Hormones for Depression in the Menopause

A while back I wrote a post about what you should know about depression in the menopause. It is a topic that I have come to be particularly passionate about since finishing my MSc. My specific topic of focus for my dissertation was whether hormone replacement therapy (HRT) was beneficial for menopausal depression and/or low mood.

During my time working on this dissertation, I came across opinions and research which were either 100% pro-HRT or 100% against HRT and it is my worry that when people struggling with their mental health during the menopause attend meetings with doctors or specialists to discuss this, they may be forced into a treatment that may not work for them or dissuaded from a treatment that may change their life for the better.

I want, with this blog post, to provide a balanced review of the existing research into the treatment of menopausal depression with HRT and to equip you with the knowledge you need when going into this time of your life. I honestly feel that the menopause, and its associated symptoms, is not discussed openly enough, so let’s create some dialogue about it.

Nothing Is Proven Yet

The first point I wish to make clear is that there is currently a lot of confusion and disparity in the HRT for/against menopausal depression research world.

In the world of research, there are different levels of evidence. One of the highest forms of evidence in medicine is clinical trials, where treatment is tested against placebo or against other similar treatments to see which is the most effective.

For clinical trials, the studies must be blinded meaning that the participants don’t know which treatment they are being given. Unfortunately, there are not many high-quality clinical trials for HRT and menopausal depression, in fact, I only found a total of 29 from an original 51,000 that matched the criteria I set. Of these 29 studies, each study explored different stages of the menopause, different types of HRT and different types of mood and depressive symptoms. What this means is it is very difficult to conclude anything. While the studies do overall suggest that HRT may be promising as a treatment for menopausal depression in the future, it is impossible to say this for certain at present.

So, to put it bluntly, those who tell you that the only way to treat your mood symptoms in the menopause is through HRT are biased.

About Different Types of HRT

One of the problems with the current body of research is that there are so many different types of hormones and hormone combinations for HRT. There are oestrogen therapies, and within that different types of oestrogen therapies, there are progestins that are sometimes combined with oestrogen therapies, testosterone therapies, and tibolone. When there are so many different types of hormones that can be used, and each study explores a different type of HRT, it becomes impossible to tell if any one type of HRT is more or less beneficial than another because none of them are being compared. Similarly, there are no replication studies, so each study stands by itself, with no other studies backing up their findings.

Different Types of Mood Symptoms

Another problem to mention just before we get to the evidence for or against HRT is that studies seem to explore different types of mood symptoms, from just general low mood and low quality of life to depressive symptoms to clinical depression. Where each study again focuses on something different, it makes it impossible to delineate whether HRT is more or less beneficial for a specific severity of mood or depression experiences.

What the Evidence Suggests

For Low Mood and Quality of Life

Many of those going through the menopause will not experience depression symptoms or clinical levels of depression but may experience lower moods than normal and reduced quality of life (Blumel et al., 2000).

The most common type of hormone therapy used is oestrogen replacement therapy, which can come in many forms and is sometimes combined with a progestin (synthetic progesterone). Typically, oestrogen therapy comes in the form of oestradiol or conjugated equine oestrogens (CEEs). There is some evidence that both oestradiol and CEEs improve negative moods in perimenopause (Raz et al., 2016), and when combined with a progestin, two studies documented a beneficial effect of CEEs on mood during the postmenopausal period (Bukulmez, 2001; Gleason et al., 2015).

Another type of hormone called Tibolone is a medication displaying mild oestrogenic, progestogenic and androgenic effects. It has also found to be effective for treating low mood however one study found that it was no more effective than oestrogen therapy and one study found that the benefits were also no different to the control group meaning that a group without treatment improved as much as those taking Tibolone (Davis, 2002; Inan et al., 2005; Polisseni et al., 2013).

One study I found explored the effect of testosterone therapy on psychological well-being in premenopausal women (Goldstat et al., 2003). In the period before the menopause, testosterone declines rapidly to a point where women in their 40s tend to have half the testosterone of women half their age. The study found that testosterone therapy improved general psychological well-being however the study’s primary concern was with low libido which also improved with testosterone therapy. With results like this, it is important to consider that the improvement in libido may have improved well-being rather than the HRT itself.

In postmenopausal women, however, some research suggests that HRT has very little effect on mood or quality of life (Nielsen et al., 2006). In fact, one study noted that an oestradiol+progestin combination actually worsened low mood in women who were switching to a new type of HRT from a different type of HRT (Odmark et al., 2004). Another study found that higher doses of progesterone treatment increased levels of allopregnanolone in the body and that higher levels of allopregnanolone could deteriorate mood (Andréen et al., 2005).

For Depressive Symptoms

Mild and moderate experiences of depression are much more common than severe or clinical experiences of depression during the menopause (Zeng et al., 2019). Again, there is evidence that oestrogen therapy with or without the combination of a progestin is effective for reducing depression symptoms in postmenopausal women (Cagnacci et al., 2004; Gordon et al., 2018; Onalan et al., 2005). There is, however, also evidence to suggest that oestrogen therapy is no better than placebo (Diem et al., 2018; Marinho et al., 2008; Whedon et al., 2017).

Tibolone for depressive symptoms was found to be as effective as a CEE+progestin combination in improving depression symptoms (Onalan et al., 2005; Yazici et al., 2003).

Interestingly, one study explored the effects of genistein, which is a phytoestrogen. Phytoestrogens are dietary oestrogens that are found in plant foods. They potentially offer the same benefits of HRT without the potential risks like higher risk of breast, endometrial and ovarian cancer. The study found that genistein, which is commonly found in soy products, improved depression symptoms both after one and two years of administration (Atteritano et al., 2014). While this is a promising avenue for future research, at the moment genistein has very little evidence for this specific purpose.

Testosterone is, again, largely understudied regarding its impact on depression symptoms. One study found that there was an association between testosterone levels and lowered depression symptoms, but this result was only found in Caucasian women and not in African American women (Milman et al., 2015). Another study suggested that balancing testosterone with oestrogen levels may help reduce depression symptoms, but again the research lacks a point where no conclusions can be drawn about the use of testosterone for depression symptoms (Rohr, 2002).

For Clinical Depression

The menopause has been identified as a risk factor for experiencing a first incidence of clinical depression and treatment with oestrogen therapy and tibolone has been associated with not only reduced symptomology but also with remission rates in both the perimenopausal and postmenopausal period (Kulkarni et al., 2018; Rudolph et al., 2004; Schmidt et al., 2000).

Where oestrogen therapy really seems to have an impact is where it is used alongside antidepressants. Oestrogen and antidepressants (SSRIs specifically) both respectively seem to effectively treat clinical depression in menopausal women, however when used in combination, the results out-perform the individual treatment results (Amsterdam et al., 1999; Graziottin & Serafini, 2009; Pae et al., 2008; Soares et al., 2003; Westlund Tam & Parry, 2003; Yu et al., 2004; Zanardi et al., 2007). It is not clear at the moment which treatment augments which, but it is a clear finding that oestrogen combined with SSRIs could be a superior treatment for clinical depression in the menopause.

Unfortunately, there is a lack of evidence for the use of any other types of HRT for clinical depression in the menopause.

Conclusion

What this article is not supposed to be is a deterrent from using HRT to manage your mood symptoms. There is plenty of evidence to suggest that in some cases, it can be very beneficial.

What this article is supposed to highlight is that the research is far too varied and inconclusive for a doctor to tell you that HRT is either the be-all-end-all solution to your problems or that you should never go near it. I believe that it is probably the case that the benefits of HRT will be seen on an individual basis. Certain types of HRT will work for one person and won’t work for another. I believe, unfortunately, at the moment, it is probably a case of trial and error.

If you are struggling with mood symptoms during your menopause, seek out help. It is not uncommon and many women will be experiencing these debilitating symptoms too. Talk to your doctor about your options and if you don’t feel like your doctor takes a balanced view on the treatments available, seek out another doctor. It is all about finding which treatment works for you. You do not have to suffer and you do not have to be alone.

I wish you all the best.

References

Amsterdam, J., Garcia-España, F., Fawcett, J., Quitkin, F., Reimherr, F., Rosenbaum, J., & Beasley, C. (1999). Fluoxetine efficacy in menopausal women with and without estrogen replacement. Journal of Affective Disorders, 55(1), 11–17. https://doi.org/10.1016/S0165-0327(98)00203-1

Andréen, L., Sundström-Poromaa, I., Bixo, M., Andersson, A., Nyberg, S., & Bäckström, T. (2005). Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology, 30(2), 212–224. https://doi.org/10.1016/j.psyneuen.2004.07.003

Atteritano, M., Mazzaferro, S., Bitto, A., Cannata, M. L., D’Anna, R., Squadrito, F., Macrì, I., Frisina, A., Frisina, N., & Bagnato, G. (2014). Genistein effects on quality of life and depression symptoms in osteopenic postmenopausal women: A 2-year randomized, double-blind, controlled study. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 25(3), 1123–1129. https://doi.org/10.1007/s00198-013-2512-5

Blumel, J. E., Castelo-Branco, C., Binfa, L., Gramegna, G., Tacla, X., Aracena, B., Cumsille, M. A., & Sanjuan, A. (2000). Quality of life after the menopause: A population study. Maturitas, 34(1), 17–23. https://doi.org/10.1016/S0378-5122(99)00081-X

Cagnacci, A., Arangino, S., Baldassari, F., Alessandrini, C., Landi, S., & Volpe, A. (2004). A comparison of the central effects of different progestins used in hormone replacement therapy. Maturitas, 48(4), 456–462. https://doi.org/10.1016/j.maturitas.2003.10.003

Davis, S. R. (2002). The effects of tibolone on mood and libido: Menopause, 9(3), 162–170. https://doi.org/10.1097/00042192-200205000-00004

Diem, S. J., Guthrie, K. A., Mitchell, C. M., Reed, S. D., Larson, J. C., Ensrud, K. E., & LaCroix, A. Z. (2018). Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: A randomized clinical trial. Menopause (New York, N.Y.), 25(10), 1086–1093. https://doi.org/10.1097/GME.0000000000001131

Gleason, C. E., Dowling, N. M., Wharton, W., Manson, J. E., Miller, V. M., Atwood, C. S., Brinton, E. A., Cedars, M. I., Lobo, R. A., Merriam, G. R., Neal-Perry, G., Santoro, N. F., Taylor, H. S., Black, D. M., Budoff, M. J., Hodis, H. N., Naftolin, F., Harman, S. M., & Asthana, S. (2015). Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Medicine, 12(6), e1001833; discussion e1001833. https://doi.org/10.1371/journal.pmed.1001833

Goldstat, R., Briganti, E., Tran, J., Wolfe, R., & Davis, S. R. (2003). Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause (New York, N.Y.), 10(5), 390–398. https://doi.org/10.1097/01.GME.0000060256.03945.20

Gordon, J. L., Rubinow, D. R., Eisenlohr-Moul, T. A., Xia, K., Schmidt, P. J., & Girdler, S. S. (2018). Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry, 75(2), 149–157. https://doi.org/10.1001/jamapsychiatry.2017.3998

Graziottin, A., & Serafini, A. (2009). Depression and the menopause: Why antidepressants are not enough? Menopause International, 15(2), 76–81. https://doi.org/10.1258/mi.2009.009021

Inan, I., Kelekci, S., & Yilmaz, B. (2005). Psychological effects of tibolone and sequential estrogen-progestogen therapy in perimenopausal women. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 20(2), 64–67. https://doi.org/10.1080/09513590400020963

Kulkarni, J., Gavrilidis, E., Thomas, N., Hudaib, A.-R., Worsley, R., Thew, C., Bleeker, C., & Gurvich, C. (2018). Tibolone improves depression in women through the menopause transition: A double-blind randomized controlled trial of adjunctive tibolone. Journal of Affective Disorders, 236, 88–92. https://doi.org/10.1016/j.jad.2018.04.103

Marinho, R. M., Soares, J. M., Santiago, R. C., Maganhin, C. C., Machado, F., de Miranda Cota, A. M., & Baracat, E. C. (2008). Effects of estradiol on the cognitive function of postmenopausal women. Maturitas, 60(3–4), 230–234. https://doi.org/10.1016/j.maturitas.2008.07.003

Milman, L. W., Sammel, M. D., Barnhart, K. T., Freeman, E. W., & Dokras, A. (2015). Higher serum total testosterone levels correlate with increased risk of depressive symptoms in Caucasian women through the entire menopausal transition. Psychoneuroendocrinology, 62, 107–113. https://doi.org/10.1016/j.psyneuen.2015.07.612

Nielsen, T. F., Ravn, P., Pitkin, J., & Christiansen, C. (2006). Pulsed estrogen therapy improves postmenopausal quality of life: A 2-year placebo-controlled study. Maturitas, 53(2), 184–190. https://doi.org/10.1016/j.maturitas.2005.04.003

Odmark, I. S., Bäckström, T., Jonsson, B., & Bixo, M. (2004). Well-being at onset of hormone replacement therapy: Comparison between two continuous combined regimens. Climacteric: The Journal of the International Menopause Society, 7(1), 92–102. https://doi.org/10.1080/13697130310001651526

Onalan, G., Onalan, R., Selam, B., Akar, M., Gunenc, Z., & Topcuoglu, A. (2005). Mood scores in relation to hormone replacement therapies during menopause: A prospective randomized trial. The Tohoku Journal of Experimental Medicine, 207(3), 223–231. https://doi.org/10.1620/tjem.207.223

Pae, C.-U., Mandelli, L., Han, C., Ham, B.-J., Masand, P. S., Patkar, A. A., Steffens, D. C., De Ronchi, D., & Serretti, A. (2008). Do estradiol levels influence on the cognitive function during antidepressant treatments in post-menopausal women with major depressive disorder? A comparison with pre-menopausal women. Neuro Endocrinology Letters, 29(4), 500–506.

Polisseni, A. F., Andrade, A. T. L., Ribeiro, L. C., Castro, I. Q., Brandão, M., Polisseni, F., & Guerra, M. de O. (2013). Effects of a continuous-combined regimen of low-dose hormone therapy (oestradiol and norethindrone acetate) and tibolone on the quality of life in symptomatic postmenopausal women: A double-blind, randomised study. Maturitas, 74(2), 172–178. https://doi.org/10.1016/j.maturitas.2012.11.001

Raz, L., Hunter, L. V., Dowling, N. M., Wharton, W., Gleason, C. E., Jayachandran, M., Anderson, L., Asthana, S., & Miller, V. M. (2016). Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric, 19(1), 49–59. https://doi.org/10.3109/13697137.2015.1116504

Rohr, U. D. (2002). The impact of testosterone imbalance on depression and women’s health. Maturitas, 41, 25–46. https://doi.org/10.1016/S0378-5122(02)00013-0

Rudolph, I., Palombo-Kinne, E., Kirsch, B., Mellinger, U., Breitbarth, H., & Gräser, T. (2004). Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression. Climacteric: The Journal of the International Menopause Society, 7(3), 301–311. https://doi.org/10.1080/13697130400001802

Schmidt, P. J., Nieman, L., Danaceau, M. A., Tobin, M. B., Roca, C. A., Murphy, J. H., & Rubinow, D. R. (2000). Estrogen replacement in perimenopause-related depression: A preliminary report. American Journal of Obstetrics and Gynecology, 183(2), 414–420. https://doi.org/10.1067/mob.2000.106004

Soares, C. N., Poitras, J. R., Prouty, J., Alexander, A. B., Shifren, J. L., & Cohen, L. S. (2003). Efficacy of citalopram as a monotherapy or as an adjunctive treatment to estrogen therapy for perimenopausal and postmenopausal women with depression and vasomotor symptoms. The Journal of Clinical Psychiatry, 64(4), 473–479. https://doi.org/10.4088/jcp.v64n0419

Westlund Tam, L., & Parry, B. L. (2003). Does estrogen enhance the antidepressant effects of fluoxetine? Journal of Affective Disorders, 77(1), 87–92. https://doi.org/10.1016/s0165-0327(02)00357-9

Whedon, J. M., KizhakkeVeettil, A., Rugo, N. A., & Kieffer, K. A. (2017). Bioidentical Estrogen for Menopausal Depressive Symptoms: A Systematic Review and Meta-Analysis. [Review]. Journal of Women, 26(1), 18–28. https://doi.org/10.1089/jwh.2015.5628

Yazici, K., Pata, O., Yazici, A., Aktaş, A., Tot, S., & Kanik, A. (2003). [The effects of hormone replacement therapy in menopause on symptoms of anxiety and depression]. Turk Psikiyatri Dergisi = Turkish Journal of Psychiatry, 14(2), 101–105.

Yu, Q., Yin, C.-X., Hui, Y., Yu, J., He, F.-F., Wei, J., & Wu, Y.-Y. (2004). [Comparison of the effect of fluoxetine combined with hormone replacement therapy (HRT) and single HRT in treating menopausal depression]. Zhonghua Fu Chan Ke Za Zhi, 39(7), 461–464.

Zanardi, R., Rossini, D., Magri, L., Malaguti, A., Colombo, C., & Smeraldi, E. (2007). Response to SSRIs and role of the hormonal therapy in post-menopausal depression. European Neuropsychopharmacology, 17(6–7), 400–405. https://doi.org/10.1016/j.euroneuro.2006.11.001

Zeng, L.-N., Yang, Y., Feng, Y., Cui, X., Wang, R., Hall, B. J., Ungvari, G. S., Chen, L., & Xiang, Y.-T. (2019). The prevalence of depression in menopausal women in China: A meta-analysis of observational studies. Journal of Affective Disorders, 256, 337–343. https://doi.org/10.1016/j.jad.2019.06.017

Advertisement