- Email: [email protected]
Routes of delivery for progesterone and progestins
Maturitas 57 (2007) 77–80
Routes of delivery for progesterone and progestins Regine Sitruk-Ware ∗ Rockefeller University and Population Council, New York, NY, USA
Abstract The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Vaginal progesterone gel and ring; Transdermal progestins; Metered dose transdermal system; Intrauterine delivery; Progesterone; Nestorone
1. Introduction As a consequence to the controversy related to the risk/benefit ratio of progestin use in hormonal replacement therapy (HRT), the current trend in prescribing HRT is to maintain low but therapeutic levels of progestins to ensure their beneficial effects against endometrial cancer while avoiding high circulating levels and potential deleterious effects on the breast and heart. In order to avoid the first-pass effect of steroidal hormones on the liver, non-oral routes of delivery were ∗
Tel.: +1 212 327 7045; fax: +1 212 327 7678. E-mail address: [email protected].
developed. In addition, long-acting sustained release systems offered the advantages of long-term efficacy with less problems of compliance than daily oral intake of a tablet or a pill. Certain progestins, because of their progestational potency, are effective in low doses and thus ideally suited for sustained release delivery via implants, vaginal rings, or transdermal systems, e.g. gel, metered dose transdermal system (MTDS) or patch [1,2]. Although progestins vary in progestational and antiestrogenic potency, all progestins exert a progestational effect and oppose the proliferative action of estrogen on the endometrium. The potency of individual progestins determines the dose required to achieve these effects. Molecules such as, levonorgestrel and its derivatives,
0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2007.02.015
78
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
and Nestorone® (NES) are progestins that, because of their high progestational potency, pharmacokinetic properties, and activities related to their derivative molecule have been successfully used in sustained release delivery systems. Progestins with a short half-life when given orally may benefit from a parenteral administration as its delivery via a sustained release systems, makes the molecule more available to the target tissues when delivered on a continuous basis. In addition, potent progestational molecules are best suited for delivery systems as lower doses could be used for continuous daily delivery. The most innovative methods are sustained release systems that generally have high compliance rates and are either user controlled or require no attention for extended periods of time (Table 1). Vaginal delivery of progesterone/progestin is being considered as a logical approach to meet the current HRT prescribing trend. Cicinelli and de Ziegler [3] have previously demonstrated that the delivery of progesterone to the vagina in a gel formulation applied twice weekly causes high local concentrations in the endometrium and low circulating serum levels. The same authors demonstrated a first-uterine-pass effect of vaginal delivery of progesterone that could be attributed to the rich network of arteries and veins linking the vagina to the uterus [4]. Therefore, delivering progesterone to the vagina would result in high local concentrations in the uterus with very little systemic distribution of the hormone, avoiding the potential sideeffects of systemic administration of progestins [3–5]. Progesterone is administered vaginally through a gel (Crinone® ) utilizing a bioadhesive, biocompatible polymer as a base to achieve a sustained release effect. Accurate new techniques of image analysis have shown that this progesterone vaginal therapy could eliminate the proliferative effects of estrogen treatment in postmenopausal women, despite doses as low as 45 mg of progesterone administered vaginally every other day [6]. The results suggest that the sustained release effects of the vaginal gel are clinically relevant. While gel application of progesterone twice weekly may be acceptable to some women, it may be less convenient to others and compliance would vary greatly according to the population studied. As an alternative, a vaginal ring delivering progesterone may be met with higher acceptability. Previous studies conducted with vaginal rings both for contraception and hormone
therapy indicated a high acceptability of the method as the long-acting system is under the user’s control and does not require a health provider for insertion [7,8]. In addition, the ring does not require daily attention and remains in place without being noticed by the woman or her partner. Therefore, a vaginal ring delivering a low dose of natural progesterone in a steady state would result in low plasma levels and protection of the endometrium in women receiving estrogen for menopausal therapy. Also, it may be assumed that this low dose of systemic progesterone would not have systemic deleterious effects. Results of a clinical study testing a ring delivering both E2 and P indicate that this ring can protect the endometrium and provide sufficient steroid levels to alleviate menopausal symptoms [9]. The transdermal delivery is especially advantageous for progestins that are inactive orally yet have effective transdermal absorption, such as Nestorone. While Nestorone given orally is rapidly metabolized and inactive, NES applied transdermally is highly active resulting in good systemic bioavailability. A Nestorone transdermal gel and a spray are currently in development [10,11]. The transdermal patch is another sustained release, user controlled contraceptive method that is capable of delivering progestins through the skin to the systemic circulation. It has been used for more than a decade for HRT and several doses and formulations are available for estrogen therapy. As far as the progestin is concerned, norethisterone acetate (NETA) has been essentially used for HRT in combination TDS delivering also estradiol. Four-day systems delivering low doses of 140 g/day of the progestin NETA combined with 50 g/day of estradiol have been shown to prevent endometrial hyperplasia in postmenopausal women and also maintain bone mineral density [12]. Levonorgestrel has also been used in 7-days delivery systems for HRT and also protects the endometrium from overproliferation at doses as low as 10 or 20 g/day [13]. Direct intrauterine delivery of the progestin has become recently popular. The levonorgestrel intrauterine system (LNG-IUS) (*Mirena® ), approved in the US in 2000, has been developed by the Population Council as an effective contraception for up to 5 years [14,15]. The LNG-IUS prevents pregnancy primarily via a local effect on the cervix and the endometrium. In addition,
Table 1 Selected methods of non-oral delivery of progesterone and progestins either approved or in clinical development Active agent(s)
Technology and particulars
Duration of action
Potential benefits
Vaginal delivery P ring for HRT
P 5 or 10 mg/day
Silicone elastomer, in early development
3 Months continuous
Natural P (45 mg/dose)
Bioadhesive, biocompatible polymer; approved in several countries
48 h
High local concentration of P but low serum levels expected, 3 months duration for better compliance Long retention time and low systemic levels
NETA (140 g/day) + E2 (50 g/day)
Matrix type patch, flexible film, removable inner layer, middle layer with drugs, backing layer Matrix type patch
2 patches per week
Less metabolic impact than same progestin given orally
1 patch/week
In early development MDTS® spray, in early development
Daily Daily
Once a week, good endometrial protection Non-androgenic progestin User friendly system, non-visible skin application
T-shaped polyethylene stem, steroid reservoir cylinder around stem; removal threads
5 years
P vaginal gel (Crinone® ) Transdermal methods Transdermal patch Estralis®
Transdermal patch Transdermal gel Transdermal spray Intrauterine delivery Mirena® approved in several countries
LNG (10 g/day) + E2 (50 g/day) NES NES
LNG (20 g/day)
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
Product
Long duration, Transition from peri to postmenopause, high percentage of amenorrhea
LNG, Levonorgestrel; E2, Estradiol; NES, Nestorone® ; P, progesterone; NETA, noethisterone acetate.
79
80
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
the use of this system for HRT has been recognized as a potential novel way of delivering progestins to the endometrium with minimal systemic effects and the system has been approved for HRT in several countries [15,16]. In conclusion, several new options for delivery of progesterone or progestins are now available for hormonal therapy for women with an intact uterus and receiving estrogen treatment for menopausal symptoms. The hypothesis that lower doses of the progestins that can be delivered more steadily from non-oral formulations may have less impact on the other target organs than the uterus remains to be confirmed. However, the non-oral delivery avoids the peaks and troughs in the kinetics of absorption of the steroids and therefore is likely to minimize the side-effects related to the progestins.
References [1] Sitruk-Ware R. New progestogens: a review of their effects in perimenopausal and postmenopausal women. Drugs Aging 2004;21(13):865–83. [2] Sitruk-Ware R. Delivery options for contraceptives. Drug Discov Today 2005;10(14):977–85. [3] Cicinelli E, de Ziegler D. Transvaginal progesterone: evidence for a new functional ‘portal system’ flowing from the vagina to the uterus. Hum Reprod Update 1999;5(4):365–72. [4] Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000;95(3):403–6. [5] de Ziegler D, Ferriani R, Moraes LA, Bulletti C. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens. Hum Reprod 2000;15(Suppl. 1): 149–58.
[6] Casanas-Roux F, Nisolle M, Marbaix E, Smets M, Bassil S, Donnez J. Morphometric, immunohistological and threedimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone, a new slowrelease vaginal progesterone. Hum Reprod 1996;11(February (2)):357–63. [7] Zegers-Hochschild F, Balmaceda JP, Fabres C, et al. Prospective randomized trial to evaluate the efficacy of a vaginal ring releasing progesterone for IVF and oocyte donation. Hum Reprod 2000;15(10):2093–7. [8] Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril 2004;82(1):1–12. [9] Maruo T, Mishell DR, Ben-Chetrit A, Hochner-Celnikier D, Hamada AL, Nash HA. Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy. Fertil Steril 2002;78(November (5)):1010–6. [10] Croxatto HB, Zepeda A. Transdermal contraceptive systems: innovative technology for the twenty-first century. In: Sitruk-Ware R, Bardin W, editors. Contraception. Newer Pharmacological Agents, Devices, and Delivery Systems. Marcel Dekker, Inc.; 1992. p. 101–15. [11] Sitruk-Ware R, Small M, Kumar N, Tsong YY, Sundaram K, Jackanicz T. Nestorone® clinical applications for contraception and HRT. Steroids 2003;68:907–13. [12] Rubinacci A, Peruzzi E, Modena AB, et al. Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women. Menopause 2003;10(May–June (3)):241–9. [13] Sturdee DW, van de WP, von Holst T. Endometrial safety of a transdermal sequential estradiol-levonorgestrel combination. Climacteric 2002;5(2):170–7. [14] Luukkainen T, Lahteenmaki P, Toivonen J. Levonorgestrelreleasing intrauterine device. Ann Med 1990;22(2):85–90. [15] Sitruk-Ware R, Inki P. The Levonorgestrel intrauterine system: long-term contraception and therapeutic effects. Womens Health 2005;1(2):171–82. [16] Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE. the acceptability of a small intrauterine progestogenreleasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric 2004;7(4):404–11.
Routes of delivery for progesterone and progestins Regine Sitruk-Ware ∗ Rockefeller University and Population Council, New York, NY, USA
Abstract The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Vaginal progesterone gel and ring; Transdermal progestins; Metered dose transdermal system; Intrauterine delivery; Progesterone; Nestorone
1. Introduction As a consequence to the controversy related to the risk/benefit ratio of progestin use in hormonal replacement therapy (HRT), the current trend in prescribing HRT is to maintain low but therapeutic levels of progestins to ensure their beneficial effects against endometrial cancer while avoiding high circulating levels and potential deleterious effects on the breast and heart. In order to avoid the first-pass effect of steroidal hormones on the liver, non-oral routes of delivery were ∗
Tel.: +1 212 327 7045; fax: +1 212 327 7678. E-mail address: [email protected].
developed. In addition, long-acting sustained release systems offered the advantages of long-term efficacy with less problems of compliance than daily oral intake of a tablet or a pill. Certain progestins, because of their progestational potency, are effective in low doses and thus ideally suited for sustained release delivery via implants, vaginal rings, or transdermal systems, e.g. gel, metered dose transdermal system (MTDS) or patch [1,2]. Although progestins vary in progestational and antiestrogenic potency, all progestins exert a progestational effect and oppose the proliferative action of estrogen on the endometrium. The potency of individual progestins determines the dose required to achieve these effects. Molecules such as, levonorgestrel and its derivatives,
0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2007.02.015
78
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
and Nestorone® (NES) are progestins that, because of their high progestational potency, pharmacokinetic properties, and activities related to their derivative molecule have been successfully used in sustained release delivery systems. Progestins with a short half-life when given orally may benefit from a parenteral administration as its delivery via a sustained release systems, makes the molecule more available to the target tissues when delivered on a continuous basis. In addition, potent progestational molecules are best suited for delivery systems as lower doses could be used for continuous daily delivery. The most innovative methods are sustained release systems that generally have high compliance rates and are either user controlled or require no attention for extended periods of time (Table 1). Vaginal delivery of progesterone/progestin is being considered as a logical approach to meet the current HRT prescribing trend. Cicinelli and de Ziegler [3] have previously demonstrated that the delivery of progesterone to the vagina in a gel formulation applied twice weekly causes high local concentrations in the endometrium and low circulating serum levels. The same authors demonstrated a first-uterine-pass effect of vaginal delivery of progesterone that could be attributed to the rich network of arteries and veins linking the vagina to the uterus [4]. Therefore, delivering progesterone to the vagina would result in high local concentrations in the uterus with very little systemic distribution of the hormone, avoiding the potential sideeffects of systemic administration of progestins [3–5]. Progesterone is administered vaginally through a gel (Crinone® ) utilizing a bioadhesive, biocompatible polymer as a base to achieve a sustained release effect. Accurate new techniques of image analysis have shown that this progesterone vaginal therapy could eliminate the proliferative effects of estrogen treatment in postmenopausal women, despite doses as low as 45 mg of progesterone administered vaginally every other day [6]. The results suggest that the sustained release effects of the vaginal gel are clinically relevant. While gel application of progesterone twice weekly may be acceptable to some women, it may be less convenient to others and compliance would vary greatly according to the population studied. As an alternative, a vaginal ring delivering progesterone may be met with higher acceptability. Previous studies conducted with vaginal rings both for contraception and hormone
therapy indicated a high acceptability of the method as the long-acting system is under the user’s control and does not require a health provider for insertion [7,8]. In addition, the ring does not require daily attention and remains in place without being noticed by the woman or her partner. Therefore, a vaginal ring delivering a low dose of natural progesterone in a steady state would result in low plasma levels and protection of the endometrium in women receiving estrogen for menopausal therapy. Also, it may be assumed that this low dose of systemic progesterone would not have systemic deleterious effects. Results of a clinical study testing a ring delivering both E2 and P indicate that this ring can protect the endometrium and provide sufficient steroid levels to alleviate menopausal symptoms [9]. The transdermal delivery is especially advantageous for progestins that are inactive orally yet have effective transdermal absorption, such as Nestorone. While Nestorone given orally is rapidly metabolized and inactive, NES applied transdermally is highly active resulting in good systemic bioavailability. A Nestorone transdermal gel and a spray are currently in development [10,11]. The transdermal patch is another sustained release, user controlled contraceptive method that is capable of delivering progestins through the skin to the systemic circulation. It has been used for more than a decade for HRT and several doses and formulations are available for estrogen therapy. As far as the progestin is concerned, norethisterone acetate (NETA) has been essentially used for HRT in combination TDS delivering also estradiol. Four-day systems delivering low doses of 140 g/day of the progestin NETA combined with 50 g/day of estradiol have been shown to prevent endometrial hyperplasia in postmenopausal women and also maintain bone mineral density [12]. Levonorgestrel has also been used in 7-days delivery systems for HRT and also protects the endometrium from overproliferation at doses as low as 10 or 20 g/day [13]. Direct intrauterine delivery of the progestin has become recently popular. The levonorgestrel intrauterine system (LNG-IUS) (*Mirena® ), approved in the US in 2000, has been developed by the Population Council as an effective contraception for up to 5 years [14,15]. The LNG-IUS prevents pregnancy primarily via a local effect on the cervix and the endometrium. In addition,
Table 1 Selected methods of non-oral delivery of progesterone and progestins either approved or in clinical development Active agent(s)
Technology and particulars
Duration of action
Potential benefits
Vaginal delivery P ring for HRT
P 5 or 10 mg/day
Silicone elastomer, in early development
3 Months continuous
Natural P (45 mg/dose)
Bioadhesive, biocompatible polymer; approved in several countries
48 h
High local concentration of P but low serum levels expected, 3 months duration for better compliance Long retention time and low systemic levels
NETA (140 g/day) + E2 (50 g/day)
Matrix type patch, flexible film, removable inner layer, middle layer with drugs, backing layer Matrix type patch
2 patches per week
Less metabolic impact than same progestin given orally
1 patch/week
In early development MDTS® spray, in early development
Daily Daily
Once a week, good endometrial protection Non-androgenic progestin User friendly system, non-visible skin application
T-shaped polyethylene stem, steroid reservoir cylinder around stem; removal threads
5 years
P vaginal gel (Crinone® ) Transdermal methods Transdermal patch Estralis®
Transdermal patch Transdermal gel Transdermal spray Intrauterine delivery Mirena® approved in several countries
LNG (10 g/day) + E2 (50 g/day) NES NES
LNG (20 g/day)
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
Product
Long duration, Transition from peri to postmenopause, high percentage of amenorrhea
LNG, Levonorgestrel; E2, Estradiol; NES, Nestorone® ; P, progesterone; NETA, noethisterone acetate.
79
80
R. Sitruk-Ware / Maturitas 57 (2007) 77–80
the use of this system for HRT has been recognized as a potential novel way of delivering progestins to the endometrium with minimal systemic effects and the system has been approved for HRT in several countries [15,16]. In conclusion, several new options for delivery of progesterone or progestins are now available for hormonal therapy for women with an intact uterus and receiving estrogen treatment for menopausal symptoms. The hypothesis that lower doses of the progestins that can be delivered more steadily from non-oral formulations may have less impact on the other target organs than the uterus remains to be confirmed. However, the non-oral delivery avoids the peaks and troughs in the kinetics of absorption of the steroids and therefore is likely to minimize the side-effects related to the progestins.
References [1] Sitruk-Ware R. New progestogens: a review of their effects in perimenopausal and postmenopausal women. Drugs Aging 2004;21(13):865–83. [2] Sitruk-Ware R. Delivery options for contraceptives. Drug Discov Today 2005;10(14):977–85. [3] Cicinelli E, de Ziegler D. Transvaginal progesterone: evidence for a new functional ‘portal system’ flowing from the vagina to the uterus. Hum Reprod Update 1999;5(4):365–72. [4] Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000;95(3):403–6. [5] de Ziegler D, Ferriani R, Moraes LA, Bulletti C. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens. Hum Reprod 2000;15(Suppl. 1): 149–58.
[6] Casanas-Roux F, Nisolle M, Marbaix E, Smets M, Bassil S, Donnez J. Morphometric, immunohistological and threedimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone, a new slowrelease vaginal progesterone. Hum Reprod 1996;11(February (2)):357–63. [7] Zegers-Hochschild F, Balmaceda JP, Fabres C, et al. Prospective randomized trial to evaluate the efficacy of a vaginal ring releasing progesterone for IVF and oocyte donation. Hum Reprod 2000;15(10):2093–7. [8] Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril 2004;82(1):1–12. [9] Maruo T, Mishell DR, Ben-Chetrit A, Hochner-Celnikier D, Hamada AL, Nash HA. Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy. Fertil Steril 2002;78(November (5)):1010–6. [10] Croxatto HB, Zepeda A. Transdermal contraceptive systems: innovative technology for the twenty-first century. In: Sitruk-Ware R, Bardin W, editors. Contraception. Newer Pharmacological Agents, Devices, and Delivery Systems. Marcel Dekker, Inc.; 1992. p. 101–15. [11] Sitruk-Ware R, Small M, Kumar N, Tsong YY, Sundaram K, Jackanicz T. Nestorone® clinical applications for contraception and HRT. Steroids 2003;68:907–13. [12] Rubinacci A, Peruzzi E, Modena AB, et al. Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women. Menopause 2003;10(May–June (3)):241–9. [13] Sturdee DW, van de WP, von Holst T. Endometrial safety of a transdermal sequential estradiol-levonorgestrel combination. Climacteric 2002;5(2):170–7. [14] Luukkainen T, Lahteenmaki P, Toivonen J. Levonorgestrelreleasing intrauterine device. Ann Med 1990;22(2):85–90. [15] Sitruk-Ware R, Inki P. The Levonorgestrel intrauterine system: long-term contraception and therapeutic effects. Womens Health 2005;1(2):171–82. [16] Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE. the acceptability of a small intrauterine progestogenreleasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric 2004;7(4):404–11.