Systemic Bioavailability of Estriol Following Single and Repeated Vaginal Administration of 0.03 mg Estriol Containing Pessaries

Abstract

A prospective monocentric open-label and single-arm trial was performed in 19 postmenopausal women with diagnosed vaginal atrophy. The aim was to determine the extent of a systemic exposure to estriol (CAS 50-27-1). Administration of estriol containing pessaries was daily for 21 days. In order to establish a pharmacokinetic profile after single as well as multiple vaginal doses of 0.03 mg estriol blood samples were taken after the first vaginal administration as well as at day 21 after the last administration. Moreover, in order to control for accumulation additional blood samples were taken predose at days 6, 11 and 16.

Results:

The initial administration increased the population mean estriol plasma concentration to a maximum of 42.1 pg/ml 1 h after dosing. However, already 12 h after administration the estriol concentration had again dropped below 5 pg/ml (lower limit of quantification) in all patients. Repeated administration did not result in an accumulation of estriol, since 2 h after application of the 21^st pessary, the population mean estriol concentration reached a maximum of only 11.9 pg/ml. Moreover, no severe or serious adverse events occurred, and no clinically relevant findings were reported.

Conclusion:

Single vaginal application of pessaries containing 0.03 mg estriol resulted in a very low systemic bioavailability, which decreased even more after multiple dosing confirming a favourable safety profile of low dose pessaries administered daily over 21 days.

Key words

estriol - pharmacokinetic profile - bioavailability - vaginal atrophy - low dose formulation - local treatment

• References

• 1 Stenberg A, Heimer G, Ulmsten U et al. Prevalence of genitourinary and other climacteric symptoms in 61-year-old women. Maturitas 1996; 24 (1–2) 31-36
• 2 Raz R. Hormone replacement therapy or prophylaxis in postmenopausal women with recurrent urinary tract infection. J Infect Dis 2001; 183: 74-76
• 3 Dennerstein L, Dudley EC, Hopper JL et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000; 96: 351-358
• 4 Trevoux R, Van der Velden WH, Popovic D. Ovestin vaginal cream and suppositories for the treatment of menopausal vaginal atrophy. Reproduction 1982; 6: 101-106
• 5 Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990; 12: 171-197
• 6 Clark JH, Markaverich BM. The agonistic and antagonistic effects of short acting estrogens: A review. Pharmac Ther 1983; 21: 429-453
• 7 Cardozo L, Bachmann G, McClish D et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol 1998; 92: 722-727
• 8 Suckling JA, Kennedy R, Lethaby A et al. Using creams, pessaries or a vaginal ring to apply oestrogen vaginally relieves the symptoms of vaginal atrophy, although some creams may cause adverse effects [cited 2010 Nov 10]. In: The Cochrane Database of Systemic Reviews [Internet]. Hoboken (NJ): John Wiley & Sons, Ltd; Available from: http://summaries.cochrane.org/CD001500/using-creams-pessaries-or-a-vaginal-ring-to-apply-oestrogen-vaginally-relieves-the-symptoms-of-vaginal-atrophy-although-some-creams-may-cause-adverse-effects
• 9 The North American Menopause Society . The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of the North American Menopause Society. Menopause 2007; 14: 355-363
• 10 Sturdee DW, Panay N. International Menopause Society Writing Group . Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010; 13: 509-522
• 11 AWMF online [Internet] Düsseldorf: Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. Record No. 015-062. Hormontherapie in der Peri- und Postmenopause; [cited 2009 Sep 1] Available from: http://www.awmf.org/leitlinien/detail/ll/015-062.html
• 12 Dessole S, Rubattu G, Ambrosini G et al. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause 2004; 11: 49-56
• 13 Chuery AC, Speck NM, de Moura KF et al. Efficacy of vaginal use of topical estriol in postmenopausal women with urogenital atrophy. Clin Exp Obstet Gynecol 2011; 38: 143-145
• 14 Dugal R, Hesla K, Sørdal T et al. Comparison of usefulness of estradiol vaginal tablets and estriol vagitories for treatment of vaginal atrophy. Acta Obstet Gynecol Scand 2000; 79: 293-297
• 15 Barentsen R, van de Weijer PH, Schram JH. Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol 1997; 71: 73-80
• 16 Clocuh YPA. Oestrogengabe als hormonelle Aufhellung zur Abklärung atrophischer Zellabstriche. Geburtsh u Frauenheilk 1980; 40: 1121-1129
• 17 Bottiglione F, Volpe A, Esposito G et al. Transvaginal estriol administration in postmenopausal women: a double blind comparative study of two different doses. Maturitas 1995; 22: 227-232
• 18 Biglia N, Peano E, Sgandurra P et al. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gyn Endocrinol 2010; 26 (06) 404-412
• 19 Henrikkson L, Stjernquist M, Boquist L et al. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996; 174: 85-92
• 20 Sindberg Eriksen P, Rasmussen H. Low-dose 17β-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992; 44: 137-144
• 21 Nieto C, Cano A, Estévez J et al. 0.005% Estriol vaginal gel, a new formulation delivering an ultra-low dose of estriol per application (50 µg), is a novel treatment for postmenopausal vaginal atrophy. Abstracts of the 13^th World Congress on the Menopause. Climacteric 2011; 14 (01) 86
• 22 Griesser H, Skonietzki S, Fischer T et al. Low dose estriol pessaries for the treatment of vaginal atrophy: A double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2 mg and 0.03 mg estriol. Maturitas 2012; 71 (04) 360-368
• 23 Fachinformation OeKolp® Ovula. Dr. Kade Pharmazeutische Fabrik GmbH; January 2012
• 24 Feichter G. Vaginale Zytologie: Cervix uteri und Vagina. In: Feichter G, Dalquen P. (eds.). Pathologie Band 8: Zytopathologie. Berlin, Heidelberg, New York: Springer-Verlag; 2000. 65
• 25 Klinge CM. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 2001; 29 (14) 2905-2919
• 26 Gitsch E, Golob E. Zur Frage der idealen Östrogenkonzentration in Salben bei genitaler Anwendung. Zbl Gynäkol 1962; 12: 454-458
• 27 Heimer GM, Englund DE. Effects of vaginally administered oestriol on postmenopausal urogenital disorders: a cytohormonal study. Maturitas 1992; 14: 171-179
• 28 Heimer GM, Englund DR. Plasma oestriol following vaginal administration: morning versus evening insertion and the influence of food. Maturitas 1986; 8: 239-243
• 29 Magnusson C, Baron JA, Correia N et al. Breast-cancer risk following long-term estrogen- and estrogen-progestin replacement therapy. Int J Cancer 1999; 81: 339-344
• 30 Vooijs GP, Geurts TBP. Review of the endometrial safety during intravaginal treatment with estriol. Eur J Obstet Gynecol Reprod Biol 1995; 62: 101-106
• 31 Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet Gynecol 2006; 108 (06) 1354-1360
• 32 Kaiser R, Michael-Hepp J, Weber W et al. Absorption of estriol from vaginal tablets after single and repeated application in healthy postmenopausal women. Therapiewoche 2000; 16 (03) 1-8
• 33 Heimer G, Englund D. Estriol: Absorption after Long-Term Vaginal Treatment and Gastrointestinal Absorption as Influenced by a Meal. Acta Obstet Gynecol Scand 1984; 63: 563-567
• 34 Nieto C, Delgado JL, Estévez J et al. Comparative pharmacokinetics and preliminary efficacy of two topical vaginal formulations of estriol (0.005% estriol vaginal gel, and 0.002% estriol vaginal gel) vs. the marketed reference product (Ovestinon, estriol vaginal cream 0.1%) in post-menopausal healthy volunteers. Abstracts of the 13^th World Congress on the Menopause. Climacteric 2011; 14 (01) 66