Medical References


Compiled by Garth Birdsey BPharm Grad Dip Hosp Pharm

Progesterone Absorption


1 :Cooper A; Spencer C; Whitehead MI etal. Systemic absorption of progesterone from Progest cream in postmenopausal women (letter) Lancet.1998 Apr 25;351(9111):1255-6

                This is THE article that was given so much emphasis in the medical literature as proof that progesterone does not get absorbed topically. Several “leading lights” of the gynaecological world have repeatedly quoted this article as proof, even though there are some methodological problems with the assay used and the use of progesterone and topical oestrogens in the same patients. To get a better view of this article it is suggested that you also read the following discussions.

                Lancet 1998 Sep 12;352(9131):905

                Lancet 1998 Sep 12;352(9131):905-6

2 :Leonetti HB; Longo S; Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet-Gynecol.1999 Aug;94(2):225-8

3: Burry KA; Patton PE; Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am-J-Obstet-gynecol.1999 Jun;180(6pt 1):1504-11

                These two articles, coming a year later, give a different view. Interesting that they have been given scant attention by the “leading lights”. Both give evidence of therapeutic effect from transdermal progesterone. One to give relief from the hot flushes and mood swings, the other to help protect the endometrium from estrogenic effects. Of importance the doses used were probably too low to affect bone loss, this is mentioned in the Leonetti article as is a mention of the 1 year follow up being too short.


4 :Cincinalli E;de-Ziegler D. Transvaginal progesterone:evidence for a new functional ‘portal system' flowing from the vagina to the uterus. Hum-Reprod-Update.1999 Jul-Aug;5(4):365-72

5 :Levy T; Gurevitch S; Bar-Hava I etal. Pharmacokinetics of natural progesterone administered in the form of a vaginal tablet. Hum-Reprod.1999 Mar;14(3):606-10

6 :Ross D; Cooper AJ; Pryse-Davies J etal. Randomized,double-blind,dose ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am-J-Obstet-Gynecol.1997 Oct;177(4):937-41

7: Warren MP; Biller BMK; Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: Effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am-J-Obste-Gynecol 1999;180:42-8

                All these articles give evidence that vaginally administered progesterone is well absorbed, possibly better than trans-dermal. It also gives evidence that for those women who feel they must use an estrogen supplement, vaginal progesterone, in adequate doses will protect their endometrium from the estrogenic effects.


8 : Wetzel W. Micronized progesterone: a new option for women's health care. Nurse-Pract. 1999 May:24(5):62-6,71,75-6

9 : Langer RD. Micronized progesterone: a new therapeutic option. Int-J-Fertil-Womens-Med.1999 Mar-Apr;44(2):67-73

10 :delignieres B. Oral micronized progesterone. Clin-Therapeutics 1999 Jan;21(1):41-60

11 : Warren MP; Shantha S. Uses of progesterone in clinical practice. Int-J-Fertil. 1999;44(2):96-103

12 : Wetzel W. Human identical hormones:real people,real problems,real solutions. Nurse-Pract-Forum1998 Dec;9(4):227-34

                References 8-12 group together articles that discuss the rationale behind the use of progesterone as distinct from progestagens. The article from France (10) describes some considerable experience with progesterone, although it is oral progesterone that they use, so the doses are much higher. Still the responses are encouraging. Some 500,00 French women cannot all be experiencing placebo effects!


13: Newall CA; Anderson LA; Phillipson JD. Herbal Medicines. A guide for health care professionals.

14 : Mills S; Bone K. Principles and practice of Phytotherapy: Modern herbal medicine.

                These two textbooks are both informative and very easy to read. They give balanced evidence both for and against the uses of various herbs in the treatment of menopausal symptoms. The Mills' book has a very informative section on wild yam, which will dispel all myths on its use and its ability to be transformed into progesterone by the body.


15 :Foidart JM;Colin C; Denoo X et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fert.Steril. 1998 May;69(5):963-9

                This article provides evidence that progesterone suppresses the estrogen induced proliferation of breast epithelial cells. Again progesterone protects against estrogen. In this study both estrogen and progesterone were applied to the breast as topical gels!

16 : Cohen I; Beyth Y; Altaras MM et al. Estrogen and progesterone receptor expression in postmenopausal tamoxifen-exposed endometrial pathologies. Gynecol-Oncol.1997 Oct;67(1):8-15

                Again further evidence that progesterone protects against estrogenic compounds. This time it is Tamoxifen. This article gives further proof that tamoxifen has estrogenic effects on the endometrium in menopausal women. This should ring alarm bells in women with breast cancers who are being treated with tamoxifen,especially if they still have their uterus!

17 : Homberg L; Anderson H, for the HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer- is it safe?), a randomised comparison: trial stopped. Lancet 2004;363:453-55

18 : Chlebowski RT; Col N. Menopausal hormone therapy after breast cancer. Lancet 2004;363:410-11

                The HABITS trial puts to rest the notion that after breast cancer treatment including that with tamoxifen you can use oestrogens to overcome the “menopausal “ symptoms. All it did was increase the risk of recurrence! What is interesting in this study was that all HRT regimens used contained oestrogens and synthetic progestins. The risk was greatest in those women treated with tamoxifen or had HRT prior to the initial diagnosis of breast cancer. Of importance was that the trial did not include the use of placebo or alternative treatments for hot flushes!


19: The writing group for the PEPI trial. Effects of estrogen/progestin regimens on heart disease risk factors in postmenopausal women.JAMA.1995 Jan 18;273(3):199-208.

                The famous PEPI trial, often quoted and often mis-quoted. It depends on which company you support or product you wish to sell. The conclusions of this trial are confusing as they say that unopposed estrogen is the best method, but do recognise the problem of endometrial hyperplasia. So the next best method is continuous estrogen with cyclicle medroxyprogesterone(provera). However they forget to mention the third arm of the study which used oral micronized progesterone which had the same results as the estrogen and provera arm! And they say the drug companies have no influence on publishing studies! If you can it is worth reading the comments that have followed this study.

                JAMA 1995 Dec 6;274 (21):1676

                JAMA 1995 Dec 6;274 (21):1675 and 1675-6

20: Heart and Estrogen/progestin Replacement Study (HERS) Research group. Randomized trial of estrogen plus estrogen for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998 Aug 19;280(7):605-13

                This is an equally famous and land mark study. It really debunks the notion that conventional HRT protects menopausal women from heart disease. So it puts into doubt the use of HRT as a routine protection for heart disease in menopausal women, it may in fact be harmful in the first 12 months! As you would expect from such a study there are multitudes of letters and comments. 16 published comments and discussions followed in the 6 months after the study was published. So it really set minds working.

21: Kuller LH. Hormone replacement therapy and coronary heart disease. A new debate. Med-Clin-North-Am. 2000 Jan;84(1):181-98

22: Mercuro G; Pitzalis L; Podda A. et al. Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women. Am-J-Cardiol. 1999 Jul 15; 84(2):214-8


23: Million Women Study Collaborators. Breast Cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27

24: Hulley S; Furberg C; Barrett-Connor E; et al. Noncardiovascular Disease Outcomes During 6.8 years of Hormone Therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA 2002;288:58-66

25: Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women, Principal results from the Women's health Initiative Randomized Controlled Trial. JAMA 2002;288:321-333

26: Lacey JV; Mink PJ; Lubin JH et al. Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer. JAMA 2002;288:334-341

27: Fletcher SW and Colditz GA Failure of Estrogen plus Progestin Therapy for Prevention. JAMA 2002;288:366-367

28: Wassertheil-Smoller S;Hendrix SL;Limacher M et al. Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women. The Women's Health Initiative: A randomised Trial. JAMA 2003;289:2673-2684

29: Rapp SR ;Edpeland MA; Shumaker SA et al. Effect of Estrogen plus Progestin on Global Cognitive Function in Postmenopausal Women. The Women's Health Initiative Memory Study: A randomised controlled trial. JAMA 2003;289:2663-2672

30: Shumaker SA;Legault C; Rapp SR et al. Estrogen plus Progestin and the incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. The Women's Health Initiative Memory Study: a Randomized Controlled Trial. JAMA 2003; 289:2651-2662

                All these references, 23-30, give compelling evidence against the combination of oestrogen and synthetic progestins. All used equine oestrogens (Premarin) and medroxyprogesterone (Provera). The combination proved to give no protection to women in regards memory, failing cognitive function and the progression of dementia. In fact it looks like the combination may accelerate the decline! I stress that this is long- term use, over 5 years. So compelling evidence for not being on such therapy for more than 5 years.

                The editorial written by Fletcher and Colditz, put the whole argument into perspective. The combination of synthetic oestrogens and progestins provides little protection to menopausal women, rather they suggest, the therapy does actual harm.