When a person takes toremifene and feels irritability, apathy or, on the contrary, a surge of energy, the question arises: is this the action of the drug or of the circumstances in which it is used? The editorial team looked into how a selective estrogen receptor modulator affects the brain, what is known from clinical data, and why the picture may be opposite in men and women.
Estrogens, the brain and emotions
Estrogen receptors of two types - alpha and beta - are widely represented in the brain: in the hypothalamus, hippocampus, amygdala and prefrontal cortex. Through them estradiol affects the metabolism of serotonin, norepinephrine and dopamine, thermoregulation, sleep and memory. Therefore any drug that changes the estrogen signal is potentially able to change well-being as well.
Toremifene belongs to the SERMs - substances that block estrogen receptors in some tissues and partially activate them in others. The nature of the action depends on the type of tissue, the set of auxiliary coactivator proteins and the level of one's own estrogens. In the mammary gland toremifene acts as an antagonist, in the bones and liver - mostly as a partial agonist.
In the hypothalamus the action of SERMs is predominantly antagonistic. This is what the class's best-known 'central' effects are associated with: hot flashes and sweating in women, and in men - an increase in the production of luteinizing hormone (LH), because the hypothalamus 'does not see' the estrogen inhibition. How deeply the drug penetrates other brain areas and what it does there has been studied far less well.
Thus, toremifene can affect mood in two ways: directly - through receptors in the brain, and indirectly - through changes in sex hormone levels, sleep quality and physical symptoms. In practice the second pathway is usually more important.
What is known about toremifene and the psyche
There are practically no dedicated studies for toremifene in which mood was the main endpoint. The main data come from clinical trials in women with breast cancer and in men with prostate cancer, where mental symptoms were recorded as adverse events.
In the drug's package insert, the most frequently mentioned adverse reactions are hot flashes, sweating, nausea, dizziness and vaginal discharge; depressive symptoms and sleep disturbances are among the rarer reports. It is important that in oncology patients the frequency of depression and anxiety is high at baseline because of the diagnosis and treatment themselves, so it is difficult to separate the drug's contribution.
In studies of toremifene in men receiving androgen deprivation for prostate cancer (in particular the work of Smith and colleagues, 2010, on fracture prevention), the drug was generally tolerated without significant psychiatric signals compared with placebo. The main adverse events were hot flashes and venous thromboembolic complications.
Thus, at the level of evidence, toremifene does not belong to drugs with a pronounced depressogenic effect. However, individual reactions are possible, especially in people with a history of depression, and they should not be dismissed.
| Factor | Possible effect on mood | Level of evidence |
|---|---|---|
| Hot flashes and night sweats | Fragmented sleep, fatigue, irritability | Well described for the SERM class |
| Direct action on brain receptors | Theoretically - changes in emotional regulation | Mostly experimental data |
| Rise in testosterone in men | May improve energy and motivation with a baseline deficiency | Indirectly, from studies of hypogonadism |
| Dizziness, nausea | Reduced overall well-being | Noted in the package insert |
Women: hot flashes, sleep and mood
In postmenopausal women, for whom toremifene is registered, their own estrogens are already low, and additional blockade of receptors in the hypothalamus often intensifies vasomotor symptoms. Hot flashes, especially nocturnal ones, are one of the most common side effects of SERMs in general.
Disturbed sleep is the most direct bridge between hot flashes and mood. Several nighttime awakenings each night over weeks lead to chronic fatigue, reduced concentration and emotional lability. Many patients describe this as a 'change in character', although the primary cause is physiological.
In such cases the doctor may consider non-drug measures (a cool bedroom, avoiding alcohol and spicy food in the evening, cognitive behavioral therapy for insomnia) and, if necessary, non-hormonal drugs for hot flashes. Hormone replacement therapy in breast cancer is usually contraindicated.
A separate point is the psychological burden of the prolonged treatment of an oncological disease. Screening for depression and anxiety is recommended for oncology patients regardless of the type of therapy, and a worsening of mood on toremifene is a reason to discuss this with a doctor rather than to 'endure' it.
Men: hormonal shifts and the context of steroid withdrawal
In men the situation is the opposite. By blocking the estrogen feedback in the hypothalamus and pituitary, toremifene increases the secretion of LH and FSH, and following them the production of testosterone by the testes. Together with testosterone, estradiol also rises, because aromatization is not suppressed. For a man with low testosterone this may mean an improvement in energy and mood.
However, in the sports environment SERMs most often appear in the context of anabolic steroid withdrawal. It is precisely this period that is associated with the highest risk of depressive symptoms: after prolonged suppression of the hypothalamic-pituitary-gonadal axis, testosterone drops sharply, and recovery can take months. Reviews by Kanayama and colleagues and Rahnema and colleagues describe depression, apathy and reduced libido as typical signs of steroid-induced hypogonadism.
In such a situation it is easy to attribute a worsening of mood to toremifene, although the cause is a hormonal 'dip', or, conversely, to attribute to the drug an improvement that is actually natural recovery. There are no controlled studies that would separate these effects in former steroid users.
It is also important that estradiol in men is needed for normal libido and well-being. The study by Finkelstein and colleagues (2013) showed that part of the effects attributed to testosterone are actually mediated by estrogens. Therefore SERMs, which partially block estrogen action, could theoretically affect the emotional sphere differently depending on the hormonal background.
How to distinguish the drug's action from other causes
The practical approach is to record the baseline state and monitor the dynamics. It is useful to pay attention to several questions:
- Were there episodes of depression or anxiety disorder before starting treatment?
- Does the worsening of mood coincide with the appearance of hot flashes and sleep disturbances?
- What levels of testosterone, estradiol, LH and FSH do the tests show during this period?
- Have other factors changed - training load, stress, alcohol or stimulant use?
- Are other drugs being taken that may affect the psyche?
For self-assessment you can use standardized questionnaires such as the PHQ-9, but they do not replace a specialist's consultation. The questionnaire result is useful as a starting point for a conversation with a doctor.
There are symptoms for which you must seek help immediately: thoughts of self-harm, pronounced helplessness, loss of interest in everything, lasting more than two weeks, or abrupt changes in behavior. This applies to any situation, regardless of whether it is related to the drug.
Independent 'corrections' - adding other hormonal agents, abruptly stopping or changing the regimen - can only worsen hormonal instability. The decision to continue or discontinue toremifene is made by the doctor.
Editorial conclusions
Toremifene has no proven pronounced effect on mood, but it is able to change well-being indirectly - through hot flashes, sleep disturbances and shifts in sex hormone levels.
In postmenopausal women the main mechanism is vasomotor symptoms and insomnia; in men the drug usually raises testosterone, and mental problems are more often associated with the context of steroid withdrawal than with the SERM itself.
A worsening of mood during treatment is a medical matter worth discussing with a doctor rather than explaining as 'a side effect that must be endured'.
We also recommend familiarizing yourself with our articles 'Toremifene and libido', 'Toremifene in the recovery of the hormonal system: what studies say' and 'Side effects of toremifene'.
References
- Fareston (toremifene citrate) tablets. Prescribing information. U.S. Food and Drug Administration.
- Smith MR, Morton RA, Barnette KG, et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2010;184(4):1316–1321.
- Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022.
- Kanayama G, Hudson JI, Pope HG Jr. Long-term psychiatric and medical consequences of anabolic-androgenic steroid abuse: a looming public health concern? Drug Alcohol Depend. 2008;98(1–2):1–12.
- Rahnema CD, Lipshultz LI, Crosnoe LE, et al. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril. 2014;101(5):1271–1279.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
