Transdermal testosterone replacement through genital skin

Transcription

1 Transdermal testosterone replacement through genital skin Virgil A. Place, Linda Atkinson, Della A. Prather, Nancy Trunnell, and F. Eugene Yates Contents 1 Introduction Methods Selection of subjects Design of the Testoderm testosterone transdermal system Efficacy of Testoderm testosterone transdermal system Evaluation of systemic and topical safety Assays Studies Pharmacokinetics (Study A) Twelve-week study (Study B) Extended use study (Study C) Statistical analyses Results Completion of studies Daily plasma testosterone profile (Study A) Twelve-week study (Study B) Subjective reports Extended use study (Study C) Effects of androgen replacement by Testoderm-TIS on gonadotropin levels Blood chemistries Discussion References 18 1 Introduction Dreams of rejuvenation of the aging male through the agency of testicular essences dates back at least to Berthold (1849) who transplanted rooster testes into capons with salubrious effect. He was followed by Brown-Sequard who reported similar benefits from self-injection of aqueous (and therefore probably inert) extracts of dog and guinea pig testes (1889). By 1918 Stanley and Kelkar were implanting testes from a dead human into a living person. Working at San Quentin prison at a time when there were on the average three executions per year, "valuable material for this kind of work became available." The eleven implants all became necrotic, but transiently produced (claims of) enhanced mood. More recently testosterone or its derivatives have been given orally, by intramuscular injections, by percutaneous creams or by subcutaneous implants E. Nieschlag et al. (eds.), Testosterone Springer-Verlag Berlin Heidelberg 199

2 166 Virgil A. Place et al. (Nieschlag et al. 1976; Skakkebaek et al. 1981; Gooren 1986). Testosterone itself is not useful orally because of the high first pass inactivation. Oral testosterone undecanoate is de-esterified in the intestinal mucosa and therefore presents a high flux of native testosterone to the liver (Geelen et ai. 1977). Buccal tablets of 17 a-methyltestosterone have fallen into disregard because of the hepatotoxicity associated with the derivative and its low potency. Intramuscular injections of single or mixed testosterone esters (propionate, phenyl-propionate, isocaproate, cypionate, enanthate, and decanoate) commonly have been used at one- to fourweek intervals. Subcutaneous testosterone pellets typically are implanted once every four months. The effects of these various routes of administration oftestosterone and testosterone derivatives on plasma levels of total and free testosterone, on luteinizing hormone (LH), and sex hormone binding globulin (SHBG) have recently been reconsidered by Conway et ai. (1988). Failure of current products to achieve the daily physiologic pattern of testosterone as reviewed in the previous papers indicated the need to utilize programmed delivery to mimic the circadian rhythm of this hormone. ALZA Corporation has specialized in the development of trans dermal therapeutic systems such as Transderm Scop, Transderm-Nitro and Estraderm marketed by Ciba-Geigy and Catapres-TIS marketed by Boehringer Ingelheim. A trans dermal product for testosterone replacement therapy has been studied in clinical trials for the past five years. Our work with other transdermal systems provided extensive knowledge of the dependence of delay of transport on storage effects from skin areas with thick stratum corneum. This phenomenon was confirmed in early studies with testosterone. In contrast to skin in other areas, the human male genital skin has uniquely thin stratum corneum and also a rich and superficial vascular network. These are essential characteristics for rapid drug absorption and dissemination beyond the local site. We therefore focused on development of systems that could be comfortably worn on genital skin. Adhesives and solubolizing agents are frequently skin irritants. Our resulting system is adhesive free and, when properly used, it provides flexibility and intimate contact to the changing contours of genital skin. Proper use includes dry shaving the scrotum every one to two weeks, application of the system with warm hands, then compressing it into place for ten seconds. After application, continuing close contact is aided if the patient wears close-fitting underwear. The unphysiological pattern of plasma testosterone following intramuscular injections has been described in previous chapters (Nieschlag and Behre; Snyder and Lawrence 198; Sokal et ai. 1982). These wide swings in testosterone levels over two weeks are to be contrasted with a normal circadian pattern of morning peak and evening nadir (Bremner et ai. 1983; Nieschlag 1974). Testosterone levels in older men are often lower than those in younger men and have an attenuated morning peak. However, it should be noted that the daily patterns of testosterone are highly variable even among young men (Spratt et ai. 1988). Of the 2 "normal" men (ages years) studied by Spratt et ai., comparisons of morning values (4-1 h) to afternoon values (16-2 h) of total testosterone showed that in three men the levels were the same at both

3 Transdermal testosterone replacement through genital skin 167 times of the day, in seven they were higher in the evening and in ten higher in the morning. As is now well known, LH and FSH have episodic pulsatile or even near-periodic patterns in plasma. It is less clear that plasma levels of testosterone (which has a longer half life than the gonadotropins) have physiologically significant high frequency (ultradian rhythmic) components (for recent data see Spratt et al. 1988). However, over a period of several days, different daily patterns of administration of testosterone in castrated rats have been claimed to lead to separation of sexual from aggressive behaviors. The separation was said to be dependent on pattern of exogenous testosterone and not on total dose (Taylor et al. 199). We now report an approach to testosterone replacement, using native testosterone delivered transdermally through scrotal skin. Delivery was accomplished by Testoderm testosterone transdermal systems (ITS) worn for 22 h per day. They were designed to generate a smooth circadian pattern of testosterone levels in plasma, with a peak occurring 3-5 h after application. When applied at 8 h, these new delivery systems produced plasma testosterone levels simulating the normal circadian rhythm common in many young men, with the highest levels occurring before 12 h. Fourteen clinics have evaluated Testoderm systems and some have reported their experience (Ahmed et al. 1988; Bals-Pratsch et al and 1988; Carey et al. 1988; Cunningham et al. 1989; Findlay et al. 1987, 1989; Korenman et al. 1987). 2 Methods 2.1 Selection of subjects Seventy-eight hypogonadal men in the U. S. ages years participated in these studies for periods up to five years. Written informed consent was obtained and the studies were approved by local Institutional Review Boards. The average age at entry was 47 years. Criteria for participation included hypogonadism (primary or secondary) requiring replacement therapy, and morning serum testosterone concentrations < 6.9 nmolll in subjects who had never received androgen replacement therapy, or < 8.6 nmolll after washout in those who had received prior treatment (1 ng/ dl = 3.47 nmolll). The etiologies of primary hypogonadism were: Klinefelter's syndrome, cryptorchidism, mumps orchitis, orchidectomy or testicular damage, fetal maldevelopment, autoimmune disease, postoperative ischemia, vasogenic testicular failure, or idiopathic failure. Among those with secondary hypogonadism, the etiologies included: hypothalamic or pituitary tumor with gonadotropin deficiency, empty sella syndrome, or idiopathic hypogonadotropic hypogonadism. The time since diagnosis of hypogonadism ranged from -44 years. Eightyfive percent of the subjects had received prior androgen therapy by intramuscular injection. These were not entered into the study until they had been withdrawn from injection therapy for at least four weeks, at which time we obtained baseline endocrine data and ratings of mood, energy level, frequency of sexual thoughts

4 168 Virgil A. Place et al. and a record of sexual activity from daily diaries completed during a one-week period just prior to starting the study. The prestudy diary week coincided with wearing of placebo systems. The health of subjects was evaluated by standard medical history, physical examination including palpation of the prostate, urinalysis, hematology, blood chemistry screens including liver function tests and lipids, and prostatic acid phosphatase (PAP). Patients were excluded for prostatic abnormalities (bladder outlet obstruction, prostatic enlargement, or elevated serum levels of acid phosphatase). Other criteria for exclusion included a hematocrit> 52%, use of glucocorticoids, chronic use of tranquilizers, or a history of alcoholism or drug abuse. 2.2 Design of the Testodenn testosterone transdennal system The Testoderm testosterone transdermal systems (ITS) to deliver native testosterone through scrotal skin were manufactured by the ALZA Corporation (Palo Alto, California, USA). Each Testoderm consisted of a soft flexible backing of spun-bonded polyester and a layer of ethylene-vinyl acetate copolymer containing the testosterone (.25 mg/ cm 2 ). The transdermal systems were available in two sizes: 4 or 6 cm2 (containing 1 or 15 mg testosterone, respectively). Each system was worn for 22 h per day during which time the systems delivered approximately 2.4 mg or 3.6 mg of testosterone. The systems are designated here as Testoderm-ITS 2.4 mg and Testoderm-ITS 3.6 mg. The systems were rectangular with rounded comers and adhered to the shaved scrotal skin by means of the cling qualities of the polymer. The systems were applied to the shaved scrotum and changed daily. Some patients with inadequate scrotal skin area have successfully worn the system on the penile shaft. After removal of the system, the testosterone remaining on the skin was determined by wiping the skin with isopropanol three times. Residues of <21lg12 cm 2 were measured (unpublished data). Even if transferred in toto by contact to a female sexual partner, these were clinically insignificant amounts of steroid. 2.3 Efficacy oftestodenn testosterone transdennal system Total serum testosterone, dihydrotestosterone (DHT) and estradiol concentrations were compared with the population normal ranges for the assays to assess absolute blood levels achieved. The treatment levels were also compared with baseline concentrations obtained for each patient to assess incremental blood levels achieved. Therapy was considered effective if a patient's total serum testosterone level during a day of wearing a Testoderm-ITS reached 12 nmolll or more, 3-5 h after system application. The dose delivered in vivo was determined by assaying residual drug in the systems worn on the day prior to, and the day of, blood sampling (two systems) in each study week for all patients. The difference between the residual testosterone in the system and the amount in unworn systems was taken as the measure of testosterone disappearance from the systems and the indicator of dose delivered.

5 Transdermal testosterone replacement through genital skin 169 Subjective evaluations of the treatments by both patients and physicians were also used as measures of efficacy. Patients ranked their mood, energy level and frequency of sexual thoughts by marking a prearranged scale in the daily diaries. Patients also recorded information on their sexual activity, noting frequencies of waking erections, spontaneous erections, intercourse, masturbation and orgasms. Changes in these variables were assessed by comparing the frequencies of sexual activity during baseline and treatment periods. In addition, a global assessment by both patient and physician of overall health and well-being, noting changes from previous clinic visits, was recorded by the physician at each visit. 2.4 Evaluation of systemic and topical safety We assessed the safety of this form of therapy by looking for changes in the following variables: standard blood chemistries including lipids; hematologic profile; urinalysis; prostatic acid phosphatase; vital signs; periodic physical and prostate examinations, assessment of urinary frequency, symptoms of retention or obstruction. Evaluations by both patient and investigator of the patient's overall health and well-being were also taken into account. Local tolerance of Testoderm-TIS on the scrotum was evaluated both by the physician's examination of the site of system application and by the patient's recording in his daily diary any discomfort while wearing the system. The physician also examined the skin site for irritation or swelling after removal of a system. 2.5 Assays Endocrine Sciences, Tarzana, CA performed radioimmunoassays for testosterone, DHT, gonadotropins and estradiol. They also assayed sex hormone binding globulin (SHBG), which binds both testosterone and DHT, using the steroid binding method. In these assays, the range of testosterone in normal males (all ages and all times of day or night) is nmol/i; range of DHT is 1-3 nmol/i, and range of estradiol is 3-13 pmol/1. Because DHT is an active androgen itself (Mooradian et al. 1987), we also calculated the sum of DHT and testosterone as "total androgen." Core Endocrine Labs., Hershey, PA assayed bioavailable (nonshbg bound) testosterone, bioavailable DHT and 3a-androstanediol glucuronide. Blood chemistries including lipids were analyzed at Pathology Laboratories, Los Gatos, CA. Each of the 14 clinics involved in the study separately reported hematological data and urinalyses. ALZA Corporation analyzed the residual testosterone in systems removed after 22 h of wearing. 2.6 Studies Pharmacokinetics (Study A) This five-week study was conducted in a single blind, randomized crossover design. Patients had a minimum four-week washout from previous intramuscular injection therapy prior to entering the study. Patients received either active Tes-

6 17 Virgil A. Place et al. toderm systems or placebo systems of similar appearance. Each placebo was administered daily for one week and on the final day blood samples were drawn (26 men) at, 1,2,3,4,8, 12, and 22 h after application. After four to five weeks of wearing active systems in order to achieve steady state, blood was sampled on the final day using the same schedule as for the placebo. The systems were then removed, and at.5, 1 and 2 h after removal additional blood samples were taken. The pharmacokinetics of testosterone delivered by Testoderm-ITS 2.4 mg and Testoderm-ITS 3.6 mg were compared to each other and to placebo data. From the resulting serum concentration profiles, the peak value (ernax), the time to maximum (Trnax), and the area under the curve (AUC) were obtained for each subject Twelve-week study (Study B) Twenty-five patients who completed Study A, above, were treated with active Testoderm systems for 12 more weeks, with measurements made at the end of each week. The nominal dose was increased from 2.4 mg/ day to 3.6 mg/ day after four weeks. An additional 53 patients with no prior experience with Testoderm were enrolled in the 12-week study (after a minimum of four weeks of washout from previous intramuscular injection therapy). The total number enrolled was therefore 78 patients Extended use study (Study C) Sixty-two patients, all of whom had participated in Study B continued with daily application of Testoderm systems (2.4 or 3.6 mg/day) for one year or longer. Observations were made at two-month intervals. More than 5 patients used Testoderm systems for two years or more. Hormone and clinical chemistry measurements were made at four-month intervals in this long-term study Statistical analyses We compared serum hormone concentrations in various treatment groups by analysis of variance using a general linear model. 3 Results 3.1 Completion o/studies Twenty-six patients completed the five-week pharmacokinetic study (Study A). Table 1 shows the discontinuation rates for the efficacy (Study B) and chronic safety (Study C) studies. Only 13 and 1% of the patients, respectively, left the studies because of their own or the physician's conclusion that the method was ineffective. Fewer than 2% of patients from either study discontinued. Forty-

7 Transdermal testosterone replacement through genital skin 171 Table 1. Discontinuation from Testoderm TM Studies Reason Study B (12 weeks) Study C (One year) n % n % Total enrolled Total discontinuing Intercurrent illness Personal Perceived lack of efficacy Center withdrew Table 2. Scrotal skin tolerance of Testoderm system treatment Parameter No. affirmative/ % with total responses complainta Itching Discomfort Irritation Swelling a No subject discontinued because of these minor side effects. four patients have continued using the method for four or more years (not shown). Table 2 indicates the incidence of local, scrotal skin effects of wearing Testoderm-TIS as reported by the patients' daily diaries. The irritation was minor and transient and no patient discontinued the studies for these reasons. 3.2 Daily plasma testosterone profile (Study A) Figure 1 shows the mean (± SE) serum testosterone concentration over 24 h during the seventh day of wearing placebo or active Testoderm systems. Maximum serum concentrations were observed 3-5 h after application of the active systems. The mean peak serum concentrations were approximately 12 nmolll for Testoderm-TIS 2.4 mg and 17 nmolll for Testoderm-TIS 3.6 mg. The respective average peak increments above placebo levels were approximately 9 and 14 nmolll-linear proportional responses to the normal doses (2.4/3.6=.66; 9/14 =.64). Mean area under the curve (without subtraction of placebo levels) was 223.6±131.9nmol-h/l and 332.2±211.1 nmol-h/l for Testoderm-TIS 2.4 mg and Testoderm-TIS 3.6 mg, respectively, again, a linear proportional response to dose (224/332 =.67). Both treatments differed significantly (p <.1) from baseline (placebo) and from each other.

8 172 Virgil A. Place et al. 24 I SE (n) -=: " E c: 18 (7) Q) c: Qj V; V; Q) I / o mg/day (26) TTS off o Study time (h) Fig. 1. Study of24 h serum concentration profile of total testosterone in subjects wearing place bo (., n=26), Testoderm-TIS 2.4mg (_, n=1) or Testoderm-TIS 3.6mg (e, n=7). The Testoderm systems were applied to the scrotum immediately after the experimental zero hour blood sample was taken and were then worn continuously for 22 h at which time they were removed. The data represent means ± SE for each sampling time 18,-- I SE. n= 42, mg ----, - 6 -=: " E c: Q) c o Q; V; o V;.& c: Q) '" ~ D 15 ~ , m , placebo J.J.llLU.JaL...J OJ <J) o " OJ c e OJ V; o V; OJ I- Study week Fig. 2. Weekly serum emax levels of total testosterone obtained 3-5 h after application (t max) of a Testoderm-TIS (left ordinate). In the figure the time periods labeled 2.4 mg and 3.6 mg refer to the weeks during which subjects were wearing Testoderm-TIS delivering 2.4 mg/ day or Testoderm-TIS delivering 3.6 mg per day. The dose of testosterone delivered over the 22 h of wearing on the day of measurement was estimated from residual hormone in used systems compared with the contents of unused systems (right ordinate)

9 Transdermal testosterone replacement through genital skin Twelve-week study (Study B) Figure 2 shows the protocol and testosterone results for 42 subjects who wore placebo systems for one week, and then Testoderm-ITS 2.4 mg for four weeks followed by Testoderm-TTS 3.6 mg for another eight weeks. Peak plasma testosterone levels increased steadily during the first three weeks of exposure. By week 4 a steady-state was reached with no difference between week 3 and 4 mean peak serum testosterone. The steady state levels of testosterone (Cnax) produced by Testoderm-ITS 3.6 mg (weeks 5-12) were significantly higher than the levels obtained by the smaller system (2.4 mg/ day) during week 4 (p <.1). In 54 subjects in this study estradiol levels increased from a baseline value of approximately 4 pmolll to 6 pmolll 12 weeks later (p <.1), remaining in the normal range for men. Table 3. Total and bioavailable hormone and hormone binding globulin levels of28 patients using Testoderm systems (Mean ± SE (Range) Normal range Total testosterone, nmolll Baseline: 3.59±.6 Dose 1: 1.1 ± 1.2 Dose 2: 14.4 ± 1.4 Bioavailable testosterone, nmolll Baseline: 1. ±.3 Dose 1: Dose 2: 6.9 ±.8 Total dihydrotestosterone, nmolll Baseline:.5 ±.1 Dose 1: 4.9 ±.7 Dose 2: 6.5 ±.7 (.4-1.9) ( ) ( ) (.3-7.1) (.5-9.1) ( ) (.2-2.1) ( ) ( ) nmol/l nmolll nmolll Bioavailable dihydrotestosterone, nmolll Baseline:.1 ±.2 (.3-.4) Dose 1 : 1.4 ±.2 (.4-4.8) Dose 2: 2.1 ±.2 ( ) 3a Androstanediol glucuronide, nmolll Baseline: 45.2 ± 5.2 ( ) Dose 1: ±11.3 ( ) Dose 2: ± 11.2 ( ) Sex hormone binding globulin, nmolll Baseline: 37.5 ± 3.4 ( ) Dose 1: 36.2 ± 3.2 ( ) Dose 2: 32.9 ± 2.8 ( ) (not known) nmolll 1-73 nmolll These assays were performed at Core Endocrine Laboratories, Hershey, PA. Dose 1 =2.4 mg/day; Dose 2=3.6 mg/day. In all cases the levels on Dose 1 and Dose 2 were significantly (p <.D1) above baseline hypogonadal values except for SHBG.

10 174 Virgil A. Place et al. Table 3 shows the serum values from 28 patients of total testosterone, bioavailable testosterone, total DHT, bioavailable DHT, 3a androstanediol glucuronide (3a Adiol-G) and SHBG found during weeks 3-4 on Testoderm-TTS 2.4 mg and during weeks on Testoderm-TTS 3.6 mg in this study. Normal ranges for the assays used in Core Endocrine Laboratories are presented for comparison. The averaged data show that total testosterone, bioavailable testosterone and 3a Adiol-G all reached the normal range. At dose 2 the group average total DHT levels exceeded the normal range. 3.4 Subjective reports Figure 3 shows the weekly mean change over baseline for mood and energy according to self-assessment during 12 weeks of therapy on Testoderm-TTS. Changes are plotted against the values for total peak testosterone concentration achieved during the therapy. Figure 4 shows similar data for sexual responses consisting of waking erections or spontaneous erections noted by the subjects themselves. The subjective improvements increased with duration of exposure to testosterone replacement up to four weeks and were statistically significant (p <.1). They were maintained through the 12-week study. 3.5 Extended use study (Study C) We report serum levels of testosterone, DHT, the ratio of testosterone and DHT and estradiol after 3, 15 and 27 months in a cohort of 48 patients continuing on.6 Q) c: ; <J>. '" E.g Q) '" c: : '" u c: Q) '" ::::! Energy Mood Treatment week Testosterone (nmol/l) Fig. 3. Mean changes from baseline week in self-ratings of mood and energy levels (scale of to 4, low to high) plotted against peak total serum values of testosterone for each week of active Testoderm-lTS therapy. Note that most of the changes were accomplished within the first month of wearing the system

11 Transdermal testosterone replacement through genital skin 175 3, 2.5 Waking erections Spontaneous erections 1.2",12 Treatment week '" ~ (/) C (l) > ~ (l) (/) '" ~ u c c (l) '" ~ 2, 1,5 1,,5 o Testosterone (n mol/ l) Fig.4. Changes in sexual responses during 12 weeks of therapy with Testoderm-TTS. Note that most of the effects were achieved by the end of the first month of wearing the systems 2 A c :::: ~ 15 c '" ;;; '" '" 2 ' " e c: 1 e c: ;;; 5 ~ f- lo f- B 7 D :::- 6 ' ::: E 1 ' 5 * =- " ~ 4 <: a:; 'in 5 ii 'in 'in UJ 2 '" u >- J::. 3 is 27 cs MOnlhS of realm n Fig. 5. Mean values for a cohort of 48 subjects for testosterone (A). DHT (B). the ratio oftestosterone and DHT (C) and estradiol (D) at 3,15 and 27 months of treatment "

12 176 Virgil A. Place et al. Table 4. Fraction of patients using Testoderm testosterone transdermal systems achieving nor mal testosterone and total androgen concentrations Mean serum level (nmol/i) 12-week study (study B) No. patients/total Extended use study (study C) No. patients/total Total testosterone ~ <1 Fraction % Fraction % 35/ / Total androgens (total testosterone + total DHT) ~ < / / Testoderm trans dermal testosterone replacement. Steady state plasma levels of the three hormones are reached by the fourth week (not shown) of daily application of Testoderm-TTS 3.6 mg. The levels of testosterone and estradiol remain unchanged at 3, 15 and 27 months (Fig.S). Dihydrotestosterone concentrations tended to decrease during the second year of use with the ratio of testosterone and DHT increasing concomitantly. Table 4 presents the fraction of patients achieving normal testosterone and total androgen concentrations. The treatment brought the mean total androgen (testosterone + DHT) levels into normal ranges in 8% of the patients at 3 months and one year. Ten subjects have worn the systems for 2 years, 9 for 3 years, and 46 men have completed their fourth year or more. 3.6 Effects of androgen replacement by Testoderm-ITS on gonadotropin levels Serum LH concentrations in 36 subjects with primary hypogonadism were obtained. In 16 of the 36 patients elevated LH levels declined to normal during the first year of treatment. In the remaining subjects LH decreased from initially elevated levels, though not to normal. FSH levels were usually unchanged but in a few patients fell to the normal range. The mean serum testosterone levels in those patients initially hypergonadotropic who showed a return of LH levels to normal (51 miu/ml) was greater than 17 nmolll Blood chemistries Mean values for serum electrolytes, prostatic acid phosphatase, and hepatic function tests, urinalyses and hematology were within normal ranges both at baseline and after continued wearing of Testoderm-TTS 3.6 mg for 27 months or more. Average nonfasting values for serum cholesterol, HDL-cholesterol, and LDL-cholesterol were within normal ranges both at baseline and during sustained therapy. Mean triglycerides were high (non-fasting blood samples) and did not change significantly during the study. Mean concentrations of choles-

13 Transdermal testosterone replacement through genital skin c: " 'a; ~ E 2 _ :::: 5 E 5 Cl.E ~ 2-,S 1...J 4 4 Q; I >-... iii 3 -- Q) '(ij ct> 3 Ciii Q;.s:: ~:!!.5 iii e.> 2 Q) 2.t:;.s:: C;; me.>.s:: 1 I 1 I- A B C Months of trea tment Fig. 6. Mean values for a cohort of 48 subjects for total cholesterol (AJ. high density lipoprotein cholesterol (HDL) (B) and the ratio of cholesterol and HDL (C) at 3, 15 and 27 months of treatment terol, HDL and LDL for the group declined significantly (p <.1) during the first 12 months of therapy (11 %, 15%, and 13%, respectively) and remained unchanged thereafter, in a cohort of 48 men through 27 months (Fig. 6). A 53 year old man who had been hypo gonadal for three years following surgical removal of a prolactinoma was found to have benign prostatic hyperplasia (BPH) 16 months after the start of therapy which was interrupted for 1 months. No other cases of BPH nor any cases of prostatic cancer were observed during the study. 4 Discussion The testosterone-containing transdermal systems used in the present studies were designed to deliver physiologic amounts of the natural androgen testosterone in a pattern that would produce a peak 3-5 h after application, with elevated, but gradually declining levels for the rest of the 24 h period. Blood levels of testosterone in many normal young adult males have a diurnal pattern (Marrama 1982 ; Leymarie et al. 1974; Nieschlag 1974; Bremner et al. 1983). Some data suggest that the total blood testosterone levels decline with aging in normal men, particularly through loss of the morning peak (Bremner et al. 1983). The 24 h patterns at all ages exhibit substantial inter- and intra-subject variation both in the peak levels achieved and the timing of the peak (Spratt et al ; Bremner et al. 1983). DHT levels were elevated to approximately three times the normal average during therapy with Testoderm systems presumably because of 5-a reduction of testosterone during transit through scrotal skin (Kuttenn et al. 198), although we did not test that assumption. Because DHT itself is an active androgen within many cells, it is likely that the elevated DHT levels associated with Testoderm therapy contributes to the overall androgen replacement. There are no known adverse side effects of elevated DHT itself, at these levels in plasma. Testosterone is the primary endogenous androgen secreted by the human testis, but in many secondary sex tissues, the activity of testosterone seems to depend on local tissue

14 178 Virgil A. Place et al. conversion to DHT by 5-a reductase. Testosterone and DHT circulate partly bound to the hepatic protein SHBG. Albumin also binds these two hormones but more loosely. Most current evidence suggests that the unbound and albuminbound testosterone are available to target cells by simple diffusion. DHT is more tightly bound than testosterone to SHBG and can displace testosterone from SHBG. In our study the ratio of bioavailable testosterone to total testosterone was.68 in the presence of elevated DHT, in comparison to the ratio ofbioavailable testosterone/total testosterone of.56 at lower, normal DHT levels. The elevated DHTis apparently displacing greater quantities of testosterone from the SHBG, making the testosterone more bioavailable. Very little of the.5 mg DHT typically cleared per 24 h is believed to become available to target cells. Our finding that 3a Adiol-G was in the normal range despite elevated serum DHT agrees with this concept and indicates that the abnormally high DHT is not extensively metabolized in peripheral target tissues. In addition, we have not observed any unusual clinical signs of androgen excess such as hirsutism or acne. Once in the cell nucleus, testosterone- or DHT-receptor complex initiates transcription events and cellular changes related to androgen activity. Despite the importance of DHT as an androgen, not all target tissues require the conversion of testosterone to DHT; in some cases, testosterone itself(or other active testosterone metabolites) may be sufficient for the full expression of the androgenic response. The single case of benign prostatic hyperplasia we observed is not unusual for a patient in that age group who recently became hypogonadal. There are few studies in the literature citing the incidence of prostatic problems with androgen replacement therapy although they are believed to be uncommon. However, BPH and/or prostatic cancer may occur (Jackson et al. 1989) and physicians should take precautions to exclude prostatic disease initially and schedule periodic examinations whenever prescribing such therapy. Hypogonadism in men may be primary or secondary, according to whether the defect in androgen production is in the testis or the hypothalamic-pituitary system. Hypogonadism in men with levels of testosterone below 1 nmolll requires replacement therapy to sustain bone mineral density, muscle mass, sexual activity, and acceptably normal mood and vigor. Currently available therapies for androgen replacement in male hypogonadism are not satisfactory, as noted before. The performance of the new trans dermal therapeutic system, Testoderm-TTS for the administration of physiologic quantities of the natural hormone testosterone for androgen replacement in male hypogonadism was designed to provide greater convenience, improved patient compliance, smoother therapy by eliminating overdose/underdose swings of plasma levels, and simulation of a common circadian pattern of androgen levels in blood without raising estradiol levels above the normal range. The data presented in Figures 1 and 5 illustrate that the design objective was achieved. Eighty percent of the hypogonadal subjects treated by our new method had total androgen levels within the normal range. It appears that during the first three to four weeks of wearing a Testoderm system the flux of testosterone from the delivery system through the scrotal skin may increase even though the delivery system parameters are unchanged (see

15 Transdermal testosterone replacement through genital skin 179 Fig.2). We have no explanation for this phenomenon but note that it implies that the clinical efficacy of Testoderm-TIS should not be judged until patients have been using the systems for at least one month, after which time a steady state seems assured. The data in Figures 3 and 4 indicate that during the initial three to four weeks many patients will gain improvements in mood, energy and sexuality that relate directly to the increase in testosterone. These improvements then persist. A possible adverse effect of testosterone replacement with the Testoderm systems was the increase in total cholesterollhdl ratio during the first several weeks of therapy, in spite of a decrease in total cholesterol. During the following two years of therapy, total cholesterol continued to decline slightly, but significantly, but with no further decrease in HDL concentrations. Because of the suspected relationship between serum lipids and coronary heart disease, the trend of a decrease in HDL and cholesterol is of particular interest. The magnitude of mean changes in serum cholesterol, HDL and LDL observed in our studies is consistent with that reported for use of testosterone ester injections as replacement therapy (Godsland et al. 1987). In their review, Godsland et al. (1987) concluded that "the role of sex hormones in the normal metabolism of plasma lipoproteins remains uncertain." The Testoderm systems were well tolerated, as judged by the low incidence of local skin irritation. In over 9, patient-days of chronic daily wearing no patient discontinued because of local intolerance. We believe the data reported here show that testosterone replacement in hypogonadal males using a transdermal scrotal route provides a circadian rhythm in testosterone and is safe and effective. It is physiologically superior to intramuscular injection and oral therapy because it avoids the overdose/underdose variations and the mood swings associated with injections and provides greater efficacy with fewer side effects than oral preparations. Acknowledgements. These studies were funded by the ALZA Corporation and carried out at 14 locations. We thank the chief investigators and their associates at each clinic, listed below, for their participation: Peter J.Snyder, M.D. Joann Findlay, M. D. Glenn R.Cunningham, M.D. Ronald Swerdloff, M. D. Shalender Bhasin, M. D. Eberhard Nieschlag, M. D. Richard Santen, M. D. Andrea Manni, M. D. Rafeeq S. Ahmed, M. D. Stanley G. Korenman, M. D. Ronald M. Krauss, M. D. Thomas Musliner, M. D. University of Pennsylvania, Philadelphia, PA Veterans Administration Medical Center, Houston, TX Harbor-UCLA Medical Center, Torrance, CA Max Planck Clinical Research Unit for Reproductive Medicine, Miinster, Federal Republic of Germany Pennsylvania State University, Hershey, PA Veterans Administration Medical Center, Sepulveda, CA Alta Bates Hospital, Berkeley, CA

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