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BRIEF REPORT |
Developmental Endocrinology Branch (S.N.K., H.G., L.M.N.), National Institute of Child Health and Human Development and Department of Pharmacy (K.A.C.), National Institutes of Health, Bethesda, Maryland 20892; and the Department of Pharmaceutics (N.A.M.), University of Utah, Salt Lake City, Utah 84112
Address all correspondence and requests for reprints to: Karim A. Calis, Pharm.D., M.P.H., B.C.P.S., B.C.N.S.P., F.A.S.H.P., F.C.C.P., Clinical Center Pharmacy Department, National Institutes of Health, Building 10, Room 1S-259, 10 Center Drive (MSC 1196), Bethesda, Maryland 20892. E-mail: kcalis{at}nih.gov.
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Abstract |
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Objective: The objective of the study was to evaluate an investigational testosterone transdermal patch (TTP) designed to deliver the normal ovarian production rate of testosterone.
Design: This was an open-label study (2-month baseline period followed by 2-month treatment period).
Patients: Nine women with sPOF and a history of regular bleeding patterns on standard estrogen/progestogen cyclic treatment participated in the study. One subject with abnormal baseline levels was excluded.
Intervention: Four consecutive 28-d cycles of transdermal estradiol (E2; 0.1 mg/d) and sequential oral medroxyprogesterone acetate (MPA; 10 mg/d for the last 12 d of each cycle). During cycles 3 and 4, an investigational TTP (nominal delivery 150 µg/d) was applied twice weekly to the abdomen.
Main Outcome Measures: Steady-state pharmacokinetic profiles of free and total testosterone and scheduled vaginal bleeding patterns were studied.
Results: The mean (95% confidence interval) of the time-average free testosterone levels during TTP treatment was 7.5 (4.9–9.9) pg/ml; 26.0 (17.2–34.6) pmol/liter (with E2), and 6.9 (4.9–8.8) pg/ml; 23.9 (17.2–30.5) pmol/liter (with E2 and MPA). The confidence intervals of the means include the upper limit of normal for premenopausal women, i.e. 6.8 pg/ml (23.5 pmol/liter), although the mean values are slightly above this.
Conclusions: The addition of TTP to cyclic E2/MPA therapy in women with sPOF produced mean free testosterone levels that approximate the upper limit of normal. A 3-yr study to assess safety and effectiveness in this population is in progress.
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Introduction |
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In this pilot study, we investigated the steady-state pharmacokinetics, safety, and tolerability of an investigational testosterone transdermal patch (TTP) designed to deliver 150 µg/d (Watson Laboratories, Inc., Salt Lake City, UT, and Procter & Gamble Pharmaceuticals, Cincinnati, OH) in young women with sPOF receiving standard sequential estrogen/progestogen therapy. The primary objective was to assess the serum concentration profiles of free and total testosterone before and during application of the TTP. Secondary objectives were to evaluate serum estradiol and SHBG levels, local tolerability, and the effects of the TTP on vaginal bleeding patterns and clinical safety parameters.
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Subjects and Methods |
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This pilot study was approved by the Institutional Review Board of the National Institute of Child Health and Human Development, National Institutes of Health (NIH; Bethesda, MD). All women provided informed written consent. Nine women with sPOF were recruited for this study from those who had participated in a screening protocol (6). To be eligible for the study, women had to fulfill the following inclusion criteria: 1) diagnosis of sPOF before the age of 40 yr; 2) age between 18 and 42 yr; 3) no hysterectomy; 4) no contraindications for hormone therapy; 5) history of regular bleeding patterns on our standard estrogen/progestogen cyclic treatment; 6) body mass index (BMI; kilograms per meter squared) between 19 and 30; 7) alcohol use less than two drinks per day; 8) smoking fewer than two cigarettes per day; 9) baseline free testosterone levels below the upper normal limit [6.8 pg/ml (23.57 pmol/liter); Esoterix Endocrinology, Calabassas Hills, CA]; and 10) no major illnesses. One of the nine enrolled patients was subsequently noted to have abnormally low levels of SHBG at screen (30 nmol/liter) and elevated baseline levels of free testosterone (10.5 pg/ml; 36.40 pmol/liter) and was therefore excluded.
Study design
This open-label pharmacokinetic study consisted of a screening evaluation as previously described (6), a 2-month control (baseline) period, and a 2-month treatment period.
Screening evaluation (6) was conducted during the prior 3 months, before study enrollment.
Study protocol. The patients received four consecutive 28-d cycles of estrogen/progestogen therapy, consisting of transdermal estradiol (E2) (Alora, 0.1 µg/d; Watson Laboratories) applied twice weekly to the thigh and sequential oral medroxyprogesterone acetate (MPA; Provera, 10 mg/d; Pfizer, Groton, CT) taken during the last 12 d of each cycle. During cycles 3 and 4, the patients also applied the investigational TTP twice weekly to the abdomen. Each patient returned for interim study visits at wk 2 and 4 of cycle 2 (E2/MPA, baseline period) and wk 2 and 4 of cycle 4 (E2/MPA/TTP, treatment period). Compliance was determined by a count of the used patches at each visit.
Investigational TTPs were supplied by Watson Laboratories (7, 8, 9).
Hormone sampling. Steady-state serum concentration profiles of free and total testosterone (T), E2, and SHBG were measured during wk 2 (without MPA) and wk 4 (with MPA) of cycles 2 (baseline) and 4 (TTP treatment). Blood samples were drawn at 0, 1, 2, 4, 8, 12, 24, 48, 72, and 96 h after application of the estradiol and testosterone patches. The blood sampling started between 0700 and 0900 h.
Scheduled vaginal bleeding patterns, safety, and local skin tolerability assessment
Scheduled vaginal bleeding patterns. A daily bleeding diary was provided to the patients, which required them to record daily the presence of any bleeding and to grade it with respect to amount.
Laboratory and androgenic assessments. Liver function tests and lipids were analyzed during the baseline period and the treatment period. Hirsutism scores were assessed using the Ferriman and Gallwey score (10).
Skin tolerability assessment. Skin appearance at the current TTP application sites and the surrounding sites were evaluated for any signs of irritation or contact allergy at each clinic visit. Patch adherence was also evaluated at each clinic visit.
Laboratory methods
Liver function tests and lipids were analyzed at the NIH Clinical Center using standard methods. All hormone analyses were performed on frozen serum by Esoterix Endocrinology. Total T and E2 were measured by specific RIAs after extraction in hexane-ethyl acetate and column chromatography. The free T concentration was determined as the product of the percent free T, measured by equilibrium dialysis, and the total T concentration. SHBG was measured by immunoradiometric assay. Normal ranges for free T, total T, and E2 correspond to an Esoterix database of normal cycling women between the ages of 16 and 46 yr (7). The normal range for SHBG is that reported by Esoterix for premenopausal women.
Statistical analysis
The primary end points of the study were the changes in free and total T levels produced by the TTP. The secondary end points included the possible effects of TTP treatment on estradiol and SHBG levels and safety parameters, e.g. vaginal bleeding patterns, hirsutism and acne score, lipid levels, insulin, and liver function tests.
The statistical significance of the differences between free and total T levels at baseline and during TTP treatment was assessed using a paired t test (two tail; alpha = 0.05). The statistical analyses were performed using Microsoft Office Excel (Redmond, WA).
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Results |
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The mean age of the patients was 34 yr (range 28–41 yr). Six women were white, one was black, and one was Hispanic. The mean (SEM) BMI was 24.7 (0.6) kg/m2. All eight patients completed the four treatment cycles and pharmacokinetic evaluations.
Hormone profiles
Table 1
gives the mean (SEM, range) of the pharmacokinetic parameters derived from the free T, total T, E2, and SHBG profiles at baseline (BLavg) and during the TTP treatment (Cavg). The mean (95% confidence intervals) time-average free T levels during TTP treatment were 7.5 (4.9, 9.9) pg/ml; 26.0 (17.2, 34.6) pmol/liter (without MPA) and 6.9 (4.9, 8.8) pg/ml; 23.9 (17.2, 30.5) pmol/liter (with MPA); upper limit of normal range 6.8 pg/ml; 23.5 pmol/liter. Free and total T profiles varied similarly (Fig. 1). There were no statistically significant effects of MPA treatment (wk 2 vs. wk 4) on any of the pharmacokinetic parameters for free and total T (Table 1).
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). The SHBG levels showed little variation over the 96-h sampling periods and fell within the normal range for premenopausal women (40–120 nmol/liter). There was a small (
10%) but statistically significant decrease in SHBG levels during TTP treatment at wk 2 (P = 0.048) and wk 4 (P = 0.031) and a similar decrease with MPA observed during cycle 4 (P = 0.019) (Table 1). Safety parameters
Scheduled vaginal bleeding patterns. While on transdermal T administration, the patients continued to have scheduled vaginal bleeding patterns, with no significant changes in the onset or duration of vaginal bleeding. No endometrial biopsies were required (no unscheduled vaginal bleeding).
Laboratory and androgenic assessments. No serious adverse events were reported during transdermal T administration and no significant changes were observed in the liver panel, lipid profile, or fasting insulin levels (data not shown). None of the women experienced hirsutism or other signs of androgen excess during T administration.
Local skin tolerability assessment. No patient had to discontinue usage related to local skin irritation.
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Discussion |
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Most studies have shown that women with sPOF have significantly lower T levels than regularly menstruating women (3, 4, 5). Hypoandrogenism might explain why two thirds of young women with sPOF have significantly reduced bone mineral density, despite taking standard estrogen/progestogen hormone therapy (11). Increasing evidence suggests that androgens have important biological roles in women, such as maintaining bone mass (12, 13, 14) and normal sexual function (9, 12). This raises the possibility that androgen in addition to estrogen therapy may be necessary for adequate sex-steroid replacement therapy in women with sPOF.
The TTP used in this protocol has been previously tested in surgically menopausal women with impaired sexual function (9) and androgen-deficient women with HIV/AIDS (7, 8) but has not been used in young women with sPOF and an intact uterus.
Combining the results obtained with and without concomitant MPA, the mean time-averaged increments in serum free and total T levels were 4.8 pg/ml (16.6 pmol/liter) and 34 ng/dl (1.17 nmol/liter), respectively. These increments are somewhat greater than observed in a prior pharmacokinetic study of the 150 µg/d patches in 11 oophorectomized women who were withdrawn from estrogen therapy (15). Differences in the clearance rate of T and BMI in the two groups (i.e. less body fat in young women with sPOF) may account for the different findings.
Women with sPOF are younger, compared with oophorectomized women, and have normal adrenal androgen production (2). Therefore, young women with sPOF may require smaller doses of TTP, designed to achieve ovarian testosterone production (i.e. 150 µg/d).
An important factor influencing T clearance is the level of SHBG, which binds T and lowers its free fraction. Oral estrogens produce a marked dose-dependent increase in SHBG levels, whereas oral androgens produce a marked decrease (16). Androgenic progestogens given orally also lower SHBG levels (16). In contrast, transdermal E2 and T exert weaker hepatic effects and have a smaller influence on SHBG levels (17). In our study the women with sPOF received transdermal E2 patches and had SHBG levels within the normal range. As expected (16), during TTP treatment, the SHBG levels decreased by about 10%. A similar decrease was observed with oral MPA, consistent with the recent findings of Nugent et al. (18).
The pharmacokinetic findings of this pilot study show that in women with sPOF, the addition of 150 µg/d transdermal T to the usual estrogen/progestogen regimen increased the mean time-average free T to levels approximating the upper limit of the normal range during both the estrogen-only and the estrogen and progestogen phase of the cycle. To explore the potential of transdermal T therapy in preventing osteoporosis, a 3-yr prospective, double-blind, randomized, placebo-controlled study is presently being conducted at the NIH to compare the efficacy of the standard estrogen/progestogen regimen vs. estrogen/progestogen/T treatment in protecting women with sPOF from bone loss.
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Acknowledgments |
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Footnotes |
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First Published Online September 20, 2005
Abbreviations: BLavg, Area under curve at baseline divided by 96 h; BMI, body mass index; Cavg, area under the curve on the TTP divided by 96 h; E2, estradiol; MPA, medroxyprogesterone acetate; sPOF, spontaneous premature ovarian failure; T, testosterone; TTP, testosterone transdermal patch.
Received March 30, 2005.
Accepted September 8, 2005.
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References |
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