Drug products: Nolvadex, Nolvadex®, Tamoxifen Ebb, Tamoxifen Mylan, Tamoxifen Nordic Drugs, Tamoxifen Orifarm, Tamoxifen Sandoz, Tamoxifen-Ratiopharm
ATC code: L02BA01
Substances: tamoxifen, tamoxifen citrate
Studies have shown some differences in the effect of tamoxifen on the neuroendocrine regulation of growth hormone and fat metabolism between women and men. In breast cancer, aromatase inhibitors have shown to be more effective than tamoxifen in postmenopausal women, however, a study showed that the overall survival in men was better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor.
It has been seen that the growth of lung adenocarcinoma cell lines from women is blocked by antiestrogens. In contrast, lung adenocarcinoma cells from men were not responsive to antiestrogens.
In melanoma, a greater benefit in response towards tamoxifen was seen in trials with female predominance. The sex differences in the effect of tamoxifen on hepatocellular carcinoma patients remain unclear.
Tamoxifen is a selective estrogen receptor modulator, indicated for the palliative and adjuvant treatment of estrogen receptor positive breast cancer. However, it has also been used in patients with lung adenocarcinoma, hepatocellular carcinoma, melanoma, McCune Albright syndrome in children, and pubertal gynecomastia [1, 2].
Controlled studies on differences between men and women regarding pharmacokinetics of tamoxifen are lacking. Different dosing between men and women is not recommended by the pharmaceutical company .
It is known that there are substantial differences in the etiology of female and male breast cancer, with the latter arising more frequently as a result of BRCA2 gene mutations with differential effects of single nucleotide polymorphisms by patient’s sex, among other molecular profile differences . Luminal A is the predominant subtype in men, which is rarely of basal cell types and never HER2 positive .
It has been seen that aromatase inhibitors (AI) are more effective than tamoxifen in postmenopausal women [5-8], thus it was suggested that the same could be true in men with breast cancer. A study published in 1978 was the first to report a beneficial effect of tamoxifen in metastatic male breast cancer with all 3 patients gaining responses lasting for >6 months . There have been several studies showing variable results on AI and tamoxifen treated male breast cancer [10-17]. In a multicenter study of 31 men with metastatic breast cancer treated with tamoxifen, complete or partial response occurred in 15 (48%) .
A retrospective study (257 men, 2785 women) treated with hormonal therapy (316 women and 158 men treated with tamoxifen), showed that the 5-year overall survival in tamoxifen treated patients was similar in women and men (85.1% and 89.2% respectively) . In contrast, AI treatment was associated with poorer survival of men with breast cancer compared to women . After a median follow-up of 42 months, those treated with AI had a 1.5-fold increased mortality rate compared with those treated with tamoxifen .
There have been no randomized trials of adjuvant or palliative chemotherapy in men with breast cancer and the reported series have been small, with variations in regimens and dosage. Thus, no conclusions can be drawn regarding the role of tamoxifen for men with breast cancer.
In a randomized trial (10 healthy postmenopausal women, 10 healthy men), tamoxifen attenuated growth hormone (GH) response to stimulation with arginine in women, but not in men. The overall reduction in GH response in women by the higher dose of tamoxifen (20 mg) was 88%. On the other hand, tamoxifen reduced mean insulin-like growth factor 1 (IGF-I) levels and increased sex hormone binding globulin (SHBG) levels in both women and men. This effect on circulating IGF-I levels was not different between men and women, whereas its effect on SHBG was greater in women. In men, tamoxifen increased luteinizing hormone (LH) and testosterone concentrations in a dose-dependent manner .
Similarly, another study (10 healthy postmenopausal women, 10 healthy men) found that the suppressive effect of tamoxifen on fat metabolism is sex-dependent. The study showed that tamoxifen significantly reduced the mean GH response to arginine stimulation, the circulating IGF-I levels, postprandial fat oxidation and carbohydrate oxidation in women . Whereas in men, tamoxifen did not affect the GH response to stimulation but reduced mean IGF-I levels and increased mean testosterone levels. Furthermore, fat and carbohydrate oxidation were not affected by tamoxifen in men . In women and men, tamoxifen did not change serum levels of total cholesterol, HDL, or glucose. In men opposite to in women, tamoxifen reduced triglyceride levels .
A bioinformatics analysis (gene expression data were collected from 2352 men and 1751 women) of sex-linked molecular alterations and therapies in cancer predicted that women are sensitive, and men are resistant to tamoxifen treatment of lung adenocarcinoma . A study showed that lung adenocarcinoma cell lines from women proliferated in response to E2, and that growth was blocked by antiestrogens. In contrast, lung adenocarcinoma cells from men were not responsive to E2 or antiestrogens .
Androgens, estrogens, and their receptors, are involved in signaling of commonly mutated melanoma pathways, thus it is a hormone-sensitive tumor. For this reason, tamoxifen has been considered as a possible therapy for melanoma . A meta-analysis on tamoxifen treatment for advanced melanoma, including 9 studies (764 men, 526 women), showed a tendency towards benefit of tamoxifen in the group with higher women/men ratio. The treatment effect was consistent regardless of the dose or sex of participants, however, a greater benefit in response towards tamoxifen was seen in trials with female predominance .
In a systematic review including 10 trials on tamoxifen treatment in patients with hepatocellular carcinoma (in total 1709 patients), most patients were men in all studies (range, 71-89%). The influence of patient’s sex on treatment effects was not a primary objective in any of the trials . One trial reported no difference in survival between men and women in post-hoc analysis . Another trial reported a benefit of tamoxifen for men without major hepatic insufficiency, but no benefit for women [26-27].
Bone loss has been seen in premenopausal women, but not in men . In men, the most commonly reported adverse events in retrospective studies and reviews have been loss of libido, weight gain, hot flushes and mood alterations [28-32].
The dual attenuation of GH secretion and hepatic IGF-I production indicates that tamoxifen may induce a GH deficiency, and it is known that this condition can lead to hepatic steatosis that can progress to severe liver disease [33, 34]. Hepatic steatosis has been described as a frequent and reversible adverse effect of tamoxifen treatment in breast cancer patients , but the mechanism remains unclear. Even though the sample size of the studies is small, the authors suggest that women could be at greater risk than men [3, 4].
Tamoxifen can inhibit menstruation in some premenopausal women . Pregnancy should be avoided in women of childbearing potential on tamoxifen treatment and within two months after treatment. Non-hormonal contraceptive methods is recommended for women of childbearing potential . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-10-03
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson