Drug delivery systems for hormone therapy

Journal of Controlled Release 112 (2006) 1 – 14 www.elsevier.com/locate/jconrel

Review

Drug delivery systems for hormone therapy Jin-Wook Yoo, Chi H. Lee ⁎ Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City, MO 64110, USA Received 24 October 2005; accepted 24 January 2006 Available online 13 March 2006

Abstract Various types of formulations and delivery devices have been developed for hormone therapy (HT) and their modes of hormone action and patient responses have been evaluated. Although the Women's Health Initiative (WHI) reported the controversial results on estrogen/progestin combination therapy, HT still remains a primary therapeutic option for the treatment of menopausal symptoms and osteoporosis. As a novel alternative to HT may not be probable in clinical use for the next decade, the currently available formulations containing estrogen and progestogen should be properly optimized for HT. The extensive reviews and comparisons on the characteristics of various types of HT could lead to the development of an efficient delivery formulation which maximizes patient compliance and minimizes adverse effects for individual users. © 2006 Elsevier B.V. All rights reserved. Keywords: Hormone therapy; Drug formulations; Delivery systems; Estrogens; Progesterones

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . Sex steroid hormones for HT . . . . . . . . . . . . . . . 2.1. Oestrogen (estrogens) . . . . . . . . . . . . . . . 2.2. Progesterone/progestogens/progestins . . . . . . . 2.3. Mechanism of action of estrogens and progestins . 2.4. SERMs and STEARS . . . . . . . . . . . . . . . Risks and benefits of hormone therapy . . . . . . . . . . 3.1. Benefits of HT . . . . . . . . . . . . . . . . . . 3.1.1. Vasomotor symptoms and quality of life . 3.1.2. Urogenital symptoms . . . . . . . . . . . 3.1.3. Osteoporosis . . . . . . . . . . . . . . . 3.1.4. Colorectal cancer . . . . . . . . . . . . . 3.1.5. Cardiovascular disease . . . . . . . . . . 3.2. Risks of HT . . . . . . . . . . . . . . . . . . . . 3.2.1. Breast cancer . . . . . . . . . . . . . . . 3.2.2. Endometrial cancer . . . . . . . . . . . . 3.2.3. Venous thromboembolism (VTE) . . . . 3.2.4. Stroke . . . . . . . . . . . . . . . . . . 3.2.5. Ovarian cancer . . . . . . . . . . . . . . Delivery systems for HT . . . . . . . . . . . . . . . . . 4.1. Oral preparations . . . . . . . . . . . . . . . . . 4.1.1. Estrogen tablets . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: +1 816 235 2480; fax: +1 816 235 5190. E-mail address: [email protected] (C.H. Lee). 0168-3659/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2006.01.021

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4.1.2. Progesterone tablets and capsule 4.1.3. Combination tablets . . . . . . . 4.2. Sublingual and buccal delivery. . . . . . 4.3. Transdermal delivery . . . . . . . . . . . 4.3.1. Transdermal gels . . . . . . . . 4.3.2. Transdermal emulsions . . . . . 4.3.3. Transdermal patches. . . . . . . 4.3.4. Subcutaneous implant (pellet) . . 4.3.5. Transdermal spray (metered dose 4.4. Intranasal spray (pulsed estrogen therapy) 4.5. Intrauterine devices (IUDs). . . . . . . . 4.6. Vaginal preparations . . . . . . . . . . . 4.6.1. Vaginal cream, pessary and gel . 4.6.2. Vaginal tablet . . . . . . . . . . 4.6.3. Vaginal ring . . . . . . . . . . . 4.7. Injections . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Since the introduction of the first estrogen replacement therapy in 1942, hormone therapy (HT) has been used to improve the quality of life of women suffering from acute symptoms of menopause, such as hot flashes, night sweats, insomnia, increased fatigue and irritability, depression, skin changes, vaginal dryness and incontinence and osteoporosis [1– 5]. Aging women in all countries hope spend the rest life comfortably, which in turn means being offered efficient therapeutic strategies for overcoming any adversity from the menopause. There is significant evidence that HT provides to some degree long-term protection against cardiovascular disease and colon cancer [4]. The most common formulations of HT currently used are the oral tablets and transdermal patches. However, more than a half of women who begin HT in a form of oral or transdermal products discontinued treatment within the first year due to several limitations of those routes. Moreover, the effects of hormone treatment on menopause are quite controversial ever since the publication of the negative results from the Women's Health Initiative study (WHI) [4], which showed that the overall health risk including breast cancer exceeded benefits from the use of the CEE (conjugated equine estrogens) plus MPA (medroxyprogesterone acetate). Its long-term safety and efficacy still remain as a great concern since then. However, WHI study is yet to be generalized for individual variances because subjects in WHI were more obese and older than patients selected in most epidemiological studies. From the formulation point of view, WHI evaluated outcome based on a specific formulation (i.e. Prempro®, oral administration of CEE (0.625 mg) / MPA (2.5 mg)) whose results may not be applicable to other HT formulations. It is well known that the pharmacological effects of HT can vary according to doses, types of formulations, and routes of administration [6,7]. Nonetheless, many women remained on HT in an internal medicine practice for a variety of reasons [8] and HT still

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remains a valuable therapeutic option for the treatment of postmenopausal symptoms, such as vasomotor symptoms and osteoporotic fracture [9]. As a novel alternative to HT may not be probable in clinical use for the next decade, HT for postmenopausal women should be optimized based on the mode of action of sex steroid hormones, patient response, doses and routes of administration of estrogen and progesterone. Consequently, it is worth evaluating the mechanisms by which estrogen and progestin exert their effects on human body and developing a new delivery system with minimum dose and adverse drug effects, and maximum drug efficacy as well as patients' compliance. We herein review the characteristics of various HT formulations and delivery systems, whose comparison in merits and shortfalls may lead to the most suitable and efficient formulation of HT. 2. Sex steroid hormones for HT 2.1. Oestrogen (estrogens) Estrogens are endogenous hormones with numerous physiological activities. There are three principle forms of estrogen found in the human body: estrone, estradiol and estriol, also known as E1, E2 and E3, respectively. The most potent naturally occurring estrogen in humans is 17-β-estradiol (E2) followed by estrone (E1) and Estriol (E3). Estradiol, estrone and estriol are derived from androgenic precursors (androstenedione or testosterone) through aromatization of the A-ring. Estradiol is oxidized reversibly to estrone, and both estradiol and estrone can be converted to estriol. Estradiol is the predominant estrogen during the premenopausal period. However, after menopause, estradiol levels drop more than estrone so that estrone becomes the predominant estrogen. For postmenopausal therapy, conjugated equine estrogens (CEE), which is a mixture of more than ten different estrogens including estrone sulfate and equilin sulfate as the major constituents, is most commonly prescribed as an oral formulation

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in the United States. In Europe, 17-β-estradiol is widely used either orally as micronized estradiol or estradiol valerate, transdermally by means of a patch, percutaneously in the form of a gel, intravaginally as a cream or rings, or intranasally through an aerosol spray. Synthetic derivatives from natural human estrogens (e.g. ethinyl estradiol which is the most common estrogen used in contraception but not in HT) have been developed to increase potency of estrogen. Herbal phytoestrogens, which are a source of natural plant estrogens, are of increasing interest as a potential alternative for women who are concerned about the potential risks of the conventional HT. 2.2. Progesterone/progestogens/progestins Progestogen is a hormone that acts like natural progesterone in the body, while progestin is its synthetic version. During the menstrual cycle, progesterone ensues the uterine lining for pregnancy by increasing the blood supply. If a fertilized egg does not implant itself, a drop in progesterone triggers shedding of the uterine lining. Due to this activity, the FDA originally approved progestogens for a short-term use in the treatment of premenopausal women with amenorrhea, a condition in which periods stop. Progestogens are used to prevent uterine cancer that has been linked with estrogen use, even though the longterm effects of progestogens are unknown. Natural progesterone is present in a form of crystal, which showed poor absorption after oral administration. Although intestinal absorption of progesterone can be improved by the micronization process, its bioavailability (around 10%) after oral administration of micronized progesterone is limited by the extensive hepatic metabolism [10]. Among synthetic progestins available for therapeutic use, oral medroxyprogesterone acetate (MPA) has been most widely used. Currently, there is no longterm data available for its adverse effects. Alternatives to MPA include norgestrel, norethisterone acetate, dydrogesterone, norpregnane derivatives and micronized progesterone [11]. 2.3. Mechanism of action of estrogens and progestins Estrogen receptors (ERs) regulate gene transcription and cell signaling, and play a key role in normal breast development and the initiation and progression of breast cancer. There are at least two different estrogen receptors, ERα and ERβ. Each ER subtype plays a distinctive role in estrogen action, and activated ER can interact with target genes directly within promoters or indirectly through transcription factors [12]. The responses to estrogen depend on the relative expression level of ER subtypes. Whereas both subtypes can activate transcription, ERα appears to be a more robust activator than ERβ, and when both receptors are expressed, ERβ can moderate ERα activity [7]. The tissue-specific differences in the distribution of the ERα and ERβ, and the different binding affinities for steroidal and non-steroidal estrogenic compounds make it possible to develop pharmaceuticals which are different from estradiol in their action on the estrogen-target organs and tissues [13]. ER also can inhibit the transcriptional factors, such as NF-KappaB,

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yielding in part the anti-inflammatory actions in brain and the cardiovascular system [14], and the antiresorptive actions in bone [15]. Estrogen can participate in extranuclear signaling events in various tissues including cardiovascular, digestive and neural system [16,17]. Similar to ER, the progesterone receptor exists as two separate isoforms (PR-A and PR-B), which regulate the expression of progestogen-dependent factors in a different manner [18] and have been investigated as a drug discovery target [19]. In analogy to the selective estrogen receptor modulators (SERMs), which selectively inhibit the estrogen effect on the endometrium but not other tissues, progesterone receptor modulators might reduce adverse effects caused by the additional progestogen [7]. As cell-specific regulators of progestin action are further delineated, the development of tissue-specific progesterone receptor modulators might be a promising approach to HT. 2.4. SERMs and STEARS The ER-ligand complex exerts different pharmacological activities in each cell. For example, tamoxifen functions as an antagonist in the breast but is an agonist in bone and uterus [20], leading to the reclassification of tamoxifen as a selective estrogen receptor modulator (SERM), a compound whose relative agonist/antagonist activities can differ among cell types. SERMs are non-steroidal, estrogen receptor binding compounds which were initially used as ER antagonist for the treatment of infertility and breast cancer. SERMs, such as clomiphene, tamoxifen, raloxifene and toremifene are currently available, and among them only Raloxifene (Evista®, Eli Lilly) is prescribed for postmenopausal osteoporosis. Lasofoxifene, a third-generation of SERMs, is under the in vivo evaluation process [21]. Some adverse effects of SERMs were also reported. SERMs are likely to aggravate hot flushes and vaginal dryness, which limit their acceptability in postmenopausal women [22]. Although SERMs do not relieve vasomotor symptoms, there is evidence that a combination of classical estrogen and SERM may bring a relief with fewer side effects than reported with current treatment [23]. Improvements in the molecular knowledge on the function, distribution and modulation of ERs in different target organs are necessary to develop organ-specific and receptor specific SERMs [24]. Also, pathway selective ER ligand, such as WAY-1699 that specifically antagonizes NF kappa B transcriptional activity, was recently introduced as a specifically selective inflammatory modulator [25]. Tibolone (Livial®, Organon, Roseland, NJ) is a synthetic steroid with an agonistic effect on estrogen, progesterone and androgen receptors. Tibolone is SERM-like but has different effects on estrogen, acting as a selective, tissue estrogenic activity regulator (STEAR). Tibolone prevents postmenopausal osteoporosis without stimulating the endometrium, negating a progestin requirement [26]. Unlike SERMs, tibolone alleviates postmenopausal vasomotor symptoms as effectively as conventional HT (CEE + MPA) and also relieves vagina atrophy and dryness [26–

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28]. Tibolone was reported to decrease harmful estrogenic action on breast cells [29], but the recent observational study showed that tibolone conferred bigger breast cancer risk [30]. Further studies are needed to accurately assess the effects of tibolone on breast cancer risk. 3. Risks and benefits of hormone therapy Since the report of the WHI trial results, the benefits of HT have been in dispute. Although the results from WHI study and the HERS (Heart and Estrogen/Progestin Replacement Study) showed that risks of HT outweighed its benefits, many experts believe that the risks have been overestimated and those findings cannot be generalized for all postmenopausal women or all HT regimens [1,7,9,31]. HT still remains valuable for many postmenopausal women and their benefits definitely outweigh the potential risks [32]. The followings are risks and benefits of HT for postmenopausal women. 3.1. Benefits of HT 3.1.1. Vasomotor symptoms and quality of life There is no doubt that HT improves quality of life during the menopause and in the immediate postmenopausal years when women are suffering from vasomotor changes, such as hot flush and night sweats. HT also affected sleep which is one of the earliest symptoms of estrogen deficiency [9,33]. Most HTs are effective for the alleviation of menopausal vasomotor symptoms, where HT has been given for at least 2–3 years. 3.1.2. Urogenital symptoms Long-term estrogen deficiency during the postmenopausal period may elicit morphological changes in the genital tract and bladder, which resulted in changes in sexual function, vaginal dryness and urinary symptoms. Urogenital atrophy favorably responds to estrogen therapy with similar effects exerted by other estrogens [2]. Vaginal oestrogen preparations for a local relief are particularly useful for women who are reluctant to take oral HT. 3.1.3. Osteoporosis Osteoporosis is a significant cause of morbidity and mortality in postmenopausal women. Osteoporosis is characterized by reduced bone mass that leads to increased bone porosity, impaired structure and consequently an increased risk of fracture. The bone loss commences in the first year after menopause and is arrested within 6 years after the onset of menopause. The overall bone loss during this phase is estimated to be approximately 15% [5]. By increasing bone mineral density (BMD) and reducing fracture rate, HT has a clear role in preventing osteoporosis in postmenopausal women. The WHI study also demonstrated that HT is effective in end-point fracture prevention [4]. Most HT preparations commercially available for osteoporosis contain estrogen. HT containing raloxifene (Evista®, Eli Lilly, Indianapolis, IN) was recently launched in the market for the treatment of osteoporosis, but HT in a combination of CEE and MPA is reported to be more

effective in the treatment of osteoporosis than HT containing raloxifene alone [34]. 3.1.4. Colorectal cancer Colorectal cancer is the second most common cancer in women after breast cancer in countries, such as USA, UK and Australia [35]. A variety of studies demonstrated that HT reduced the risk of colorectal cancer [36,37]. In addition, the WHI study also confirmed that HT reduced the risk of colorectal cancer [4]. 3.1.5. Cardiovascular disease Cardiovascular disease is the leading cause of death in postmenopausal women [38]. It was widely believed that HT reduced the risk of cardiovascular disease by up to 50% [38– 40], but the HERS [41] and HERS II [36] showed no effects of HT on cardiovascular disease. The potential benefits of HT for cardiovascular disease are controversial. The risk of acute coronary events for women, especially for those who have undergone a premature surgical menopause, increases exponentially with age [42]. Since the extent to which oestrogen beneficially contributes to cardiovascular disease has not been proven yet, the use of HT for primary and secondary prevention of cardiovascular disease should not be recommended [9]. 3.2. Risks of HT 3.2.1. Breast cancer Even though the risk of breast cancer in general is considered to be bigger among HT users, the size of the risk is still controversial. The Million Women Study reported that there was an increased breast cancer incidence and mortality among women taking HT [43]. A large meta-analysis study [44] showed that no significant increase in breast cancer risk was observed for women using HT for less than five years, but for women who used oestrogen with or without a progestin more than five years, a relative risk of 1.35 was reported, confirming that the risk of breast cancer caused by estrogen is treatmentduration dependent. The WHI study also confirmed that the combined HT (CEE/MPA) posed the risk of breast cancer more seriously after four years of treatment [4]. However, the study on the treatment with CEE-alone did not show any major risks [45], suggesting that the concurrent use of a progestin may confer a significantly greater risk of breast cancer than oestrogen alone [46,47]. It is not known how different preparations or routes of administration within the same classes of estrogen-only or a combined HT influence the risk of breast cancer. Moreover, the optimal duration of HT use is still in dispute. Women may need individualized risk–benefit evaluations to decide whether or not they should take HT and its treatment-duration [32]. 3.2.2. Endometrial cancer Unopposed oestrogen in general is not acceptable for women who have not had a hysterectomy because it is known to cause endometrial hyperplasia and increase the risk of endometrial cancer [48]. Co-prescription of progestogen has been widely

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recommended in this situation; however, the endometrial risk has not been completely protected by a regimen of oestrogen with cyclic progestogen [49]. As a variety of progestin delivery systems including intrauterine devices and vaginal and transdermal preparations are under the evaluation process, the optimal regimen of progestin against endometrial risks needs to be primarily defined. 3.2.3. Venous thromboembolism (VTE) It is now well known that HT increases the risk of venous thromboembolism with the highest risk during the first year of use [4,36,50,51]. According to Scarabin et al. [52], the type of HT can significantly affect the VTE risk, whereas oral therapy was more closely associated with VTE than the transdermal route. 3.2.4. Stroke In the HERS, a continuous combined HT had no effect on the stroke risk in postmenopausal women who had a known cardiovascular disease [41]. However, the WHI study reported that there was a significant increase in the hazard ratio for stroke, notably for ischemic stroke [4,45]. The risk of stroke is significantly bigger in older women, which should be taken into consideration in the selection of the optimal HT regimen for a symptom relief. 3.2.5. Ovarian cancer The risk of ovarian cancer was significantly greater with long-term unopposed oestrogen use [53], which was confirmed by a group of women with a prior hysterectomy as they were more likely to use long-term unopposed oestrogen therapy. However, the WHI studies reported that neither oestrogen-only nor combined HT increased the onset of ovarian cancer [4,45]. Further studies seem to be needed to verify the risk of ovarian cancer by oestrogen use. 4. Delivery systems for HT Various types of hormone delivery systems are commercially available (Tables 1–4). Each formulation has its advantages and disadvantages as shown in Table 5. Some of advanced hormone delivery systems have also been used for contraceptives.

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Table 1 Oral preparations Brand name

Active ingredients Company

Indications

DOAe

Estrogen Premarin®

CEEa

Wyeth

Daily

Estrace®

Micronized 17β-estradiol

Warner Chilcott

Gynodiol® Ogen® Ortho-EST®

Fielding Ortho-McNeil Women First HealthCare Esterified estrogen Monarch Synthetic Duramed conjugated estrogen Raloxifene Eli Lilly (SERMsb) Tibolone Oreganos (STEARsc)

Vasomotor symptoms Urogenital symptoms Osteoporosis

Menest® Cenestin®

Evista® Livial®

Estropipate

Combination Prempro® CEE and MPAd (continuous) Premphase® CEE and MPA (cyclic) FemHRT® Ethinyl estradiol, norethindrone acetate (continuous) OrthoEstradiol and Prefest® norgestimate (continuous) Activella® 17-beta estradiol, norethindrone acetate (continuous) Progesterone Provera® Cycrin® Amen® Aygestin® Norlutate® Prometrium® Micronor®

MPA

Norethindrone acetate Micronized progesterone Norethindrone

Wyeth

Vasomotor symptoms Osteoporosis Vasomotor symptoms Urogenital symptoms Osteoporosis

Vasomotor symptoms Urogenital symptoms Osteoporosis

Daily

Pfizer Endometrial Wyeth hyperplasia Reed and Carnrick Wyeth Parke-Davis Solvay

Daily

Wyeth Warner Chilcott

Ortho-McNeil

Novo Nordisk

Ortho-McNeil

Endometrial hyperplasia Contraception

4.1. Oral preparations

Nor-QD®

Oral preparations have been most frequently served as a firstline therapy (Table 1). A significant number of clinical trials have been reported since its introduction. Dosages in tablets are easy to be taken and familiar to patients, and usually cheaper than other formulation types. In addition, women with high cholesterol, low high-density lipoprotein (HDL) and normal triglyceride level will benefit more from oral formulations than other formulations, because oral oestrogen lowers total cholesterol and low-density lipoprotein (LDL) and raises HDL [54]. However, oral formulations have poor systemic bioavailability because of substantial hepatic first-pass effects, which requires high doses in the formulation [55]. This may

The product information above was obtained from the prescribing information of each product. a Conjugated equine estrogen. b Selective estrogen receptor modulators. c Tissue estrogenic activity regulators. d Medroxy progesterone acetate. e Duration of action.

Watson Laboratories

cause potentially harmful side effects, such as over expression of liver proteins including rennin substrate, eliciting metabolic changes including triglyceridemia, and an increase in the concentration of bile salts leading to gallbladder disease [56].

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Table 2 Transdermal preparations Brand name Patch Estraderm®

Climara® Vivelle® Vivelle-Dot® Alora®

Active ingredients

Table 3 Vaginal preparations Company

Indication

DOA

Micronized Novartis 17β-estradiol Rorer (reservoir) Micronized 17β- Berlex estradiol (matrix) Novogyne

Vasomotor symptoms

Twice a week

Urogenital symptoms Osteoporosis

Once a week

Esclim®

Fempatch®

Climara Pro® 17β-estradiol / levonorgestrel (matrix) (continuous) CombiPatch® 17β-estradiol / norethindrone acetate (matrix) (continuous)

Twice a week

Watson Pharma Women First HealthCare ParkeVasomotor Davis symptoms Urogenital symptoms Berlex Vasomotor symptoms

Twice a week

Novogyne

Twice a week

Brand name Active ingredients Cream Estrace®

Micronized 17β-estradiol Ogen® Estropipate Premarin® CEE Synapause® Estriol Ovestin® Gel Prochieve®

Twice a week

Pessary Ovestin® Once a week

Tablet Vagifem®

Ring Estring® Femring®

Gel Estrogel®

Emulsion Estrasorb®

Implant Riselle®

Spray Evamist™

17β-estradiol

Solvay

Vasomotor symptoms Urogenital symptoms

Daily

Estradiol hemihydrate

Novavax

Vasomotor symptoms

Daily

17β-estradiol

Organon

Vasomotor symptoms Osteoporosis

6 months

Vasomotor symptoms

Daily

Vivus

Warner Chilcott Pfizer Wyeth Organon

Daily

Urogenital symptoms

Micronized progesterone

Columbia Assisted Reproductive Every Technology other day Endometrial hyperplasia

Estriol

Organon

Urogenital symptoms

Daily

Estradiol hemihydrate Estriol

Novo Nordisk Organon

Urogenital symptoms

Daily

Micronized 17β-estradiol Estradiol acetate

Pfizer

Urogenital symptoms

Warner Chilcott

Vasomotor symptoms Urogenital symptoms

Daily

3 months

The product information above was obtained from the prescribing information of each product.

4.1.1.2. Esterified estrogens. Esterified estrogen (Menest®, Monarch, Bristol, TN; Estratab®, Solvay) is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, and used for low-dose therapy with the same efficacy and few side effects as compared to CEE [58,59]. Table 4 Nasal spray, IUD and injections Brand name

17β-estradiol

DOA

Once a week

Ovestin® Vasomotor symptoms Urogenital symptoms

Company Indications

The product information above was obtained from the prescribing information of each product.

Due to the side effects, oral therapy may not be the suitable option for HT [57]. The followings oral formulations for HT are currently available in the market. 4.1.1. Estrogen tablets

Active ingredients

Company Indications

DOA

IUD Minera®

Levonorgestral

Schering

Endometrial hyperplasia

5 years

Nasal spray Aerodiol®

Estradiol

Servier

Vasomotor symptoms

2 sprays daily

Vasomotor symptoms Vasomotor symptoms

3–4 weeks Amonth

Contraception

3 months 12–14 weeks

Injection Depo®-Estradiol Depo-Testadiol®

4.1.1.1. Conjugated equine estrogen (CEE). Conjugated equine estrogen (Premarin®, Wyeth, Philadelphia, PA) had been one of the most prescribed drugs in the United States for a long time. As of November 2003, approximately 9 million American women were still taking it, even though the number of patients was down from the 12 million in 1999. CEE is metabolized into active estradiol upon systemic absorption.

Depo-Provera® Depo-subQ provera 104™

Estradiol cypionate Testosterone and estradiol cypionate MPA suspension

Pfizer

Endometrial hyperplasia

The product information above was obtained from the prescribing information of each product.

J.-W. Yoo, C.H. Lee / Journal of Controlled Release 112 (2006) 1–14 Table 5 Advantages and disadvantages of formulations for HT Formulation

Advantages

Disadvantages

Tablet

Easy to take Easily reversible Cheap Cholesterol benefit Rapid, burst absorption Convenient Easily reversible First choice for patient with high triglycerides or gut problems High compliance

Should be taken daily Side effects due to high dose

Sublingual/buccal Patch

Implants

Prolonged effect (4–8 months) Less expensive

Intrauterine devices Virginal preparation

Nasal spray

Injections

Direct effect to the uterine mucosa High efficiency for vaginal symptoms Easily reversible Easy to use Easily reversible Pulsed therapy Convenient Prolonged effect (1–4 months)

Not intensively studied Can be easily detached Irritation on the skin Expensive Frequent change (once or twice a week) Surgical procedure required Not easily reversible Tachyphylaxis Progestogens need to be continued after last implant Only for progesterone delivery Long-term risk of endometrial proliferation (for long-term use progestogen is suitable) Should be sprayed daily Nasal irritation possible Not continuously released Pain upon injection

References: [2,54,68–70,73,87,93,104,105,112,113].

4.1.1.3. Micronized estrogens. Orally administered 17βestradiol in its usual crystalline state is less clinically effective than other estrogens. However, micronization of estradiol increases the available surface size, aqueous dissolution rate and intestinal absorption rate, thus enhancing oral efficacy [60]. Oral micronized estrogen was proven to be safe, efficacious and well accepted in menopausal women [61,62]. It also showed beneficial effects on bone density in a low dose [63]. Estrace® (Warner Chilcott, UK) and Gynodiol® (Fielding, Maryland Height, MO) contain a plant-based natural estrogen as a major component and are currently available in the market. 4.1.1.4. Estropipate. Estropipate, piperazine oestrone sulphate, (Ortho-Est®, Women First HealthCare, San Diego, CA; Ogen®, Pfizer) is made from purified crystalline estrone, which is weaker than other estrogens, being solubilized as the sulfate and stabilized with piperazine. The clinical study of estropipate with progesterone demonstrated that it is effective on prevention of bone loss by reducing serum lipoproteins in postmenopausal women [64]. 4.1.1.5. Synthetic conjugated estrogens (SCE). Cenestin® (Duramed, Cincinnati, OH) is the first plant-based synthetic conjugated estrogen which contains a blend of nine synthetic

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estrogenic substances. It is also known as a plant version of CEE because those nine synthetic estrogenic substances are components of CEE. SCE was reported to exert neuroprotective effects comparable to CEE in vivo and therefore could reduce the risk of Alzheimer's disease in postmenopausal women [65]. 4.1.2. Progesterone tablets and capsule MPA (medroxy progesterone acetate) (Provera®, Pfizer; Cycrin®, Wyeth) is the most commonly prescribed progesterone in HT. Another synthetic progesterone, norethindrone (Micronor®, Ortho-McNeil), is widely used for low-dose therapy, thus producing fewer side effects. Norethindrone acetate (Aygenstin®, Wyeth; Norlutate®, Parke-Davis) is approximately twice as potent as norethindrone alone and has less incidence of breakthrough bleeding than other progesterones [66]. It is usually prescribed for women who suffer side effects from MPA. Prometrium® Capsule (Solvay) contains micronized natural progesterone which is dissolved in peanut oil. Natural progesterone has fewer side effects than other progesterones, but is much more expensive. 4.1.3. Combination tablets Both Prempro® (Wyeth) and Premphase® (Wyeth) contain CEE and MPA. The major difference between two pills is the progesterone regimen. Prempro® is taken on continuous basis (progesterone daily) and Premphase® on cyclic basis (progesterone for last two weeks of every month). Despite the WHI report on the negative aspects of Prempro®, it is still widely used. Its low-dose formulations are also available in the market. Different from Prempro®, FemHRT® (Warner Chilcott) contains ethinyl estradiol, which is most widely used in oral contraceptives, and norethindrone acetate, which has fewer side effects than MPA. It is generally taken on a continuous basis. Ortho-Prefest® (Ortho-McNeil) has a unique regimen; a constant-estrogen and intermittent-progestogen regimen (the daily administration of estrogen for three days followed by estrogen with progestogen for three days), which was shown to be very effective in relieving menopausal symptoms [67]. 4.2. Sublingual and buccal delivery Although estradiol tablets are designed for being swallowed, certain preparations of estradiol can be administered sublingually. Different from 17β-estradiol which by itself is water-insoluble, the micronized form and hydroxypropyl-βcyclodextrin estradiol have a rapid, burst-like absorption via oral mucosa into the systemic circulation, yielding a sufficient therapeutic serum level [68–70]. This may reduce possible liver toxicity by bypassing fist-pass metabolism. Fewer metabolisms are also likely to produce higher levels of estradiol and lower levels of its less-active metabolites, estrone and estriol. Sublingual administration of micronized estradiol and progesterone were effective in preventing bone loss by increasing bone mineral density [71]. Sublingual delivery of sex steroid hormones has many advantages as compared to other non-oral routes. It is less irritating and more convenient, which lead to

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better patient compliance. Nevertheless, the sublingual form of HT has not been extensively studied. Buccal delivery of estrogen has similar advantages to sublingual delivery. Low-dose of estradiol administered via buccal mucosa significantly reduced hot flushes as compared to placebo and showed good patient compliance [72]. More comparative investigations should be needed to define the therapeutic efficiency of both sublingual and buccal delivery of HT.

odorless, and becomes a dried form at the application site in a few minutes. It rarely exerts skin irritation. 4.3.2. Transdermal emulsions Estrasorb® (Novavax, Malvern, PA) is launched in 2003 as the first topical, lotion-like nanoemulsion for the treatment of vasomotor symptoms. Estrasorb® employs a micellar nanoparticle technology which utilizes oil and water nanoemulsions to encapsulate estradiol hemihydrate. Estrasorb® delivers 17βestradiol systemically through topical application.

4.3. Transdermal delivery Transdermal formulations, such as patches and gel forms, have been so popular that the number of developed formulations kept increasing [73]. Absorption of estrogens occurs by a slow, passive diffusion through the lipid domains of the stratum corneum, followed by rapid diffusion through the viable epidermis and dermis, and ultimately the microcirculation of the skin [74]. Non-oral administration of sex steroids, including transdermal patches, gels and subcutaneous implants, has been attempted to avoid the first-pass metabolism after oral administration, which produces high levels of less biologically active estrone and conjugates [75]. As a result, much lower doses of estrogen are required for the transdermal formulations than the oral formulations. Moreover, hepatic protein synthesis which is induced by first pass effect can be avoided by transdermal route [76–78]. Unopposed estrogen delivery via transdermal route is not contra-indicated in woman with an intact uterus, but progestogens are mandatory for 10–14 days per month. Estrogen generally have the beneficial effects on the lipoprotein profile by increasing high-density lipoprotein (HDL) and decreasing low-density lipoprotein (LDL) levels [41]. Since the beneficial effects of estrogens on the LDL level arise from direct hepatic actions, the transdermal route may not influence the lipid profile in the blood [73]. The ease and convenience of application may improve compliance and tolerability of percutaneous estradiol gel. However, the therapeutic efficiency of transdermal delivery systems may be hampered by adherence failures, noncompliance secondary to skin irritation or cosmetic concerns. In addition, variability in the absorption rate among individual patients was reported [79]. 4.3.1. Transdermal gels The first system used for estrogen delivery through skin was the application of estrogen dissolved into a water–alcohol solvent in a form of gel for the treatment of postmenopausal symptoms [80]. In this mode of delivery, high inter-individual variability in absorption of estrogen has been observed, mainly because absorption of estradiol from a transdermal gel is greatly dependent on the application sites [81,82]. Percutaneous estradiol gel showed high tolerability and less side effects including moderate-to-severe hot flushes in post menopausal women [83]. EstroGel® (Solvay) has been in the Europe market for more than 25 years, but approved in the U.S. only in 2004. EstroGel® contains 17β-estradiol in a hydro-alcoholic gel base which renders a controlled release profile. It is clear and

4.3.3. Transdermal patches Among various forms of estradiol administration through skin, one of the most popular forms is transdermal patch. Transdermal patches have a drug reservoir containing estradiol solubilized in either an ethanol-container gel [84] or a homogenous adhesive matrix delivery system [85]. The following two types are available in the market for the delivery of estradiol. 4.3.3.1. Conventional reservoir patches. The first transdermal patch for HT was Estraderm® (Novartis, Switzerland) which was launched in Europe in 1985 and has been widely used ever since. Estraderm® is a thin, round, transparent patch comprised of 5 layers including a membrane-controlled reservoir system which releases 17β-estradiol in an ethanolic solution through a rate-limiting membrane upon application to intact skin [86]. The transdermal patch has the same limitations in acceptance as most of transdermal formulations. The adhesive loaded in the patch can cause skin irritation and redness under and around the application sites due to allergic reactions, especially in hot and humid weather [87]. At least 2% of Estraderm® users stop using the patch because of skin irritation. 4.3.3.2. Transdermal matrix patches. Similar to the reservoir patch, the matrix patches continuously release and steadily deliver 17β-estradiol, maintaining a stable blood level of estrogen. They are flat, translucent and less visible. They are convenient to use due to the greater adhesiveness of the patch and have a low incidence of skin reactions [88]. The matrix system comprises three layers, which are translucent polymeric film, estradiol dissolved adhesive layer and peelable protective liner. Clinical studies showed that matrix patches had beneficial effects on bone density in postmenopausal women but high dose of estradiol in a matrix patch was associated with greater side effects, such as breast pain [89]. Low-dosed estrogen therapy in a matrix patch can be used for relieving climacteric symptoms [90]. Climara® (Berlex, Montville, NJ) was first introduced as the matrix patch in 1995. A year later, Vivelle® (Novogyne, Miami, FL) was introduced in the market and most recently VivelleDot® (Novogyne) came out with a new super-tiny patch. Fempatch® (Parke-Davis) is a low-dose estrogen patch, while CombiPatch® (Novogyne) and Climara Pro® (Berlex) are the matrix patches which release both estrogen and progesterone. Esclim® is similar to most of matrix patches, but is stretchable, thus demonstrating better compliance than other matrix patches.

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4.3.4. Subcutaneous implant (pellet) The implant formulations are an efficient delivery system for estrogens especially for women with hysterectomy, libido problems, depression, or severe osteoporosis and those who have suffered adverse effects with an oral therapy. A subcutaneous pellet for HT had been widely used during the 1960s and 1970s, but not currently. Estradiol in a form of crystalline pellets can be subcutaneously implanted under local anesthetic, which should be performed by a healthcare professional. Immediate reversal may not be possible because retrieval of the pellet is difficult. The pellets would dissolve slowly, releasing hormone into the fatty tissues and then into the bloodstream. Sufficient evidence supported that estradiol implant improve various symptoms including bone density in nearly all women and depression in the climacteric woman, in pre-menstrual depression or in post-natal depression [91,92]. There was a report on bleeding incidents which may be caused by the relatively high estradiol levels. Tachyphylaxis may occur to patients with frequent usages of high doses [93]. An intensive investigation on the formulation variances which regulate the release rate of the hormone in a suspended and controlled pattern should be followed to improve efficacy of the subcutaneous implants. 4.3.5. Transdermal spray (metered dose transdermal spray, MDTS) The novel metered-dose topical aerosol (MDTA) formulation containing a permeation enhancer significantly enhanced the transdermal delivery of estradiol [94]. MDTA allows a clinically relevant dose of estradiol to be delivered in postmenopausal women with once daily dosing. A metered dose transdermal spray (MDTS®) called Evamist has been developed by Vivus (Mountain View, CA). Evamist (Estradiol MDTS®, Vivus), which entered into Phase 3 clinical test in late 2004, contains a low-dose of estrogen and is aimed to alleviate symptoms associated with menopause, such as hot flashes. Evamist is fast drying, non-irritating and invisible upon application. Evamist releases estradiol into the blood stream, maintaining an efficient concentration level for over 24 h. 4.4. Intranasal spray (pulsed estrogen therapy) Intranasal administration of estrogens and/or progestins has been investigated for several decades [95–99]. The intranasal route has distinctive advantages over the oral or other alternative routes [57,100]; avoidance of first-pass metabolism, thus maintaining the physiological ratio of estrone to estradiol, easy dosage adjustments and more consistent absorption rate, the lower incidence of withdrawal and breakthrough bleeding, and irritation. Aerodiol® (Servier, France) is an aqueous nasal spray formulation containing 17β-estradiol which is randomly conjugated with methylated β-cyclodextrin that solubilizes the steroid hormone. Aerodiol® is available in some European countries to treat symptoms of oestrogen deficiency in postmenopausal women. Nasally administered estradiol introduced the new concept of pulsed estrogen therapy by displaying

9

a distinctive pulsed kinetic. Estradiol administered via nasal route was rapidly absorbed, reaching the maximal plasma concentrations after 10–30 min and returning to the levels of untreated postmenopausal women within 12 h, thus avoiding the continuously elevated plasma level of estrogen [101]. In clinical studies, the pulsed estrogen therapy via nasal route was shown to be as effective as oral and transdermal therapy in alleviating postmenopausal symptoms and atrophic vaginal mucosa [101–103]. Moreover, a significantly lower incidence of mastalgia and uterine bleeding was observed, suggesting that breast and uterus have a lower sensitivity to a pulsed exposure of estrogen [104,105]. Although Aerodiol® is mainly used for the treatment of menopausal symptoms, it showed the same effectiveness as transdermal estrogen patches in preventing postmenopausal bone loss by increasing bone mineral density [106,107]. Accordingly, the pulsed estrogen therapy through intranasal route is considered to be an innovative approach for the delivery of sex steroids in postmenopausal women. Further progress has been made on a multi-pulse drug delivery system consisted of a biodegradable polymeric microchip implant which provides a long-term pulsed drug release [108]. This strategy takes advantages of merits from both pulsed therapy and implantable systems. An intranasal delivery of progesterone in various formulations has also been investigated. Most studies showed that intranasal administration significantly enhanced the bioavailability of progesterone as compared to the oral route [109–111]. However, at present no commercial product is available in the market. 4.5. Intrauterine devices (IUDs) For postmenopausal women, IUDs have been widely used for delivering progestogens along with estrogens because this route could reduce side effects caused by estrogens [112]. For this reason, various “frameless” and “framed” intrauterine systems are currently under evaluation for their usefulness in postmenopausal women. Especially, intrauterine devices (IUDs) are fundamentally advantageous as a site specific delivery of progestogens, because progesterone has a short biological half life (15 min) and needs to be repeatedly administered to achieve the effective concentration and subsequently to elicit its pharmacological activity. Most IUDs have served as a long-acting steroidal contraceptive system. Minera® (Schering), which is an IUD containing progestin and being primarily designed for the contraceptive purpose, is also used for protection against the endometrium in HT [113]. 4.6. Vaginal preparations More than 50% of postmenopausal women experience moderate to severe symptoms related to atrophic modifications in the genitourinary tract [114]. Many postmenopausal women, who do not want to use systemic HT, may still prefer treatments of vaginal symptoms. Vaginal hormone therapy has been very efficient for the relief of local postmenopausal vaginal symptoms [2]. However, since the vagina opts for steroid

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absorption and vaginal delivery, like transdermal therapy, is not subjected to gastrointestinal conversion of estradiol to estrone, the systemic therapy via vaginal route is considered to alleviate both vasomotor and urogenital symptoms [115]. Formulations, such as estradiol ring and cream, are currently available for this purpose. Since women are generally discouraged from long-term usage of HT, low-doses of estrogen are recommended for the treatment of vaginal and urethral (genitourinary) dryness and weakening after menopause. As estradiol has a higher affinity for ER and longer nuclear retention time as compared to estriol and conjugated estrogens, lower doses are sufficient to obtain the same effect as estrogen on pathological symptoms and cytology of the vaginal mucosa [116,117]. Low-doses of vaginal estrogen are generally not accompanied by progestin because vaginal therapy is thought to have only a local effect. Equivalent endometrial safety, efficacy in the relief of the symptoms and signs of urogenital estrogen deficiency were demonstrated from patients who have used a low-dose estradiolreleasing vaginal ring or a vaginal estradiol tablet for 12 months [118]. However, there still remains a concern about the longterm risk of endometrial proliferation, which requires careful monitoring. Since the local low-dose estrogen therapy has shown neither systemic absorption nor changes in serum estradiol level, HT through vaginal route is not considered to be efficient in protecting against osteoporosis or hot flushes caused by menopause [119]. However, a few reports revealed potential of vaginal therapy for systemic absorption of estrogen accompanied with beneficial effects on bone and lipids [120]. 4.6.1. Vaginal cream, pessary and gel Vaginal cream and pessary were the first generation of the vaginal formulation for estrogen. Vaginal cream containing conjugated estrogen induced vaginal maturation at one fourth dose of oral therapy. It also relieved vasomotor symptoms with a higher dose, but they are rarely used for this purpose due to low compliance and requirement of long-term undisrupted application [121]. An estriol cream improved vaginal symptoms in 83% of treated women among whom more than half showed complete symptom relief [122]. However, stickiness, nonuniform absorption and inconvenience of repeated applications are cited as the major disadvantages [123]. Moreover, symptoms may reoccur within 1–2 months of interruption of treatment [117]. Pessaries have been as effective as creams, but many women feel discomfort with their use [124,125]. Various commercial products for vaginal creams and pessaries, such as Synapause® (Oragnon) and Ovestin® (Oragnon), are available in the markets. Prochieve® (Columbia, Rockville Centre, NY) is a bioadhesive vaginal gel containing micronized progesterone in an oilin-water emulsion system. The progesterone is partially soluble in both the oil and water phase of the vehicle with the majority of the progesterone existing as a suspension, which facilitates controlled, sustained absorption of progesterone through vaginal tissue. Bioavailability of progesterone administered through vaginal gel was greater than that orally administered

(Prometrium®). Progesterone gel showed less variability in blood concentrations than oral progesterone, thus providing a more reliable delivery of progesterone [126]. 4.6.2. Vaginal tablet Vagifem® (Novo Nordisk, Denmark) is the most widely used vaginal estrogen tablet. It is made of a hydrophilic cellulosederived mucoadhesive matrix. Unlike creams, Vagifem® tablets come in preloaded with disposable applicators whose thin, smooth form is easily inserted into the vagina, so there is no mess at the application site. Vagifem® provides clean, comfortable and convenient relief for the symptoms of atrophic vaginitis. It was as effective in treating postmenopausal atrophic vaginitis as most of commonly used estrogen-containing vaginal creams [127]. It was also demonstrated that the vaginal tablet had greater patient compliance and a lower withdrawal rate as compared with vaginal cream therapy [118]. Vagifem® hydrates in contact with moisture, yielding a controlled release of soluble estradiol. Ovestin® is also a vaginal tablet available in the market. 4.6.3. Vaginal ring Vaginal rings, initially manufactured for contraceptive purposes, showed high compliance due to easy insertion and removal and less vaginal discomfort, and high efficacy due to self-control. Vaginal ring has been used as an alternative dosage form for the delivery of hormones due to constant and gradual release of the hormone over a prolonged period of time [118,128–136]. It appears that vaginal rings overcome the limitations of the treatment modalities, such as stickiness, nonuniform absorption and inconvenience of repeated applications [137]. The vaginal ring may either remain in place or be withdrawn for up to a maximum of 2 h during the sexual intercourse [138]. Estring® (Pfizer) and Femring® (Warner Chilcott) are currently available products as a vaginal ring. Femring® is intended for simultaneous treatment of both systemic vasomotor and vaginal symptoms but Estring® is intended only for urogenital symptoms. Since all the currently available vaginal rings contain only estradiol, the main concern on their applications is endometrial hyperplasia. If women with a uterus are taking estrogen even in low doses, they should be given progestogen to prevent endometrial hyperplasia or carcinoma. Vaginal ring aimed for delivering both estrogen and progesterone showed a potential to be used as an alternative to long-term hormone replacement therapy for endometrial protection [123]. The ring product containing a combination of hormones (estrogen/progesterone) is not yet available in the market. 4.7. Injections Intramuscular injection is one of the standard forms of testosterone replacement therapy for male. Intramuscular injection for HT was occasionally used before transdermal patches became popular, but at present rarely used. Intramuscular injection is convenient and generally well tolerated as it does not require frequent administration. It has several

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disadvantages. Since intramuscular injection is not on a continuous release basis, a large amount of intramuscular injection of estrogen results in very high circulating levels of estrogen shortly after the injection and then the level falls rapidly. Immediate reversal is impossible and there is a pain on injection. Depo®-Estradiol (Pfizer) contains estradiol cypionate which is oil-soluble. Depo-Testadiol® (Pfizer) contains androgenic hormone; testosterone cypionate and estradiol cypionate. Both are prescribed only for the relief of vasomotor symptoms. Depo-Provera® (Pfizer) containing MPA is prescribed in most cases for contraceptive purpose, but is also used for protection against endometriosis. 5. Conclusions Various formulations, such as tablets, patches, sprays and rings, are available in the market for HT. Currently available HTs have both benefits and adverse effects. Most HT still remains valuable for the treatment of menopausal symptoms in which the benefits are likely to outweigh the adverse effects. Improvement should be achieved on known safety issues, such as reduction of breast cancer incidence, cardiovascular problems and individualized symptoms. SERMs and SPRMs seem to have potential to become next generation of HT, but those other than raloxifene are still several years away from clinical application. At this point, the extensive reviews and comparisons on various types of formulations containing estrogens and progesterone could lead to an optimal formulation for HT with increased efficacy, enhanced patient compliance and reduced adverse effects. References [1] H.P. Schneider, The view of The International Menopause Society on the Women's Health Initiative, Climacteric 5 (2002) 211–216. [2] L. Cardozo, G. Bachmann, D. McClish, D. Fonda, L. Birgerson, Metaanalysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee, Obstet. Gynecol. 92 (1998) 722–727. [3] E. Seeman, Osteoporosis: trials and tribulations, Am. J. Med. 103 (1997) 74S–87S (discussion 87S–89S). [4] J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, C. Kooperberg, M.L. Stefanick, R.D. Jackson, S.A. Beresford, B.V. Howard, K.C. Johnson, J.M. Kotchen, J. Ockene, Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial, JAMA 288 (2002) 321–333. [5] G. Mazzuoli, M. Acca, D. Pisani, D. Diacinti, A. Scarda, L. Scarnecchia, M.T. Pacitti, E. D'Erasmo, S. Minisola, G. Bianchi, G. Manfredi, Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study, Bone 26 (2000) 381–386. [6] M.B. O'Connell, Pharmacokinetic and pharmacologic variation between different estrogen products, J. Clin. Pharmacol. 35 (1995) 18S–24S. [7] J.L. Turgeon, D.P. McDonnell, K.A. Martin, P.M. Wise, Hormone therapy: physiological complexity belies therapeutic simplicity, Science 304 (2004) 1269–1273. [8] J. Ness, W.S. Aronow, E. Newkirk, D. McDanel, Use of hormone replacement therapy by postmenopausal women after publication of the Women's Health Initiative Trial, J. Gerontol. A. Biol. Sci. Med. Sci. 60 (2005) 460–462.

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[9] S.R. Davis, I. Dinatale, L. Rivera-Woll, S. Davison, Postmenopausal hormone therapy: from monkey glands to transdermal patches, J. Endocrinol. 185 (2005) 207–222. [10] F.Z. Stanczyk, Pharmacokinetics of progesterone administered by the oral and parenteral routes, J. Reprod. Med. 44 (1999) 141–147. [11] R. Sitruk-Ware, Progestogens in hormonal replacement therapy: new molecules, risks, and benefits, Menopause 9 (2002) 6–15. [12] J.M. Hall, J.F. Couse, K.S. Korach, The multifaceted mechanisms of estradiol and estrogen receptor signaling, J. Biol. Chem. 276 (2001) 36869–36872. [13] H. Kuhl, Mechanisms of sex steroids. Future developments, Maturitas 47 (2004) 285–291. [14] E. Vegeto, S. Belcredito, S. Etteri, S. Ghisletti, A. Brusadelli, C. Meda, A. Krust, S. Dupont, P. Ciana, P. Chambon, A. Maggi, Estrogen receptoralpha mediates the brain antiinflammatory activity of estradiol, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 9614–9619. [15] S.C. Manolagas, S. Kousteni, R.L. Jilka, Sex steroids and bone, Recent Prog. Horm. Res. 57 (2002) 385–409. [16] R.M. Losel, E. Falkenstein, M. Feuring, A. Schultz, H.C. Tillmann, K. Rossol-Haseroth, M. Wehling, Nongenomic steroid action: controversies, questions, and answers, Physiol. Rev. 83 (2003) 965–1016. [17] M.E. Mendelsohn, Genomic and nongenomic effects of estrogen in the vasculature, Am. J. Cardiol. 90 (2002) 3F–6F. [18] P. Kastner, A. Krust, B. Turcotte, U. Stropp, L. Tora, H. Gronemeyer, P. Chambon, Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B, EMBO J. 9 (1990) 1603–1614. [19] M. Oettel, W. Elger, T. Gräser, C. Holz, P. Lähteenmäki, V. Patchev, What is past is prologue: estrogen/progestin replacement tomorrow, Gynecol. Endocrinol. 10 (2001) 68–90. [20] D.P. McDonnell, C.E. Connor, A. Wijayaratne, C.Y. Chang, J.D. Norris, Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators, Recent Prog. Horm. Res. 57 (2002) 295–316. [21] W.P. Weisenburger, A.R. Hagler, M.S. Tassinari, Pre- and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague–Dawley rats, Birth Defects Res. B. Dev. Reprod. Toxicol. 71 (2004) 171–184. [22] B. Ettinger, D.M. Black, B.H. Mitlak, R.K. Knickerbocker, T. Nickelsen, H.K. Genant, C. Christiansen, P.D. Delmas, J.R. Zanchetta, J. Stakkestad, C.C. Gluer, K. Krueger, F.J. Cohen, S. Eckert, K.E. Ensrud, L.V. Avioli, P. Lips, S.R. Cummings, Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators, JAMA 282 (1999) 637–645. [23] F. Labrie, M. El-Alfy, L. Berger, C. Labrie, C. Martel, A. Belanger, B. Candas, G. Pelletier, The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health? Endocrinology 144 (2003) 4700–4706. [24] C. Palmieri, E.W. Lam, D. Vigushin, R.C. Coombes, Value of SERMs in postmenopausal women, Lancet 363 (2004) 1477–1478. [25] C.C. Chadwick, S. Chippari, E. Matelan, L. Borges-Marcucci, A.M. Eckert, J.C. Keith Jr., L.M. Albert, Y. Leathurby, H.A. Harris, R.A. Bhat, M. Ashwell, E. Trybulski, R.C. Winneker, S.J. Adelman, R.J. Steffan, D. C. Harnish, Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 2543–2548. [26] R.A. Moore, Livial: a review of clinical studies, Br. J. Obstet. Gynaecol. 106 (Suppl 19) (1999) 1–21. [27] M. Hammar, S. Christau, J. Nathorst-Böös, T. Rud, K. Garre, A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptom, BJOG 105 (1998) 904–911. [28] H.J. Kloosterboer, Tibolone: a steroid with a tissue-specific mode of action, J. Steroid. Biochem. Mol. Biol. 76 (2001) 231–238.

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