| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Endocrinology and Medicine, University of Manchester, Hope Hospital (H.M.B., W.R.R.), Salford, United Kingdom M6 8HD; and Manchester Royal Infirmary (F.C.W.W.), Manchester, United Kingdom M13 9PL
Address all correspondence and requests for reprints to: Dr. H. M. Buckler, Department of Endocrinology and Medicine, University of Manchester, Hope Hospital, Eccles Old Road, Salford, United Kingdom M6 8HD.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
T in the premenopausal woman is secreted directly by the ovaries and is converted peripherally from androstenedione in approximately equal proportions. The menopause is associated with a decline in circulating estrogen levels and a decrease in androstenedione levels due to a fall in ovarian production (9, 10, 11). Although postmenopausal ovarian secretion of T can be similar to that in younger women (11), the overall blood production rate and circulating T levels may fall during and after the menopausal transition (10, 11, 12, 13, 14, 15) as a result of the decline in peripheral conversion from its major precursor, androstenedione. However, it also appears as if a fall in T production may precede the menopause as a decrease in premenopausal women has been described such that T levels in women in their forties have been found to be around 50% lower than those in their twenties (16, 17).
Other adrenal androgens, dehydroepiandrosterone and dehydroepiandrosterone sulfate, also decrease with age, but this process appears to be independent of the menopausal transition (18).
Thus, although the postmenopausal ovary remains an important source of T secretion, a decline in total circulating T can occur with age and results from a combination of ovarian failure, decreasing adrenal secretion, and peripheral conversion. This relative androgen deficiency is much more pronounced in women who have undergone bilateral oophorectomy, with serum T falling by 50% (19).
The relative androgen deficiency state in postmenopausal and ovariectomized women may be associated with a reduction in quality of life and sexual dysfunction (5, 6), and there is increasing awareness that androgens may be of therapeutic value in postmenopausal women in whom low doses of androgens are being increasingly used with estrogen for the treatment of loss of libido (7). Androgens may also have a potential therapeutic role in the treatment of postmenopausal osteoporosis and fracture prevention (8).
However, all the currently marketed androgen preparations are designed for replacement therapy for male hypogonadism, and there is currently no information concerning the most appropriate dose or the optimal mode or route of T delivery in women. Low doses of sc T implants have been used successfully in women for the treatment of postmenopausal sexual dysfunction (7) when 100-mg implants were used, which represents a daily delivery rate of around 1 mg T/24 h.
We have therefore carried out a pharmacokinetic study on the two existing T preparations [oral T undecanoate (TU) and sc T pellets] using lower doses than that available for the treatment of male hypogonadism. In addition, these were compared with a new matrix transdermal delivery system for T in an attempt to achieve more physiological and stable levels suitable for androgen therapy in women.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The three delivery systems for T in women were investigated in separate studies, each of which was granted ethical approval by the Salford and Trafford ethical committee.
Study 1: TU. Ten healthy postmenopausal women receiving estrogen hormone replacement therapy [50-mg estradiol (E2) sc implants; mean ± SD age, 55.2 ± 2.6 yr;, mean body mass index (BMI), 24.1 ± 2.1kgs/m2] who had never previously received androgen therapy were included. Three different doses of oral TU were investigated in the same subjects at least 1 month apart: 1) 40 mg TU at 0 h, 2) 20 mg TU at 0 and 6 h, and 3) 10 mg TU at 0 and 6 h; these were administered with a standard meal (15 g fat). Blood samples were obtained twice before and then hourly for 12 h after TU treatment.
Study 2: sc T pellets. Thirty women (mean age, 53.1 ± 3.2 yr; BMI, 23.9 ± 1.7 kg/m2) receiving sc E2 therapy for menopausal symptoms but who had continued to complain of low libido or reduced feelings of well-being were studied. E2 therapy used 50-mg E2 implants (Organon Laboratories, UK) implanted sc in the lower abdominal wall and monitored as previously described (20). No woman had previously received androgen therapy. They were randomized in a double blind fashion to receive a either a 100-mg T pellet (n = 15) or a placebo pellet (n = 15) implanted sc at the same time as their next E2 implant. Serum T levels were measured before the implant on two occasions and monthly for 6 months.
Study 3: transdermal T. Six healthy female volunteers with regular menstrual cycles (mean age, 33.4 ± 2.1 yr; mean BMI, 23.2 ± 1.9 kg/m2) took part in all four parts of the study to assess the pharmacokinetics of a novel matrix transdermal delivery system (Ethical Pharmaceuticals, UK) for T in women. All were using nonhormonal contraception. All transdermal patches were applied to the lower anterior abdominal wall. Patches containing three different estimated T delivery rates were examined: 840, 1100, and 3000 µg T/24 h for transdermal patch 1 (TD1), TD2, and TD3, respectively. The study was conducted in four parts as outlined below.
1) TD1 or TD2 patches were applied to the patient at 0800 h, and a blood sample was taken immediately before this. The patches were left on for 24 h, and blood was taken hourly for 8 h after the application and then every 4 h until the patch was removed. Additional samples were then taken hourly for the next 8 h and at 4-h intervals for the following 48 h.
2) TD2 was applied on day 1 and left in situ for 7 days before removal. T levels were measured before the attachment of the patch and twice daily for 10 days at 0800 and 2000 h.
3) This study was performed to monitor circulating levels of T and attainment of a steady state during multiple twice weekly applications of TD2. The TD2 patch was applied to the anterior wall at 0800 h on day 1 (Tuesday), removed at 0800 h an day 4 (Friday), and replaced by a new patch. This weekly cycle of patch changes on Tuesday and Friday was repeated for a total of 4 weeks so that a new patch was applied on days 1, 4, 8, 11, 15, 18, 22, and 25. Samples were obtained immediately before application of the patch and 24 h after a new patch was applied. The final patch was applied on day 25 and removed on day 29, and samples were taken twice weekly until day 39.
4) This study was similar to study 3, except the patch used was TD3.
RIAs
T. The T concentration in plasma samples were measured by in-house RIA after diethyl ether extraction. The limit of detection of the assay is 0.5 nmol/L, and intraassay (n = >200 samples) and interassay (n = 20 assays) coefficients of variation over the range 0.5–35 nmol/L are less than 6 and less than 10%, respectively. Cross-reactivities with dihydrotestosterone and TU are less than 4 and less than 0.02%, respectively.
Statistical analysis
Data are presented as the mean ± SD or as the median and range as appropriate and were analyzed using the Mann-Whitney U test and Student’s t test as applicable.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A median peak T level of 18.0 nmol/L (range, 5.8–64.0 nmol/L;
normal range, 0.0–2.4 nmol/L) was achieved at 2.8 ± 0.7 h
(mean ± SD) after the ingestion of a single 40-mg
capsule. T levels remained elevated for 10.0 ± 0.8 h
(P < 0.01), falling back to baseline by 12 h
(Fig. 1
).
|
T levels rose to a median of 9.8 (range, 8.1–22.7 nmol/L) at 3.0 ± 0.4 h after the ingestion of 10 mg TU. With the second 10-mg dose, T levels increased to a median of 12.1 (range, 7.8–28.7 nmol/L) 4.0 ± 0.3 h postingestion and remained elevated at 7.5 (range, 2.5–28.7 nmol/L; P < 0.001) after 12 h. There was no difference in the peak T levels between the 20- and 10-mg doses.
The absorption pattern for TU varied considerably within subject, such
that peak T levels were greater in some subjects after a 20-mg dose
compared to those after a 40-mg capsule (Fig. 2).
|
Preimplant T levels were similar in both groups (T implant group,
1.5 ± 0.3 nmol/L; placebo group, 1.4 ± 0.5; mean ±
SD). T levels reached peak values (8.9 ± 1.7 nmol/L;
Fig. 3) 1 month after pellet implantation
and then declined to 2.9 ± 0.4 nmol/L at 6 months, which was
still significantly higher than the baseline (P <
0.01).
|
T levels rose rapidly (within 6 h) after application of TD1
and TD2 and remained relatively constant. Peaks of 3.2 ± 1.0 and
4.1 ± 1.6 nmol/L (mean ± SD), respectively, at
24 h were seen (Fig. 4). The T
concentration fell to baseline levels within 6 h after patch
removal.
|
). Basal levels
were reached 2 days after patch removal.
During the twice weekly application of TD2, T levels rose briskly after
application of the first patch and remained elevated (P
< 0.01) throughout the study. There was no progressive increase in the
plasma T concentration with continued twice weekly transdermal T
treatment (Fig. 5a). The peak (24 h
post-TD application; 4.2 ± 0.3 nmol) and the trough (immediately
before the next TD application; mean trough level, 3.2 ± 0.3
nmol/L) levels were stable throughout the treatment period. Peak T
levels were consistently higher than the troughs (P <
0.01).
|
), a pattern similar to
that with TD2 was seen. Mean peak and trough levels (7.5 ± 0.9
and 4.0 ± 0.4 nmol/L, respectively) were significantly different
(P < 0.01) throughout.
The terminal half-life, mean retention time, maximum serum
concentration, time to reach maximum serum levels, and area under the
concentration vs. time curve for single dose application of
TD1 and TD2 are shown in Table 1. Table 2 shows the maximum serum
concentration, C-min, area under the concentration vs. time
curve, time to reach maximum serum levels, and peak trough fluctuation
for the multiple dose studies (TD2 and TD3).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
An orally active preparation of T (TU) may be a more suitable as well as a more convenient method of administering androgens to women. TU is widely used for androgen replacement in hypogonadal men in some countries in recommended doses of 40 mg, three or four times daily. Our study of androgen replacement in women examined the pharmacokinetics of lower doses (10–40 mg) of TU. Despite this dose reduction the present results show that oral TU produced inappropriately high T levels at all doses examined. A wide individual variation in T levels was also apparent between subjects. This suggests that TU is unpredictably absorbed in women as it is in men (peak concentrations of 11.5–60.1 nmol/L with a dose of 80 mg twice daily) (22) and adolescent boys (23).
Subcutaneous T implants have been available for the treatment of male hypogonadism for many years. They do not produce short-lived high T peaks, but result in more stable T levels over reasonable periods of time (24, 25). Low doses of sc T implants have been used in women for the treatment of postmenopausal sexual dysfunction (7, 8, 26). Thomm et al. (26) showed a 5-fold increase in plasma T levels after a 100-mg T implant, with peak levels occurring at 1–2 months with a return to pretreatment levels by 5 months, representing an initial daily delivery rate of around 1 mg T/24 h. Further studies showed that 100- and 50-mg T implants produce peak T levels of 6.7 (7) and 3.5 nmol/L (8), respectively, at 1 month. Our study using 100-mg T implants gave rise to peak T levels of 8.9 nmol/L 1 month after insertion followed by a gradual fall. Thus, although sc T treatment appears to be clinically effective (7, 8), the T levels achieved are high and are characterized by substantial rises and falls over several months.
In an attempt to produce a controlled release preparation that can deliver stable and physiological T levels in postmenopausal women, we have investigated a novel matrix transdermal drug delivery system that offers several advantages, including rapid perfusion through the skin, painless delivery, increased compliance, and avoidance of the first pass hepatic metabolism. The systems were applied only to a single site, the anterior abdominal wall. Potential differences in drug delivery characteristics with different sites were not investigated.
It is not known what target levels of T are required to restore sexual
function and well-being, and preserve bone mass in postmenopausal
women. We have empirically based our studies on 100-mg T sc implants
that initially delivered about 1 mg T/24 h (26), giving rise to mean
level of approximately 4.0 nmol/L in postmenopausal women over the
6-month period. The new matrix transdermal delivery systems were
therefore designed for delivering around 1 mg T/24 h and producing
similar circulating levels of steroid, and this was achieved with the
TD2 patch (1100 µg/24 h). Similar levels were produced after twice
weekly application of this patch over a 4-week period (mean peak and
trough levels of 4.0 and 3.2 nmol/L). It has also been reported that a
50-mg sc T implant (delivering a mean T level of 
3.5 nmol/L) also
improves sexual dysfunction in postmenopausal women (8); thus, TD1 (840
µg/24 h) may also be suitable, as we achieved similar levels of T
with this patch. The TD3 patch (3000 µg/24 h) produced T levels
similar to those seen in the first month after insertion of a 100-mg T
implant (8.9 nmol/L in the present study). The overall production rate
of T in women falls from around 250 µg/24 h premenopausally to 180
µg/24 h postmenopausally (11). The levels achieved in this study are
much higher than the normal female physiological range and could lead
to virilization with prolonged use. TD3 is therefore unsuitable for
women, but it may have a potential role in the treatment of men with
low levels of T.
These preliminary data show that the transdermal route can be used successfully to generate stable levels of T in women for hormone replacement with twice weekly applications. Further investigation is required to determine the optimal delivery rate dose and dosing frequency suitable for clinical use in women of this novel transdermal delivery system.
We conclude that the established methods of delivering T have a variety of drawbacks when used in women, and that the new matrix delivery system represents a major advance in androgen therapy with a number of advantages particularly suited for clinical use in women. It produces and maintains stable T levels within narrow ranges with little within- and between-subject variation, is easy to use and remove, requires no nursing or medical staff to administer, and is well tolerated. This technology opens the way to controlled studies on the value of androgen therapy for postmenopausal women, will allow the best therapeutic range to be established, and provides a highly controllable way of treating women with T in a far more physiological manner than is possible with existing methods.
|
Footnotes |
|---|
Received March 16, 1998.
Revised August 5, 1998.
Accepted August 11, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  F. Fabregues, J. Penarrubia, M. Creus, D. Manau, G. Casals, F. Carmona, and J. Balasch Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial Hum. Reprod., December 3, 2008; (2008) den428v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Balasch, F. Fabregues, J. Penarrubia, F. Carmona, R. Casamitjana, M. Creus, D. Manau, G. Casals, and J. A. Vanrell Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH Hum. Reprod., July 1, 2006; 21(7): 1884 - 1893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Arlt Androgen therapy in women Eur. J. Endocrinol., January 1, 2006; 154(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.M. Rivera-Woll, M. Papalia, S.R. Davis, and H.G. Burger Androgen insufficiency in women: diagnostic and therapeutic implications Hum. Reprod. Update, September 1, 2004; 10(5): 421 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Miller Androgen Deficiency in Women J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2395 - 2401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. V. Obiezu, E. J. Giltay, A. Magklara, A. Scorilas, L. J.G. Gooren, H. Yu, D. J.C. Howarth, and E. P. Diamandis Serum and Urinary Prostate-specific Antigen and Urinary Human Glandular Kallikrein Concentrations Are Significantly Increased after Testosterone Administration in Female-to-Male Transsexuals Clin. Chem., June 1, 2000; 46(6): 859 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Davis Androgen Replacement in Women: A Commentary J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1886 - 1891. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) are shown.
