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Categories available are: Androgens; Estrogens; Progesterone; Bone: Brain; Breast; Cardiovascular; Formulations; Menopausal Symptoms; Premenopause; Progestin; Safety; Uterus.
1. - The physiologic role and use of estriol. Paoletti J.
Int J Pharm Compounding 2009;13(4)270-275.
Estriol has an important physiological role in the prevention of breast cancer by balancing the effects of the stronger estrogens, estradiol and estrone, effectively acting as an anti-estrogen. The author explains this phenomenon and explains a rationale for appropriate dosing of estriol relative to estradiol in bioidentical hormone replacement therapy.
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2. - Bioidentical testosterone cream: a rare cause of postmenopausal virilisation. Ogilvie CM, Levenberg R, Milsom SR.
Aust N Z J Obstet Gynaecol 2009;49(1):116-7
Whether bioidentical or synthetic, hormones are powerful substances and must be dosed appropriately. This is a report of 2 cases of postmenopausal women using 0.1 mg/mL testosterone cream for low libido symptoms. After coming to their doctors with symptoms of virilization, including acne, facial hair, and muscle growth, both women were found to have 20 times the normal level of free testosterone in their blood. Regular testing is essential during any kind of hormone replacement to ensure that normal, physiological levels of a hormone are achieved.
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3. - Safety of maternal testosterone therapy during breast feeding. Glaser RL, Newman M, Parsons M, Zava D, Glaser-Garbrick D.
Int J Pharm Compounding 2009;13(4):314-317.
This was a study of testosterone levels in maternal blood, the infant's blood, and breast milk, after a nursing mother was given testosterone in the form of sublingual drops, vaginal cream, and a pellet implant. None of the delivery methods resulted in a significant increase of testosterone in breast milk or the infant's blood, although levels were raised in the maternal blood showing that the testosterone was absorbed after all 3 delivery methods. The testosterone therapy was effective in relieving symptoms of testosterone deficiency in the mother and was safe for the breast-fed infant.
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4. - Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J.
Menopause 2009; 16(5):923-31.
This randomized, placebo-controlled, double-blind clinical trial looked at the effects on libido and sexual function of 3 doses of DHEA or placebo vaginal suppositories applied with an applicator daily at bedtime for 12 weeks in 216 postmenopausal women with vaginal dryness. Potent beneficial effects were seen with all 3 DHEA doses in the 4 aspects of sexual function studied: sensation, lubrication, orgasm, and dryness during intercourse. DHEA converts naturally to active estrogens and androgens in tissues, and these hormones produced the beneficial effects on sexual function without raising systemic hormone levels.
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5. - Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J.
Menopause 2009; 16(5):907-22.
This randomized, placebo-controlled, double-blind trial studied the effects of 3 doses of DHEA or placebo given as daily vaginal suppositories for 12 weeks in 216 postmenopausal women with vaginal dryness. The suppositories were inserted at bedtime using an applicator. All measures of vaginal changes (pH, percentage of vaginal parabasal and supeerficial cells, vaginal secretions, and symptoms) showed an improvement after 2 weeks of treatment with all 3 DHEA doses compared to placebo. The cream did not cause serum steroid hormone levels to increase, unlike estrogen Formulations applied intravaginally. DHEA converts naturally to active androgens, such as testosterone, in tissues, and this local conversion is postulated as causing the beneficial effects on vaginal physiology without raising systemic hormone levels.
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6. - The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Krapf JM, Simon JA.
Maturitas. 2009; 63(3):213-9.
This article reviews testosterone's role in sexual function in women. Research is going on to study the safety and effectiveness of transdermal testosterone therapy in women with low sexual desire, sometimes called HSDD (hypoactive sexual desire disorder) if it leads to distress. The prevalence of this disorder is highest in women who are surgically menopausal, i.e., they have had both ovaries removed, which results in a sudden decline in testosterone levels that leads to a reduced desire for sex and less satisfying sex. The authors review clinical studies of transdermal testosterone therapy, both with and without estrogen, concluding that it is safe and effective in women struggling with HSDD.
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7. - Hormone therapy and risk of myocardial infarction: a national register study. Lokkegaard E, Andreasen AH, Jacobsen RK, Nielsen LH, Agger C, Lidegaard O.
Eur Heart J 2008;29(21):2660-8.
This large population study of Danish postmenopausal women found that transdermal estrogen therapy was associated with a significantly lower risk of myocardial infarction than oral unopposed estrogen therapy amongst those using hormone replacement therapy (HRT). The risk of myocardial infarction increased with longer duration of HRT in younger but not older women. A continuous HRT regimen resulted in the greatest risk of myocardial infarction in all age groups, while no increased risk compared to non-HRT users was seen for unopposed estrogen, cyclic estrogen/progestogen HRT, or tibolone. The type of progestogen or dose of estrogen did not appear to affect risk.
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8. - Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY.
BMJ 2008;336(7655):1227-31
This meta-analysis of 17 studies of postmenopausal women found that those using oral estrogens had an increased risk of thromboembolism compared with those using transdermal estrogens, particularly during the first year of treatment. Even in women with pre-existing risk factors for thromboembolism, transdermal estrogen use did not confer additional risk.
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9. - Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. L'Hermite M, Simoncini T, Fuller S, Genazzani AR.
Maturitas 2008;60(3-4):185-201.
This detailed review examines the way different types of hormone replacement therapy (HRT) affect the cardiovascular system, the brain, and the risk of breast cancer. It discusses the research that shows that non-oral estrogens have more favorable cardiovascular effects, such as improved blood pressure control and lower risk of thrombosis. It discusses the benefits of using natural progesterone rather than synthetic progestins in association with estrogens in HRT. Natural progesterone has a beneficial effect on blood vessels and the brain, and confers less or even no risk of breast cancer, compared with synthetic progestins.
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10. - Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product. Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr.
J Clin Pharmacol 2005; 5(6):614-9.
In 12 healthy, postmenopausal women, steady state levels of progesterone in the blood were measured in a randomized crossover study comparing topical progesterone cream (Pro-gest®, 40 mg twice daily x 12 days ) with oral micronized progesterone (Prometrium®, 200 mg daily x 12 days). There was no significant difference noted in mean steady state levels between the two products as measured by area under the curve (AUC) of progesterone levels in whole blood. This indicates that equivalent blood levels of progesterone can be achieved with substantially lower doses of topical progesterone cream than with oral micronized progesterone.
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11. - Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice. Wright JV.
Ann N Y Acad Sci. 2005;1057:506-24.
This review discusses the types of estrogens used in bioidentical hormone replacement, including their dosages and routes of administration. The author advocates the use of natural hormones because of the problems with using non-human identical synthetic hormones, highlighted largely by the Women's Health Initiative trial. However, bioidentical estrogens must be properly monitored to ensure appropriate dosing, just as is common for thyroid hormone replacement. The metabolism of estradiol to estrone and estriol is discussed. The author advocates the use of iodine supplements, which stimulate the metabolism of estradiol towards estriol. The amount of circulating estriol relative to estradiol and estrone is important in breast cancer risk: the greater the relative amount of estriol, the lower the breast cancer risk.
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12. - Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B, Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M.
Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004. Blood 2004; 104(11 Pt 1):414b-415b(Abstract 5318).
No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNF?, and IL-6) was observed, despite significant symptomatic improvement compared to placebo, in 30 women receiving 20 mg/day progesterone cream for 4 weeks. This finding indicates a lack of potential adverse effects of progesterone on the cardiovascular system, particularly with respect to risk of coronary artery disease and stroke. The authors conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy, and have led to an increase in stroke, do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.
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13. - A perspective on HRT for women: picking up the pieces after the Women's Health Initiative trial - Part 2. Gillson GR, Zava DT.
Int J Pharm Compounding 2003;7(5):330-8.
The authors review clinical evidence for the benefits of bioidentical progesterone over synthetic progestins. While both protect the uterine lining from proliferation caused by estrogens, progesterone has beneficial effects on cardiovascular health. The synergy between progesterone and estradiol , each "turning on" the other's receptors, has the added benefit of allowing the estradiol dosage to be reduced. Oral and transdermal dosing of bioidentical progesterone are discussed.
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14. - A perspective on HRT for women: picking up the pieces after the Women's Health Initiative trial - Part 1. Gillson GR, Zava DT.
Int J Pharm Compounding 2003;7(4):250-6.
This article discusses some fundamental aspects of safer hormone replacement therapy that may have been overlooked in the debate surrounding bioidentical versus synthetic hormones: Oral delivery of hormones is not optimal; application of hormones to the skin (transdermal application) has many important advantages; and synthetic progestins are not acceptable as a substitute for natural progesterone. The evidence for and principles behind these factors are presented.
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15. - Pharmacokinetic comparison of progesterone capsules with a progesterone gel after vaginal administration. Kleinstein J, Schlegelmilch R, Mazur D, Vens-Cappell B.
Arzneimittelforschung 2002; 52(8):615-21.
Twenty-four women participated in this randomized controlled, crossover study comparing the bioavailability and pharmacokinetics of a vaginal progesterone capsule (200 mg/dose) vs a progesterone vaginal gel (90 mg/dose). Both were well tolerated, and no differences were noted with respect to safety. The vaginal capsule delivered more progesterone, however peak concentrations between the two preparations didn’t differ.
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16. - Distribution and metabolism of topically applied progesterone in a rat model. Waddell BJ, O'Leary PC.
J Steroid Biochem Mol Biol 2002; 80(4-5): 449-55.
Following topical application of a commercially available progesterone cream, concentrations of fat and water-soluble metabolites of progesterone were measured in various tissues (uterus, kidney, salivary gland, liver) as well as plasma and urine. The topically applied progesterone was demonstrated to be well absorbed and had distribution and metabolism patterns similar to that seen with intravascular progesterone delivery.
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17. - Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Cicinelli E, de Ziegler D, Galantino P, Pinto V, Barba B, Morgese S, Schonauer S.
Am J Obstet Gynecol 2002;187(3):556-60.
In this study of 35 postmenopausal women, twice-weekly administration of a progesterone vaginal gel (45 mg P4/day) sufficiently protected the endometrium in women receiving transdermal estradiol (0.05 mg/d) as revealed by endometrial thickness and histology. The authors present vaginally applied progesterone as a viable option for hormone replacement therapy at menopause.
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18. - The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B.
J Clin Endocrinol Metab 2002;87(10):4536-40.
This randomized prospective study evaluated and compared the effects of ten days treatment with oral and vaginal micronized progesterone (MP) and medroxyprogesterone acetate (MPA) on glucose metabolism, lipid profiles, and hormonal parameters in 28 patients with polycystic ovary syndrome (PCOS). Oral MPA and oral MP decreased luteinizing hormone (P = 0.028, P = 0.009, respectively) and total testosterone (P = 0.013, P = 0.037, respectively) levels. There was no change in hormonal parameters with vaginal MP. Basal insulin decreased (P = 0.021) and insulin sensitivity increased significantly in the oral MPA group. Low density lipoprotein cholesterol (LDL) and lipoprotein (a) levels decreased only in the MPA group. This study concluded that MPA and oral MP may reduce insulin sensitivity in patients with PCOS. Vaginal MP had no effect on glucose metabolism and lipid profiles.
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19. - Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study. Shantha S, Brooks-Gunn J, Locke RJ, Warren MP.
J Womens Health Gend Based Med 2001;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.
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20. - Progesterone and progestins: applications in gynecology. de Ziegler D, Fanchin R.
Steroids 2000;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.
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21. - Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women. O'Leary P, Feddema P, Chan K, Taranto M, Smith M, Evans S.
Clin Endocrinol (Oxf) 2000;53(5):615-20.
Absorption of progesterone as provided in a topical preparation of “natural” progesterone cream to 6 premenopausal and 6 postmenopausal women was demonstrated via salivary hormone levels. Salivary progesterone concentrations reached their peak 1-4 hrs after application. A five-fold increase in mean levels was seen in the premenopausal group. Serum progesterone levels were not significantly different from baseline in either group, and serum progesterone was not seen as an effective measure of absorption of topically applied progesterone.
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22. - Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Burry KA, Patton PE, Hermsmeyer K.
Am J Obstet Gynecol 1999;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®; 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.
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23. - Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease. Plu-Bureau G, Le MG, Thalabard JC, Sitruk-Ware R, Mauvais-Jarvis P.
Cancer Detect Prev 1999;23(4):290-6.
This cohort study followed 1150 premenopausal French women diagnosed with benign breast disease. Topical progesterone cream, a common treatment for mastalgia in Europe, had been prescribed to 58% of the women. Follow-up accumulated 12,462 person-years. There was no association noted between progesterone cream use and breast cancer risk. Furthermore, women who had used both progesterone cream and an oral progestogen had a significant decrease in breast cancer risk (RR= 0.5) as compared to women who did not use progesterone cream. There was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. These results suggest there are no deleterious effects caused by percutaneous progesterone use in women with benign breast disease.
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24. - Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M.
Arterioscler Thromb Vasc Biol 1997; 17(11): 3071-8.
Oral hormone replacement therapy postmenopausally has been associated with an increased risk of stoke due to thromboembolism. This randomized, placebo-controlled study evaluated the differing effects of oral and transdermal estrogen/progesterone therapy or placebo on hemostasis. Oral, but not transdermal therapy was seen to increase the susceptibility of clotting in healthy post-menopausal women 45-64 years. The authors concluded that route of administration of hormones can affect the incidence of clotting, with oral hormone replacement increasing risk, and transdermal hormone replacement demonstrating no negative effect on clotting.
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25. - Transvaginal administration of progesterone. Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R.
Obstet Gynecol 1997;90(3):396-401.
Three different doses of transvaginal progesterone gel were administered to 40 estrogen-deprived women aged 25-41 years. Estradiol was administered orally for 28 days, with progesterone added vaginally on alternate days from days 15-27. Plasma gonadotropins, E1, E2 and progesterone were measured, and an endometrial biopsy was obtained to assess endometrial status and estrogen and progesterone receptor determinations. Transvaginal progesterone induced normal secretory transformation despite low serum progesterone levels, suggesting a direct transit of progesterone into the uterus, or “first uterine pass effect.”
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26. - Absorption of micronized progesterone from a nonliquefying vaginal cream. Kimzey LM, Gumowski J, Merriam GR, Grimes GJ Jr, Nelson LM.
Fertil Steril 1991; 56(5):995-6.
The pharmacokinetics are compared between orally administered micronized progesterone, and that administered through a vaginal cream. Oral progesterone is extensively metabolized prior to reaching the target tissues, and progesterone metabolites may comprise a significant amount of progesterone measured in the serum. When compared, vaginal application sustained progesterone levels over a longer period of time than orally administered progesterone.
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27. - Transdermal delivery of steroids. Sitruk-Ware R.
Contraception 1989; 39(1): 1-20.
This review summarizes the advantages of delivering steroids through the skin, as well as reviews skin biology. The authors make a strong case for the choice of transdermal delivery of hormones (especially estrogen, progesterone, and testosterone) for both male and female patients with respect to safety, efficacy, and ease of use and predict this delivery method to make a significant impact on the quality of care for both male and female patients.
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28. - Absorption of oral progesterone is influenced by vehicle and particle size. Hargrove JT, Maxson WS, Wentz AC.
Am J Obstet Gynecol 1989;161(4):948-51.
This small sample study shows that significant serum progesterone levels can be achieved by oral administration of progesterone. Efficacy of absorption is improved using micronization in oil Formulations.
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29. - Plasma levels of progesterone after vaginal, rectal or intramuscular administration of progesterone. Nillius SJ, Johansson ED.
Am J Obstet Gynecol 1971;110(4):470-7.
Plasma levels of progesterone equivalent to normal luteal phase levels were obtained using 25 mg of injected progesterone or 100 mg via rectal or vaginal administration at 8 hours after administration.
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