CLIMACTERIC 2004;7:347–356 hormone therapy: gels and patches

G. Samsioe

Lund University Hospital, Lund, Sweden

Key words: HORMONE THERAPY, TRANSDERMAL, GELS, PATCHES,

ABSTRACT Hormone therapy (HT) in the climacteric has a number of beneficial effects including mitigation of climacteric symptoms and prevention of . Administration of HT via the transdermal route avoids hepatic first-pass metabolism and therefore the high plasma levels of metabolites that are associated with . 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 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 + 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 is metabolized in the gut skeletal system, increasing bone mass and and liver to and other metabolites, high reducing the risk of fractures. In the WHI study, doses are necessary to achieve therapeutic tissue HT reduced 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 , 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 during tance in women with low endogenous androgens repeated (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 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 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 , 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. , 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 to receive estradiol gel (1 mg applied formed 17b-estradiol Cmax values for the two daily) or an estradiol patch (50 mg/day applied formulations were outside the interval of 0.80– twice weekly), both given in combination with 1.25, thus indicating that the products were not oral dydrogesterone (10 mg for the first 12 days of bioequivalent. The size of the application area each cycle), for 1 year24. Both treatments resulted also has an effect (studies with a gel have shown in a comparable improvement in climacteric that the smallest application areas are associated symptoms, with significant reductions in hot with optimal estradiol absorption and bioavail- flushes, sweating, dry vagina, insomnia and ability12), as does the frequency of adminis- depressive mood (p 5 0.05) after the first 2 weeks. tration13. The type of patch is also important, The time courses for the reduction of hot flushes in with the newer matrix patches generally leading to both groups are shown in Figure 2. more stable and consistent delivery of estra- diol14,15. Differences are also seen, however,

) 100 between different formulations of the same type Gel (n = 55) 16,17 of patch . 80 Patch (n = 54)

60

EFFICACY 40

Climacteric symptoms 20 Alleviation of climacteric symptoms is the main Visual scale analogue (mm 0 reason why women seek treatment with HT. The 0 124 8 26 52 efficacy of gel18–24 and patch25–32 formulations Weeks for the management of climacteric symptoms is Figure 2 Average symptom score for hot flushes well recognized, and both are as effective as oral during treatment with gel or patch formulations for administration. For example, in a 2-year open 12 months24. Reproduced with permission from Hirvo- study in which 173 postmenopausal women with nen et al.24

Table 1 Reduction in incidence of climacteric symptoms after 2 years of treatment with gel or oral formulations22 1 mg estradiol gel (n = 84) 2 mg estradiol gel (n = 32) 2 mg estradiol valerate (n = 57) Baseline Endpoint Baseline Endpoint Baseline Endpoint Hot flushes 89.2% 6.5%* 90.6% 10.5%* 89.2%* 13.3%* Night sweats 83.3% 19.6%* 93.8% 26.3%* 91.2%* 20.0%* *p 5 0.001 versus baseline

Climacteric 349 Gels and patches Samsioe

Smokers Osteoporosis 8 Non-smokers The bone-preserving effect of HT is also inde- **p < 0.01 pendent of the route of administration. As with 4 climacteric symptoms, both gel22,24 and patch23 formulations are effective in preventing bone loss 0 and this protective effect is similar to that seen ** with oral HT regimens. In a randomized, -4 parallel-group study, 84 women received estra- diol gel (1 mg applied daily) combined with oral -8 MPA (20 mg/day for the last 14 days of each cycle) and 57 received oral estradiol valerate % change in bone mineral density -12 (2 mg/day) for 21 days combined with oral MPA (10 mg/day for the last 10 days of each cycle)24. Biochemical markers of bone resorption were Transdermal Oral Placebo significantly reduced with both treatments after 2 years. Of the markers showing reduced bone Figure 3 Percentage change in bone mineral content formation, alkaline phosphatase decreased sig- after 2 years of treatment with oral or transdermal nificantly in both groups, whilst osteocalcin hormone therapy or placebo in smokers and non- smokers35. Reproduced with permission from Jensen & decreased significantly only in the gel group. In Christiansen35 the direct comparative study described pre- viously24, the effects of both the gel and patch treatments on bone mineral density were com- parable. Alkaline phosphatase fell significantly icant increased risk of cardiovascular disease in from 159.3 + 44.6 IU/l to 134.4 + 32.2 IU/l women starting treatment 20 years or more after (p 5 0.001) after 12 months in the gel group the menopause36, there is no evidence that this and from 165.5 + 43.2 IU/l to 154.9 + 43.7 IU/l applies to transdermal regimens. Indeed, this is (p 5 0.01) in the patch group. Overall, bone supported by a recent publication in which the mineral density increased by 0.3% in the gel risk of VTE was statistically significantly in- group and fell by 0.3% in the patch group; the creased by oral (relative risk, 3.5) but not by comparative change in a group of reference transdermal therapy (relative risk, 0.9)37. women who did not receive treatment was Both gel and patch formulations appear to have 7 0.9%. similar effects on cardiovascular risk parameters, The difference becomes overt in smokers. In a such as the lipid profile, the hemostatic system, recently published study by Va¨lima¨ki and collea- inflammatory markers and glucose metabolism. gues, estradiol gels were as effective in smokers as However, there are some clear differences be- in non-smokers34. When directly comparing tween the effects of transdermal and oral HT transdermal to oral therapy in smokers and non- regimens. In general, transdermal regimens have a smokers, another study conducted in 110 post- more beneficial effect on plasma triglyceride levels menopausal women found no difference in the and less effect on high density lipoprotein (HDL) change in bone mass between transdermal (3 mg levels. Both routes are associated with reduced estradiol gel on days 1–24, no treatment on days total and low density lipoprotein (LDL) cholester- 25–28) and oral (2 mg estradiol valerate on days ol, albeit somewhat more pronounced with oral 1–11, 2 mg estradiol valerate plus 1 mg cyproter- therapy38–41. Further, more detailed, investigation one acetate on days 12–21, no treatment on days of LDL cholesterol particles has indicated that, 22–28) therapy in non-smokers, but a markedly because transdermal, but not oral, estrogen is better effect with the transdermal approach than capable of reducing triglyceride concentrations, it with oral therapy in smokers (Figure 3)35. results in larger LDL cholesterol particles that are resistant to oxidation38. Thus, the antioxidant effect of estrogen is preserved or even improved EFFECTS ON CARDIOVASCULAR with transdermal HT. In contrast, oral HT RISK FACTORS reduces the particle size and oxidative suscept- Although the WHI study suggested that oral ibility of LDL cholesterol and can therefore have continuous HT is associated with an increased an atherogenic effect, even if plasma levels of LDL risk of VTE1, and a subtle, statistically insignif- cholesterol are lowered.

350 Climacteric Gels and patches Samsioe

With regard to the hemostatic system, trans- being abundant was 36/643 (5.6%) with the patch dermal estradiol has been shown to reduce plasma compared with 19/578 (3.3%) with the gel levels of fibrinogen and factor VII, both of which (p 5 0.05). Overall, 8.5% of women in the gel are important risk factors for cardiovascular group and 1.8% in the patch group reported no disease42. In contrast, changes in the hemostatic bleedings. There were no differences between the system induced by oral HT have generally been in treatments with regard to time of onset of a prothrombotic direction. The inflammatory bleeding, duration of bleeding and frequency of marker C-reactive protein, a strong independent spotting or breakthrough bleeding. There was a predictor of cardiovascular disease in otherwise significant (p 5 0.001) increase in endometrial healthy postmenopausal women, has been shown thickness (as assessed by transvaginal sonography) to increase during oral HT. This increase in C- after 12 months in both groups. It should be reactive protein is accompanied by a decrease in remembered that the 50 mg daily release dose was the anti-inflammatory growth factor insulin-like chosen as this resulted in similar area under the growth factor-1. Recent evidence has shown that curve estradiol levels as did a 2 mg/day oral dose. these effects are directly related to first-pass Hence, the free fraction of estradiol, and thereby hepatic metabolism and therefore do not occur the hormonal influence, is greater with a 50 mg in women given transdermal regimens43. Finally, patch compared with a 2 mg tablet. This was neither patch nor gel formulations appear to have demonstrated in a recent large population study in any negative effects on glucose and insulin which the efficacy with regard to several para- metabolism44,45. Indeed, one recent study suggests meters, as well as a number of side-effects, was there is less of an impact on the oral glucose greater in patch users49. This is also the most tolerance test with transdermal administration in plausible explanation for the occurrence of more women with the metabolic syndrome46. bleeding problems in patch users compared with oral users of continuous combined HT regimens, as too high a dose induces more marked endo- SAFETY AND TOLERABILITY metrial effects, be it atrophy or endometrial Endometrial safety and bleeding profile stimulation. This is illustrated by a comparison (n = 441) of bleeding profiles between an oral As unopposed estrogen may lead to endometrial formulation containing 2 mg estradiol and two hyperplasia and carcinoma, a progestogen should patch formulations containing 50 or 25 mg estra- be added to all regimens in non-hysterectomized diol, all of which were combined with women. Good endometrial protection is achieved acetate50. As shown in Figure 4, with oral progestogens, such as MPA, used in the percentage of women with no bleeding was combination with transdermal estrogens, either as greater with the oral formulation than with the patches or gels19,20,22–24,47. This endometrial patch containing 50 mg estradiol, but not with the safety is comparable to that seen with oral patch containing 25 mg estradiol. combinations of estrogens and progestogens. Pro- gestogens may also be given transdermally and it has been suggested that this may minimize some of the adverse effects of oral administration48. 90 10 cm2 E2/NETA 80 25/125 µg Both gels and patches are associated with good 20 cm2 E2/NETA bleeding profiles, although the exact bleeding 70 50/250 µg 60 Oral E2/NETA pattern is dependent on a range of factors, 2/1 mg including the dosing schedule, the types of 50 40 estrogen and progestogen, and the time since 30 menopause. There have been reports of a tendency 20 towards more abundant bleeding with patches 10 than with gels, possibly due to an increased 0 endometrial thickness. In a direct comparison 0–12 13–24 25–36 37–48 between estradiol gel (1 mg applied daily) and an with ofno women bleeding Percentage Weeks estradiol patch (50 mg/day applied twice weekly), Figure 4 Percentage of women with no bleeding both combined with oral dydrogesterone (10 mg during treatment with oral hormone therapy containing for the first 12 days of each cycle), there was 2 mg estradiol and two patch formulations containing tendency towards heavier bleeding in the patch 50 or 25 mg estradiol50. Reproduced with permission group24. The number of bleedings recorded as from Mattsson et al.50

Climacteric 351 Gels and patches Samsioe

only 2/60 women (3.3%) complained of transient Adverse events mild itching with the gel24. In contrast, 28/60 As lower doses of estrogen are required in women (46.7%, p 5 0.001) using the patch transdermal than in oral formulations, and reported skin irritation; erythema and itching circulating levels of metabolites are lower, trans- were the most frequently reported events, whilst dermal HT in general tends to be associated with swelling and skin peeling were seen occasionally. fewer systemic side-effects such as breast tender- Direct comparative studies in hot and humid ness and metrorrhagia22. Oral HT is also countries also showed benefits for gels59,60. associated with an increased risk of gallstone formation, due to a reduction in bile acid synthesis and reduced output to the biliary system, and ACCEPTABILITY AND COMPLIANCE venous thromboembolism37. Current recommendations for short-term use of The incidence of systemic side-effects tends to HT around the time of the menopause mean that be similar amongst transdermal formulations. there is little effect on fracture risk in later life. However, there appear to be some differences Once HT is discontinued, there is an immediate between patches and gels with respect to local skin resumption of bone loss at a rate similar to that irritation and application site reactions. Patches seen in untreated women. In order to reap the may cause local reactions11,13–15,26,27,31,32,51–54, benefits of reduced bone loss and fracture risk, including erythema, itching, spots, pruritus, long-term HT is required and good compliance is eczema, scaling, blisters and burning sensations, essential. with itching usually being cited as the most Compliance with HT is considered to be rather disabling symptom. Reservoir patches appear poor61. The main reasons for non-compliance to be associated with a relatively high incidence include side-effects, such as breast tenderness and of local skin reactions, ranging from 22% to weight gain, the return of menstrual bleeding and 70% for erythema, 8% to 30% for itching fear of cancer, whilst improvements in overall and 2% to 46% for pruritus/edema, and these quality of life and a treatment schedule that is reactions are frequently given as the reason for simple and unproblematic are likely to improve discontinuation. Erythema, itching and pruritus compliance. It is important to remember, how- are also seen with matrix patch formulations, the ever, that the type of HT selected should be incidences ranging from 8% to 79%, 0% to tailored to suit each individual woman. Unfortu- 20% and 0% to 29%, respectively. These local nately, many women fail to inform their doctor reactions are usually caused by an irritative effect when they stop taking HT and therefore fail to of the patch itself, rather than by the active benefit from other therapies including several HT agent55. However, transdermal administration options that may be more suitable. can occasionally lead to allergic sensitization Factors associated with the menopause that to the active drug and compromise subsequent impinge on quality of life include urogenital, use via other routes of administration56.Skin psychic and vasomotor disorders and skin reactions to patches tend to be more common changes. In a direct comparison of HT with and/or more severe in tropical countries that are symptomatic treatment, 499 postmenopausal wo- hot and humid57,58. men with vasomotor symptoms were randomized Gels tend to be associated with a lower to receive HT (transdermal estradiol plus oral incidence of local skin reactions. Skin irritation chlormadinone acetate) or veralipride for 6 was reported in 1.7% of 173 women during the months62. All assessments of quality of life, first year of treatment with estradiol gel (1 or including health, psychological well-being, sleep 2 mg applied daily)22. This percentage remained problems, sexual behavior and social life, were low during the second year of treatment (3%). improved to a significantly greater extent with HT Similarly, in a 1-year study in 395 women using than with symptomatic treatment. Transdermal the same estradiol gel formulation (1 mg applied estrogen has also been shown to relieve vaginal daily), mild or moderate erythema was reported dryness and dyspareunia and to have positive by 0.8–1.2% of women and severe itching by effects on satisfaction with frequency of sexual 0.3%20. Only 1% of the women discontinued the activity, sexual fantasies, degree of enjoyment, study due to skin irritation. vaginal lubrication and pain during intercourse63. A direct comparative study between estradiol All these factors contribute to an improvement in gel (1 mg applied daily) and an estradiol patch quality of life and are likely to encourage women (50 mg/day applied twice weekly) reported that to continue with treatment.

352 Climacteric Gels and patches Samsioe

Hyper-estrogenic side-effects tend to be more in combination with oral micronized progesterone common with oral than with transdermal HT due resulted in significant improvements in hot flushes, to the higher doses and the higher circulating peak night sweats, sleep disturbances, nervousness, hormone levels (as demonstrated in the pharma- depressive mood, difficulties in concentrating, cokinetic data). Indeed, studies have shown that vertigo, , joint pain and palipitations18. women are more likely to be compliant to When the women were asked their opinion of the transdermal therapy than oral therapy. In one gel compared with a patch, 97.5% considered the study, involving more than 300 women, 79% of gel more pleasing and 91.5% considered it more those using transdermal HT continued treatment practical. The fact that a gel is invisible once for more than a year compared with 54% of those applied is important, as many women feel using oral HT64. embarrassed about using treatment for the meno- In a direct comparative cross-over study, 80 pause and would prefer that any such medication postmenopausal women received estradiol gel is discreet and unlikely to be noticed by others. (1.5 mg applied daily) and a patch formulation Women may also experience problems with the of estradiol (50 mg/day applied twice-weekly), adhesiveness of patches, with approximately 10% each given for 25 days with a 6-day interval of patches falling off53. This directly jeopardizes between the two cycles65. Using a self-adminis- the effectiveness of treatment, as well as meaning tered questionnaire, both treatments were judged that women are less likely to continue with as convenient, fast and easy to use by more than therapy. 90% of the women. However, the gel was rated significantly better than the patch in terms of visual aspects, with 100% of women finding the CONCLUSIONS gel not at all annoying, compared with 49% who Transdermal administration of HT avoids hepatic found the patch not at all annoying. The first-pass metabolism and therefore avoids the percentage of women who reported itching, skin high doses and circulating hormone levels that reddening, problems with application and disrup- may account for some of the side-effects seen with tion during intimacy with a partner was also oral HT. It also avoids the increase in C-reactive significantly higher with the patch than with the protein that occurs with oral regimens and that gel (Figure 5). may be associated with adverse cardiovascular In an observational study involving 589 post- consequences. Transdermal HT is available as menopausal women, treatment with estradiol gel either a patch or a gel, both of which are equally

12 Gel (n = 80) ** Patch (n = 80) 10 * *p < 0.05 vs. gel **p < 0.01 vs. gel 8

* * 6

4

Percentage of women Percentage

2

0 Itching Skin Skin Problems Disruption Disruption reddening eruptions with to everyday during application life intimacy with a partner

Figure 5 Percentage of women reporting problems after treatment for 25 days with gel or patch formulations65

Climacteric 353 Gels and patches Samsioe effective in treating climacteric symptoms and be short-term, compliance is a factor that is of reducing the risk of osteoporotic fractures. Gels, pivotal importance to attain the longer-term however, tend to have fewer incidences of skin benefits of HT on bone in symptomatic women. irritation and a more cosmetic appeal. Transder- mal administration of HT could therefore possibly Conflict of interest Nil. improve compliance. Although current recom- mendations suggest that HT use should generally Source of funding Nil.

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