Transdermal Hormone Therapy: Gels and Patches
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CLIMACTERIC 2004;7:347–356 Transdermal hormone therapy: gels and patches G. Samsioe Lund University Hospital, Lund, Sweden Key words: HORMONE THERAPY, TRANSDERMAL, GELS, PATCHES, MENOPAUSE ABSTRACT Hormone therapy (HT) in the climacteric has a number of beneficial effects including mitigation of climacteric symptoms and prevention of osteoporosis. Administration of HT via the transdermal route avoids hepatic first-pass metabolism and therefore the high plasma levels of estrogen metabolites that are associated with oral administration. Patch formulations have traditionally been the most common form of transdermal HT. However, as patches may be associated with local skin reactions, gel formulations have been developed in an attempt to improve acceptability and compliance with transdermal HT. Patch and gel formulations are equally as effective in treating climacteric symptoms and improving bone mineral density, and the effects are comparable to those achieved by oral HT. INTRODUCTION The efficacy of climacteric short-term hormone ence between the routes of administration therapy (HT) in relieving symptoms, such as hot regarding the risk of breast cancer. flushes, night sweats and urogenital problems, is The number of possible HT options has well established. Despite the recent results from increased dramatically over the last few years. A the Women’s Health Initiative (WHI)1 and the wide range of oral formulations is now available, Heart and Estrogen/progestin Replacement Study many of which aim to make bleeding patterns (HERS) II2 studies concerning an increased risk more acceptable. New transdermal delivery sys- of venous thromboembolic (VTE) events during tems, such as matrix patches and gels, have also the early phase of treatment with oral contin- been developed. uous conjugated equine estrogens + Transdermal HT offers certain benefits over medroxyprogesterone acetate, it remains indis- oral regimens. Because the majority of orally putable that HT has long-term benefits on the administered estradiol is metabolized in the gut skeletal system, increasing bone mass and and liver to estrone and other metabolites, high reducing the risk of fractures. In the WHI study, doses are necessary to achieve therapeutic tissue HT reduced hip and vertebral fracture rates by levels. In contrast, transdermal administration one-third compared with placebo1. It is also avoids hepatic first-pass metabolism, thus permit- important to remember that the types of ting the use of lower doses of estradiol and estrogen and progestogen, the dosage and avoiding high plasma levels of estrone. Transder- duration of treatment, and the route of admin- mal therapy is particularly indicated in women istration may influence the potential risks with hypertriglyceridemia, at high risk for or associated with HT. According to the Million previous cholelithiasis, persistent or recurring Women study3, there seems to be little differ- symptoms due to fluctuating levels of plasma Correspondence: Professor G. Samsioe, Department of Obstetrics and Gynecology, Lund University Hospital, 221 85 Lund, Sweden REVIEW Received 24-12-03 ª 2004 International Menopause Society Revised 07-06-04 DOI: 10.1080/13697130400012239 Accepted 23-06-04 Gels and patches Samsioe estradiol, and those who require perioperative sequential progestogen must be added to any HT4. It has also been suggested that the transder- estrogen treatment in order to avoid endometrial mal route is preferable in women who smoke stimulation and hence an increased risk of more than ten cigarettes per day. Furthermore, hyperplasia and subsequent carcinoma. women with migraine, diabetes or its pre-stage, the metabolic syndrome, may benefit from the more stable plasma concentrations obtained with ABSORPTION transdermal applications. The less pronounced Percutaneous administration circumvents hepatic liver effects seen with transdermal routes result in first-pass metabolism, thereby avoiding the fluc- less alteration of estrogen-induced hepatic protein tuations in plasma hormone levels and high synthesis. Levels of sex hormone binding globulin plasma levels of estrogen metabolites seen after (SHBG) and thyroxin binding globulin remain oral administration. This effect is illustrated in a virtually unchanged, which could be of impor- comparison of estradiol pharmacokinetics during tance in women with low endogenous androgens repeated transdermal patch (50 mg/day applied or thyroxine levels5. Serum levels of free testoster- twice-weekly) or oral (2 mg daily, micronized) one are also unchanged by transdermal therapy, administration7. Plasma concentrations of estra- whilst there is a clear reduction with oral therapy. diol and estrone were relatively constant during For example, in a study conducted in 27 transdermal administration and remained within postmenopausal women, serum free testosterone the range normally encountered in women during levels were significantly increased after 12 weeks the early follicular phase. In contrast, oral dosing with oral estradiol (2 mg/day) but were un- was associated with large pulses of estradiol and changed with transdermal estradiol (50 mg/day) estrone shortly after administration and steady- or placebo (Figure 1)6. In addition, transdermal state plasma concentrations were considerably therapy may be preferred by women who find pill- higher than seen with transdermal administration. taking an inconvenience or, for sociocultural The average daily concentrations of estradiol and reasons, an imposition. estrone to which the women were exposed were, Patch formulations have traditionally been the respectively, 12.0 and 9.4 times higher with oral most common means of transdermal application than with transdermal administration. In a com- of HT and many conventional and matrix patches parison between estradiol gel (1.5 mg applied are now available containing a range of estradiol daily) and oral estradiol valerate (2 mg daily), concentrations. Unfortunately, patches may be peak estradiol levels were lower with the gel but associated with local skin reactions, and these are there were no differences with regard to the a common reason for discontinuation. As the absorption rate8. Plasma estrone levels were 3–8- adhesive, rather than the active content, is fold higher with the tablet than with the gel. The generally the cause of these reactions, transdermal transdermal route therefore resulted in more gel delivery systems have now been developed that physiological concentrations of estradiol and may have advantages with regard to these effects. metabolites, and the daily variation was similar In women with an intact uterus, continuous or to that seen in a normal menstrual cycle. Estradiol absorption appears to be equally good whether administered as a gel or a patch8–10. For example, pharmacokinetic parameters (mean and 16 0 weeks *p < 0.001 vs. baseline maximum estradiol and estrone concentrations, 12 weeks 14 estrone : estradiol ratio and AUC0-72) were similar 12 with 17b-estradiol administered as a gel (1.5 mg 10 applied daily) or a patch (50 mg/day applied every 8 3 days)9. The only difference was a greater day-to- 6 day variation over the 3-day application period 4 * with the patch than with the gel. The same patch 2 formulation (50 mg/day applied every 3 days) was 0 used in a comparison with another gel (1.5 mg Serum free testosterone (nmol/l)Serum testosterone free Oral estradiol Transdermal Placebo applied daily)8. There were no differences between estradiol the treatments with regard to peak concentrations Figure 1 Serum levels of free testosterone at baseline of estradiol and bioavailability. However, the and after 12 weeks of treatment with transdermal or fluctuation between peak and trough estradiol oral estradiol therapy or placebo6 levels was significantly greater with the patch than 348 Climacteric Gels and patches Samsioe with the gel (89% vs. 67%, p 5 0.05). Estradiol climacteric complaints were randomized to either absorption has also been compared between the estradiol gel (1 or 2 mg applied daily) plus oral same gel (1 mg applied daily) and a novel matrix- medroxyprogesterone acetate (MPA) (10 mg/day type patch (50 mg/day applied twice-weekly)10. for the last 14 days of the cycle) or oral estradiol The absorption was similar with both formula- valerate (2 mg/day) for 21 days combined with tions, although there was again a greater oral MPA (10 mg/day for the last 10 days of each fluctuation between peak and trough levels with cycle), all regimens were associated with similar the patch as compared with the gel. A relatively significant improvements in climacteric com- high variability was observed with both treat- plaints22. Efficacy was assessed by interview in ments. which the women graded their symptoms as mild, It is important to note that site and area of moderate or severe. The reductions in the most application, frequency of administration and common climacteric symptoms, hot flushes and formulation may all have significant effects on night sweats, are shown in Table 1. Similar effects drug delivery via the transdermal route. For were seen in a comparison between estradiol gel example, two 7-day patch formulations demon- (1.5 mg applied daily) and oral conjugated com- strated bioequivalence when applied to the bined estrogen (0.625 mg/day)23. abdomen, but not when applied to the buttocks11. In a direct comparison between gel and patch When applied to the buttocks, the bioequivalence formulations, 120 postmenopausal women were confidence intervals for the ratio of log-trans- randomized