- Email: [email protected]
Sublingual absorption of micronized 17β-estradiol
Sublingual
absorption of micronized
ANDRE
M.
BURNIER,
PURVIS
L.
MARTIN,
17/3-estradiol
M.D. M.D.
SAMUEL
S. C:. YEN,
M.D.
PATRICIA
BROOKS,
R.N.
La Jolla, Cnlifhziu The sublingual absorption rates, the sustained effects, the biologic activity, and the metabolism of micronized 17p-estradiol (E2) were measured in 10 postmenopausal women. E2 (0.5 mg) was administered in a single sublingual dose to five of the patients. An alternate-day schedule with the same dosage was used for the other five patients. In the single-dose study, a twenty-six fold increase in serum E, and a ninefold increase in serum estrone (E,) concentrations were observed 1 hour after the sublingual deposition of E2 (0.5 mg). Serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly decreased within 6 hours. The rise in E2 was early and peaked in the first 2 hours. The rise in E, was slower and progressive, reaching its maximum thirteenfold increase at 4 hours, and remained two and one half times the baseline of 29 pglml at 24 hours, whereas Ez returned to the baseline level of 24 pglml. When micronized E2 was given in a dosage of 0.5 mg subfingually every other night, increased circulating levels of estrogens continued to be elevated at a minimum two and one-half fold baseline level for the week of study. (AM. J. OBSTET. GYNECOL. 140:146, 1991.)
form of i7@-estradiol (E,) in a daily dose of 0.2 mg in a cream vehicle has been shown in recent studies by Martin and associates’ to be more rapidly, completely, and physiologically absorbed from the vagina than from the oral route. Levels of E, in the blood which are normal for the follicular phase of premenopausal women with regular cycles are rapidly reached and sustained by postmenopausal women on daily vaginal estrogen cream therapy, with minimal conversion to estrone (Et). The alternate sublingual route of administration of micronized E, was tried clinically, with good response in the relief of menopausal symptoms, but there is a dearth of information in the literature concerning its absorption by that route. The present report undertakes to fill this gap by determining the rate and the degree of absorption of sublingually administered Ez as indicated by its serum levels, its biologic activity as reflected by suppression of THE
MICRONIZED
From the Department Medicine, University
of Reproductive Medicine, of Califmia, San Diego.
School
Presented $ invitation at the Forty-seventh Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Monterey, California, October 6-1 I, 1980. Reprint requests: Andre M. Burnier, M.D., 550 Washington St., San Diego, California 92039.
146
of
serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and its metabolism as evaluated by its conversion to E,.
Material and methods Ten healthy postmenopausal women between the ages of 55 and 65 volunteered for this study. informed consent was obtained from each woman. All prior estrogen therapy had been withdrawn for a minimum of 1 month. All subjects showed clinical evidence of endogenous estrogen deficiency, all with vaginal atrophy and some with vasomotor flushes that appeared after estrogen therapy was withdrawn. Two groups were formed. The first group of five patients comprised a single-dose study and received 0.5 mg of micronized E, sublingually (one-half tablet of commercially available Estrace 1 mg). The women reported to the menopause clinic at 8 AM on a Monday, had a baseline sample of blood drawn, and were given sublingually a 0.5 mg (one-half) tablet of Ez. Samples of blood were obtained 1, 2, 4, 6, 8, 10, and 24 hours after complete disappearance of the half tablet, and again on days 7, 14, 2 1, and 28. The half tablets of micronized E, were found to dissolve and disappear within 1 to 2 minutes when placed under the tongue. The second group of five patients formed the alternate-day study. The women reported at 8 AM on a OOOZ-9378/81/100146+05$00.50/0
0 1981 The C. V. Mosby
Co.
Volume Number
140 2
Sublingual
absorption
Table I. Serum estrogen and gonadotropin concentrations prior to and after sublingual containing 0.5 mg of micronized l’la-estradiol (0.5 mg Estrace-single-dose study) Estnme*
Pretreatment controls Time posttreatment 1 hr 2 hr 4 hr 6 hr 8 hr 10 hr 24 hr 1 wk 2 wk 3 wk 4 wk
(pglml)
29.0 + 270.4 346.6 384.8 378.0 302.2
5.5
k 78.3t f 93.9t 2 89.9-f
k 73.lt k 37.3t
216.8 2 51.4t 104.2 f 21.lt 30.0 30.6 35.2 36.4
+ f + +
17PEstradioP
5.5 4.7 4.1 5.1
23.4
(pglml)
k
773.6 402.2 133.4 82.0 68.8 47.6 24.4 17.5 16.0 16.2 22.6
5.6
2 289.8$ f 161.1$ zk 30.6t
f
lO.Ot
f f k * f f f
15.41 6.05 2.2 4.1 2.5 2.6 6.5
FSH*
of micronized
absorption
(mIUlm1)
E2
of half a tablet
LH*
(mIUlm1)
92.2 rt 12.3
61.1 f
85.9 2 9.1
50.0 2 13.4$ 52.1 2 19.7
73.5 76.0 65.7 68.9 84.4 82.1 85.7 93.7 90.2 84.8
2
2.9
147
13.3
f 11.4
41.5 f 13.6t
+ 7.08 f 8.45 k 13.9 k 11.4
32.1 + 4.98 43.2 -c 7.2 49.0 2 12.2$ 52.9 " 5.4
+ 10.9
51.7 2 6.9
k 14.4 * 10.7 + 8.5
53.3 f 51.2 2 46.4 +
6.9 9.7 3.9
*Mean f SE. tP < 0.01 (One-tailed t test). $P < 0.05 (One-tailed t test). $P < 0.025 (One-tailed t test). Table II. Serum estrogen and gonadotropin concentrations containing 0.5 mg of micronized 17P-estradiol every other Estrone*
Pretreatment controls Day 1, 12 hr Day 2, 36 hr Day 3, 12 hr Day 4, 36 hr Day 7, 12 hr Day 14, 36 hr Day 21, 12 hr
(pgiml)
17~EstradioP
19.0 + 4.5 192.2 f. 53.9t 52.8 f
prior to and after sublingual absorption evening at 9 PM (0.5 mg Estrace-very
9.6t
169.8 f 40.2t 68.8 + 15.3$ 206.8 zk 49.4$ 56.8 f 14.7t
190.8 + 47.3$
(pglml)
FSH*
(mIUld)
12.4 ? 3.9
108.0 + 4.1
50.4 36.6 29.8 21.0 40.6 16.8 58.6
84.6 102.6 104.3 82.6 96.9 99.8 84.6
2 8.6$ + 18.4 f 6.0 f 6.4 +: 10.88 + 3.2 f 17.50
"
6.3$
+ 19.9 f 19.8 + +2 +
12.00 16.8 20.0 16.5
of half a tablet other day) LH*
(miVld)
73.7 + 11.2 54.5 k 13.49
71.3 + 12.2 76.5 62.7 70.6 64.6 53.7
f 12.7 + 13.68 2 9.2 2 8.2 f 8.5
*Mean 2 SE. tP < 0.025 (One-tailed t test). $P < 0.01 (One-tailed t test). $P < 0.05 (One-tailed t test). Monday for the drawing of baseline samples of blood, and then were sent home after being given a 1 month supply of 0.5 mg of E2 (1 mg scored tablets precut in half), with instructions to place half a tablet under the tongue at 9 PM of that same day, then every other day at 9 PM-continuously for a month. Samples of blood were drawn 12 hours later at 9 AM, and every day at 9 AM for 4 consecutive days, then at weekly intervals on Monday at 9 AM, for 3 more weeks. Serum El, Ez, FSH, and LH were measured by radioimmunoassays.*Gonadotropin values were expressed as mlU/ml. All samples in a serial study were measured in a single assay. The data were analyzed statistically by the Student’s one-tailed t test.
Results Single-dose study. Table I shows the mean levels of circulating El, E2, FSH, and LH; the pretreatment
levels were all in the normal postmenopausal range, with a significantly higher concentration of E, than Ez. After the sublingual absorption of 0.5 mg of micronized Ez, there was a ninefold increase within 1 hour in serum levels of E, and a twenty-six fold increase in the levels of Ez. At 10 hours, the increase was eightfold for E, and only twofold for EP. At 24 hours, the level of E, still showed a significant three and onehalf fold increase, whereas E2 had gone back to the baseline level (Fig. 1). At 1 to 4 weeks, El, Ez, FSH, and LH all were in the pretreatment baseline range. Alternate-day study. Table II shows the mean levels of circulating El, Ez, FSH, and LH. Pretreatment levels were also in the normal postmenopausal range, with higher concentrations of El than Ez. After the alternate-night sublingual absorption of 0.5 mg of micronized El, there was an average tenfold increase within 12 hours in serum levels of El, and a threefold increase in levels of Et, with a corresponding drop in FSH of
148
Burnier et al.
3200
Table III. Effect of sublingual absorption of Ei on cornified vaginal cells (‘% cornified cells, mean ? SE)
3000 2800 2600 2400 2200 2000
Single dose of
0.5mgE,(N = 5) Pretreatment At 28 days
9.6 t 14.50 0
.4ltmkzte-duy dosage
vf
0.5 mg E, (N = 5)
0 53.4
+ “3. I
P < 0.005.
1800 I” f v %
:
1600 1400
1200 1000 800 400 400
200 0
-10
-20 -30 -40
-50 -60
-lWi --e0 2
4
6
8
10 24
liOUftS Fig. 1. Relative changes in serum estrogen and gonadotropin concentrations after the sublingual administration of a single half tablet containing 0.5 mg of micronized 17@-estradiol. 21.6% and LH of 26.0% below baseline. At 36 hours, the average increase was still two and one half fold for E,, but EQ, FSH, and LH dropped only slightly on the average, but not significantly so. In both groups, vaginal smears for maturation index were carried out at the pretreatment visit and again at the last visit (Table III). The single-dose women experienced marked worsening of their vasomotor symptoms, and a decrease in the average number of cornihed cells. In the alternate-day women, symptoms attributable to estrogen dehciency subsided or were markedly ameliorated. By the twenty-eighth day, then vaginal cornihcation had strikingly improved.
Comment The findings of this study demonstrated that micronized Ez was rapidly absorbed from the sublingual mucosa in postmenopausal women, resulting in serum EZ levels which rose to a peak within an hour and then dropped back rapidly to levels close to baseline. In contrast, as the E2 level dropped, the level of E, gradually
and steadily increased, presumably through conversion from E, to E,, reaching a peak at 2 to 4 hours and a sustained, significantly higher level until 24 hours. Thus, serum levels of E, and E2 were reached after sublingual administration of only 0.3 mg of micronized E2 which compared closely with serum levels that followed the oral administration of 2 mg of micronized EP. four times the sublingual dose.” Early studies by Kyan and Engel showed that the small bowel can convert IX2 to E,. Conversion also occurs when E2 is applied sublingually, which suggests that another major pathway for this metabolism also exists, possibly the reticuloendothelial system. since the region of’ the neck is very rich in lymphatic channels and lymphoid tissue. Bypassing of the portal circulation would appear to be a potential advantage of the sublingual route for patients with liver disease. Kecent reports in the literature suggest an occasional link between the prolonged use of oral contraceptives and the development of liver tumors.’ Bypassing the liver should be important if such patients were later to need estrogen therapy. Clinically, sublingual E2 taken in a dose as small as 0.5 mg every other day brought on marked improvrment in vaginal atrophy. with complete reversal of the maturation index to an estrogeni;led pattern. This alternate-day timing was chosen after preliminary clinical trials had shown that it was the minimal amount which still produced an acceptable degree of subjective relief from symptoms attributable to the menopause.’ Yen and associates,” Martin and associates,’ and Schift and associate? have shown that vaginal E2 accomplishes physiologic sustained estrogenization with minimal doses, without a high conversion rate to E,, and for many patients this would seem to be the preferable route of administrat.ion. Nevertheless, a substantial number of patients objects to the messiness of vaginal creams, or to the daily manipulation necessary for insertion of a tablet into the vagina. For them, sublingual micronized E, may well be the alternate method of choice. The significance of this new information is that a 0.3 mg dose of micronized Ez is absorbed quickly and efficiently into the circulation and reaches levels comparable to those with oral administration of a 2 mg
Volume Number
140 2
Sublingual absorption of micronized E2 149
dose. The conversion of E, to E, after sublingual administration is similar to the conversion after oral administration, even though the gastrointestinal tract is bypassed. This differs from vaginal absorption, in which case this major conversion does not take place.
We would like to thank Mr. Daniel W. Williams for the statistical evaluations, Ms. Jill Audad and Mr. William Hopper for their excellent technical assistance, and Ms. Cathie Drew for her administrative assistance.
REFERENCES
1. Martin, P. L., Yen, S. S. C., Burnier, A. M., and Hermann, H.: Systemic absorption and sustained effects of vaginal estrogen creams, J.A.M.A. 242:2699, 1979. 2. Yen. S. S. C.. Llerena. 0.. Little. B.. and Pearson. 0. H.: Disappearance rates of endogenous luteinizing hbrmone and chorionic gonadotropin in man, J. Clin. Endocrinol. Metab. 28: 1763, 1968. 3. Yen, S. S. C., Llerena, L. A., Pearson, 0. H., and Littell, A. S.: Disappearance rates of endogenous follicle-stimulating hormone in serum following surgical hypophysectomy in man, J. Clin.
Endocrinol.
Metab.
30:325,
1970.
4. DeVane, G. W., Czekala, N. M., Judd, H. L., and Yen, S. S. C.: Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease, AM. J. OBSTET. GYNECOL. 121:496, 1975.
Discussion DR. GILBERT A. WEBB, San Francisco, California. This paper is a continuation of a series of papers dealing with the absorption rates, biologic activity, and the metabolism of micronized 17p-estradiol (E2) by these same authors, beginning in 1972. It had been shown that Ez was ineffectual when given orally. However, the first of the series of studies begun in 1972 showed that the micronized preparation allowed effecive absorption and metabolism, and, therefore, relief of associated menopausal symptoms. Since that time, these authors have demonstrated the absorption, sustained effects, and metabolism of Ez in the micronized preparation by vaginal administration. The current paper dealing with the sublingual absorption of Ez has demonstrated some very interesting phenomena. As the authors have pointed out from Ryan’s original work, the intestinal mucosa will convert E2 to El, thus giving a high degree of metabolization of the micronized Ez to estrone (E,) when given orally. However, they demonstrated in the study on vaginal absorption that this did not occur. It has also been shown that, when drugs are administered rectally, they bypass the portal circulation. Therefore, this bypassing of the portal circulation has been postulated to minimize the conversion of vaginally administered Ez to El, since the same circulation patterns exist. In the current study, it was interesting that the sublingual administration of Ez gave a very high initial concentration of E$. but that there was conversion by an unknown pathway to El in essentially the same proportion that was observed with oral administration. It will be very interesting to see whether these authors are able to discover how this conversion occurs. They have
Yen, S. S. C., Martin,
P. L., Burnier,
A. M., Dzekala,
N. M.,
Greaney, M. 0.. Jr., and Callantine, M. R.: Circulating
es-
tradiol, estrone and gonadotropin levels following the administration of orally active 17p-estradiol in postmenopausal women, J. Clin. Endocrinol. Metab. 40:518, 1975.
Ryan, K. J.. and Engel, L. L.: The interconversionofestrone and estradiol by human tissue slices, Endocrinology 52:287, 1953. Nissen, E. D., and Kent, D. R.: Liver tumors and oral contraceptives, Obstet. Gynecol. 46:460, 1975. Schiff, I., Tulchinsky, D., and Ryan, K. J.: Vaginal absorption of estrone and 17&estradiol, Fertil. Steril. 28:1063, 1977.
postulated that this may occur in the reticuloendothelial system. It seems unlikely that the blood circulating through the liver would be responsible for the conversion, since the absorption sublingually and vaginally would give the same rate of liver profusion. Thus, a very interesting finding awaits further elucidation. The fact that the sublingual method of absorption yields such good clinical results, as demonstrated in the relief of postmenopausal symptoms, allows one to utilize this method of administration of this hormone if it is necessary to bypass the liver or portal circulation. The speculation has been that the passage of estrogen through the portal circulation with the use of oral contraceptives has possibly contributed to the benign liver tumors observed. It would be interesting to see whether the sublingual administration of oral contraceptives would minimize or prevent that particular problem. One of the most interesting findings was that the authors demonstrated blood levels of both estrone and 17/l-estradiol with the use of a sublingual dose one quarter of the oral dose. This would certainly seem to be a very significant economic advantage, as well as reducing the total dose of estrogens administered to these patients. The relationship between the use of estrogens and the initiation of uterine malignancy has certainly been a subject of considerable discussion. Estrone has been postulated to be the estrogen that predominantly stimulates carcinogenesis. Therefore, advantages supposedly reside in the use of an Ez preparation that is not converted to estrone. The authors demonstrated that this was not feasible with the sublingual method, but that it is feasible with the vaginal method.
150
Burnier et al.
These authors are to be congratulated for their COW tinued interest in a drug which is very usef’ul ill preventing menopausal symptoms and effective in estrogen replacement therapy. It is hoped that they will continue their investigation of the means bp lvhich the body metabolizes E2 to E,. DR. LEO LAGASSE, Los Angeles, Calif’ornia. Any method of’ delivery of estrogenic hormone that would achieve the desired effect with reduced dosage and noi rely upon the liver would seem to be beneficial. Dr. Howard Judd, of our endocrinology division, has stresssed that, it’ one can decrease the’involvement of the liver in hormone metabolism, then some of’ the complications of hormone therapy, such as blood pressure problems. can be avoided. If‘ one can achieve an equivalent ef’f’ect by taking a smaller dose, then the risk-to-benefit ratio would swing in t‘avor of’ benefits. Reduced incidence of osteoporosis, alleviation of’ hot flashes, and the maturation of’ vaginal mucosa, all arc important benefits. Certainly, there are risks. The chief one is the risk of’ endometrial cancer. Between 19’iO and 197.5, the incidence of’ endometrial cancer iticreased by W,, in Caucasian women. There was essentially no increase in incidence during the preceding 50 years. There is no evidence that estrogen-associated endometrial tumors are of’ lower grade, demonstrate less myometrial invasion, are seen with lower stage, and demonstrate a lower death rate. Nevertheless, the large increase in estrogen-associated cases is apparent. There is some evidence that increases in rhe risk of cancer are related to both duration of drug therapy and the dose administered. The lowest effective dose is the best. The suggestion of‘this study that a dose given sublingually is more effective than one given by the oral route, and, therefore. that a smaller dose can be used, is ~~setul
inf’ormation. A large nuniber of women could benellt tram these data. 1%‘~ look forward to laboratory and clinical studies which will explore tltrther this route of estrogen administration. DR. PURVIS MARTIN, San Diego, (;alifijrllia. 1 \\ould like to emphasize some of’ the clinical practicalities of this work. .4r the present time in ww ~~~mop;l~~sc clinic. WC LIW micronized estradiol, or Estracc, in two thirds of our patients. It is more physiologic than other clinicall!~ available estrogens. M’e are using as much vaginal Estrace in tablets as orally. We think that the vaginal route is much more physiologic. The bottom line is. it’ YOU want to bypass the liver. there are two I\-ays to do it \rittl Estracc. Use the 1 mg tablet. which is almost colorless. rather than the 2 m g tablet. which colors clothing blue. Give a half milligram sublingually CYTJ-~ other (lay. and ~OLI will achieve a ver!’ good symptomatic result whiclt IS \‘er)- acceptable to the patients. Or !Y,U GUI give halt ;I milligram of Estracc vaginallp ever) other da\ ~JKI produce the physiologic estrogen lc\el o! ;I prrmenopausal woman, lvithout conversion to cstrone. \Vcbelieve that the tnost physiologic !~-a\ of administering estrogen is vaginally. and this is act-cp~ablc to at least 5% ot the patients. The next most ph\siologic- route is sublingually, with a much lowel- effecti\-c dose than tn the least physiologic route, which is orallv. DR. BURNIER (Closing). In answer tc, Dr. \Veber’s question, the endotnetrium was not tnonitorcd during this stud\-. \l’ith t’egard to the vaginal maturzatioll index. tllere was JIO improvement. as would be cxpec ted. i monrh af’ter a single dose of estrogen: whereas patients who received 0.5 mg of micronized estradiol e\‘rry other clay showed marked improvement in their vaginal atroph\~.
absorption of micronized
ANDRE
M.
BURNIER,
PURVIS
L.
MARTIN,
17/3-estradiol
M.D. M.D.
SAMUEL
S. C:. YEN,
M.D.
PATRICIA
BROOKS,
R.N.
La Jolla, Cnlifhziu The sublingual absorption rates, the sustained effects, the biologic activity, and the metabolism of micronized 17p-estradiol (E2) were measured in 10 postmenopausal women. E2 (0.5 mg) was administered in a single sublingual dose to five of the patients. An alternate-day schedule with the same dosage was used for the other five patients. In the single-dose study, a twenty-six fold increase in serum E, and a ninefold increase in serum estrone (E,) concentrations were observed 1 hour after the sublingual deposition of E2 (0.5 mg). Serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly decreased within 6 hours. The rise in E2 was early and peaked in the first 2 hours. The rise in E, was slower and progressive, reaching its maximum thirteenfold increase at 4 hours, and remained two and one half times the baseline of 29 pglml at 24 hours, whereas Ez returned to the baseline level of 24 pglml. When micronized E2 was given in a dosage of 0.5 mg subfingually every other night, increased circulating levels of estrogens continued to be elevated at a minimum two and one-half fold baseline level for the week of study. (AM. J. OBSTET. GYNECOL. 140:146, 1991.)
form of i7@-estradiol (E,) in a daily dose of 0.2 mg in a cream vehicle has been shown in recent studies by Martin and associates’ to be more rapidly, completely, and physiologically absorbed from the vagina than from the oral route. Levels of E, in the blood which are normal for the follicular phase of premenopausal women with regular cycles are rapidly reached and sustained by postmenopausal women on daily vaginal estrogen cream therapy, with minimal conversion to estrone (Et). The alternate sublingual route of administration of micronized E, was tried clinically, with good response in the relief of menopausal symptoms, but there is a dearth of information in the literature concerning its absorption by that route. The present report undertakes to fill this gap by determining the rate and the degree of absorption of sublingually administered Ez as indicated by its serum levels, its biologic activity as reflected by suppression of THE
MICRONIZED
From the Department Medicine, University
of Reproductive Medicine, of Califmia, San Diego.
School
Presented $ invitation at the Forty-seventh Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Monterey, California, October 6-1 I, 1980. Reprint requests: Andre M. Burnier, M.D., 550 Washington St., San Diego, California 92039.
146
of
serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and its metabolism as evaluated by its conversion to E,.
Material and methods Ten healthy postmenopausal women between the ages of 55 and 65 volunteered for this study. informed consent was obtained from each woman. All prior estrogen therapy had been withdrawn for a minimum of 1 month. All subjects showed clinical evidence of endogenous estrogen deficiency, all with vaginal atrophy and some with vasomotor flushes that appeared after estrogen therapy was withdrawn. Two groups were formed. The first group of five patients comprised a single-dose study and received 0.5 mg of micronized E, sublingually (one-half tablet of commercially available Estrace 1 mg). The women reported to the menopause clinic at 8 AM on a Monday, had a baseline sample of blood drawn, and were given sublingually a 0.5 mg (one-half) tablet of Ez. Samples of blood were obtained 1, 2, 4, 6, 8, 10, and 24 hours after complete disappearance of the half tablet, and again on days 7, 14, 2 1, and 28. The half tablets of micronized E, were found to dissolve and disappear within 1 to 2 minutes when placed under the tongue. The second group of five patients formed the alternate-day study. The women reported at 8 AM on a OOOZ-9378/81/100146+05$00.50/0
0 1981 The C. V. Mosby
Co.
Volume Number
140 2
Sublingual
absorption
Table I. Serum estrogen and gonadotropin concentrations prior to and after sublingual containing 0.5 mg of micronized l’la-estradiol (0.5 mg Estrace-single-dose study) Estnme*
Pretreatment controls Time posttreatment 1 hr 2 hr 4 hr 6 hr 8 hr 10 hr 24 hr 1 wk 2 wk 3 wk 4 wk
(pglml)
29.0 + 270.4 346.6 384.8 378.0 302.2
5.5
k 78.3t f 93.9t 2 89.9-f
k 73.lt k 37.3t
216.8 2 51.4t 104.2 f 21.lt 30.0 30.6 35.2 36.4
+ f + +
17PEstradioP
5.5 4.7 4.1 5.1
23.4
(pglml)
k
773.6 402.2 133.4 82.0 68.8 47.6 24.4 17.5 16.0 16.2 22.6
5.6
2 289.8$ f 161.1$ zk 30.6t
f
lO.Ot
f f k * f f f
15.41 6.05 2.2 4.1 2.5 2.6 6.5
FSH*
of micronized
absorption
(mIUlm1)
E2
of half a tablet
LH*
(mIUlm1)
92.2 rt 12.3
61.1 f
85.9 2 9.1
50.0 2 13.4$ 52.1 2 19.7
73.5 76.0 65.7 68.9 84.4 82.1 85.7 93.7 90.2 84.8
2
2.9
147
13.3
f 11.4
41.5 f 13.6t
+ 7.08 f 8.45 k 13.9 k 11.4
32.1 + 4.98 43.2 -c 7.2 49.0 2 12.2$ 52.9 " 5.4
+ 10.9
51.7 2 6.9
k 14.4 * 10.7 + 8.5
53.3 f 51.2 2 46.4 +
6.9 9.7 3.9
*Mean f SE. tP < 0.01 (One-tailed t test). $P < 0.05 (One-tailed t test). $P < 0.025 (One-tailed t test). Table II. Serum estrogen and gonadotropin concentrations containing 0.5 mg of micronized 17P-estradiol every other Estrone*
Pretreatment controls Day 1, 12 hr Day 2, 36 hr Day 3, 12 hr Day 4, 36 hr Day 7, 12 hr Day 14, 36 hr Day 21, 12 hr
(pgiml)
17~EstradioP
19.0 + 4.5 192.2 f. 53.9t 52.8 f
prior to and after sublingual absorption evening at 9 PM (0.5 mg Estrace-very
9.6t
169.8 f 40.2t 68.8 + 15.3$ 206.8 zk 49.4$ 56.8 f 14.7t
190.8 + 47.3$
(pglml)
FSH*
(mIUld)
12.4 ? 3.9
108.0 + 4.1
50.4 36.6 29.8 21.0 40.6 16.8 58.6
84.6 102.6 104.3 82.6 96.9 99.8 84.6
2 8.6$ + 18.4 f 6.0 f 6.4 +: 10.88 + 3.2 f 17.50
"
6.3$
+ 19.9 f 19.8 + +2 +
12.00 16.8 20.0 16.5
of half a tablet other day) LH*
(miVld)
73.7 + 11.2 54.5 k 13.49
71.3 + 12.2 76.5 62.7 70.6 64.6 53.7
f 12.7 + 13.68 2 9.2 2 8.2 f 8.5
*Mean 2 SE. tP < 0.025 (One-tailed t test). $P < 0.01 (One-tailed t test). $P < 0.05 (One-tailed t test). Monday for the drawing of baseline samples of blood, and then were sent home after being given a 1 month supply of 0.5 mg of E2 (1 mg scored tablets precut in half), with instructions to place half a tablet under the tongue at 9 PM of that same day, then every other day at 9 PM-continuously for a month. Samples of blood were drawn 12 hours later at 9 AM, and every day at 9 AM for 4 consecutive days, then at weekly intervals on Monday at 9 AM, for 3 more weeks. Serum El, Ez, FSH, and LH were measured by radioimmunoassays.*Gonadotropin values were expressed as mlU/ml. All samples in a serial study were measured in a single assay. The data were analyzed statistically by the Student’s one-tailed t test.
Results Single-dose study. Table I shows the mean levels of circulating El, E2, FSH, and LH; the pretreatment
levels were all in the normal postmenopausal range, with a significantly higher concentration of E, than Ez. After the sublingual absorption of 0.5 mg of micronized Ez, there was a ninefold increase within 1 hour in serum levels of E, and a twenty-six fold increase in the levels of Ez. At 10 hours, the increase was eightfold for E, and only twofold for EP. At 24 hours, the level of E, still showed a significant three and onehalf fold increase, whereas E2 had gone back to the baseline level (Fig. 1). At 1 to 4 weeks, El, Ez, FSH, and LH all were in the pretreatment baseline range. Alternate-day study. Table II shows the mean levels of circulating El, Ez, FSH, and LH. Pretreatment levels were also in the normal postmenopausal range, with higher concentrations of El than Ez. After the alternate-night sublingual absorption of 0.5 mg of micronized El, there was an average tenfold increase within 12 hours in serum levels of El, and a threefold increase in levels of Et, with a corresponding drop in FSH of
148
Burnier et al.
3200
Table III. Effect of sublingual absorption of Ei on cornified vaginal cells (‘% cornified cells, mean ? SE)
3000 2800 2600 2400 2200 2000
Single dose of
0.5mgE,(N = 5) Pretreatment At 28 days
9.6 t 14.50 0
.4ltmkzte-duy dosage
vf
0.5 mg E, (N = 5)
0 53.4
+ “3. I
P < 0.005.
1800 I” f v %
:
1600 1400
1200 1000 800 400 400
200 0
-10
-20 -30 -40
-50 -60
-lWi --e0 2
4
6
8
10 24
liOUftS Fig. 1. Relative changes in serum estrogen and gonadotropin concentrations after the sublingual administration of a single half tablet containing 0.5 mg of micronized 17@-estradiol. 21.6% and LH of 26.0% below baseline. At 36 hours, the average increase was still two and one half fold for E,, but EQ, FSH, and LH dropped only slightly on the average, but not significantly so. In both groups, vaginal smears for maturation index were carried out at the pretreatment visit and again at the last visit (Table III). The single-dose women experienced marked worsening of their vasomotor symptoms, and a decrease in the average number of cornihed cells. In the alternate-day women, symptoms attributable to estrogen dehciency subsided or were markedly ameliorated. By the twenty-eighth day, then vaginal cornihcation had strikingly improved.
Comment The findings of this study demonstrated that micronized Ez was rapidly absorbed from the sublingual mucosa in postmenopausal women, resulting in serum EZ levels which rose to a peak within an hour and then dropped back rapidly to levels close to baseline. In contrast, as the E2 level dropped, the level of E, gradually
and steadily increased, presumably through conversion from E, to E,, reaching a peak at 2 to 4 hours and a sustained, significantly higher level until 24 hours. Thus, serum levels of E, and E2 were reached after sublingual administration of only 0.3 mg of micronized E2 which compared closely with serum levels that followed the oral administration of 2 mg of micronized EP. four times the sublingual dose.” Early studies by Kyan and Engel showed that the small bowel can convert IX2 to E,. Conversion also occurs when E2 is applied sublingually, which suggests that another major pathway for this metabolism also exists, possibly the reticuloendothelial system. since the region of’ the neck is very rich in lymphatic channels and lymphoid tissue. Bypassing of the portal circulation would appear to be a potential advantage of the sublingual route for patients with liver disease. Kecent reports in the literature suggest an occasional link between the prolonged use of oral contraceptives and the development of liver tumors.’ Bypassing the liver should be important if such patients were later to need estrogen therapy. Clinically, sublingual E2 taken in a dose as small as 0.5 mg every other day brought on marked improvrment in vaginal atrophy. with complete reversal of the maturation index to an estrogeni;led pattern. This alternate-day timing was chosen after preliminary clinical trials had shown that it was the minimal amount which still produced an acceptable degree of subjective relief from symptoms attributable to the menopause.’ Yen and associates,” Martin and associates,’ and Schift and associate? have shown that vaginal E2 accomplishes physiologic sustained estrogenization with minimal doses, without a high conversion rate to E,, and for many patients this would seem to be the preferable route of administrat.ion. Nevertheless, a substantial number of patients objects to the messiness of vaginal creams, or to the daily manipulation necessary for insertion of a tablet into the vagina. For them, sublingual micronized E, may well be the alternate method of choice. The significance of this new information is that a 0.3 mg dose of micronized Ez is absorbed quickly and efficiently into the circulation and reaches levels comparable to those with oral administration of a 2 mg
Volume Number
140 2
Sublingual absorption of micronized E2 149
dose. The conversion of E, to E, after sublingual administration is similar to the conversion after oral administration, even though the gastrointestinal tract is bypassed. This differs from vaginal absorption, in which case this major conversion does not take place.
We would like to thank Mr. Daniel W. Williams for the statistical evaluations, Ms. Jill Audad and Mr. William Hopper for their excellent technical assistance, and Ms. Cathie Drew for her administrative assistance.
REFERENCES
1. Martin, P. L., Yen, S. S. C., Burnier, A. M., and Hermann, H.: Systemic absorption and sustained effects of vaginal estrogen creams, J.A.M.A. 242:2699, 1979. 2. Yen. S. S. C.. Llerena. 0.. Little. B.. and Pearson. 0. H.: Disappearance rates of endogenous luteinizing hbrmone and chorionic gonadotropin in man, J. Clin. Endocrinol. Metab. 28: 1763, 1968. 3. Yen, S. S. C., Llerena, L. A., Pearson, 0. H., and Littell, A. S.: Disappearance rates of endogenous follicle-stimulating hormone in serum following surgical hypophysectomy in man, J. Clin.
Endocrinol.
Metab.
30:325,
1970.
4. DeVane, G. W., Czekala, N. M., Judd, H. L., and Yen, S. S. C.: Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease, AM. J. OBSTET. GYNECOL. 121:496, 1975.
Discussion DR. GILBERT A. WEBB, San Francisco, California. This paper is a continuation of a series of papers dealing with the absorption rates, biologic activity, and the metabolism of micronized 17p-estradiol (E2) by these same authors, beginning in 1972. It had been shown that Ez was ineffectual when given orally. However, the first of the series of studies begun in 1972 showed that the micronized preparation allowed effecive absorption and metabolism, and, therefore, relief of associated menopausal symptoms. Since that time, these authors have demonstrated the absorption, sustained effects, and metabolism of Ez in the micronized preparation by vaginal administration. The current paper dealing with the sublingual absorption of Ez has demonstrated some very interesting phenomena. As the authors have pointed out from Ryan’s original work, the intestinal mucosa will convert E2 to El, thus giving a high degree of metabolization of the micronized Ez to estrone (E,) when given orally. However, they demonstrated in the study on vaginal absorption that this did not occur. It has also been shown that, when drugs are administered rectally, they bypass the portal circulation. Therefore, this bypassing of the portal circulation has been postulated to minimize the conversion of vaginally administered Ez to El, since the same circulation patterns exist. In the current study, it was interesting that the sublingual administration of Ez gave a very high initial concentration of E$. but that there was conversion by an unknown pathway to El in essentially the same proportion that was observed with oral administration. It will be very interesting to see whether these authors are able to discover how this conversion occurs. They have
Yen, S. S. C., Martin,
P. L., Burnier,
A. M., Dzekala,
N. M.,
Greaney, M. 0.. Jr., and Callantine, M. R.: Circulating
es-
tradiol, estrone and gonadotropin levels following the administration of orally active 17p-estradiol in postmenopausal women, J. Clin. Endocrinol. Metab. 40:518, 1975.
Ryan, K. J.. and Engel, L. L.: The interconversionofestrone and estradiol by human tissue slices, Endocrinology 52:287, 1953. Nissen, E. D., and Kent, D. R.: Liver tumors and oral contraceptives, Obstet. Gynecol. 46:460, 1975. Schiff, I., Tulchinsky, D., and Ryan, K. J.: Vaginal absorption of estrone and 17&estradiol, Fertil. Steril. 28:1063, 1977.
postulated that this may occur in the reticuloendothelial system. It seems unlikely that the blood circulating through the liver would be responsible for the conversion, since the absorption sublingually and vaginally would give the same rate of liver profusion. Thus, a very interesting finding awaits further elucidation. The fact that the sublingual method of absorption yields such good clinical results, as demonstrated in the relief of postmenopausal symptoms, allows one to utilize this method of administration of this hormone if it is necessary to bypass the liver or portal circulation. The speculation has been that the passage of estrogen through the portal circulation with the use of oral contraceptives has possibly contributed to the benign liver tumors observed. It would be interesting to see whether the sublingual administration of oral contraceptives would minimize or prevent that particular problem. One of the most interesting findings was that the authors demonstrated blood levels of both estrone and 17/l-estradiol with the use of a sublingual dose one quarter of the oral dose. This would certainly seem to be a very significant economic advantage, as well as reducing the total dose of estrogens administered to these patients. The relationship between the use of estrogens and the initiation of uterine malignancy has certainly been a subject of considerable discussion. Estrone has been postulated to be the estrogen that predominantly stimulates carcinogenesis. Therefore, advantages supposedly reside in the use of an Ez preparation that is not converted to estrone. The authors demonstrated that this was not feasible with the sublingual method, but that it is feasible with the vaginal method.
150
Burnier et al.
These authors are to be congratulated for their COW tinued interest in a drug which is very usef’ul ill preventing menopausal symptoms and effective in estrogen replacement therapy. It is hoped that they will continue their investigation of the means bp lvhich the body metabolizes E2 to E,. DR. LEO LAGASSE, Los Angeles, Calif’ornia. Any method of’ delivery of estrogenic hormone that would achieve the desired effect with reduced dosage and noi rely upon the liver would seem to be beneficial. Dr. Howard Judd, of our endocrinology division, has stresssed that, it’ one can decrease the’involvement of the liver in hormone metabolism, then some of’ the complications of hormone therapy, such as blood pressure problems. can be avoided. If‘ one can achieve an equivalent ef’f’ect by taking a smaller dose, then the risk-to-benefit ratio would swing in t‘avor of’ benefits. Reduced incidence of osteoporosis, alleviation of’ hot flashes, and the maturation of’ vaginal mucosa, all arc important benefits. Certainly, there are risks. The chief one is the risk of’ endometrial cancer. Between 19’iO and 197.5, the incidence of’ endometrial cancer iticreased by W,, in Caucasian women. There was essentially no increase in incidence during the preceding 50 years. There is no evidence that estrogen-associated endometrial tumors are of’ lower grade, demonstrate less myometrial invasion, are seen with lower stage, and demonstrate a lower death rate. Nevertheless, the large increase in estrogen-associated cases is apparent. There is some evidence that increases in rhe risk of cancer are related to both duration of drug therapy and the dose administered. The lowest effective dose is the best. The suggestion of‘this study that a dose given sublingually is more effective than one given by the oral route, and, therefore. that a smaller dose can be used, is ~~setul
inf’ormation. A large nuniber of women could benellt tram these data. 1%‘~ look forward to laboratory and clinical studies which will explore tltrther this route of estrogen administration. DR. PURVIS MARTIN, San Diego, (;alifijrllia. 1 \\ould like to emphasize some of’ the clinical practicalities of this work. .4r the present time in ww ~~~mop;l~~sc clinic. WC LIW micronized estradiol, or Estracc, in two thirds of our patients. It is more physiologic than other clinicall!~ available estrogens. M’e are using as much vaginal Estrace in tablets as orally. We think that the vaginal route is much more physiologic. The bottom line is. it’ YOU want to bypass the liver. there are two I\-ays to do it \rittl Estracc. Use the 1 mg tablet. which is almost colorless. rather than the 2 m g tablet. which colors clothing blue. Give a half milligram sublingually CYTJ-~ other (lay. and ~OLI will achieve a ver!’ good symptomatic result whiclt IS \‘er)- acceptable to the patients. Or !Y,U GUI give halt ;I milligram of Estracc vaginallp ever) other da\ ~JKI produce the physiologic estrogen lc\el o! ;I prrmenopausal woman, lvithout conversion to cstrone. \Vcbelieve that the tnost physiologic !~-a\ of administering estrogen is vaginally. and this is act-cp~ablc to at least 5% ot the patients. The next most ph\siologic- route is sublingually, with a much lowel- effecti\-c dose than tn the least physiologic route, which is orallv. DR. BURNIER (Closing). In answer tc, Dr. \Veber’s question, the endotnetrium was not tnonitorcd during this stud\-. \l’ith t’egard to the vaginal maturzatioll index. tllere was JIO improvement. as would be cxpec ted. i monrh af’ter a single dose of estrogen: whereas patients who received 0.5 mg of micronized estradiol e\‘rry other clay showed marked improvement in their vaginal atroph\~.