Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0352
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3431-3434
Copyright © 2005 by The Endocrine Society
Effects of Oral and Transdermal Estradiol Administration on Levels of Sex Hormone-Binding Globulin in Postmenopausal Women with and without a History of Intrahepatic Cholestasis of Pregnancy
A. Ropponen,
K. Aittomäki,
V. Vihma,
M. J. Tikkanen and
O. Ylikorkala
Departments of Obstetrics and Gynecology (A.R., O.Y.), Clinical Genetics (K.A.), and Medicine (V.V, M.J.T.), Helsinki University Central Hospital, FIN-00029, Helsinki, Finland
Address all correspondence and requests for reprints to: Olavi Ylikorkala, Professor, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HUS, Helsinki, Finland. E-mail: olavi.ylikorkala{at}hus.fi.
 |
Abstract
|
|---|
SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67–171% in the control group, but the response was smaller (42–121%) in the ICP group. Addition of MPA decreased SHBG levels by 14–18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.
|
Introduction
|
|---|
SHBG, THE MOST important transport protein for sex steroids in human plasma (1), is synthesized mainly in the liver (2). Plasma SHBG regulates the bioavailable fraction of steroids and also their access to target cells (3). The gene coding for SHBG resides in chromosome region 17p (4), and at least three variants of the gene have been described. A missense mutation (P156L) in the gene is accompanied by reduced secretion of SHBG, and a single-nucleotide deletion in exon 8 results in a truncated protein, which is not secreted (4). A polymorphic pentanucleotide repeat in the promoter of the SHBG gene influences transcriptional activity (5), which is also controlled by hepatocyte nuclear factor-4 (6). Several other factors affect the synthesis of SHBG, because hypothyroidism, hyperinsulinemia, non-insulin-dependent diabetes mellitus (3), and a hyperandrogenic state (4) are associated with low circulating levels of SHBG.
Levels of SHBG decline after the onset of menopause because of falling levels of estrogens (7). Oral estrogen therapy is accompanied by elevations in SHBG concentrations (2), but transdermal estrogen therapy does not usually affect SHBG levels (2, 8); however, small increases in SHBG levels have also been reported (9). Hormone therapy-induced changes in SHBG concentrations can be of clinical significance, because estrogens not bound to SHBG finally determine the estrogenic effects of a given regimen (2).
Intrahepatic cholestasis of pregnancy (ICP), which complicates approximately one in 100 pregnancies, manifests itself as itching of the skin and elevated levels of bile acids and liver transaminases usually in the third trimester of pregnancy (10). The cause of ICP is unknown, but it often occurs in families. Mutations in the ABCB4 gene encoding a member of the ATP binding cassette (ABC) family of membrane transporters have been identified in a small number of patients with ICP (11). Regardless of the exact molecular mechanism, ICP is considered to be caused by insufficient liver capacity to metabolize the high amounts of placenta-derived sex steroids during pregnancy. Accordingly, ICP disappears soon after delivery, although the increased risk of gallstones suggests a permanent hepatobiliary dysfunction in these women (10, 12). This is also supported by evidence that the use of high-dose oral contraceptives may trigger elevations of liver enzyme activity in these women (13).
No data exist on the circulating levels of SHBG in women with a history of ICP before and during the use of postmenopausal hormone therapy (HT). Therefore, we designed a trial to assess the effects of both oral and transdermal estrogen therapy, with and without progestin, on SHBG in postmenopausal women with and without a history of ICP.
|
Subjects and Methods
|
|---|
With the permission of the local Ethics Committee we enrolled 40 postmenopausal women, of whom 20 had a history of ICP. The volunteers received thorough written and verbal information on the conduct of the study, and informed consent was obtained from all of them. The women were randomized to receive increasing doses (2 mg for 14 d; 4 mg for 14 d) of estradiol (E2) either orally (Progynova, E2 valerate; Schering AG, Berlin, Germany) or transdermally from a patch (50 µg/24 h for 14 d; 100 µg/24 h for 14 d) (FemSeven; Merck KgaA, Darmstadt, Germany). The study was blinded in that during both treatment periods, each woman took both oral tablets (active or placebo) and used patches (placebo or active). After 4 wk use of E2 only, each subject (including the hysterectomized women) took 10 mg of medroxyprogesterone acetate (MPA) (Lutopolar; Orion Pharma, Espoo, Finland) orally for 14 d concomitantly with the highest E2 dose. After a 4-wk washout period, the subjects crossed over to the other treatment. Two women in the ICP group and one in the control group used thyroxine, and these three as well as all the others were clinically euthyroid. The study protocol has been presented in detail before (14).
Serum SHBG concentrations before and after each treatment period were measured by time-resolved fluoroimmunoassay (AutoDELFIA SHBG; Wallac Oy, Turku, Finland). The coefficient of intraassay variation is less than 5%. To minimize the impact of interassay variation, the SHBG assessments were carried out in one assay batch. The levels of liver transaminases and E2 were also determined as described before (14).
Statistical analyses were carried out using SPSS version 11.0. Because we used a crossover design, the possibility of a period effect was tested by using the Mann-Whitney U test, where we compared the differences between the periods in the two groups (those beginning with oral E2 and those beginning with the transdermal treatment). No period effect was detected. The possibility of treatment period interaction was also investigated by means of the Mann-Whitney U test, where we compared the average responses to the two treatments and found them to be the same regardless of the order of treatment. Because of the skewed distribution of SHBG values, the data are expressed as median with 95% confidence intervals (CI) [according to Altman’s Statistics (15)]. To better illustrate the responses of SHBG to HT, we calculated changes in SHBG concentrations from basal to 2, 4, and 6 wk of oral or transdermal treatment. A nonparametric test (Wilcoxon signed-rank test) was used to compare SHBG values at baseline and during follow-up. The Kruskal-Wallis test was used to test changes during E2 treatment among women with a history of ICP vs. controls, when all responses to oral E2 were analyzed together. Correlation analyses were performed using Spearman’s nonparametric correlation coefficient. The level of significance was set at P < 0.05, and two-tailed tests were used.
|
Results
|
|---|
The basal level of SHBG in the ICP group (median, 49.4 nmol/liter; 95% CI, 41.0–69.7) did not differ from that in the control group (median, 50.5 nmol/liter; 95% CI, 42.9–73.7). In the ICP group, SHBG concentrations became elevated during the oral E2 regimen by 42% (2-mg dose) and 121% (4-mg dose) and in the control group, by 67 and 171%, respectively. The addition of MPA was associated with significant falls of 14 and 16% in SHBG concentrations during oral E2 in the ICP and control group, respectively (Table 1
). Transdermal E2 at 100 µg/d raised SHBG levels in the control group (P = 0.02) but not in the ICP group, whereas the addition of MPA reduced SHBG concentrations significantly both in women with and without a history of ICP (Table 1).
View this table:
[in this window]
[in a new window]
|
TABLE 1. Increases of SHBG (nmol/liter) to rising doses of oral and transdermal E2 therapy in postmenopausal women with (n = 20) and without (n = 19) a history of ICP
|
|
There were no relationships between the basal levels of serum E2 and SHBG. However, oral regimen-induced rises in serum E2 and SHBG concentrations correlated positively only in the control group: wk 0–2 (r = 0.66; P = 0.002), wk 0–4 (r = 0.49; P = 0.03), and wk 0–6 (r = 0.51; P = 0.02). In women with a history of ICP, oral regimen-induced rises in serum E2 and SHBG concentrations correlated positively only during wk 0–4 (r = 0.63; P = 0.003).
Increases in SHBG concentrations from baseline to wk 2 and to wk 4 together were significantly lower in the ICP group (median rise in SHBG, 38.2 nmol/liter) than in the control women (median, 59.4 nmol/liter) (P = 0.006), although increases in E2 concentrations did not differ between the groups (Fig. 1).
View larger version (13K):
[in this window]
[in a new window]
|
FIG. 1. The increases (wk 0–2 and 0–4 both) in the levels of serum SHBG and E2 during oral estrogen treatment in women with a history of ICP (r = 0.427; P = 0.006) and in control women (r = 0.464; P = 0.001).
|
|
|
Discussion
|
|---|
Being the most important transport protein of estrogens, SHBG regulates the unbound fraction of estrogen in plasma (1). Because only the free fraction of E2 (approximately 1–2%) binds to estrogen receptors and causes estrogenic effects (2, 3), SHBG is one of the most important regulators of estrogenic effects of a given regimen. It is also known that SHBG has receptors on the cell membrane (16). Endogenous and exogenous (2) estrogens stimulate the synthesis of SHBG in the liver, and therefore there is a possibility that women with a history of ICP, a liver dysfunction appearing during pregnancy, may be characterized by altered synthesis of SHBG. To this end, we designed the present trial on postmenopausal women complaining of hot flashes and other climacteric symptoms, of whom half had suffered from ICP and half had not.
It is clear from the results of our double-blind crossover trial that oral estrogen treatment was accompanied by significant and dose-dependent rises in serum SHBG concentrations. Because this therapy should not affect the metabolic clearance of SHBG, the increase in its circulating levels must reflect stimulated synthesis of SHBG in the liver. No such stimulation of SHBG concentrations was seen during the transdermal regimen, although the circulating levels of E2 increased. It is known that oral estrogen often leads to higher circulating levels of E2, and also to higher levels of estrone in the liver as a result of enterohepatic circulation, than transdermal estrogen regimens, and thus lower levels of intrahepatic estrogen may account for the lack of effect of transdermal estrogen on circulating SHBG concentrations. Almost 80% of bile-excreted estrone is recirculated from the intestine back to the liver, stimulating protein synthesis (2).
Our present data in the control women are in line with previous data (8, 9), but the data from women with ICP are novel. They show that a history of ICP did not affect baseline levels of SHBG, but it blunted the response of SHBG to oral estrogen. This may suggest that these women carry an unknown inborn defect in liver metabolism affecting SHBG synthesis, which becomes manifest during oral estrogen use. This may be a rather specific phenomenon, because the responses of C-reactive protein, another liver-derived protein, to these hormones, showed no difference between these study groups (14). It is possible that some genetic differences in the regulatory region of the SHBG gene may exist in a subset of ICP subjects that limit their response to estrogen (5). In theory, women with a history of ICP may become exposed to higher levels of free estrogen during the use of oral estrogen, and this may have both positive (bone effect) and negative (breast effect, gallstones) consequences. However, our trial was too short to address them, and we should also remember that many of our volunteers with a history of ICP had used oral estrogen without any known untoward effects (14). Of course, we do not know whether prolongation of estrogen treatment would have increased SHBG levels to match those in the control group.
Postmenopausal HT is commonly used in Western countries, and therefore a blunted response of SHBG to oral HT in women with a history of ICP is a significant finding, although only approximately 1% of women suffer from this disease. Low levels of circulating SHBG appear to predict diabetes and cardiovascular diseases (3, 17, 18), and postmenopausal HT, if started soon after the onset of menopause, may still protect against the development of cardiovascular disorders (19), although it failed to do so in the Women’s Health Initiative Study (20). Clearly, an epidemiological study on women with a history of ICP is warranted.
In conclusion, oral but not transdermal estrogen stimulates the synthesis of SHBG in the liver. A history of ICP was not accompanied by any differences in basal levels of serum SHBG, but the increases of SHBG after oral estrogen were blunted in these women.
|
Footnotes
|
|---|
This work was supported by grants from the research funds of the Helsinki University Central Hospital.
First Published Online March 22, 2005
Abbreviations: CI, Confidence interval; E2, estradiol; HT, hormone therapy; ICP, intrahepatic cholestasis of pregnancy; MPA, medroxyprogesterone acetate.
Received February 18, 2005.
Accepted March 10, 2005.
|
References
|
|---|
- Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA 1991 Sex hormone-binding globulin: anatomy and physiology of a new regulatory system. J Steroid Biochem Mol Biol 40:813–820[CrossRef][Medline]
- Samsioe G 2002 The role of ERT/HRT. Best Pract Res Clin Obstet Gynaecol 16:371–381[CrossRef][Medline]
- Pugeat M, Moulin P, Cousin P, Fimbel S, Nicolas MH, Crave JC, Lejeune H 1995 Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk. J Steroid Biochem Mol Biol 53:567–572[CrossRef][Medline]
- Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL 2002 Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest 109:973–981[CrossRef][Medline]
- Hogeveen KN, Talikka M, Hammond GL 2001 Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence. J Biol Chem 276:36383–36390[Abstract/Free Full Text]
- Jänne M, Hammond GL 1998 Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter. J Biol Chem 273:34105–34114[Abstract/Free Full Text]
- Sarrel PM 2002 Androgen deficiency: menopause and estrogen related factors. Fertil Steril 77:S63–67
- Serin IS, Ozcelik B, Basbug M, Aygen E, Kula M, Erez R 2001 Long-term effects of continuous oral and transdermal estrogen replacement therapy on sex hormone binding globulin and free testosterone levels. Eur J Obstet Gynecol Reprod Biol 99:222–225[CrossRef][Medline]
- Kramer GR, Kramer RR, Ogden BW, Kilpatrick RE, Gimpel TL, Castracane VD 2003 Variability of serum estrogens among postmenopausal women treated with the same transdermal estrogen therapy and the effect on androgens and sex hormone binding globulin. Fertil Steril 79:534–542[CrossRef][Medline]
- Lammert F, Marschall HU, Glantz A, Matern S 2000 Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 33:1012–1021[CrossRef][Medline]
- Jacquemin E 2001 Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis 21:551–562[CrossRef][Medline]
- Savander M, Ropponen A, Avela K, Weerasekera N, Cormand B, Hirvioja ML, Riikonen S, Ylikorkala O, Lehesjoki AE, Willamson C, Aittomaki K 2003 Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 52:1025–1029[Abstract/Free Full Text]
- Drill VA 1973 Benign cholestatic jaundice of pregnancy and benign cholestatic jaundice from oral contraceptives. Am J Obstet Gynecol 119:165–174
- Ropponen A, Aittomäki K, Tikkanen M, Ylikorkala O 2005 Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab 90:142–146[Abstract/Free Full Text]
- Altman DY, Machin D 2002 Statistics with confidence. 2nd ed. London: BMJ Books
- Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA 1998 Androgens, estrogens, and second messengers. Steroids 63:278–281[CrossRef][Medline]
- Hajamor S, Despres JP, Couillard C, Lemieux S, Tremblay A, Prud’homme D, Tchernof A 2003 Relationship between sex hormone-binding globulin levels and features of the metabolic syndrome. Metabolism 52:724–730[CrossRef][Medline]
- Golden SH, Maguire A, Ding J, Crouse JR, Cauley JA, Zacur H, Szklo M 2002 Endogenous postmenopausal hormones and carotid atherosclerosis: a case-control study of the atherosclerosis risk in communities cohort. Am J Epidemiol 155:437–444[Abstract/Free Full Text]
- Mikkola T, Clarkson T, Notelowitz M 2004 Postmenopausal hormone therapy before and after the women’s health initiative study: what consequences? Ann Med 36:402–413[CrossRef][Medline]
- Naftolin F, Taylor HS, Karas R, Brinton E, Newman I, Clarkson TB, Mendelsohn M, Lobo RA, Judelson DR, Nachtigall LE, Heward CB, Hecht H, Jaff MR, Harman SM 2004 The Women’s Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril 81:1498–1501[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
L. Ibanez, C. Valls, and F. de Zegher
Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-{alpha} and the neutrophil/lymphocyte ratio
Hum. Reprod.,
February 1, 2006;
21(2):
451 - 456.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
