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Added health benefits of the levonorgestrel contraceptive intrauterine system and other hormonal contraceptive delivery systems
Contraception 87 (2013) 273 – 279
Review article
Added health benefits of the levonorgestrel contraceptive intrauterine system and other hormonal contraceptive delivery systems Ian S. Fraser⁎ Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Camperdown, NSW 2006, Australia Received 27 August 2012; accepted 29 August 2012
Abstract Background: It has been recognized for well over half a century that hormonal preparations designed as contraceptives are also capable of offering health benefits through the treatment and prevention of benign gynecological disease and even some systemic conditions. Increasing attention is now being paid to the extent and detail of such added health benefits, and it is becoming clear that the long-acting, low-dose, hormonal contraceptive delivery systems may offer particular advantages in this regard. Methods: Conventional databases were thoroughly searched, especially for publications from 2006 to 2012, which addressed noncontraceptive-related indications for therapy and prevention. Results: A considerable literature now exists to demonstrate the multiple and substantial noncontraceptive health benefits of long-acting progestogen-releasing systems, especially the levonorgestrel-releasing intrauterine system. These benefits mainly relate to disturbances of menstruation and related symptoms, such as heavy menstrual bleeding (due to many causes); iron deficiency; pelvic pain, especially around endometriosis; and endometrial hyperplasia. The long-acting estrogen–progestogen systems may carry similar added health benefits to those of the combined oral contraceptives, but data are still lacking. Conclusion: Added health benefits are now becoming an important part of the contraceptive choice equation, and the long-acting delivery systems are recognized as suitable primary therapies for a range of gynecological disorders. © 2013 Elsevier Inc. All rights reserved. Keywords: Contraception; Hormonal delivery systems; Intrauterine hormonal system; Health benefits
1. Introduction Highly effective hormonal contraceptives have now been widely available for over 50 years, and many developments have resulted in novel ways of delivering improved hormonal preparations and at lower doses. The majority of the available hormonal preparations have been combined estrogen–progestogen pills with a plethora of different progestogens, but only one estrogen: ethinyl estradiol (EE). However, the most effective of these reversible hormonal contraceptive preparations have turned out to be two lowdose, long-acting, progestogen-releasing systems for intrauterine or subdermal placement. The International Committee for Contraceptive Research of the Population Council has
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been at the forefront of the development of both types of system [1], with two marketed subdermal implant systems (Norplant and Jadelle) and the very successful levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena). This hormonal contraceptive development has been a remarkable success story, but the search for even more effective, convenient and safe preparations continues [1]. Along the development path, a number of troublesome and potentially worrying possible complications were identified, including venous thromboembolism, hypertension, stroke and breast cancer. Although all of these associations are uncommon or rare, they have attracted a vast amount of research attention and financial investment. This has led directly to substantial improvements in the currently popular low-dose, combined oral contraceptive pill (COCP) preparations, to greatly reduced incidence of these potential complications and to a greater understanding of their effects and mechanisms. So much so that the potential for very high
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contraceptive efficacy is now generally taken for granted in the community. In parallel with this multifaceted contraceptive development program has been a much lower-key search for hormonal preparations to treat a range of benign gynecological disorders. In fact, this search preceded the establishment of proper clinical trials to demonstrate efficacy of hormonal contraceptives — the first “hormonal” therapy being an impure “estrogen” preparation of biological origin to treat painful menstruation [2]. The first effective clinical trial of a progestogen preparation [ethynodiol diacetate 10 mg; mestranol 150 mcg (initially present as an impurity)] led to the marketing in the United States of Enovid in 1957 as a treatment for menstrual bleeding disorders [3]. This marketing approval came 2 years before the first marketing approval of the same preparation as a contraceptive. High-dose oral progestogen preparations of norethindrone, norethindrone acetate, medroxyprogesterone acetate, megestrol acetate and others were developed and marketed to treat severe cases of anovulatory and ovulatory “dysfunctional uterine bleeding” [4] and hyperplastic endometrium (“metropathia hemorrhagica”) [5]. These preparations continue to be available today for the same indications. Along this journey, it was rapidly recognized by clinicians that the “oral birth-control pill” could be conveniently used as an initial management tool for many gynecological symptoms [6], but that progestogens alone could be even more effective, albeit in much higher oral doses and often accompanied by nuisance-value side effects. Unfortunately, these attributes were not seen as being sufficiently important to merit necessary investment of clinical trial funding by the pharmaceutical industry or government funding agencies, compared with the “so-called” safety issues. Hence, valuable evidence of the noncontraceptive — or “added” — health benefits of these contraceptive methods has lagged behind that of the much rarer “safety” issues. Nevertheless, nowadays, so many different health benefits are recognized that this aspect of hormonal contraception is becoming part of the “contraceptive choice equation.” Some of these benefits are now relatively well known, but many myths persist. Different hormonal combinations and delivery approaches will result in different patterns of health benefits, and limited evidence exists for the range of benefits accompanying use of certain preparations. Consideration of “health benefits” also needs to take into account the fact that some women have preexisting medical conditions, which may negate the expected benefit.
2. Combined estrogen–progestogen delivery systems Much clinical evidence has now been accumulated which demonstrates the positive and non-contraceptive-related health benefits of estrogen–progestogen oral contraceptives. These are well known and well documented (Table 1) [6–9];
Table 1 Reported added health benefits of the oral estrogen–progestogen contraceptive pill [6–9], which are anticipated, but not proven, to also occur with longer-acting estrogen–progestogen delivery systems (combined vaginal rings; combination transdermal patches) 1. Reduction in long-term risk of endometrial cancer 2. Reduction in long-term risk of ovarian cancer 3. Reduction in risk of HMB 4. Reduction in risk of menstrual pain 5. Reduction in risk of premenstrual syndrome and premenstrual dysphoric disorder 6. Reduction in risk of other menstrually related cyclic disorders 7. Reduction in seborrhea and acne 8. Protection of fertility 9. Reduction in acute episodes of pelvic inflammatory disease 10. Slight extension of lifespan
however, the health benefits of the COCP are not the primary subject of this manuscript. Nevertheless, it is assumed that the longer-acting, estrogen–progestogen delivery systems (e.g., the combination vaginal rings, the transdermal patch and the combination once-a-month injectables) will carry similar benefits to those recorded with the COCP. Most of these hopes remain to be proven. 3. Progestogen-only delivery systems Recent clinical trial activity on added health benefits has focussed particularly on one long-acting progestogen-only delivery system: the LNG-IUS [10,11]. This system has turned out to be a remarkable advance for the treatment of many gynecological symptoms, but perhaps even more important is the recent evidence that it may prevent many symptoms and underlying conditions from developing in the first place. The literature on many of these aspects is substantial [12–14]. 3.1. The LNG-IUS There is now a large body of evidence, of variable quality, supporting the existence of a substantial range of clinical health benefits accompanying medium- to long-term use of the LNG-IUS. Most of these data have been acquired in studies utilizing the specific LNG-IUS developed jointly, from a concept proposed by Luukkainen [15], by the Population Council with the Leiras Company of Turku, Finland, and now marketed as Mirena® (Bayer Pharma). Other LNG-IUSs are being developed [16,17] and may carry similar health benefits, but current data are limited. Several reviews have addressed the issue of noncontraceptive health benefits of the LNG-IUS [10–14]. Each of these reviews has approached this particular aspect of LNGIUS action from a different perspective, but each has emphasized the broad range of important benefits. It is salutary to consider that many of the conditions which benefit from use of this system are actually adverse effects of a modern industrialized society lifestyle, where menarche occurs earlier, pregnancies are delayed and greatly reduced
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in number, lactation is minimized, and women experience many more menstrual cycles and menstruations compared with more primitive human existence [18]. Exposure to excessive numbers of menstrual cycles, with their repeated, large swings in ovarian hormone secretion, is associated with a substantial increase in risk of breast, endometrial and ovarian cancer [18] and with similar increases in occurrence of benign ovarian cysts, uterine leiomyomas, endometriosis and complaint of severe symptoms accompanying menstruation. We have not had time to evolve to cope with these rapidly changing social circumstances. However, moderate- or long-term use of combined estrogen–progestogen contraceptives or the LNG-IUS has beneficial effects in reducing the occurrence and symptomatic impact of many of these conditions. The added health benefits of the LNG-IUS can be considered from two different perspectives. 3.1.1. Therapeutic use for preexisting symptoms The LNG-IUS is now licensed in a number of countries for therapy of several symptoms, including heavy menstrual bleeding (HMB), treatment of conditions resulting from endometrial exposure to unopposed estrogen (exogenous or endogenous, and including endometrial hyperplasia) or menstrual pain (which may include endometriosis). There is also now extensive evidence to support use of the LNGIUS to treat a number of additional conditions (Table 2). 3.1.1.1. Heavy menstrual bleeding. The symptom studied most extensively for its response to LNG-IUS use is HMB [19–21]. It is now clear that most of the different underlying causes of HMB will benefit from the LNG-IUS (Table 2) provided that the patient does not have contraindications (such as a markedly distorted uterine cavity caused by submucous myomas or a uterine septum). In these indicated situations, the LNG-IUS is usually much more effective than other medical treatments for HMB, such as conventional, Table 2 Therapeutic properties of the LNG-IUS 1. HMB (multiple causes) Uterine leiomyomas [30–35] Endometrial molecular causes [36,37] Adenomyosis [38–42] Disorders of haemostasis or anticoagulation [43–49] Ovulatory disturbances (with or without endometrial hyperplasia) [50,51] 2. Iron deficiency, with or without anemia (exacerbated by HMB) [52,53] 3. Endometrial hyperplasia, with or without atypia [54–59] Endogenous unopposed estrogen exposure (Polycystic ovary syndrome) Exogenous unopposed estrogen exposure [60,61] (Estrogen replacement therapy) 4. Dysmenorrhea and pelvic pain Primary dysmenorrhea [13,14] Secondary dysmenorrhea with endometriosis [62,63] Chronic pelvic pain with endometriosis [64–67] This system has been shown to be an effective treatment for the above conditions (symptoms and/or underlying causes) in most women.
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EE-based COCPs [22,23], oral medroxyprogesterone acetate [24], tranexamic acid and nonsteroidal anti-inflammatory drugs [25]. The recent “NICE Guidelines” of the National Institute for Health and Clinical Excellence of the United Kingdom on HMB [26] have recommended the LNG-IUS as first-choice treatment for HMB, if there is no contraindication. The only low-dose oral medical therapy which approaches the LNG-IUS in efficacy for HMB is the first estradiol-based COCP, which contains estradiol valerate and dienogest and produces around an 80% reduction in measured menstrual blood loss (MBL), compared with a 90% or greater reduction with the LNG-IUS [27,28]. The LNG-IUS rivals endometrial ablation as a therapy for HMB [29] and has the additional advantages of offering highly effective contraception, rapid reversibility and other added health benefits (Table 2). These health benefits span the spectrum of HMB with leiomyomas [30–35], endometrial molecular causes [36,37], adenomyosis [38–42], disorders of haemostasis [43–49] and ovulatory disturbances [50,51], iron deficiency [52,53], endometrial hyperplasia [54–61] and pelvic pain with or without endometriosis [13,14,62–67]. The LNG-IUS has a nominal 5-year lifespan, as tested for contraception, but may require earlier replacement for HMB since declining LNG release may become insufficient to control the HMB process earlier than contraceptive efficacy is lost. There is limited evidence which indicates that the LNG-IUS may take longer to reduce MBL in women presenting with HMB than those being treated for contraceptive indications [30], and this is even more of an issue in those being treated for HMB associated with intramural myomas [35]. However, long-term reduction of blood loss in women with intramural myomas is in the same range as for women with MBL due to other causes [35]. The LNG-IUS may be a very effective long-term therapy, through several insertions of the device [68,69] and an acceptable alternative to hysterectomy [70–74]. A major additional benefit of effectively treating HMB is the correction of iron deficiency and anemia [52,53], conditions which can be associated with severe impact on daily functioning (with lethargy, lack of energy, reduced muscle functioning, adverse effects on mother and fetus in pregnancy through effects on critical enzyme systems in many tissues). Recent evidence indicates that it is the iron deficiency which causes the symptoms, even in the absence of anemia [75]. 3.1.1.2. Symptoms associated with unopposed estrogen exposure. Exogenous or endogenous unopposed estrogen exposure results in anovulation or disturbed ovulation with persistent proliferative endometrium or endometrial hyperplasia, typically associated with erratic menstrual bleeding, which may be heavy and prolonged. The LNG-IUS is a highly effective means of delivering progestogen to the uterine cavity to convert the anovulatory endometrium into a secretory and ultimately atrophic endometrium where bleeding is light and infrequent [50].
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Extensive evidence now exists to demonstrate that endometrial hyperplasia can usually be effectively treated with the LNG-IUS even in the more severe forms where adenomatous or even nuclear atypia changes are present [54–59]. Since adenomatous hyperplasia with atypia is a premalignant condition, it requires regular monitoring by specialized transvaginal ultrasound and endometrial biopsy to ensure continued suppression of the lesion by the LNGIUS [54–59]. The LNG-IUS is more effective than oral progestogens in treating endometrial hyperplasia [55]. 3.1.1.3. Pelvic pain. Pelvic pain associated with menstruation without recognized pathology (primary dysmenorrhea) usually improves greatly during LNG-IUS treatment [13,14], and even most pelvic pain associated with clearly recognized pelvic pathologies, such as endometriosis, will improve greatly with the LNG-IUS [42,62,67]. Randomized controlled trials have confirmed rapid benefit even in more severe stage 3 and 4 disease [67], and the LNG-IUS has proven to be as effective as gonadotropin-releasing hormone analogues for treating pain due to endometriosis [67]. Encouragingly, the LNG-IUS has been shown to be effective in preventing recurrence of endometriosis in women treated surgically [76,77]. 3.1.1.4. Other uses. There is increasing use of the LNGIUS in adolescents with a range of menstrually related problems, including HMB and endometriosis pain, exacerbated by physical, mental or learning disabilities [78–80]. Adolescents appear to tolerate this system well, and it provides excellent control of most symptoms. Insertion does not appear to be a major problem, although those women who have not been sexually active may need a short general anesthetic for insertion. 3.1.2. Use of LNG-IUS for primary prevention or to prevent recurrence of gynecological disease after surgery In light of the therapeutic benefits of the LNG-IUS, it seems logical to consider the possible use of the LNG-IUS to prevent recurrence of surgically treated disease and even for primary prevention of disease in women who have risk
Table 3 Pelvic pathologies that may be prevented by exposure to the LNG-IUS (either primary prevention or prevention of recurrence following surgery) 1. Uterine leiomyomas 2. Endometriosis 3. Adenomyosis 4. Acute episodes of pelvic inflammatory disease 5. Endometrial polyps 6. Perimenopausal menstrual disturbances 7. Endometrial hyperplasia Spontaneous With estrogen replacement therapy With tamoxifen 8. Endometrial adenocarcinoma 9. Infertility
factors for certain symptoms or diseases [10,11]. The conditions which may be prevented or delayed in recurrence following surgery are listed in Table 3. The primary mechanisms for such beneficial prevention of disease and symptoms include suppression of endometrial and myometrial proliferation, enhancement of apoptosis and induction of prominent decidualization of thinned endometrium. Quiescence of myometrial contractions with high-dose local levonorgestrel may contribute to reduction in uterine pain [81], but suppression of endometrial, myometrial and lesion nerve fibres may also contribute to reduction in generation of pelvic pain signals in women with endometriosis [82,83]. 3.2. Other progestogen-only delivery systems The first progestogen-only delivery systems were the long-acting injectables, such as depot medroxyprogesterone acetate, which have also been associated with noncontraceptive health benefits such as reduction of risk of acute episodes of pelvic inflammatory disease, reduction of HMB (although erratic, light bleeding may be a problem in some women), reduction of iron deficiency and anemia with HMB, treatment of endometrial hyperplasias and reduction of pelvic pain with endometriosis. However, the extent of evidence for these benefits has rarely been specifically tested and is therefore limited. Alternative hormonal delivery system developments have included the subdermal progestogen implants (Norplant and Jadelle releasing levonorgestrel and Implanon releasing etonogestrel). These systems all release their progestogen at a rate close to zero order over a period between 3 and 5 years, and result in reduced volume of bleeding with some amenorrhea and infrequent bleeding. These systems probably all produce some of the health benefits listed for other systems above, but few specific objective studies of these benefits have been carried out. Some evidence exists for a reduction in endometriosis pain with the etonogestrelreleasing implant [84] and for effective reduction of bleeding with HMB in users of levonorgestrel- and Nestoronereleasing implants and vaginal rings [85].
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[62] Vercellini P, Aimi G, Panazza S, et al. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999;72:505–8. [63] Bahamondes L, Petta CA, Fernandes A, Monteiro I. Use of the levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea. Contraception 2007; 75(6 suppl):S134–9. [64] Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993–8. [65] Alhamdan D, Bignardi T, Hardas G, Merkur H, Condous G. Mirena intrauterine system: does it improve long-term symptoms in women with chronic pelvic pain and/or endometriosis after laparoscopy? A multicentre randomized controlled trial. Rev Recent Clin Trials 2010;5:143–6. [66] Matorras R, Ballesteros A, Prieto B, et al. Efficacy of the levonorgestrel-releasing intrauterine device in the treatment of recurrent pelvic pain in multitreated endometriosis. J Reprod Med 2011;56:497–503. [67] Bayoglu Tekin Y, Dilbaz B, Altinbas SK, Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropinreleasing hormone analogue. Fertil Steril 2011;95:492–6. [68] Rönnerdag M, Odlind V. Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use. Acta Obstet Gynecol Scand 1999;78:716–21. [69] Lete I, Del Carme Cuesta M, Marín JM, et al. Acceptability of the levonorgestrel intrauterine system in the long-term treatment of heavy menstrual bleeding: how many women choose to use a second device? Eur J Obstet Gynecol Reprod Biol 2011;154:67–70. [70] Hurskainen R, Teperi J, Rissanen P, et al. Quality of life and costeffectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet 2001;357:273–7. [71] Reid PC, Mukri F. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to 2002–3. BMJ 2005;330:938–9. [72] Heliövaara-Peippo S, Halmesmäki K, Hurskainen R, et al. The effect of hysterectomy or levonorgestrel-releasing intrauterine system on lower abdominal pain and back pain among women treated for menorrhagia: a five-year randomized controlled trial. Acta Obstet Gynecol Scand 2009;88:1389–96. [73] Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril 2011;95:497–502. [74] Goñi AZ, Lacruz RL, Paricio JJP, Hernández Rivas FJ. The levonorgestrel intrauterine system as an alternative to hysterectomy for the treatment of idiopathic menorrhagia. Gynecol Endocrinol 2009; 25:581–6. [75] Von Drygalski A, Adamson JW. Ironing out fatigue. Blood 2011;118: 3191–2. [76] Vercellini P, Frontino G, De Giorgi O, et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80:305–9. [77] Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, et al. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol 2012;119:519–26. [78] Paterson H, Ashton J, Harrison-Woolrych M. A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents. Contraception 2009;79:433–8. [79] Pillai M, O'Brien K, Hill E. The levonorgestrel intrauterine system (Mirena) for the treatment of menstrual problems in adolescents with medical disorders, or physical or learning disabilities. BJOG 2010;117: 216–21.
I.S. Fraser / Contraception 87 (2013) 273–279 [80] Al-Jefout M, Palmer J, Fraser IS. Simultaneous use of a levonorgestrel intrauterine system and an etonogestrel subdermal implant for debilitating adolescent endometriosis. ANZJOG 2007;47: 247–9. [81] Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrelreleasing IUD. Clin Endocrinol 1982;17:529–36. [82] Tokushige N, Markham R, Russell P, Fraser IS. Effects of hormonal treatment on nerve fibres in endometrium and myometrium of women with endometriosis. Fertil Steril 2008;90:1589–98.
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[83] Tokushige N, Markham R, Russell P, Fraser IS. Effect of progestogens and combined oral contraceptives on nerve fibers in peritoneal endometriosis. Fertil Steril 2009;92:1234–9. [84] Yisa SB, Okenwa AA, Husemeyer RP. Treatment of pelvic endometriosis with the etonogestrel subdermal implant (Implanon). J Fam Plann Reprod Health Care 2005;31:67–70. [85] Fraser IS, Weisberg E, Minehan E, Johansson EDB. A detailed analysis of menstrual blood loss in women using Norplant and Nestorone progestogen-only contraceptive implants or vaginal rings. Contraception 2000;61:241–51.
Review article
Added health benefits of the levonorgestrel contraceptive intrauterine system and other hormonal contraceptive delivery systems Ian S. Fraser⁎ Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, Camperdown, NSW 2006, Australia Received 27 August 2012; accepted 29 August 2012
Abstract Background: It has been recognized for well over half a century that hormonal preparations designed as contraceptives are also capable of offering health benefits through the treatment and prevention of benign gynecological disease and even some systemic conditions. Increasing attention is now being paid to the extent and detail of such added health benefits, and it is becoming clear that the long-acting, low-dose, hormonal contraceptive delivery systems may offer particular advantages in this regard. Methods: Conventional databases were thoroughly searched, especially for publications from 2006 to 2012, which addressed noncontraceptive-related indications for therapy and prevention. Results: A considerable literature now exists to demonstrate the multiple and substantial noncontraceptive health benefits of long-acting progestogen-releasing systems, especially the levonorgestrel-releasing intrauterine system. These benefits mainly relate to disturbances of menstruation and related symptoms, such as heavy menstrual bleeding (due to many causes); iron deficiency; pelvic pain, especially around endometriosis; and endometrial hyperplasia. The long-acting estrogen–progestogen systems may carry similar added health benefits to those of the combined oral contraceptives, but data are still lacking. Conclusion: Added health benefits are now becoming an important part of the contraceptive choice equation, and the long-acting delivery systems are recognized as suitable primary therapies for a range of gynecological disorders. © 2013 Elsevier Inc. All rights reserved. Keywords: Contraception; Hormonal delivery systems; Intrauterine hormonal system; Health benefits
1. Introduction Highly effective hormonal contraceptives have now been widely available for over 50 years, and many developments have resulted in novel ways of delivering improved hormonal preparations and at lower doses. The majority of the available hormonal preparations have been combined estrogen–progestogen pills with a plethora of different progestogens, but only one estrogen: ethinyl estradiol (EE). However, the most effective of these reversible hormonal contraceptive preparations have turned out to be two lowdose, long-acting, progestogen-releasing systems for intrauterine or subdermal placement. The International Committee for Contraceptive Research of the Population Council has
⁎ Tel.: +61 2 9351 2478; fax: +61 2 9351 4560. E-mail address: [email protected]. 0010-7824/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2012.08.039
been at the forefront of the development of both types of system [1], with two marketed subdermal implant systems (Norplant and Jadelle) and the very successful levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena). This hormonal contraceptive development has been a remarkable success story, but the search for even more effective, convenient and safe preparations continues [1]. Along the development path, a number of troublesome and potentially worrying possible complications were identified, including venous thromboembolism, hypertension, stroke and breast cancer. Although all of these associations are uncommon or rare, they have attracted a vast amount of research attention and financial investment. This has led directly to substantial improvements in the currently popular low-dose, combined oral contraceptive pill (COCP) preparations, to greatly reduced incidence of these potential complications and to a greater understanding of their effects and mechanisms. So much so that the potential for very high
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contraceptive efficacy is now generally taken for granted in the community. In parallel with this multifaceted contraceptive development program has been a much lower-key search for hormonal preparations to treat a range of benign gynecological disorders. In fact, this search preceded the establishment of proper clinical trials to demonstrate efficacy of hormonal contraceptives — the first “hormonal” therapy being an impure “estrogen” preparation of biological origin to treat painful menstruation [2]. The first effective clinical trial of a progestogen preparation [ethynodiol diacetate 10 mg; mestranol 150 mcg (initially present as an impurity)] led to the marketing in the United States of Enovid in 1957 as a treatment for menstrual bleeding disorders [3]. This marketing approval came 2 years before the first marketing approval of the same preparation as a contraceptive. High-dose oral progestogen preparations of norethindrone, norethindrone acetate, medroxyprogesterone acetate, megestrol acetate and others were developed and marketed to treat severe cases of anovulatory and ovulatory “dysfunctional uterine bleeding” [4] and hyperplastic endometrium (“metropathia hemorrhagica”) [5]. These preparations continue to be available today for the same indications. Along this journey, it was rapidly recognized by clinicians that the “oral birth-control pill” could be conveniently used as an initial management tool for many gynecological symptoms [6], but that progestogens alone could be even more effective, albeit in much higher oral doses and often accompanied by nuisance-value side effects. Unfortunately, these attributes were not seen as being sufficiently important to merit necessary investment of clinical trial funding by the pharmaceutical industry or government funding agencies, compared with the “so-called” safety issues. Hence, valuable evidence of the noncontraceptive — or “added” — health benefits of these contraceptive methods has lagged behind that of the much rarer “safety” issues. Nevertheless, nowadays, so many different health benefits are recognized that this aspect of hormonal contraception is becoming part of the “contraceptive choice equation.” Some of these benefits are now relatively well known, but many myths persist. Different hormonal combinations and delivery approaches will result in different patterns of health benefits, and limited evidence exists for the range of benefits accompanying use of certain preparations. Consideration of “health benefits” also needs to take into account the fact that some women have preexisting medical conditions, which may negate the expected benefit.
2. Combined estrogen–progestogen delivery systems Much clinical evidence has now been accumulated which demonstrates the positive and non-contraceptive-related health benefits of estrogen–progestogen oral contraceptives. These are well known and well documented (Table 1) [6–9];
Table 1 Reported added health benefits of the oral estrogen–progestogen contraceptive pill [6–9], which are anticipated, but not proven, to also occur with longer-acting estrogen–progestogen delivery systems (combined vaginal rings; combination transdermal patches) 1. Reduction in long-term risk of endometrial cancer 2. Reduction in long-term risk of ovarian cancer 3. Reduction in risk of HMB 4. Reduction in risk of menstrual pain 5. Reduction in risk of premenstrual syndrome and premenstrual dysphoric disorder 6. Reduction in risk of other menstrually related cyclic disorders 7. Reduction in seborrhea and acne 8. Protection of fertility 9. Reduction in acute episodes of pelvic inflammatory disease 10. Slight extension of lifespan
however, the health benefits of the COCP are not the primary subject of this manuscript. Nevertheless, it is assumed that the longer-acting, estrogen–progestogen delivery systems (e.g., the combination vaginal rings, the transdermal patch and the combination once-a-month injectables) will carry similar benefits to those recorded with the COCP. Most of these hopes remain to be proven. 3. Progestogen-only delivery systems Recent clinical trial activity on added health benefits has focussed particularly on one long-acting progestogen-only delivery system: the LNG-IUS [10,11]. This system has turned out to be a remarkable advance for the treatment of many gynecological symptoms, but perhaps even more important is the recent evidence that it may prevent many symptoms and underlying conditions from developing in the first place. The literature on many of these aspects is substantial [12–14]. 3.1. The LNG-IUS There is now a large body of evidence, of variable quality, supporting the existence of a substantial range of clinical health benefits accompanying medium- to long-term use of the LNG-IUS. Most of these data have been acquired in studies utilizing the specific LNG-IUS developed jointly, from a concept proposed by Luukkainen [15], by the Population Council with the Leiras Company of Turku, Finland, and now marketed as Mirena® (Bayer Pharma). Other LNG-IUSs are being developed [16,17] and may carry similar health benefits, but current data are limited. Several reviews have addressed the issue of noncontraceptive health benefits of the LNG-IUS [10–14]. Each of these reviews has approached this particular aspect of LNGIUS action from a different perspective, but each has emphasized the broad range of important benefits. It is salutary to consider that many of the conditions which benefit from use of this system are actually adverse effects of a modern industrialized society lifestyle, where menarche occurs earlier, pregnancies are delayed and greatly reduced
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in number, lactation is minimized, and women experience many more menstrual cycles and menstruations compared with more primitive human existence [18]. Exposure to excessive numbers of menstrual cycles, with their repeated, large swings in ovarian hormone secretion, is associated with a substantial increase in risk of breast, endometrial and ovarian cancer [18] and with similar increases in occurrence of benign ovarian cysts, uterine leiomyomas, endometriosis and complaint of severe symptoms accompanying menstruation. We have not had time to evolve to cope with these rapidly changing social circumstances. However, moderate- or long-term use of combined estrogen–progestogen contraceptives or the LNG-IUS has beneficial effects in reducing the occurrence and symptomatic impact of many of these conditions. The added health benefits of the LNG-IUS can be considered from two different perspectives. 3.1.1. Therapeutic use for preexisting symptoms The LNG-IUS is now licensed in a number of countries for therapy of several symptoms, including heavy menstrual bleeding (HMB), treatment of conditions resulting from endometrial exposure to unopposed estrogen (exogenous or endogenous, and including endometrial hyperplasia) or menstrual pain (which may include endometriosis). There is also now extensive evidence to support use of the LNGIUS to treat a number of additional conditions (Table 2). 3.1.1.1. Heavy menstrual bleeding. The symptom studied most extensively for its response to LNG-IUS use is HMB [19–21]. It is now clear that most of the different underlying causes of HMB will benefit from the LNG-IUS (Table 2) provided that the patient does not have contraindications (such as a markedly distorted uterine cavity caused by submucous myomas or a uterine septum). In these indicated situations, the LNG-IUS is usually much more effective than other medical treatments for HMB, such as conventional, Table 2 Therapeutic properties of the LNG-IUS 1. HMB (multiple causes) Uterine leiomyomas [30–35] Endometrial molecular causes [36,37] Adenomyosis [38–42] Disorders of haemostasis or anticoagulation [43–49] Ovulatory disturbances (with or without endometrial hyperplasia) [50,51] 2. Iron deficiency, with or without anemia (exacerbated by HMB) [52,53] 3. Endometrial hyperplasia, with or without atypia [54–59] Endogenous unopposed estrogen exposure (Polycystic ovary syndrome) Exogenous unopposed estrogen exposure [60,61] (Estrogen replacement therapy) 4. Dysmenorrhea and pelvic pain Primary dysmenorrhea [13,14] Secondary dysmenorrhea with endometriosis [62,63] Chronic pelvic pain with endometriosis [64–67] This system has been shown to be an effective treatment for the above conditions (symptoms and/or underlying causes) in most women.
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EE-based COCPs [22,23], oral medroxyprogesterone acetate [24], tranexamic acid and nonsteroidal anti-inflammatory drugs [25]. The recent “NICE Guidelines” of the National Institute for Health and Clinical Excellence of the United Kingdom on HMB [26] have recommended the LNG-IUS as first-choice treatment for HMB, if there is no contraindication. The only low-dose oral medical therapy which approaches the LNG-IUS in efficacy for HMB is the first estradiol-based COCP, which contains estradiol valerate and dienogest and produces around an 80% reduction in measured menstrual blood loss (MBL), compared with a 90% or greater reduction with the LNG-IUS [27,28]. The LNG-IUS rivals endometrial ablation as a therapy for HMB [29] and has the additional advantages of offering highly effective contraception, rapid reversibility and other added health benefits (Table 2). These health benefits span the spectrum of HMB with leiomyomas [30–35], endometrial molecular causes [36,37], adenomyosis [38–42], disorders of haemostasis [43–49] and ovulatory disturbances [50,51], iron deficiency [52,53], endometrial hyperplasia [54–61] and pelvic pain with or without endometriosis [13,14,62–67]. The LNG-IUS has a nominal 5-year lifespan, as tested for contraception, but may require earlier replacement for HMB since declining LNG release may become insufficient to control the HMB process earlier than contraceptive efficacy is lost. There is limited evidence which indicates that the LNG-IUS may take longer to reduce MBL in women presenting with HMB than those being treated for contraceptive indications [30], and this is even more of an issue in those being treated for HMB associated with intramural myomas [35]. However, long-term reduction of blood loss in women with intramural myomas is in the same range as for women with MBL due to other causes [35]. The LNG-IUS may be a very effective long-term therapy, through several insertions of the device [68,69] and an acceptable alternative to hysterectomy [70–74]. A major additional benefit of effectively treating HMB is the correction of iron deficiency and anemia [52,53], conditions which can be associated with severe impact on daily functioning (with lethargy, lack of energy, reduced muscle functioning, adverse effects on mother and fetus in pregnancy through effects on critical enzyme systems in many tissues). Recent evidence indicates that it is the iron deficiency which causes the symptoms, even in the absence of anemia [75]. 3.1.1.2. Symptoms associated with unopposed estrogen exposure. Exogenous or endogenous unopposed estrogen exposure results in anovulation or disturbed ovulation with persistent proliferative endometrium or endometrial hyperplasia, typically associated with erratic menstrual bleeding, which may be heavy and prolonged. The LNG-IUS is a highly effective means of delivering progestogen to the uterine cavity to convert the anovulatory endometrium into a secretory and ultimately atrophic endometrium where bleeding is light and infrequent [50].
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Extensive evidence now exists to demonstrate that endometrial hyperplasia can usually be effectively treated with the LNG-IUS even in the more severe forms where adenomatous or even nuclear atypia changes are present [54–59]. Since adenomatous hyperplasia with atypia is a premalignant condition, it requires regular monitoring by specialized transvaginal ultrasound and endometrial biopsy to ensure continued suppression of the lesion by the LNGIUS [54–59]. The LNG-IUS is more effective than oral progestogens in treating endometrial hyperplasia [55]. 3.1.1.3. Pelvic pain. Pelvic pain associated with menstruation without recognized pathology (primary dysmenorrhea) usually improves greatly during LNG-IUS treatment [13,14], and even most pelvic pain associated with clearly recognized pelvic pathologies, such as endometriosis, will improve greatly with the LNG-IUS [42,62,67]. Randomized controlled trials have confirmed rapid benefit even in more severe stage 3 and 4 disease [67], and the LNG-IUS has proven to be as effective as gonadotropin-releasing hormone analogues for treating pain due to endometriosis [67]. Encouragingly, the LNG-IUS has been shown to be effective in preventing recurrence of endometriosis in women treated surgically [76,77]. 3.1.1.4. Other uses. There is increasing use of the LNGIUS in adolescents with a range of menstrually related problems, including HMB and endometriosis pain, exacerbated by physical, mental or learning disabilities [78–80]. Adolescents appear to tolerate this system well, and it provides excellent control of most symptoms. Insertion does not appear to be a major problem, although those women who have not been sexually active may need a short general anesthetic for insertion. 3.1.2. Use of LNG-IUS for primary prevention or to prevent recurrence of gynecological disease after surgery In light of the therapeutic benefits of the LNG-IUS, it seems logical to consider the possible use of the LNG-IUS to prevent recurrence of surgically treated disease and even for primary prevention of disease in women who have risk
Table 3 Pelvic pathologies that may be prevented by exposure to the LNG-IUS (either primary prevention or prevention of recurrence following surgery) 1. Uterine leiomyomas 2. Endometriosis 3. Adenomyosis 4. Acute episodes of pelvic inflammatory disease 5. Endometrial polyps 6. Perimenopausal menstrual disturbances 7. Endometrial hyperplasia Spontaneous With estrogen replacement therapy With tamoxifen 8. Endometrial adenocarcinoma 9. Infertility
factors for certain symptoms or diseases [10,11]. The conditions which may be prevented or delayed in recurrence following surgery are listed in Table 3. The primary mechanisms for such beneficial prevention of disease and symptoms include suppression of endometrial and myometrial proliferation, enhancement of apoptosis and induction of prominent decidualization of thinned endometrium. Quiescence of myometrial contractions with high-dose local levonorgestrel may contribute to reduction in uterine pain [81], but suppression of endometrial, myometrial and lesion nerve fibres may also contribute to reduction in generation of pelvic pain signals in women with endometriosis [82,83]. 3.2. Other progestogen-only delivery systems The first progestogen-only delivery systems were the long-acting injectables, such as depot medroxyprogesterone acetate, which have also been associated with noncontraceptive health benefits such as reduction of risk of acute episodes of pelvic inflammatory disease, reduction of HMB (although erratic, light bleeding may be a problem in some women), reduction of iron deficiency and anemia with HMB, treatment of endometrial hyperplasias and reduction of pelvic pain with endometriosis. However, the extent of evidence for these benefits has rarely been specifically tested and is therefore limited. Alternative hormonal delivery system developments have included the subdermal progestogen implants (Norplant and Jadelle releasing levonorgestrel and Implanon releasing etonogestrel). These systems all release their progestogen at a rate close to zero order over a period between 3 and 5 years, and result in reduced volume of bleeding with some amenorrhea and infrequent bleeding. These systems probably all produce some of the health benefits listed for other systems above, but few specific objective studies of these benefits have been carried out. Some evidence exists for a reduction in endometriosis pain with the etonogestrelreleasing implant [84] and for effective reduction of bleeding with HMB in users of levonorgestrel- and Nestoronereleasing implants and vaginal rings [85].
4. Conclusion The sum of recent evidence indicates that added health benefits are now an integral part of the contraceptive choice equation for women considering use of a hormonal contraceptive and that the LNG-IUS, in particular, is a system with proven efficacy for a wide range of gynecological conditions. References [1] Sitruk-Ware R. Contraceptive technology: past, present and future. Contraception 2012 this volume ***.
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