrated that progesterone administration suppressed cell proliferation and induced apoptosis (programmed cell death) in malignant mesothelioma cells (21 1H). This is consistent with an earlier in vitro study that found administered progesterone induced apoptosis in the breast cancer cell line, T47-D.
Shantha S, Brooks-Gunn J, Locke RJ, Warren MP. Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study. J Women Health Gend Based Med 2001 Dec;10(10):991-7.

This 3 month, multicenter randomized study evaluated the psychological side effects of a vaginally applied progesterone gel in reproductive aged women treated for hypothalamic amenorrhea or premature ovarian failure. No differences were noted in psychometric measures as evaluated by the Hopkins Symptom Checklist. Natural progesterone in a vaginal gel can be an effective treatment for women requiring hormone therapy.
Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. Contraception 1987 Oct; 36(4): 373-402.

This paper reviews the effects and benefits of oral micronized progesterone. Progesterone exhibits anti-estrogenic effects, anti-androgenic effects, and anti-mineralcorticoid effects in addition to its progestational effects. No side effects have been reported for micronized progesterone with respect to lipid profile, coagulation, or blood pressure, leading the authors to recommend micronized progesterone as suitable for treatment of PMS, menopause, irregular cycles, and pregnancy maintenance.

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