Rationale for Low-Dose Systemic Hormone Replacement Therapy and Review of Estradiol 0.5 mg/neta 0.1 mg

Adv Ther. 2008;25(6):525 551. DOI:10.1007/s12325-008-0070-6 REVIEW Rationale for Low-Dose Systemic Hormone Replacement Therapy and Review of Estradiol 0.5 mg/neta 0.1 mg Odd Erik Johansen Medical Department, Asker and Baerum Hospital, Rud, Norway Erik Qvigstad Department of Gynaecology, Ullevål University Hospital, Oslo, Norway ABSTRACT The menopausal transition is associated with several symptoms, for which both non-pharmacological and pharmacological measures are available to provide relief. However, present knowledge indicates that the former is not highly effective, and that the latter, in terms of systemic oestrogen and progestogen-based hormone replacement therapy (HRT), although being effective (e.g. on vasomotor symptoms, bleeding control, bone mineral density, vaginal atrophy and quality of life), can be associated with some caveats. Amongst these are an increased risk for coronary heart disease, breast cancer, venous thromboembolism and stroke. In recent years, literature has indicated a dose dependency for HRT on some of the caveats, hence authorities (Food and Drug Administration, and the European Medicines Agency) and menopause societies (International Menopause Society and North American Menopause Society) now recommend that women deemed in need of HRT should receive the lowest possible dose without compromising the effect of symptom relief. Estradiol 0.5 mg/norethisterone acetate (NETA) 0.1 mg, despite being a lower dose than conventional hormones, is a compound, among a few other low-dose options, that can be used in such therapy. As a first-line oral option, it has demonstrated its effectiveness (which seems comparable to other compounds), with high tolerability and, apparently, no safety concerns, in a 6-month study. Further long-term clinical trials and observational studies are mandatory in order Address correspondence to: Odd Erik Johansen, Medical department, Asker and Baerum Hospital, PO Box 83, 1309 Rud, Norway. Email: odd.erik.johansen@broadpark.no 525

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg to capture any potential harm as well as to elucidate this compound s full potential. Following a thorough literature search using PubMed and MEDLINE from the earliest publication dates through to January 2008, including results from various types of clinical trials and statements on HRT, we review the rationale for these recommendations. We also review the effects and safety of a novel ultra-low-dose oral continuous combined HRT tablet, estradiol 0.5 mg/neta 0.1 mg. Keywords: cardiovascular; HRT; mammographic density; menopause; NETA; oestrogen; pharmacological treatment; progestogen; randomised controlled trials; review INTRODUCTION Average life expectancy has increased over the last few decades, especially in the western hemisphere. The average life expectancy in the UK and USA in 2005 was 78 and 77 years, respectively, compared with 72 years in 1975. 1 However, although life expectancy has increased in both genders, women are generally expected to live longer. Given that there is an expected high increase in the prevalence of elderly people within the near future, due to the high birth rates in the 1940s and 1950s, 1 this has a large societal impact leading to a dominance of women among the adult population both in absolute and relative numbers. Hence, effective gender medicine, such as for the treatment of symptoms and signs related to post-menopausal hypoestrogenism, is warranted. Both nonpharmacological and pharmacological measures are available for such treatment. The former option has been found to be not very effective, while the latter in terms of systemic oestrogen- and progestogenbased hormone replacement therapy (HRT), although highly effective, has been associated with some caveats, i.e. increased risk for coronary heart disease (CHD), breast cancer, venous thromboembolism (VTE) and stroke. 2 Interestingly, some literature indicate at least for some of the caveats, a dose dependency for HRT, 3 8 as well as a dependency of the particular type of hormone used. 6,8 10 We review the literature on these issues and the rationale behind recommendations from authorities 11,12 and menopause societies 13,14 that women deemed in need of HRT should receive the lowest possible dose of oestrogen and progestogen. We also review the effects and safety of a novel, ultra-low-dose, oral, continuous combined (cc) HRT tablet, namely estradiol 0.5 mg/norethisterone acetate (NETA) 0.1 mg (US brand name Activella 0.5 mg/0.1 mg; Novo Nordisk A/S, Bagsvaerd, Denmark). A thorough literature search was conducted using PubMed and MEDLINE from the earliest possible publications available up to January 2008. 526

Johansen & Qvigstad The search included results from various types of clinical trials (e.g. randomised controlled trials, observational studies, safety reports) and statements on HRT. The search phrases: menopause, oestrogen, estradiol, progestogen, low dose, ultra low dose, Activella low, HRT safety and HRT side effects were used alone and in combination. The reference lists of all included manuscripts were also searched for relevant topics. POST-MENOPAUSAL SYMPTOMS AND SIGNS Oestrogen deficiency is something that all women eventually encounter as this is a naturally occurring biological phenomenon due to loss of functional ovaries. 15 This process, also called the menopause transition, describes the change from a reproductive or premenopausal period, marked by regular ovulation and cyclic menstrual bleeding, to a post-menopausal period, marked by amenorrhea. The median age for western women becoming naturally menopausal is around 50 51 years. 16 19 The menopausal age is dependent on several factors, e.g. numbers of births, smoking habits and age at menarche. For a few women the menopause transition is hardly noticed, but for the majority there will be some manifestations (Table 1). Studies have shown that the prevalence and severity of menopause symptoms may vary depending on the stage of the menopause transition (i.e. early or late); nevertheless, most women at some stage experience more than one sign or symptom. 25 For instance, in Melbourne, Australia, and in Massachusetts, USA, the prevalence of women with five or more symptoms was found to be 22% and 23%, respectively, among premenopausal women, 22% and 35% among perimenopausal women, and 36% and 32% among naturally post-menopausal women. 25,28 Unsurprisingly, the diversity of symptoms associated with menopause transition is also associated with decreased health func- Table 1. List of some symptoms and signs associated with the menopausal transition. Reference Menstrual irregularities 15 Vaginal dryness 20,26 Vasomotor disturbances (hot flushes, shivering, sweating, heat intolerance) 20 Irritability/changes in mood 21 Menstrual migraine 22 Aches, joint pain and stiffness 23 Memory impairment 24 Breast tenderness 25 Sleep disturbances 25 Sexual dysfunction, reduced lubrication and dyspareunia 20,26,27 527

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg tioning in women who report menopausal symptoms. 29 This is not only limited to a reduction in health-related quality of life, 29 but may even have a deleterious impact from a societal view (e.g. impaired relation to spouses and ability to perform work). 30 Certain subgroups of women (low social status, high body mass index, smoking, pre-existing psychological distress) seem to be at an exceptionally high risk for a more symptomatic transition, thus also having associated larger declines in health status. These declines have been compared with those seen in patients with mild diseases and are considered to have a considerable impact on the women s lives. 31,32 Although there are many symptoms and signs of the menopausal syndrome (Table 1), the first indication of an approaching menopause is usually menstrual irregularities with a shortening of the premenopausal cycle (initially shortened by 2 3 days), due to a shorter duration of the follicular phase. 15 The most frequent symptom, affecting 60% 90% of western women, is hot flushes. Hot flushes may be defined as a subjective experience of intense heat, sweating, flushing or chills, initiating typically from the upper body although most frequently in the face, neck and chest. This typical symptom may be objectified by measurements of skin temperature or core temperature and usually lasts from a few seconds to 10 minutes, with an average duration of 4 minutes. 19 Hot flushes are ranked as the most troublesome symptom, 29 especially in the early years 20 after the onset of menopause. Still, it is not uncommon for women who have been post-menopausal for 10 years or more to have symptoms. Berg et al. 33 conducted a study that included women aged 60 62 years. More than one in four (27%) suffered from sweating and hot flushes and 10% of women who were more than 15 years post-menopause still had moderate to severe climacteric symptoms. 33 This was also demonstrated in another study, where it was found that the maximal prevalence of hot flushes was about 60% at 52 54 years of age, declining to 30% at 60 years, and to 9% at 72 years. 34 There are several factors that predict vasomotor symptoms including a symptomatic mother, 35 present smoking, 36,37 late menopausal age (>53 years), 38 and high body mass index. 37,38 They are also more common in post-menopausal women with low estradiol or estrone concentrations than in those with high concentrations 19 and in those with lower levels of inhibin B and higher levels of follicle-stimulating hormone. 33 Also, high within-woman fluctuations of estradiol have been associated with hot flushes. 33 Thus, it is believed that the symptoms are due to a loss of oestrogen stimulation. 19 It is not known why not all women experience symptoms since all women ultimately experience a fall in oestrogen levels. The pathophysiology of this occurrence is not fully known, 19 although it is generally believed that hot flushes arise as a result of an alteration in the central nervous system thermoregulatory set-point, located in the anterior portion of the hypothalamus, 19 and triggered by small elevations in core body temperature (which oestrogen can induce) acting within a reduced thermoneutral zone. 38 Interestingly, women with vasomotor symptoms are character- 528

Johansen & Qvigstad ised by increased levels of oxidative stress, 39 which may render them more prone to cardiovascular disease. Nonetheless, this issue is far from clear as it has also been found that women with hot flushes have better vascular reactivity. 40 An interesting aspect of the menopause transition is that prevailing symptoms and signs are dependent on whether the women have been menopausal for a short or long duration. As outlined above, the prevalence of hot flushes, considered an early sign in the menopausal transition (although for some also present at age >70 years), declines with years since menopause. 37,41 In contrast, the prevalence of some other manifestations and signs increase with years. Two of the most common are related to local urogenital manifestations (atrophic changes in the vagina leading to vaginal dryness 20,26 and dyspareunia 20,26,27 or even discharge; urination dysfunction and recurrent urinary tract infections 42 ) and osteopenia (eventually osteoporosis), 43 both due to oestrogenic deprivation. Urogenital manifestations such as vaginal dryness were experienced by 25% of women at 1 year post-menopause, and by nearly 50% among those at 3 years postmenopause. 25 These data are in line with a study reporting an odds ratio of 1.0 for severe versus no/slight symptoms related to vaginal dryness among women aged 50 53 years, whereas among those aged 58 64 years the odds ratio was 1.95. 37 Other manifestations such as repeated urinary tract infections, itch and discharge have been reported with a prevalence of 13% among 61-year-old women, while smarting pain and dyspareunia were reported with prevalences of 15% and 38%, respectively. 42 Osteopenia, osteoporosis and risk of fractures also increases with years since menopause. In a large US study among women with a diverse background, the relative risk (RR) for a new fracture within 1 year was 1.18 for women 10 19 years post-menopause and was 1.51 for women 30 years since menopause. 43 TREATMENT OPTIONS FOR POST-MENOPAUSAL SYMPTOMS AND SIGNS Although many symptoms and signs are associated with the menopausal transition, not all are subject to direct interventions. Still, the most bothersome symptom, i.e. hot flushes, is modifiable through both non-pharmacological (at least to a certain degree) and pharmacological interventions. They differ in terms of efficacy, as do the side-effect profiles of currently available treatment options. Non-pharmacological Options Since there is a relation between estradiol levels and menopausal symptoms and signs, it might be expected that interventions that interfere with these levels may trigger some of the symptoms. The intake of various foods (hot beverages, monosodium glutamate, sodium nitrite) 19 may trigger symptoms. Ingested nutrition may also have the propensity to reduce the menopausal symptoms as shown with soy nut consumption. 44 However, the effect 529

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg is relatively sparse, as shown recently for some of the most popular treatments based on foods or supplements enriched with phytoestrogens, a plant-derived chemical which has an oestrogenic action. In a large Cochrane review, phytoestrogens were found to have no effect in the alleviation of menopausal symptoms. 45 In spite of this knowledge, it is estimated that herbal supplements and natural preparations are used on a very large scale. 46 Another non-pharmacological treatment option that might modulate oestrogen fluctuations, or by other mechanisms have a positive impact on the menopausal symptoms, is physical exercise. Although population-based prospective studies have shown that vigorous physical exercise is associated with lower intensity of hot flushes, 37,47 the documentation for this treatment is also scarce. 46,48 In fact, in another recent Cochrane review the conclusions regarding the effectiveness of exercise could not be made due to a lack of trials. 48 Thus, there is a need for more effective treatment options. Among these are pharmacological treatments, which first and foremost are based on hormones that stimulate the oestrogen and progestogen receptors, i.e. HRT. Nonetheless, non- HRT-based therapy has been shown to have some effect. Non-HRT Options Certain antidepressant medications (selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, veralipride [an antidopaminergic drug] and moclobemide [a selective monoamine oxidase-a inhibitor]), centrally active alpha-adrenergic antihypertensive agonists (clonidine and methyldopa) and the gamma-aminobutyric acid analogue anticonvulsive gabapentin are some of the non-hrt-based therapies that provide some evidence of efficacy in terms of rendering symptom control. 49 In 2007, the first serotonin norepinephrine reuptake inhibitor (desvenlafaxine succinate; Pristiq, Wyeth, USA) received an approvable letter from the Food and Drug Administration (FDA) for the management of moderate to severe vasomotor symptoms. However, the effects of non- HRT treatments are less than those of HRT and few trials have been published. 49 Generalisability beyond the small clinical populations studied could be limited, perhaps with the exception of desvenlafaxine succinate. 50 Adverse effects and costs may further prohibit use for many women. Although these therapies may be useful for highly symptomatic women who cannot take HRT, they are not optimal choices for most women. 49 The market for non-hrt treatment is assumed to be very low, and these treatment options are not further considered in this review. HRT Options HRT is available in various regimens either as unopposed oestrogen therapy or as oestrogen therapy in combination with progestogens, in which any type of oestrogen (human, esters, conjugated or synthetic) can be used. Recently, a class of HRT that regulates oestrogenic activ- 530

Johansen & Qvigstad ity in a tissue-selective way has appeared: STEAR (selective tissue estrogenic activity regulator). The only marketed compound is tibolone, which is a derivative of norethynodrel (a progestogen) and, when ingested, is broken down into metabolites with oestrogenic, progestagenic and androgenic effects. 51 Clinically, this compound offers similar symptom control as oestrogen-based therapy. 52 HRT may be administered by various routes: oral, transdermal, vaginal, nasal or as an implant. This review concentrates on the effects of systemic oral treatment, although both transvaginal and transdermal administration are considered to some degree. One of the most important distinctions between the two latter administration forms versus oral treatment is that oral oestrogen is subject to substantial intestinal and hepatic first-pass metabolism, 53,54 necessitating relatively high doses. Hence, with the elimination of enterohepatic metabolism of the drugs through transdermal or vaginal administration it is possible to administer a lower dose, although it is only transdermally delivered oestrogens that are efficacious in modulating menopausal symptoms of systemic origin (e.g. vasomotor symptoms). Nevertheless, some problems related to transdermal oestrogen administration are its association with variable absorption rates between women, 55 local skin irritation, 56 lack of discretion and the loss of patches in 4% 8% of cases due to poor adhesion. 57 On the other hand, non-oral use, due to the omittance of first-pass metabolism, might have a favourable side-effect profile due to its lesser stimulation of liver proteins, although direct comparative studies with definite endpoints are still lacking. Benefits with HRT Systemic oestrogen-based therapy s most powerful effect is in reducing vasomotor symptoms, 13,19 particularly hot flushes, which can be reduced by 50% 100%. 19 In addition, many other beneficial impacts can also be expected. Of special note is the impact of HRT on reducing the risk of bone fractures 58 due to its effect on bone mineral density and osteoporosis. Although this has been known for many years, 59 more recent data indicate that this is even the case for very low dosages of oestrogen and progestogens, whether it is conjugated equine oestrogen (CEE) (i.e. less than 0.625 mg daily) and medroxyprogesterone (MPA), 60 unopposed transdermal estradiol (0.014 mg daily), 61 or estradiol (0.5 mg) and NETA (0.25 mg), 62 and tibolone 1.25 mg. 63 Interestingly, estradiol 0.25 mg has been shown to reduce bone turnover to a similar degree to that seen with conventional doses (1.0 mg), and the lowest dose (0.25 mg) has a side-effect profile similar to that of placebo. 64 The fact that oestrogen at lower than conventional doses has a beneficial impact on the bone is further supported by findings that transvaginally administered oestrogens seem to provide a small, but significant, effect on bone mineral density. 65 Other particular benefits of HRT are regarding vaginal atrophy and related problems, in particular dyspareunia. 13,14,66 Even low-dose compounds seem to be ben- 531

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg eficial. 67 Such manifestations most often occur later in the menopausal transition where local oestrogen therapy is often preferred, 68 but it is interesting that even for local treatment, a lower than conventional dose of estradiol (10 μg vaginal tablet) seems to offer symptom alleviation, although general improvements were better with the higher dose (25 μg). 69 The effects of HRT on other sequelae of urogenital ageing, including urinary frequency and urgency, urinary incontinence, and urinary tract infections, are less clear, perhaps because these conditions have more complex multifactorial causes not clearly related to oestrogen deficiency or tissue ageing. 14,68 Many of the other manifestations of the menopausal transition are also subject to HRT modulation, such as sleep disturbances and a depressed mood, 70 but whether this holds true for lower than conventional doses of HRT has not been determined. It is nonetheless an undisputable fact, due to its pleiotropic effects, that HRT improves health-related quality of life in women with post-menopausal complaints. 71 74 Cognitive functioning, however, does not seem to be improved with HRT in studies performed to date, although there is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. 75 Another issue seldom brought up when discussing benefits of HRT is its propensity on reducing diabetes incidence, which has consistently been shown to be around 30% in large randomised control studies. 76,77 Added to this finding comes registered studies reporting that women with diabetes using systemic HRT have better blood glucose control. 78 It is still important to point out that, to date, HRT is not recommended as a measure for diabetes prevention. Caveats with HRT One important caveat with oral or transdermal unopposed oestrogen treatment, besides common side effects such as bloating, weight gain and fluid retention, is an increased risk of endometrial hyperplasia, as well as endometrial carcinoma, 79,80 due to its proliferative stimulus. This risk does not apply to transvaginal oestrogen administration, 81 probably due to the low systemic absorption. To counteract this specific unwanted, systemic effect of oestrogen, progestogen, which can transform an oestrogen-stimulated endometrium into becoming secretory (hence preventing endometrium hyperplasia and protecting against malignant transformation), is therefore combined with such treatment. Progestogens are available in a variety of compounds, and most can be classified as either 17-hydroxyprogesterone derivatives (e.g. MPA, dydrogesterone and progesterone) or as 19-nortestosterone derivatives (e.g. NETA, norethisterone, levonorgestrel or dienogest). The most commonly used are the 19-nortestosterone derivatives (in particular NETA) and MPA, of which the former seem to be more potent in terms of offering endometrium protection. 82 Adding a progestogen fully counteracts the risk for endometrial hyperplasia, as well as endometrial carcinoma, even at 532

Johansen & Qvigstad very low doses. 79 Kurman et al. carried out a study of 1176 women who were given 1 mg unopposed estradiol or a cc regimen of 1 mg estradiol with one of three different doses of NETA (0.1 mg, 0.25 mg, 0.5 mg). The incidence of hyperplasia at the end of this 12-month study was 13.8% in the unopposed estradiol group, compared with less than 1% in each of the cc HRT groups. 83 Interestingly, progestogen in a cc HRT regimen seems to offer better protection of the endometrium than if sequential HRT are given. 84 Also of interest is that some progestogens support and enhance the effects of oestrogens on symptom relief and bone mineral density. 85 The Women s Health Initiative study Other possible adverse effects of currently available hormone treatment were highlighted in the Women s Health Initiative (WHI) study that included 16,608 women with a mean age of 63.3 years in the USA. Half of the women received an HRT consisting of CEE 0.625 mg combined with MPA 2.5 mg, and the other half of the women received placebo; all were followed for a mean of 5.2 years. 2 The disease rates originally reported in this study, as well as the beneficial or neutral impacts, are presented in Table 2. However, the WHI study design and results have been under massive criticism, for example for allowing elderly women without climacteric symptoms to be included, for including many patients with subclinical cardiovascular disease, for a very complex study design and high drop-out rate. 86 91 The negative findings were broadly presented in the media towards the general population, and had a large impact on the use of systemic HRT globally. In Denmark, for example, a 65% reduction in the use of HRT was observed between 2002 and 2004, 92 and the prevalence of current users of HRT Table 2. Disease rates and beneficial/neutral impact (cases) for women on conjugated equine oestrogen (CEE) plus medroxyprogesterone (MPA) or placebo in the Women s Health Initiative study.2 CEE+MPA Placebo (n=8506) (n=8102) HR (95% CI) Coronary heart disease 164 122 1.29 (1.02, 1.63) (MI, silent MI, coronary death) Invasive breast cancer 166 124 1.26 (1.00, 1.59) VTE 151 67 2.11 (1.58, 2.82) Stroke 127 85 1.41 (1.07, 1.85) Colorectal cancer 45 67 0.63 (0.43, 0.92) Fractures 650 788 0.76 (0.69, 0.85) Endometrial cancer 22 25 0.83 (0.47, 1.47) Death 231 218 0.98 (0.82, 1.18) CI=confidence interval; HR=hazard ratio; MI=myocardial infarction; VTE=venous thromboembolic disease. 533

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg in women aged 50 57 years in 2002 was reduced to 19% 28%. In a Finnish study among HRT users, women reported that their most common source of information concerning the benefits of HRT was the physician (74%), while the most common source of information concerning the risks was the media (78%). 93 Nonetheless, it is not easy to present complex messages in the media, and in a qualitative study in 2003 among women that actually stopped using HRT, despite being highly symptomatic, reasons for doing so were given with emotional overtones such as worry, confusion, anger and grief. 94 Interestingly, although the negative message relatively easily reached the public opinion, among prescribing physicians and gynaecologists in Scandinavia, their own or spouses HRT use in 2004 did not change much after the 2002 WHI publication as the prevalence of current users was still relatively high (70% 80%). 95 Modulation of the WHI Study Results and Dose Dependency for Adverse Impact In recent years, several re-analyses of the WHI study have been published, which moderate the original findings for impact of HRT on CHD and breast cancer. 96,97 More importantly, from a clinical and safety perspective, there is now evidence supporting a dose dependency in relation to both oestrogens and progestogens on unfavourable outcomes, discussed below, which even seems to be related to type of oestrogen and progestogen used. Coronary Heart Disease In a WHI re-analysis, no adverse impact on CHD was seen in women who initiated HRT treatment less than 20 years after the onset of menopause or who were younger than 70 years at initation. 96 This was also underscored in a coronary artery calcium score substudy of the WHI trial in patients receiving unopposed oestrogen that found, among women 50 to 59 years old at enrolment, that the calcified-plaque burden in the coronary arteries after trial completion was lower than in those assigned to placebo. 97 Similar conclusions have been drawn in other studies, 8,98 100 and in a meta-analysis lower mortality was seen if HRT was initiated before the age of 60. 101 Due to this, the term window of opportunity has arisen, to reflect the finding that relatively early HRT initiation may offer some cardiovascular protection. 102 However, it should be stressed that HRT to date is not recommended as a prophylactic measure for CHD. Also of note is the evolving evidence that oestrogen receptor protein (alpha or beta) distribution, 103 as well as polymorphisms of the oestrogen receptor-1 genotype, 104 can play a role in the development of cardiovascular disease. Nonetheless, it is probably still many years until a clinically relevant use of pharmacogenetics in HRT is available. Breast Cancer The WHI study did not shown any increase in breast cancer risk in the oestrogen-only arm, 105 hence progestogen seems 534

Johansen & Qvigstad to play an important role. As previously seen, the risk of breast cancer diagnosis is elevated in women using HRT, and continues to rise with increased duration of use. This effect is reduced after cessation of HRT and seems to largely, if not wholly, disappear after approximately 5 years, 106 although a recent study claimed this to be the case after only 2.5 years. 107 Nevertheless, it is generally believed that HRT increases the risk of breast cancer, although the use of HRT is not associated with a worse outcome. 108 In fact, HRT before the diagnosis of breast cancer has even been shown to result in more favourable primary tumours, with a lower incidence of recurrences and a better overall survival rate. 109,110 One of the reasons that HRT is thought to increase the risk of breast cancer is related to the fact that it can increase mammographic density, which is a predictor of breast cancer. 111 Interestingly, there also seems to be a dose dependency for HRT as shown in a study where increased risk was observed in 60% of those receiving higher doses of progestin compared with 16.7% in those receiving a lower dose. 3 Increased risk has also been reported to be dependent on regimens, i.e. higher in those using cc HRT (39%) compared with those using cyclic HRT (15%) or unopposed oestrogen (<5%). 9 The dose-dependent relationship has also been found in other studies, 4 hence the dosage of HRT could play a role in promotion of breast neoplasms, analogous to its dosage-related promotion of endometrial cancer. 112 It is important to stress that mammographic density is a surrogate marker. This was illustrated for tibolone, which has been shown to have a neutral or lesser impact on breast density as compared with no treatment, 113 placebo 114 or oestrogencontaining products. 115,116 A previously observed increased risk for breast cancer with tibolone in an observational study 117 could have been explained due to preferential prescribing to women already at a higher risk for breast cancer. 118 However, in the LIBERATE study (Livial Intervention Following Breast Cancer: Efficacy, Recurrence And Tolerability Endpoints) a randomised, placebo-controlled trial in women with a history of breast cancer and serious climacteric complaints, 119 terminated in May 2007 following the advice from the data safety monitoring board and the advisory board there was a tendency for more breast cancer cases in the tibolone-treated group. 120 This illustrates that although baseline mammographic density correlates with breast cancer risk, this does not necessarily apply to the increase in mammographic density induced by HRT. Venous Thromboembolic Disease Although HRT increases the risk for idiopathic VTE among post-menopausal users 2- to 3-fold, 2,5 7 a study among users of CEE for more than 12 months showed that the risk was dose dependent with a RR for an event of 2.1, 3.3 or 6.9 for doses of 0.325 mg, 0.625 mg and 1.25 mg, respectively. 5 This has also been found in other studies, 6,7 hence low-dose HRT formulations seem to offer the lowest potential for such complications. The route of administration may also 535

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg play a role as showed in a study investigating VTE in women using oral HRT (mean dose of oestrogen, 1.5 mg) or transdermal oestrogen (66% of subjects received preparations delivering 50 μg per day). This trial showed that the increase in risk was limited to the oral HRT users, not the transdermal users, 121 which might be explained by the lesser stimulation of liver proteins with the latter. 53,54 In the same study, 121 no difference between unopposed oestrogen and combined progestogen/oestrogen was seen, which is at variance with other studies, 6 underscoring that the risk might also be modulated by the type of gestagen used. Stroke An increased risk for stroke in patients using HRT has been shown in other trials besides the WHI. However, it seems like this risk is conferred first and foremost to women previously relatively healthy, 107 and not to those with a previous cardiovascular event. 122,123 The adjusted RR for stroke in a prospective observational study (the Nurses Health Study) among women using HRT (CEE+MPA) was 0.54 (95% confidence interval [CI]: 0.28, 1.06), 1.35 (CI: 1.08, 1.68) and 1.63 (CI: 1.18, 2.26), respectively, among users of CEE doses of 0.3 mg, 0.625 mg or 1.25 mg. 8 Here progestogen also seems to play a role as when analyses were confined to women taking 0.625 mg CEE only, the RR was 1.24 (95% CI: 0.95, 1.62), rising to an RR of 1.54 (95% CI: 1.12, 2.11) for women taking CEE+MPA. 8 Animal studies lend further support to this, where in rabbit cerebral arteries, MPA treatment caused a higher development in arterial tension compared with NETA, 10 although this remains to be proven in humans. Other Common Side Effects The dose and type of HRT also seem to be important for less serious adverse effects. This was seen in a study investigating the lowest possible oestrogen dose for vasomotor symptom relief, where the number of women who discontinued because of adverse events (bleeding and breast pain most commonly reported) tended to increase with increased dosage of estradiol. 124 A similar tendency was seen in a transdermal HRT study 67 and in a study investigating the lowest possible oestrogen dose for reducing bone turnover. 64 Breast pain seems also to correlate with the impact of HRT on breast density, since this was reduced with agents that did not increase mammographic density. 114 Future Directions of HRT Since there is a plethora of evidence supporting a dose dependency for oral oestrogens and progestogens on several unfavourable outcomes, the use of the lowest efficacious HRT dose, i.e. the lowest possible dose of oestrogen to achieve symptom relief and the lowest possible dose of progestogen to protect the endometrium, has become a requirement from regulatory authorities such as the European Medicines Agency 11 536

Johansen & Qvigstad and the FDA. 12 Recent HRT treatment guidelines from the International Menopause Society 13 and the North American Menopause Society 14 also have incorporated this. The low-dose concept seems particularly relevant for offering elderly women a safe and efficacious treatment as, due to physiological reasons, they are in need of lower doses as a result of slower metabolism of steroids and less lean fat mass. 125 The definition of the lowest dose is less clear. In 2001, the classical and arbitrary classification of different oestrogen preparations suggested that a low dose of CEE, estradiol, estradiol valerate, and transdermal estradiol were 0.3 mg, 1 mg, 1 mg, and 0.0025 mg, respectively, whereas standard doses were 0.625 mg, 2 mg, 2 mg, and 0.0050 mg. 126 However, at the 6th IMS workshop in Italy, December 2006, 127 a new class the ultra low dose for oral oestrogen preparations containing 0.5 mg estradiol was proposed. Although the availability of systemic treatment options varies in different countries, it is clear that most available HRT is in fact not low dose, and to date no oral, and only some, transdermal formulations 61,67 can be classified as ultra low dose. Thus, since there are few products in line with current recommendations, 11 14 treatment that offers both low concentrations of hormones at the same time as being clinically effective is warranted. The remainder of this review deals with such a newly launched product, estradiol 0.5 mg/neta 0.1 mg (Novo Nordisk A/S) for oral use. CLINICAL BENEFITS OF ESTRADIOL 0.5 MG/NETA 0.1 MG This cc HRT compound is indicated for oestrogen deficiency symptoms in women more than 1 year after menopause with an intact uterus. 128,129 In the USA it also has the additional indication of preventing post-menopausal osteoporosis for women at significant risk of osteoporosis after careful consideration of nonoestrogen medications. 129 Its clinical documentation to date comes from a 6-month, randomised, multicentre trial in healthy post-menopausal women (mean age, 55.5 years) with an intact uterus, receiving estradiol 0.5 mg/neta 0.1 mg or placebo, sponsored by Novo Nordisk A/S. 130 In addition, one group received estradiol 0.5 mg/neta 0.25 mg, but these results are not discussed here as this compound is not available on the market. The women included had a minimum of seven moderate to severe hot flushes per day, or 50 per week. Moderate was defined as hot sensation or flush with perspiration that does not interfere with daily activities and severe was defined as hot sensations with perspiration that stops any present activity. The trial was conducted in a total of 575 women. 130 The primary objective was to assess the mean change in the number of moderate to severe hot flushes per week and the mean change in severity score of moderate to severe hot flushes from baseline to week 8. 130 Secondary objectives included assessments of hot flush weekly weighted score, vaginal atrophy, sleep disturbances, bleeding pattern and Greene Climacteric 537

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg Scale, 130,131 as well as an evaluation of several safety parameters, e.g. impact on mammographic density 132 and endometrium. 131 Efficacy of Estradiol 0.5 mg/ NETA 0.1 mg Compared with placebo, estradiol 0.5 mg/neta 0.1 mg significantly reduced the number of moderate to severe hot flushes, beginning at treatment week 3 (Figure 1A). 130 Symptom severity was also significantly reduced by week 3 compared with placebo, with further improvement by week 12, as well as a reduction in the hot flush weekly weighted score at all assessed time points (4, 8, 12 and 24 weeks). 130 The proportion of women reporting no difficulty in sleeping improved with HRT (increased from 15% to 55% vs 19% to 35% in the placebo group), as did some parameters related to urogenital symptoms (decrease in vaginal dryness, increase in endometrial maturation value and ph). 130 However, not all parameters were improved (burning or itching, dyspareunia, dysuria and stress incontinence). 130 In months 1 6 the amenorrhoea rate (defined as absence of any vaginal bleeding or spotting) with estradiol 0.5 mg/neta 0.1 mg was only slightly less than placebo, although statistically significantly lower in most months (Figure 1B), 131 and the breakthrough bleeding during the study was reported to be 11% 14%, as compared with 3% 7% in the placebo group. The withdrawal rates due to bleeding were the same in both groups (n=1; 1%). 131 Safety of Estradiol 0.5 mg/neta 0.1 mg The majority of adverse events occurred with similar frequency between the HRT and placebo groups and were classified as mild or moderate in severity. Breast-related symptoms (breast discomfort, breast pain, breast tenderness) were similarly reported by 3% of subjects. 132 Serious adverse events were reported with an incidence of 3% and the distribution of these events was similar in both groups 130 ; cardiovascular events occurred in 4% and 6%, respectively, among users receiving estradiol 0.5 mg/neta 0.1 mg or placebo and one patient died of a myocardial infarction (placebo group). 130 There was a low trial drop-out rate (9% and 20%, respectively, in the estradiol 0.5 mg/neta 0.1 mg and placebo groups) 130 and adverse events as a reason for withdrawal were noted in 6% of subjects treated with HRT, compared with 8% in the placebo group. 130 Mammographic density was investigated in a subpopulation of 255 women. 132 The mammograms were performed both at the screening visit and after 6 months, and were evaluated visually and digitally. At screening, mean breast density assessed by digitised quantification was 21.3% and 20.7% for estradiol 0.5 mg/neta 0.1 mg and placebo, respectively. After 24 weeks of treatment the values were 21.1% and 21.4%, respectively. Hence, no overall treatment differences were detected between the treatment group and placebo by digitised assessment, which also was the case for visual assessment according to the Wolfe classification and the percentage scale. 132 538

Johansen & Qvigstad Figure 1. Impact of estradiol 0.5 mg/neta 0.1 mg versus placebo in the intent-to-treat population on (A) reducing the number of moderate to severe hot flushes by week,130 (B) percentage of participants with amenorrhea by month,131 and (C) changes in mean endometrial thickness measured by transvaginal ultrasound.131 * P<0.05 versus placebo. (A) 80 70 Estradiol 0.5 mg/neta 0.1 mg Placebo Mean number of hot flushes 60 50 40 30 20 10 0 * * * * * 4 8 12 16 20 24 Treatment length, weeks (B) Amenorrhea, % of women 100 80 60 40 * * * * * 20 0 1 2 3 4 5 6 Treatment length, months Estradiol 0.5 mg/neta 0.1 mg Placebo Figure continued overleaf 539

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg Figure 1. (Cont d.) (C) Mean endometrial thickness, mm 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Estradiol 0.5 mg/neta 0.1 mg Placebo Baseline At 6 months Endometrial thickness was assessed by transvaginal ultrasound, and there a was a slight increase in the mean endometrial thickness in both the treatment and placebo groups over the course of the trial (Figure 1C). 131 However, mean endometrial thickness at the screening visit as well as at the end of the trial was always within reported normal range for post-menopausal women on no hormone therapy (<5 mm). An endometrial thickness above 5 mm was observed in 10% (n=19) and 5% (n=8) in the estradiol 0.5 mg/neta 0.1 mg and placebo groups, respectively. 131 Comparison of Treatment Alternatives and Positioning of Estradiol 0.5 mg/ NETA 0.1 mg in the Systemic Treatment Armamentarium These data on estradiol 0.5 mg/neta 0.1 mg support previous findings that lower than conventional doses of systemic cc HRT offer symptom control with a high degree of tolerability, and no apparent safety concerns. The findings also support that low-dose HRTs are effective in reducing vasomotor symptoms and provide bleed-free cycles. The impact on the endometrium (in line with previous lowdose findings for NETA doses of 0.1 mg 83 and CEE 0.3 mg/mpa 2.5 mg 144 ) and in particular the breast, supporting the dose dependency of hormone treatment on this caveat from previous investigations, 3,4 is somewhat reassuring, although this was only a 6-month study. Since this is a novel compound, no head-to-head comparison with any oral or transdermal product has been performed. However, short-term efficacy (6 12 months) as evaluated by indirect comparisons with other selected mid- to low-range dosages of oral cc HRT products seems comparable (Table 3), or better, on most parameters investigated although such indirect comparisons are difficult to interpret due to differences in study design, length (6 12 months) and inclusion criteria. Still, effects on urogenital manifestations 540

Johansen & Qvigstad Table 3. Changes in selected key parameters for various HRT compounds in various studies of 6 12 months duration. Impact on Reduction of Proportion of patients mammographic density Breast Drop-out hot flushes, % bleed free, % (Wolfe increase), % tenderness, % rate, % E2 0.5 mg/neta 0.1 mg 81130 95131 0132 1132 9130 E2 1 mg/neta 0.5 mg 63133 79133 30135 54133 25133 74.9134 9.8134 15.4134 E2 2 mg/neta 1 mg 70136 93136 46116 22.1137 30137 E2V 1 mg/dng 2 mg 75138 NG138 52139 4.4138 NG138 E2V 1 mg/mpa 2.5 mg 69.9140 85140 23140 6.6140 9140 E2V 1 mg/dro 2 mg 84.4141 71 86141 NG141 8.9141 8141 Tibolone 2.5 mg 52133 89133 2116 20133 25133 81.7134 3.2134 21.8134 CEE 0.3 mg/mpa 1.5 mg 90142 94.5143 NG142,143 7142 14 19142 CEE 0.45 mg/mpa 1.5 mg 90142 91.8143 NG142,143 12142 14 19142 CEE=conjugated equine oestrogen; DNG=dienogest; DRO=drospirenone; E2=estradiol; E2V=estradiol valerate; HRT=hormone replacement therapy; MPA=medroxyprogesterone; NETA=norethisterone acetate; NG=not given. 541

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg seem inferior to conventional dosages, 130 which is in line with some, 143 but not all low- or ultra-low-dose studies. 67 Local urogenital manifestations as such should not be the reason alone for prescribing systemic conventional-dose HRT. 68 Questions that remain unanswered are the effects of ultra-low-dose HRT on other manifestations of the menopausal transition such as irritability, mood, and memory for which there is not much data and is particularly lacking for low- and ultra-low-dose HRT. Perhaps more importantly, another unanswered question is the long-term impact on osteoporotic fractures (there is a clear beneficial dose-response with oestrogen on bone mineral density) as well as effects on cardiovascular events and malignant cell transformations in the breast and endometrium. CONCLUSION In view of the recent debate that has focused on a dose dependency of the increased risks associated with use of oral progestogen-oestrogen cc regimens, the use of HRT containing a lower dose of both oestrogen and progestogen is preferred, and the dose of each hormone component should be lowered as much as possible while still maintaining efficacy and safety for the individual patient. 11,12 We believe that this ultra-low-dose compound offers patients deemed in need of oral HRT an added benefit as compared with the other oral treatment options currently available, and is an alternative to the already available ultra-low-dose transdermal formulations. Nonetheless, it is imperative to conduct further long-term studies, to see if this compound can offer particular advantages, in particular with regards to breast cancer and cardiovascular complications, as well as to capture any potential harm. ACKNOWLEDGEMENTS OEJ and EQ have no shares in companies marketing or producing drugs that are mentioned in this paper and do not benefit financially or in any other manner from writing the review. They both have received travel grants, speaking fees, support for research and/or fees for consulting services from Novo Nordisk. REFERENCES 1. United Common Database. Available at: http://unstats.un.org/unsd/cdb/cdb_series_ xrxx.asp?series_code=13630. Accessed 10 January 2008. 2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women s Health Initiative randomized controlled trial. JAMA. 2002;288:321 333. 3. Topal NB, Ayhan S, Topal U, Bilgin T. Effects of hormone replacement therapy regimens on mammographic breast density: the role of progestins. J Obstet Gynaecol Res. 2006;32:305 308. 4. Bremnes Y, Ursin G, Bjurstam N, Lund E, Gram IT. Different types of postmenopausal hormone therapy and mammographic density in Norwegian women. Int J Cancer. 2007;120:880 884. 542

Johansen & Qvigstad 5. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348:981 983. 6. Wu O. Postmenopausal hormone replacement therapy and venous thromboembolism. Gend Med. 2005;2(suppl 1):S18 S27. 7. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977 980. 8. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933 941. 9. Burger H, Archer D, Barlow D, et al. Practical recommendations for hormone replacement therapy in the peri- and postmenopause. Climacteric. 2004;7:210 216. 10. Pedersen SH, Pedersen NG, Dalsgaard T, Lund CO, Nilas L, Ottesen B. Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand white rabbit. Climacteric. 2004;7:12 22. 11. European Medicines Agency. CHMP guideline on clinical investigations of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. Document ref: EMEA/CHMP/021/97 rev 1. London: EMEA; 13 October 2005. Available at: http://www.tga.gov.au/docs/ pdf/euguide/emea/002197enrev1.pdf. 12. Food and Drug Administration. Guidance for industry. Estrogen and estrogen/ progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms. Recommendations for clinical evaluation. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); January 2003. 13. Board of the International Menopause Society. IMS updated recommendations on postmenopausal hormone therapy. Climacteric. 2007;10:181 194. 14. North American Menopause Society. Estrogen and progestogen use in periand postmenopausal women: March 2007 position statement of the North American Menopause Society. Menopause. 2007;14:168 182. 15. Santoro N. The menopause transition: an update. Hum Reprod Update. 2002;8:155 160. 16. Rödström K, Bengtsson C, Lissner L, Björkelund C. Reproducibility of selfreported menopause age at the 24-year follow-up of a population study of women in Gøteborg, Sweden. Menopause. 2005;12:275 280. 17. Bengtsson C, Lindquist O, Redvall L. Menstrual status and menopausal age of middle-aged Swedish women. A population study of women in Gøteborg 1968 69 and 1974 75. Acta Obstet Gynecol Scand. 1981;60:269 275. 18. Hammar M, Berg G, Fåhraeus L, Larsson- Cohn U. Climacteric symptoms in an unselected sample of Swedish women. Maturitas. 1984;6:345 350. 19. Stearns V, Ullmer López JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360:1851 1861. 543

Advances in Therapy Efficacy of Estradiol 0.5 mg/neta 0.1 mg 20. Maartens LW, Leusink GL, Knottnerus JA, Smeets CG, Pop VJ. Climacteric complaints in the community. Fam Pract. 2001;18:189 194. 21. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health. 2001;91:1435 1442. 22. Lipton RB, Goadsby P, Silberstein SD. Classification and epidemiology of headache. Clin Cornerstone. 1999;1:1 10. 23. Freeman EW, Sammel MD, Lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110:230 240. 24. Woods NF, Smith-DiJulio K, Percival DB, Tao EY, Taylor HJ, Mitchell ES. Symptoms during the menopausal transition and early postmenopause and their relation to endocrine levels over time: observations from the Seattle Midlife Women s Health Study. J Womens Health. 2007;16:667 677. 25. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351 358. 26. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril. 2001;76:456 460. 27. Lindau ST, Schumm LP, Laumann EO, Levinson W, O Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762 774. 28. Avis NE, Kaufert PA, Lock M, McKinlay SM, Vass K. The evolution of menopausal symptoms. Baillieres Clin Endocrinol Metab. 1993;7:17 32. 29. Kumari M, Stafford M, Marmot M. The menopausal transition was associated in a prospective study with decreased health functioning in women who report menopausal symptoms. J Clin Epidemiol. 2005;58:719 727. 30. Hardy R, Kuh D. Change in psychological and vasomotor symptom reporting during the menopause. Soc Sci Med. 2002;55:1975 1988. 31. Marmot MG, Stansfeld S, Patel C, et al. Health inequalities among British civil servants: the Whitehall II study. Lancet. 1991;337:1387 1393. 32. Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ. 1993;307:836 840. 33. Berg G, Gottwall T, Hammar M, Lindgren R, Gottgall T. Climacteric symptoms among women aged 60 62 in Linkøping, Sweden, in 1986. Maturitas. 1988;10:193 199. 34. Rödström K, Bengtsson C, Lissner L, Milsom I, Sundh V, Björkelund C. A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause. 2002;9:156 161. 35. Staropoli CA, Flaws JA, Bush TL, Moulton AW. Predictors of menopausal hot flashes. J Womens Health. 1998;7:1149 1155. 36. Whiteman MK, Staropoli CA, Langenberg PW, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003;101:264 272. 37. Li C, Samsioe G, Borgfeldt C, Lidfeldt J, Agardh CD, Nerbrand C. Menopauserelated symptoms: what are the background 544