Changes in serum estrogen levels in women during tamoxifen therapy

doi:10.1016/S0002-9610(97)00072-X

The American Journal of Surgery

Volume 173, Issue 5, May 1997, Pages 399-402

https://doi.org/10.1016/S0002-9610(97)00072-X Get rights and content

Background

Tamoxifen is considered an antiestrogen against breast cancer, yet it has known estrogenic side effects. We hypothesized that long-term administration of tamoxifen may significantly increase circulating estrogen levels in women with breast cancer.

Methods

Serum dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) levels were prospectively measured in 47 breast cancer patients before and during tamoxifen therapy for 2 years. Differences in baseline and peak hormone levels during treatment were compared, and significance was determined by paired Student's t test.

Results

Mean DHEA levels increased by 133% from 61 mg/L to 142 mg/L (P <0.001) and mean E2 levels increased by 239% from 28 pg/mL to 95 pg/mL (P <0.05). Mean E1 levels increased by 264% from 42 pg/mL to 153 pg/mL (P = 0.06).

Conclusions

Long-term tamoxifen therapy can be associated with increased serum levels of DHEA, E1, and E2. Elevated serum estrogens may explain tamoxifen's estrogenic effects and may represent a mechanism for the development of drug resistance.

References (21)

GolderMP et al.
Plasma hormones in patients with advanced breast cancer treated with tamoxifen
Europ J Cancer
(1976)
PommierRF et al.
The mechanism of hormone-sensitive breast cancer progression on antiestrogen therapy
Arch Surg
(1987)
DnistrianAM et al.
Chemohormonal therapy and endocrine function in breast cancer patients
Cancer
(1985)
SzamelI et al.
Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer
Oncology
(1986)
LonningPE et al.
Clinical pharmacokinetics of endocrine agenrs used in advanced breast cancer
Clin Pharmacokinet
(1992)
LoveRL et al.
Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer
NEJM
(1992)
RutqvistLE et al.
Cardiac and thromboembolic morbidity among postmenopausal women with earlystage breast cancer in a randomized trial of adjuvant tamoxiten
J Natl Cancer Inst
(1993)
FisherB et al.
Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Adjuvant Breast and Bowel Project (NSABP) B-14
J Natl Cancer Inst
(1994)
FornanderT et al.
Adjuvant tamoxifen in earlystage breast cancer: effects on intercurrent morbidity and mortality
J Clin Oncol
(1991)
PathakDN et al.
DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems
Carcinogenesis
(1994)

There are more references available in the full text version of this article.

Cited by (41)

The Effect of Raloxifene Treatment on Lipid Profile in Elderly Individuals: A Systematic Review and Meta-analysis of Randomized Clinical Trials
2021, Clinical Therapeutics
Citation Excerpt :
For instance, although we observed a promising reduction in LDL-C and even TC concentrations induced by raloxifene, tamoxifen is seemingly the SERM with the greatest biological plausibility and clinical magnitude for increasing HDL-C levels.55 In this sense, we did not find a significant increase in HDL-C. Among the SERMs, there is probably a divergence in modulating HDL-C because raloxifene is not able to increase serum estrogen levels, unlike tamoxifen,56 in which estrogens increase HDL-C levels by increasing the apolipoprotein-AI synthesis57 or decreasing its breakdown.58 Lowering HDL-C levels together with hypertriglyceridemia is also an important risk factor for atherosclerotic cardiovascular disease.59–61
To perform a systematic review and meta-analysis of randomized clinical trials (RCTs) to elucidate the effects of raloxifene on the lipid profile in elderly individuals.
A systematic review and meta-analysis of RCTs was performed following the PRISMA statement. Data on triglycerides (TGs), total cholesterol (TC), HDL-C, and LDL-C were extracted. Relevant publications up to October 2020 were detected through searches in the PubMed/MEDLINE, Web of Science, Scopus, and Embase databases. Changes were reported as weighted mean differences (WMDs) and 95% CIs using random-effects models.
Nine studies were selected, with a duration of intervention ranging from 2 and 12 months and a raloxifene dose of 60 to 120 mg/d. Studies were performed in healthy individuals and in those with disorders, such as osteoporosis, type 2 diabetes, and kidney disease required long-term hemodialysis. Overall, TG (WMD, −6.50 mg/dL; 95% CI, −34.18 to 21.20 mg/eL; P = 0.646), LDL-C (WMD, −17.86 mg/dL; 95% CI, −42.44 to 6.72 mg/dL; P = 0.154), and HDL-C (WMD, 2.35 mg/dL; 95% CI, −1.14 to 5.84 mg/dL; P = 0.187) levels did not change significantly after the administration of raloxifene. In contrast, TC levels decreased after raloxifene therapy (WMD, −6.59 mg/dL; 95% CI, −13.13 to −0.05 mg/dL; P = 0.048).
Raloxifene therapy decreased TC levels but did not alter TG, HDL-C, and LDL-C concentrations in elderly individuals. Regarding the LDL-C levels, although the finding lacked statistical significance, we believe that there was a mean reduction that deserves further clinical attention as much as TC.
Are sex discordant outcomes in COVID-19 related to sex hormones?
2020, Seminars in Oncology
Citation Excerpt :
The study rationale is that isotretinoin decreases ACE2 expression and tamoxifen is involved in vesical transport, cellular pH, prevention of lung fibrosis, and reduction of serum TGFβ-1 levels. Not mentioned is the potential effects of tamoxifen on testosterone and estrogen [37,38]. In men treated with tamoxifen, an increase in testosterone was observed clinically [37].
COVID-19 has a clear sex disparity in clinical outcome. Globally, infection rates between men and women are similar; however, men are more likely to have more severe disease and are more likely to die. The causes for this disparity are currently under investigation and are most likely multifactorial. Sex hormones play an important role in the immune response with estrogen seen as immune boosting and testosterone as immunosuppressing. Additionally, an important protease involved in viral entry, TMPRSS2, is regulated by androgens. Many observational and prospective studies are ongoing or initiating to further examine the role of sex hormones in SARS-CoV-2 infection and if modulation of them is a realistic treatment option.
The vibrational spectroscopic studies and molecular property analysis of Estradiol, Tamoxifen and their interaction by density functional theory
2018, Journal of Molecular Structure
Citation Excerpt :
Edward Baral and et al. [13] found that Tamoxifen enhanced the cytotoxic activity of effector cells isolated from human tumors when autologous tumor targets were used. The change in the Serum dehydroepiandrosterone (DHEA), estrone (El) and estradiol (E2) levels in women were prospectively measured by Sharon S. Lum and et al. [14] during Tamoxifen therapy for the treatment of the breast cancer cells. The present research work is undertaken to study the molecular geometrical parameters, vibrational modes, Natural Bond Orbital (NBO) analysis, HOMO-LUMO for charge transfer mechanism and thermo dynamical properties for the biomolecule Tamoxifen, Estradiol and Estradiol + Tamoxifen using the computational techniques.
In the present work Tamoxifen, Estradiol and their interaction are studied using the experimental and theoretical methodologies. The spectral characterization was made by using Raman, FTIR, DFT and VEDA calculation. The optimization of the molecules have been studied using basis set B3LYP/6–31 G(d,p). Complete vibrational assignment of Tamoxifen, Estradiol and Estradiol + Tamoxifen have been attempted and the potential energy distribution and normal mode analysis had also been carried out to determine the contributions of bond oscillators in each normal mode. We have optimized several binding modes of Estradiol and Tamoxifen and taken the lowest energy conformer in our interest. The molecular geometry, HOMO-LUMO energy gap, molecular hardness (η), ionization energy (IE), electron affinity (EA), total energy and dipole moment were analyzed. The observed experimental and the scaled theoretical results were found in good agreement.
Separate and simultaneous binding of tamoxifen and estradiol to human serum albumin: Spectroscopic and molecular modeling investigations
2018, Journal of Molecular Liquids
Citation Excerpt :
It has been the endocrine therapy for hormone-positive early breast cancer in post-menopausal women, although aromatase inhibitors have been proposed [19]. Lum et al. observed that the long-term tamoxifen therapy can be associated with increased serum levels of estrogen hormones especially EST [20]. A decade later, Gjerde et al. indicated that there are the significant correlations between the serum concentrations of tamoxifen, N-dedimethyltamoxifen, and tamoxifen-N-oxide and estrogens (P < 0.05) [21].
In the recent years, tamoxifen has been often co-administrated with estradiol to treatment of breast cancer. Hence, we examined the interaction of two anti-breast cancer drugs, tamoxifen and estradiol, with human serum albumin (HSA) using spectroscopic and molecular modeling techniques. The quenching of intrinsic fluorescence and docking were used to calculate binding affinity and location, while the RLS, synchronous fluorescence and CD spectroscopy were done to investigate the effect of these drugs on protein conformational changes, both separately and simultaneously. While the photo-stability of drugs increased in the presence HSA, the enhancement of RLS intensity was attributed to the formation of a new complex between the two drugs and the protein. Both drugs showed a strong ability to quench the fluorescence of HSA via static mechanism. The fluorescence quenching action at different temperatures and enhancement of RLS intensity were much stronger when the two drugs co-existed, whereas the binding affinity of both drugs were partially affected by each other, which demonstrate that two drugs bind to distinct/different location on HSA via hydrophobic interactions. On the other hand, appearance of new peak at 405 nm accompanying with quenching of HSA fluorescence at 340 nm by tamoxifen revealed that the drug binds near the protein Trp residue in subdomain IIA, which confirmed the docking results. Furthermore, synchronous fluorescence and CD data clearly indicate that the conformation of HSA was changed upon addition of the drugs which can affect the physiological functions of HSA and binding of other drugs.
False Increase of Estradiol Levels in a 36-Year-Old Postmenopausal Patient with Estrogen Receptor-Positive Breast Cancer Treated with Fulvestrant
2016, Clinical Breast Cancer
Citation Excerpt :
Few studies have previously shown that AIs, including letrozole, can cause cross- reactivity with immunoassays and lead to falsely increased serum estradiol readings.10 Tamoxifen, a SERM with some estrogen receptor agonist properties, has been shown to cause increased estradiol levels,12,13 although these studies used immunoassays to quantify estradiol levels. Fulvestrant, which has no known agonist effects, has never been reported to cause falsely increased estradiol levels or cross-reactivity with estradiol immunoassays.
Age, photoperiod and estrogen dependent variations in the shell gland and the expression of AVT in the ovary of Japanese quail
2012, Steroids
Present work was undertaken to describe (i) age dependent (prepuberal-3, 4, 5 and 6 weeks old, puberal and actively laying 8 and 12 weeks old and aged 78 weeks old) (ii) photoperiodic response dependent (photosensitive and photorefractory) and sex steroid dependent (estradiol benzoate and its antagonist tamoxifen treated) variation in the ovary and shell gland activity of Japanese quail (Coturnix coturnix japonica). Further, in view of the role of neurohypophysial peptide arginine vasotocin (AVT) in many physiological processes including age/reproduction related oviposition, expression of ir-AVT was also monitored in the ovary of quail. All the parameters associated with histodifferentiation increased rapidly during the developing stages followed by a decrease in old age, which also increased in reproductively quiescent photorefractory birds following estradiol treatment and decreased in reproductively active photosensitive quail following tamoxifen treatment. Using AVT-specific antibody, expression of immunoreactive AVT (ir-AVT) observed in the ovary of photosensitive quail was not detected in the photorefractory quail. However, administration of estrogen in the photorefractory quail stimulated the growth and activity of ovary and shell gland also resulted in the expression of ovarian ir-AVT. On the other hand, tamoxifen eliminated the localization of ir-AVT in the ovary of photosensitive quail in addition to a decrease in the shell gland protein and alkaline phosphatase activity. It is concluded that estrogen not only affects the growth and differentiation of ovary and oviduct including shell gland but also regulates the expression of ovarian AVT. It is also suggested that in addition to reported paracrine effect of AVT in the shell gland of Japanese quail for oviposition, ovarian AVT may also affect ovarian function (ovulation), and in part, this regulation is estrogen dependent.

View all citing articles on Scopus

: Presented at the 83rd Annual Meeting of the North Pacific Surgical Association, Seattle, Washington, November 8–9, 1996.

View full text

Changes in serum estrogen levels in women during tamoxifen therapy

Background

Methods

Results

Conclusions

Europ J Cancer

The mechanism of hormone-sensitive breast cancer progression on antiestrogen therapy

Arch Surg

Chemohormonal therapy and endocrine function in breast cancer patients

Cancer

Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer

Oncology

Clinical pharmacokinetics of endocrine agenrs used in advanced breast cancer

Clin Pharmacokinet

Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer

NEJM

Cardiac and thromboembolic morbidity among postmenopausal women with earlystage breast cancer in a randomized trial of adjuvant tamoxiten

J Natl Cancer Inst

Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Adjuvant Breast and Bowel Project (NSABP) B-14

J Natl Cancer Inst

Adjuvant tamoxifen in earlystage breast cancer: effects on intercurrent morbidity and mortality

J Clin Oncol

DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems

Carcinogenesis