8 December 2014

A recent review written by three Finnish psychiatrists supports the use of estrogens, perhaps together with antidepressants, for depression and anxiety in perimenopausal women [1]. Depressive symptoms are experienced by 15–50% of women during the menopausal transition and up to 30% of perimenopausal depression is severe enough to be regarded as a depressive disorder. This problem, described as 'reproductive depression' [2] occurs with fluctuations of gonadal hormones in the form of premenstrual depression, postnatal depression and climacteric depression. In the menopausal age group, the depression, anxiety and loss of self-confidence are at their worst in the 2–3 years of the transition period before the cessation of periods. Toffol and colleagues, in their review of the literature, have come to the conclusion that hormone therapy may contribute to the alleviation of menopause-related depressive symptoms. They claim that the administration can be followed across time and should be specifically individualized. In cases of more severe depressive disorders, a combination of antidepressants and hormone therapy should be considered. This view has also been proposed by others [3,4].

Comment

The perimenopause is usually accompanied by more-or-less-impairing climacteric symptoms of hot flushes, palpitations and tachycardia as well as some degree of psychological symptoms of sleep impairment, anxiety, panic attacks and depressive symptoms. The proportion of perimenopausal women suffering depressive symptoms ranges between 15% and 50%. It is possible that the fluctuations in estrogen levels and their eventual fall increase the risk in women who are vulnerable. These are particularly women who have had a premorbid history of psychiatric problems, particularly anxiety and depression related to reproductive events such as menstruation, post pregnancy and the contraceptive pill.

The cause of this hormone-responsive depression is unclear but, in our present state of knowledge, it is certain that gonadal hormones produce many effects on the central nervous system. In the adult brain, estrogen and progestogen receptors are widely expressed in different regions. Estrogen receptors are present not only in the hypothalamus but also in the hippocampus, amygdala, cerebellum, pituitary, cerebral cortex and glial cells. The mechanism is even more complex in that there are different types of estrogen receptors which are expressed in different brain regions and in different cells within the same brain region and even in the same cell in the same region. Therefore, the final effects induced by estrogens change depending on the type of receptor to which they bind. Target genes include those responsible for neurotransmitters, serotonin and GABA. The role of progesterone is even more complicated as it is involved in the control of opioidergic, sertoninergic and cholinergic systems with anxiolytic effects.

In a detailed review of the literature, Toffol and colleagues conclude that estrogens are more effective in treating depression in perimenopausal women than in those who are postmenopausal regardless of the presence or otherwise of vasomotor symptoms [1]. This is certainly true. Estrogens may improve mood by removing the tiredness following severe hot flushes and night sweats or removing the dyspareunia of vaginal atrophy, but the effect on severe depressive disorder is less convincing. The most recent studies have used transdermal estradiol given by patches or gels compared with the earlier studies that used oral preparations of estradiol or conjugated equine estrogens [5]. The authors stress that the progestogen component counteracted the beneficial effects of estrogen in combined preparations. This progesterone intolerance is the fundamental cause of premenstrual depression and a major factor in the symptomatic difficulties that many postmenopausal women without depression find when taking standard hormone replacement therapy preparations [6].

The paper by Toffol and colleagues is a most welcome review of this controversial topic, particularly as it is written by psychiatrists, who, as a group, have been reluctant to accept the role of estrogens in depression, although the benefits of such therapy in a well-defined group of women have been reported in good scientific trials for more than 20 years. The message is getting through slowly to psychiatrists [7]. There are many women whose long-term depression is triggered by reproductive events throughout their lives, starting as premenstrual depression at puberty. This cyclical depression becomes worse with age and these women may only have 10 days without depression each month. But they do have monthly runs of good days, which is an important diagnostic point since these women predictably fail to respond to antidepressants and are frequently misdiagnosed as having bipolar disorder [8]. This depression usually disappears with pregnancy, but women with reproductive depression will develop severe postnatal depression which can be treated effectively by transdermal estrogens, even in those women who have failed to respond to antidepressants. When the periods return, the cyclical premenstrual depression returns, becoming worse with age and following the inappropriate use of many antidepressants or mood-stabilizing drugs. The next stage is depression around the time of the perimenopause. It is clear that most menopausal symptoms are worse in the menopausal transition, the 3–5 years before the periods cease. Toffol and colleagues stress that the response to estrogens is greater in the transition than in the postmenopausal years. The tragedy is that these women are given only antidepressants. Such is the reluctance to prescribe estrogens that antidepressants have even been recommended for the treatment of vasomotor symptoms. A combination of estrogens and antidepressants is recommended by the authors. This is a bold statement from the authors but, while supporting this advice, I would stress the importance of transdermal estrogens first and the addition of antidepressants if necessary.

John Studd
London PMS and Menopause Centre, London, UK

References

1. Toffol E, Heikinheimo O, Partonen T. Hormone therapy and mood in perimenopausal and postmenopausal women: a narrative review. Menopause 2014 September 8. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/25203891

2. Studd W, Nappi RE. Reproductive depression. Gynecol Endocrinol 2012;28(Suppl 1):42-5
http://www.ncbi.nlm.nih.gov/pubmed/22394303

3. Graziottin A, Serafini A. Depression and the menopause: why antidepressants are not enough? Menopause Int 2009;15:76-81
http://www.ncbi.nlm.nih.gov/pubmed/19465674

4. Studd JW. A guide to treatment of depression in women by estrogens. Climacteric 2011;14:637-42
http://www.ncbi.nlm.nih.gov/pubmed/21878053

5. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977;4:31-47
http://www.ncbi.nlm.nih.gov/pubmed/322905

6. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71
http://www.ncbi.nlm.nih.gov/pubmed/9286739

7. Craig MC. Should psychiatrists be prescribing oestrogen therapy to their female patients? Br J Psychiatry 2013;202:9-13
http://www.ncbi.nlm.nih.gov/pubmed/23284147

8. Studd J. Severe premenstrual syndrome and bipolar disorder: a tragic confusion. Menopause Int 2012;18:82-6
http://www.ncbi.nlm.nih.gov/pubmed/22611228