CLIMACTERIC 2014;17:517–519
Editorial
Perimenopausal hormonal contraception – can we do better? Nick Panay and Anna Fenton EDITORS-IN-CHIEF
‘It is not the size of each individual carbon footprint but the number of carbon footprints we should be more concerned with!’1. By 2015 it is predicted that the total world population will reach 6 billion. Approximately 50% of pregnancies are unplanned and 50% of these are due to failure of a contraceptive method. An increasing proportion of these unwanted pregnancies are in women in their forties onwards. Although the average monthly probability of conception declines by 50% as women enter their forties, it is estimated that 80% of women are still able to conceive in this age group. The oldest verified mother to conceive naturally was 59 years of age2! There are a number of potential problems associated with pregnancies in women over the age of 40. For example, a significant proportion (approximately one-third) of these pregnancies is likely to be medically or surgically terminated compared to one-fifth in younger women. The risk of spontaneous miscarriage due to genetic abnormalities is increased. In ongoing pregnancy, maternal and perinatal mortality and morbidity are exacerbated by pre-eclampsia, pre-term labor, growth restriction, placental abruption and gestational diabetes. There has been inadequate health education regarding the problems of pregnancy in the perimenopausal age group and insufficient resources have been allocated to the avoidance of unwanted pregnancy and sexually transmitted infections. There are many factors leading to failure to use contraception or failure of the method itself, including access, social and cultural reasons. Recent data linking combined oral contraceptive (COC) usage with a low risk of breast cancer have once again been reported in the media in alarming terms3. These headlines, which often omit to mention the 50% reduction of ovarian and endometrial cancer with long-term COC usage, only serve to discourage initiation and encourage non-adherence to contraception, thus increasing the risks of unwanted pregnancy. Three of the most important factors determining contraceptive usage are acceptability, efficacy and safety of the method itself; optimization of these factors relies on ongoing contraceptive research and development, both to refine pre-existing methods and to produce new methods to widen the armamentarium of choices for women approaching the menopause transition.
© 2014 International Menopause Society DOI: 10.3109/13697137.2014.955446
Enhancing non-contraceptive benefits The perimenopause is a time when periods often become prolonged, heavy and painful. Physical and psychological premenstrual symptoms often deteriorate and merge with symptoms of the menopause. As androgen levels fall, this decrease can impact adversely on energy levels and sexual desire. This can be compounded by orally administered estrogen which elevates levels of sex hormone binding globulin, thus reducing bioavailable testosterone further. If these and other problems were ameliorated by hormonal contraception, this would increase the likelihood that hormonal contraception would be taken up and used reliably through to the menopause transition. It is therefore essential that the safety of the method permits usage into mid-fifties by which stage the majority of women are postmenopausal.
Evolution of hormonal contraceptive choices for the perimenopause The extension of the age limit for COC usage in healthy non-smokers to 50 years significantly improved choice for perimenopausal women. Standard 30/35 μg ethinylestradiol COCs may deliver an unnecessarily high dosage for this age group. Lower-dose COCs containing 20 μg ethinylestradiol reduce estrogenic side-effects and venous thromboembolic (VTE) risks without significantly reducing contraceptive efficacy. However, breakthrough bleeding is a recognized sideeffect of lower-dose COCs and may reduce adherence. Women switching directly to hormone replacement (HRT) from the COC can be encouraged by recent data showing no excess risk of breast cancer following prior long-term COC usage4. 17β-Estradiol COCs appear to have less metabolic impact on procoagulant factors than ethinylestradiol COCs. The shorter half-life of estradiol reduces first-pass hepatic effects on coagulation. Estradiol pills may be particularly suitable for women over 40 years, bridging the gap between contraception and HRT. This would provide an excellent solution
Editorial for women who currently have to stop COCs at 50 years. However, preferential prescribing for ‘at risk’ women and for those over 50 years of age should be avoided until long-term observational data on VTE and arterial risks are reported from ongoing post-marketing surveillance trials. Third- and fourth-generation COCs vary according to their progestogen component and may afford additional health benefits. COCs with progestogens such as drospirenone, cyproterone acetate and dienogest are licensed in many countries for their non-contraceptive benefits, e.g. acne, premenstrual dysphoric disorder and heavy menstrual bleeding; this is particularly important for women over 40 in whom these problems are common. It is disappointing that the VTE risks of these pills have been overstated by epidemiologists and the media. The incidence of VTE is very low and significantly less than pregnancy5. To avoid cycle-related symptoms, COCs have been prescribed off-label for many years as back-to-back regimens; in many countries, licensed continuous, longer-cycle and flexible regimens are now available. Reduction or avoidance of the hormone-free interval increases contraceptive efficacy by maximizing endogenous cycle suppression. Tolerability is further enhanced through reduction of hormone withdrawal symptoms and reduction of painful, heavy periods. Recent developments, involving the addition of androgens to combined pill preparations to enhance sexuality, should be particularly targeted to the perimenopausal age group who are at greatest risk of low sexual desire. Women in their forties and beyond have typically been prescribed the progestogen-only pill (POP) to minimize VTE risk. The drawback with the low-dose POP is that its mechanism of action relies on very careful administration with only a 3-h window each day. The higher-dose desogestrel POP has two main advantages compared to low-dose POPs: reliable ovulation inhibition in over 99% of cycles and a 12-h intake window. Although ovulation is suppressed, endogenous estradiol levels are maintained within the physiological range. However, the main drawback with any POP is the high incidence of breakthrough bleeding which is particularly problematic in the perimenopause. There is no proven benefit of POPs for cycle-related symptoms and they may induce continuous premenstrual syndrome (PMS)-type progestogenic side-effects. The levonorgestrel intrauterine system (IUS) is an excellent choice for women requiring contraception in the over-forties. Not only does it provide reliable contraceptive cover but it will also benefit women with heavy periods and can be used as the progestogen component of HRT. However, there can
Panay and Fenton be initial irregular bleeding and systemic PMS-type side-effects. The recent development of a lower-dose, smaller system releasing 12 μg of levonorgestrel per 24 h (rather than 20 μg) is a significant development for the perimenopausal woman. It is even easier to fit and reduces the risk of systemic progestogenic side-effects. However, it is not as effective at producing amenorrhea and is not licensed for use as the progestogen component of HRT6. A 10 μg IUS (menopause levonorgestrel system) was proven to give adequate endometrial protection in HRT studies7. It would be a shame to miss the opportunity of extending the indication of the 12 μg system for usage in HRT, thus enhancing its benefits for progestogen-intolerant perimenopausal women who need estrogen therapy. Depot progestogens are not currently recommended for women in their fifties because of concern that the prolonged hypoestrogenic state will increase the risk of osteoporosis. However, the development of preparations with ‘add back’ estrogen will enhance prospects for using these preparations as both contraception and HRT in perimenopausal women. Implantable etonogestrel progestogen rods provide excellent contraception but, as with the POP, have the drawback of inducing irregular bleeding patterns in more than 50% of users. The perimenopausal fluctuation of hormone levels makes it more likely that these women will have bleeding problems with this method. The advantage is that estradiol levels are not suppressed despite ovulation being inhibited and therefore not exposing the user to additional risk of osteoporosis.
CONCLUSION Modern prescribing of contraception in the perimenopause should not only be aimed at preventing pregnancy but also at enhancing quality of life and primary prevention of various conditions. This is particularly important for perimenopausal women because quality of life and sexuality are often reduced due to unpredictable changes in their endogenous hormone levels. Technological advances in the content and regimen of newer hormonal contraceptives have the potential to facilitate this objective but must be more targeted to the special needs of this age group. The ongoing development of new regimens containing selective estrogen and progestogen receptor modulators could further enhance benefits and minimize risks. It is through appropriate resource allocation, education and maximization of health benefits that prevention of unwanted pregnancy in the approach to the menopause will be optimized.
References 1. Gullibaud J. Personal communication, 2010 2. http://www.guinnessworldrecords.com/world-records/12000/ oldest-mother-to-conceive-naturally-. Accessed 11.08.2014
518
3. Beaber EF, Buist DS, Barlow WE, Malone KE, Reed SD, Li CI. Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age. Cancer Res 2014;74:4078–89
Climacteric
Editorial 4. Thorbjarnardottir T, Olafsdottir EJ, Valdimarsdottir UA, Olafsson O, Tryggvadottir L. Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older. Acta Oncol 2014;53: 752–8 5. Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International
Climacteric
Panay and Fenton Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014;89:253–63 6. Melvin L, Scott J, Craik J. Jaydess® levonorgestrel intrauterine system. J Fam Plann Reprod Health Care 2014;40:165–9 7. Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE; Multicenter MLS Investigators. The acceptability of a small intrauterine progestogen-releasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric 2004;7:404–11
519
Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Editorial
Perimenopausal hormonal contraception – can we do better? Nick Panay and Anna Fenton EDITORS-IN-CHIEF
‘It is not the size of each individual carbon footprint but the number of carbon footprints we should be more concerned with!’1. By 2015 it is predicted that the total world population will reach 6 billion. Approximately 50% of pregnancies are unplanned and 50% of these are due to failure of a contraceptive method. An increasing proportion of these unwanted pregnancies are in women in their forties onwards. Although the average monthly probability of conception declines by 50% as women enter their forties, it is estimated that 80% of women are still able to conceive in this age group. The oldest verified mother to conceive naturally was 59 years of age2! There are a number of potential problems associated with pregnancies in women over the age of 40. For example, a significant proportion (approximately one-third) of these pregnancies is likely to be medically or surgically terminated compared to one-fifth in younger women. The risk of spontaneous miscarriage due to genetic abnormalities is increased. In ongoing pregnancy, maternal and perinatal mortality and morbidity are exacerbated by pre-eclampsia, pre-term labor, growth restriction, placental abruption and gestational diabetes. There has been inadequate health education regarding the problems of pregnancy in the perimenopausal age group and insufficient resources have been allocated to the avoidance of unwanted pregnancy and sexually transmitted infections. There are many factors leading to failure to use contraception or failure of the method itself, including access, social and cultural reasons. Recent data linking combined oral contraceptive (COC) usage with a low risk of breast cancer have once again been reported in the media in alarming terms3. These headlines, which often omit to mention the 50% reduction of ovarian and endometrial cancer with long-term COC usage, only serve to discourage initiation and encourage non-adherence to contraception, thus increasing the risks of unwanted pregnancy. Three of the most important factors determining contraceptive usage are acceptability, efficacy and safety of the method itself; optimization of these factors relies on ongoing contraceptive research and development, both to refine pre-existing methods and to produce new methods to widen the armamentarium of choices for women approaching the menopause transition.
© 2014 International Menopause Society DOI: 10.3109/13697137.2014.955446
Enhancing non-contraceptive benefits The perimenopause is a time when periods often become prolonged, heavy and painful. Physical and psychological premenstrual symptoms often deteriorate and merge with symptoms of the menopause. As androgen levels fall, this decrease can impact adversely on energy levels and sexual desire. This can be compounded by orally administered estrogen which elevates levels of sex hormone binding globulin, thus reducing bioavailable testosterone further. If these and other problems were ameliorated by hormonal contraception, this would increase the likelihood that hormonal contraception would be taken up and used reliably through to the menopause transition. It is therefore essential that the safety of the method permits usage into mid-fifties by which stage the majority of women are postmenopausal.
Evolution of hormonal contraceptive choices for the perimenopause The extension of the age limit for COC usage in healthy non-smokers to 50 years significantly improved choice for perimenopausal women. Standard 30/35 μg ethinylestradiol COCs may deliver an unnecessarily high dosage for this age group. Lower-dose COCs containing 20 μg ethinylestradiol reduce estrogenic side-effects and venous thromboembolic (VTE) risks without significantly reducing contraceptive efficacy. However, breakthrough bleeding is a recognized sideeffect of lower-dose COCs and may reduce adherence. Women switching directly to hormone replacement (HRT) from the COC can be encouraged by recent data showing no excess risk of breast cancer following prior long-term COC usage4. 17β-Estradiol COCs appear to have less metabolic impact on procoagulant factors than ethinylestradiol COCs. The shorter half-life of estradiol reduces first-pass hepatic effects on coagulation. Estradiol pills may be particularly suitable for women over 40 years, bridging the gap between contraception and HRT. This would provide an excellent solution
Editorial for women who currently have to stop COCs at 50 years. However, preferential prescribing for ‘at risk’ women and for those over 50 years of age should be avoided until long-term observational data on VTE and arterial risks are reported from ongoing post-marketing surveillance trials. Third- and fourth-generation COCs vary according to their progestogen component and may afford additional health benefits. COCs with progestogens such as drospirenone, cyproterone acetate and dienogest are licensed in many countries for their non-contraceptive benefits, e.g. acne, premenstrual dysphoric disorder and heavy menstrual bleeding; this is particularly important for women over 40 in whom these problems are common. It is disappointing that the VTE risks of these pills have been overstated by epidemiologists and the media. The incidence of VTE is very low and significantly less than pregnancy5. To avoid cycle-related symptoms, COCs have been prescribed off-label for many years as back-to-back regimens; in many countries, licensed continuous, longer-cycle and flexible regimens are now available. Reduction or avoidance of the hormone-free interval increases contraceptive efficacy by maximizing endogenous cycle suppression. Tolerability is further enhanced through reduction of hormone withdrawal symptoms and reduction of painful, heavy periods. Recent developments, involving the addition of androgens to combined pill preparations to enhance sexuality, should be particularly targeted to the perimenopausal age group who are at greatest risk of low sexual desire. Women in their forties and beyond have typically been prescribed the progestogen-only pill (POP) to minimize VTE risk. The drawback with the low-dose POP is that its mechanism of action relies on very careful administration with only a 3-h window each day. The higher-dose desogestrel POP has two main advantages compared to low-dose POPs: reliable ovulation inhibition in over 99% of cycles and a 12-h intake window. Although ovulation is suppressed, endogenous estradiol levels are maintained within the physiological range. However, the main drawback with any POP is the high incidence of breakthrough bleeding which is particularly problematic in the perimenopause. There is no proven benefit of POPs for cycle-related symptoms and they may induce continuous premenstrual syndrome (PMS)-type progestogenic side-effects. The levonorgestrel intrauterine system (IUS) is an excellent choice for women requiring contraception in the over-forties. Not only does it provide reliable contraceptive cover but it will also benefit women with heavy periods and can be used as the progestogen component of HRT. However, there can
Panay and Fenton be initial irregular bleeding and systemic PMS-type side-effects. The recent development of a lower-dose, smaller system releasing 12 μg of levonorgestrel per 24 h (rather than 20 μg) is a significant development for the perimenopausal woman. It is even easier to fit and reduces the risk of systemic progestogenic side-effects. However, it is not as effective at producing amenorrhea and is not licensed for use as the progestogen component of HRT6. A 10 μg IUS (menopause levonorgestrel system) was proven to give adequate endometrial protection in HRT studies7. It would be a shame to miss the opportunity of extending the indication of the 12 μg system for usage in HRT, thus enhancing its benefits for progestogen-intolerant perimenopausal women who need estrogen therapy. Depot progestogens are not currently recommended for women in their fifties because of concern that the prolonged hypoestrogenic state will increase the risk of osteoporosis. However, the development of preparations with ‘add back’ estrogen will enhance prospects for using these preparations as both contraception and HRT in perimenopausal women. Implantable etonogestrel progestogen rods provide excellent contraception but, as with the POP, have the drawback of inducing irregular bleeding patterns in more than 50% of users. The perimenopausal fluctuation of hormone levels makes it more likely that these women will have bleeding problems with this method. The advantage is that estradiol levels are not suppressed despite ovulation being inhibited and therefore not exposing the user to additional risk of osteoporosis.
CONCLUSION Modern prescribing of contraception in the perimenopause should not only be aimed at preventing pregnancy but also at enhancing quality of life and primary prevention of various conditions. This is particularly important for perimenopausal women because quality of life and sexuality are often reduced due to unpredictable changes in their endogenous hormone levels. Technological advances in the content and regimen of newer hormonal contraceptives have the potential to facilitate this objective but must be more targeted to the special needs of this age group. The ongoing development of new regimens containing selective estrogen and progestogen receptor modulators could further enhance benefits and minimize risks. It is through appropriate resource allocation, education and maximization of health benefits that prevention of unwanted pregnancy in the approach to the menopause will be optimized.
References 1. Gullibaud J. Personal communication, 2010 2. http://www.guinnessworldrecords.com/world-records/12000/ oldest-mother-to-conceive-naturally-. Accessed 11.08.2014
518
3. Beaber EF, Buist DS, Barlow WE, Malone KE, Reed SD, Li CI. Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age. Cancer Res 2014;74:4078–89
Climacteric
Editorial 4. Thorbjarnardottir T, Olafsdottir EJ, Valdimarsdottir UA, Olafsson O, Tryggvadottir L. Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older. Acta Oncol 2014;53: 752–8 5. Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International
Climacteric
Panay and Fenton Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014;89:253–63 6. Melvin L, Scott J, Craik J. Jaydess® levonorgestrel intrauterine system. J Fam Plann Reprod Health Care 2014;40:165–9 7. Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE; Multicenter MLS Investigators. The acceptability of a small intrauterine progestogen-releasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric 2004;7:404–11
519
Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
