Safety and Adverse effects of Natural Progesterone

Safety and Adverse effects of Natural ProgesteroneSafety and Adverse effects of Natural Progesterone

I received this email from a patient:

Hello Dr Dach,

I mentioned to my mom this evening that I would start to take progesterone pills next month for a portion of my cycle. She said that a few years ago, she used a progesterone cream. She said she couldn’t remember the reason why her doctor put her on a cream instead of a pill so she wanted me to ask about the health risks that go along with taking a progesterone pill.

I didn’t think to ask Dr. Dach when I spoke with him today about the side effects of using progesterone (pill or cream). Are there any side effects that I should be concerned about or aware of? Is there any difference in health risks between the progesterone pill or cream?

Thank you all for the time that you spend with me answering questions and planning my treatment! I really appreciate it!

Sincerely, Nancy

My Reply to Nancy:

Hi Nancy,

Progesterone is the natural hormone made by the ovary after ovulation, so it is very safe with no adverse effects.  Excess dosage however, can cause drowsiness, which is helpful for treating insomnia if taken before bedtime to get a good night’s sleep.

For the cycling female, the usual dosage is 100 mg capsule twice a day with food for days 12-26 of the cycle.  If the morning progesterone dosage causes drowsiness, then this is omitted and instead both capsules are taken at night before sleep.

Progersterone is NOT a Progestin

Sometimes, a patient or even their doctor mistakenly confuses Progesterone with the Progestins.  Progestins are synthetic hormones which are chemically altered forms of Progesterone.  The Progestins are known to cause cancer and heart disease, and have other adverse effects which are not shared by natural progesterone.  For this reason, we do not prescribe Progestins in my office.  We use the safe, protective natural progesterone.

The MPA mouse breast cancer model

Medroxyprogesterone (MPA) is still being prescribed,  raking in huge profits for Pfizer.  MPA ( medroxy-progesterone) is the progestin used in the Women’s Health Initiative Study, and used by 95 million women, until 2002 when MPA was shown carcinogenic.  It is now used in the laboratory to induce breast cancer in mice.  This is called the “MPA mouse Breast Cancer Model“.(28)  Would you take a synthetic hormone used as a carcinogen to induce breast cancer in mice?  I wouldn’t recommend it. (28)

Progesterone as Breast Cancer Preventive Agent

In a DMBA induced model of breast cancer in mice, Dr Jabara found progesterone inhibited carcinogenesis. Pretreatment with progesterone markedly inhibited DMBA induction of breast cancer in mice.(1) Dr Jabara concluded, “progesterone acts directly on the mammary gland to inhibit carcinogenesis”.(1)

In vitro studies with two breast cancer cell lines by Dr Formby showed that progesterone “exhibited a strong anti-proliferative effect” and induced apoptosis in the cancer cell line expressing the progesterone receptor.(2)

Drs Ferretti and Jerry suggest a protective role for progesterone, citing the work of Rajkumar who showed a protective effect of combined estrogen and progesterone in animal models of breast cancer.(3-5)

Buy Progesterone Cream on Amazon.

Article on the origin of progesterone:

Russell Marker and the Origins of Bioidentical Hormones

Article by Dr. Mercola on Progesterone

Articles with Related Interest:

The Safety of Bio-Identical Hormones

The Importance of Bioidentical Hormones

Waking Up from the Synthetic Hormone Nightmare


1) Jabara, Anne G., and P. S. Anderson. “Effects of progesterone on mammary carcinogenesis when various doses of DMBA were applied directly to rat mammae.” Pathology 14.3 (1982): 313-316.   When smaller doses of DMBA (100 microgram or less) were applied, Progesterone pretreatment markedly reduced carcinogenesis, the inhibitory effect being statistically significant in the group dusted with the smallest dose of carcinogen. ” results support the suggestion that progesterone acts directly on the mammary gland to inhibit carcinogenesis”

2) Formby, Bent, and T. S. Wiley. “Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.” Annals of Clinical & Laboratory Science 28.6 (1998): 360-369. Progesterone inhibits growth induces apoptosis in breast cancer cells Formby Bent T S Wiley Annals Clin Lab Sci 1998

3) Ferretti, Gianluigi, Alessandra Felici, and Francesco Cognetti. “The protective side of progesterone.” Breast Cancer Research 9.6 (2007): 402.  Protective Side of Progesterone Ferretti Gianluigi Alessandra Felici Francesco Cognetti Breast Cancer Research 2007

4) Jerry, D. Joseph. “Roles for estrogen and progesterone in breast cancer prevention.” Breast Cancer Research 9 (2007): 102.  Estrogen and Progesterone in Breast Cancer Prevention Jerry D Joseph Breast Cancer Research 2007

“Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer.”

5) Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9.1 (2007): R12. Hormone-induced protection of mammary tumorigenesis genetically engineered mouse Rajkumar Lakshmanaswamy Breast Cancer Research 2007

6) Eisen, Andrea, et al. “Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers.” Journal of the National Cancer Institute 100.19 (2008): 1361-1367.  Hormone therapy and Risk of Breast Cancer in BRCA1 Mutation Carriers Eisen Andrea Journal of the Nat Cancer Institute 2008

7) Chlebowski, Rowan T., et al. “Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial.” Jama 289.24 (2003): 3243-3253. Influence of Estrogen Plus Progestin on Breast Cancer in Postmenopausal Womens Health Initiative Chlebowski Rowan T Jama 2003

8) Barrett-Connor, Elizabeth, et al. “The postmenopausal estrogen/progestin interventions study: primary outcomes in adherent women.” Maturitas 27.3 (1997): 261-274.  NIH study used by Solvay for Prometium approval.  Showing progesterone prevents endometrial hyperplasia.

9) Murkes D, Conner P, Leifland et al. Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women. Fertil Steril. 2011 Mar 1;95(3): 1188-91.  Estradiol–Oral Progesterone vs Oral Equine Estrogens–Medroxyprogesterone on Breast Cell Proliferation Murkes Daniel Fertility and sterility 2011

10) Murkes D, Lalitkumar PG, Leifland et al. Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol. 2012 Oct;28 Suppl 2:12-5. Percutaneous Estradiol oral Progesterone Less Averse Effects Than Conjugated Equine Estrogens Medroxyprogesterone in the breasts of healthy women Murkes Daniel Gyneco Endo 2012

11) Fournier A, Berrino F, Riboli E et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005; 114(3): 448-54. Breast cancer risk in relation to different hormone replacement E3N‐EPIC cohort Fournier Agnes International Journal of Cancer 2005

12) Chang KJ et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995; 63(4):785-91.

To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo.
Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery.
Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses.
Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells.
exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo.

13) Wood CE, Register TC, Lees CJ et al. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34. Effects Estradiol with micronized progesterone or medroxyprogesterone on risk markers breast cancer postmenopausal monkeys Wood Charles Breast cancer research 2007

14) Campagnoli, C., Abbà, C., Ambroggio, S., & Peris, C. (2005). Pregnancy, progesterone and progestins in relation to breast cancer risk. J Steroid Biochem, 97(5), 441-450. Carlo Campagnoli Progestins progesterone hormone replacement risk breast cancer steroid biochemistry 2005 – Copy

15) Stanczyk FZ, Paulson RJ, Roy S. Percutaneous administration of progesterone: blood levels and endometrial protection. Menopause. 2005 Mar;12(3) 232-7. Percutaneous administration of progesterone blood levels endometrial protection Stanczyk Frank Menopause 2005

16) Anasti J, Leonetti H, Wilson K. Topical progesterone cream has antiproliferative effect on estrogen-stimulated endometrium. Fertil. Steril. 2003 Jan;79(1):221-2.

17) Sendag F, Terek MC, Karadadas N. Sequential combined transdermal and oral postmenopausal hormone replacement therapies: effects on bleeding patterns and endometrial histology. Arch Gynecol Obstet. 2001 Nov;265(4):209-13.

18) Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med. 2005 Nov-Dec, 11(6):36-8.Transdermal Progesterone As Alternative Progestin in Hormone Therapy Leonetti HB Landes J Altern Ther Health Med 2005

19) Holtorf, K. (2009). The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med, 121(1), 73-85. Bioidentical Hormone Debate Safer More Efficacious Than Synthetic Kent Holtorf Postgraduate Medicine 2009

20) L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Hermite_Could_Transdermal_estradiol_Progesterone_be_Safer_HRT

21) Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Tr, 107(1), 103-111.

22) Fournier, A., Fabre, A., Mesrine, S., Boutron-Ruault, M.-C., Berrino, F., & Clavel-Chapelon, F. (2008). Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol, 26(8), 1260-1268. Use of Different Postmenopausal Hormone Therapies and Risk Invasive Breast Cancer Fournier Agnès J Clin Oncology 2008

23) Markey, C., Luque, E., Munoz-de-Toro, M., Sonnenschein, C., & Soto, A. (2001). In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod, 65, 1215-1223.In utero exposure to bisphenol A alters development tissue organization of mouse mammary gland Markey Caroline M Biology of reproduction 2001

24) Jobling S, Reynolds T, White R, et al. (1995). A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Perspect, 103:582-587.

25) Arumugam, Arunkumar, Elaine A. Lissner, and Rajkumar Lakshmanaswamy. “The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.” Reproductive Biology and Endocrinology 12.1 (2014): 66. Role of hormones aromatase inhibitors on breast tumor growth in postmenopausal mouse model Arumugam Arunkuma Rajkumar Lakshmanaswamy Repro Biology Endo 2014

26) In Vivo. 2010 Jul-Aug;24(4):553-60. Short-term pregnancy hormone treatment of N-methyl-N-nitrosourea-induced mammary carcinogenesis in relation to fatty acid composition of serum phospholipids in female Lewis rats. Lai YC1, Hamazaki K, Yoshizawa K, Kawanaka A, Kuwata M, Kanematsu S, Hamazaki T, Takada H, Tsubura A.
Short-term oestrogen and progesterone treatment (STEPT) mimics the pregnancy hormone milieu. This study compared the development of N-methyl-N-nitrosourea (MNU)-induced mammary cancer in female Lewis rats that received STEPT in early or later life.
MATERIALS AND METHODS:Rats in Groups 1 and 2 received a single intraperitoneal injection of 50 mg/kg MNU at 4 weeks old. Pellets containing 0.5 mg 17beta-estradiol and 32.5 mg progesterone (EP) were subcutaneously implanted in rats in Group 1 during 6-9 weeks old. Rats in Groups 3 and 4 received 50 mg/kg MNU at 22 weeks old and again at 23 weeks old. EP pellets were implanted in rats in Group 3 during 24-27 weeks old. At the time of EP removal and 8 weeks afterward, 4 randomly selected rats in each group were sacrificed for blood sampling. The fatty acid composition of serum phospholipids was measured by capillary gas chromatography. The remaining rats were sacrificed when they developed mammary tumours >or=1 cm in diameter or at the termination of the experiment, which was at 18 weeks old for Groups 1 and 2 and at 64 weeks old for Groups 3 and 4. Mammary cancer was histologically confirmed.
RESULTS:Group 1 had a significantly suppressed incidence of mammary cancer compared to Group 2 (7% vs. 90%), whereas the cancer incidence in Group 3 was similar to that of Group 4 (50% vs. 56%). Rats in Group 1 had significantly smaller n-6/n-3 polyunsaturated fatty acid (PUFA) ratios and higher levels of docosahexaenoic acid (DHA) than those in Group 2 at the time of EP removal but not 8 weeks after EP removal. Neither the PUFA ratios nor the DHA levels differed between Groups 3 and 4 at any time. These data suggest that the age at which STEPT is administered is important, since its mammary cancer-suppressing potential was lost in aged animals.

27) The Hormone War is Heating Up

28) Lanari, Claudia, et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocrine-related cancer 16.2 (2009): 333-350.The MPA mouse breast cancer model Lanari Claudia 2009

29)Prior, J. C. “Progesterone for Symptomatic Perimenopause Treatment–Progesterone politics, physiology and potential for perimenopause.” Facts, views & vision in ObGyn 3.2 (2011): 109.

Because P4 and E2 complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia.

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Safety and Adverse effects of Natural Progesterone
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Safety and Adverse effects of Natural Progesterone
Safety and Adverse effects of Natural Progesterone
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7 thoughts on “Safety and Adverse effects of Natural Progesterone

  1. The interface of the neurosteroid, progesterone, and GABA, an inhibitory neurotransmitter and amino acid -both- is very significant in understanding the mechanism by which GABA works, particularly in women. We have helped many women get off benzodiazepine drugs by learning this.
    In the presence of the progesterone metabolite allopregnanolone, the subunit on the GABA-AR is activated and downregulated- meaning one becomes calmer. if there is not sufficient alloprgnanolone, then GABA can become an excitatory (stimulant) molecule instead of calming. GABA is fantastic for calmness but because of these complex mechanisms, little is obvious about its uptake as it does not cross the BB in the usual sequences.

  2. A large part of the ‘problem’ is the language we use. Both progesterone USP and medroxyprogesterone are progestins. I have a strong feeling that he definitions were intentionally made confusing so that the drug versions could be passed off as a kind of progesterone. Insidious?

    regards from Larry Frieders

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  7. Hello. My name is Ružica I’m old for 56 years. I’ve been postmenopausal for six years now. I also have hypothyroidism for which I use natural hormones. a little painful and high pressure and probably the dominance of estrogen, I also have a problem with sleeping, if I do not drink my pills I do not sleep well. I also have the right hip arthrosis. I’m interested in bio-progesterone, would it be good to take it? Where can I buy it? My libido and apathy are at zero. I would like your advice. Thank you.

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