An INTERVIEW with Karen J. Miller and Steven A. Rogers, the authors of THE ESTROGEN-DEPRESSION CONNECTION

New Harbinger Publications: What is the effect of estrogen on a woman’s mood? Is this effect seen in all women?
   
Karen J. Miller and Steven A. Rogers: Very few women might think to link mood to estrogen. They may notice more mood swings around the time of menstruation or during the transition to menopause, but they may not be aware of the research suggesting that depression may be related to the fluctuation in estrogen levels that occur during key reproductive stages of a woman’s life, namely puberty, the premenstrual phase, postpartum, and menopause. Many episodes of depression in women seem to pivot around these key moments of hormonal change, when fluctuating estrogen levels leave women more susceptible to depression. These fluctuations have a psychologically destabilizing action that renders the female brain more vulnerable to developing sadness, loss of pleasure, and reductions in the quality of their appetite and sleep. In a sense, the depression that many women experience may be an unnatural response to a natural hormonal change at key reproductive stages.

One important caveat, however, is that this link between estrogen fluctuation and depression may not occur for every woman. Even though all women are exposed to changes in estrogen levels, clearly not all women become depressed. Therefore, it is probably more accurate to say there is a particular group of women who are more susceptible or vulnerable to developing depression. The factors that create this vulnerability are varied, including genetic and environmental factors, but it is this vulnerability that leaves some women more sensitive to the effects of fluctuating estrogen on mood.

NHP: How does the idea that there is a connection between estrogen and depression affect how we think of premenstrual syndrome (PMS)? Does it really exist in the way that we thought?

KJM & SAR: The idea that there is a connection between estrogen and depression changes much of our thinking about PMS. Very few men, women, or clinicians doubt the reality of PMS, but there remains some belief that PMS is either a social construction or just a common phenomenon whose symptoms are over exaggerated to elicit sympathy or some other secondary gain. Consider how often we hear statements like, “It’s just her time of the month,” or “She’s probably just having PMS.” These statements show how desensitized and immune we have become to the pain and debilitation that can accompany PMS. Unknowingly, these statements minimize or trivialize the depressive symptoms of PMS, which leads to both an under pursuit of treatment and an under administration of effective treatments.

This mindset is propagated because many individuals do not realize that the symptoms of depression, which are the most common features of PMS, appear to be intimately connected to the rise and fall of estrogen and progesterone. Estrogen peaks prior to ovulation and drops sharply toward the end of the menstrual cycle, whereas progesterone peaks after ovulation and before the menses. It is this rise in progesterone and withdrawal of estrogen that may account for some of the depressive symptoms emerging in PMS. In fact, if we were to plot the course of a woman’s mood onto the course of her menstrual cycle, the emerging picture would show depression peaking a few days before the onset of menstruation and rapidly disappearing once bleeding begins. Therefore, a woman’s mood during PMS cannot be disconnected from the hormonal and biological changes that are occurring during the luteal phases of her menstrual cycle.

This knowledge should alter the meaning that many of us ascribe to PMS. Rather than seeing the depressive symptoms of PMS as a social construction or an exaggeration, it is more appropriate to see them for what they are: a susceptibility to the changes in hormonal levels associated with the premenstrual phase of the menstrual cycle. By embracing this idea, there is less risk that PMS will be a source of shame or weakness that causes women to sit silently in their anguish and to feel helpless to control their symptoms. Instead, we are validating the experiences of women and encouraging them to pursue treatment and elicit support to maximize their lives.

NHP: Why do some women suffer from these conditions (PMS and post-partum depression) and others do not?
   
KJM & SAR: This is a good question because all women experience changes in estrogen levels following delivery and during the premenstrual phase, but not all women develop depression. The primary culprit for depression is not estrogen changes themselves, but rather a woman’s sensitivity to these changes. PMS is not the result of high progesterone and low estrogen, nor is post-partum depression the result of the elevation and sudden loss of estrogen prior to and following delivery. Rather, some women have an unusual response to natural hormonal changes in a way that lowers their threshold for developing depression. These estrogen changes may prompt a cascade of changes in serotonin, thyroid function, and other systems that result in depression, but only for a certain subset of women. It is sensitivity to these changes in levels of estrogen and progesterone that may account for differences in mood and PMS.

NHP: A recent study in the Journal of the American Medical Association analyzed data from the Women's Health Initiative concluded that women still face increased risks of stroke and breast cancer from hormone replacement therapy. What is your stance on HRT, and what are your opinions (if any) on this study?

KJM & SAR: This is a difficult question to answer for several reasons. First of all, there has been much criticism of the data collected and analyzed from the Women’s Health Initiative (WHI). At a basic level, there is criticism that the women included in the study were significantly past menopause and were typically in their mid-sixties. HRT is advocated for the initial years surrounding menopause, which occurs around age fifty-one. To begin HRT almost fifteen years after menopause is not typical, thus the sample of the women included in the WHI study has been criticized. Both the sample and the manner in which the data has been analyzed have been seen as flawed by some researchers. In addition, there have been other researchers that have conducted meta-analyses (examining many studies that are typically considered solid research) and they have found that there is no overall increase risk for breast cancer across the lifespan of a woman who has used HRT as compared to the woman who has never used HRT. Finally, there has been a recent study in JAMA that indicated that the use of ERT for seven years did not increase the risk of breast cancer in postmenopausal women with a prior hysterectomy. Given that many researchers can take a variety of stances, it is difficult to make one conclusion based on one research article. Rather the pros and cons should be weighed by every woman, with the guidance of her doctor. In addition to all this information about cancer, it is also important to consider the potential positive impact of ERT/HRT on the brain, including better verbal memory, increased brain metabolism, and better mood. These are the issues that we cover in our book.

In conclusion, the statement released by the International Menopause Society and quoted in the recent Lancet article might best summarize the situation: “Such manipulation of data can only cause unnecessary distress to the many women who are benefiting from HRT.” With this they site an example, “Risk is far better reported in absolute numbers rather than relative risk or percentage. [For example,]  the absolute risk for ovarian cancer in the study [Million Women Study] was only one extra case per 2500 women after five years and mortality was one per 3300 over five years.” These statements are very much in line with our approach as well. Let the data speak for themselves and read the original research articles, in addition to the up-to-date meta-analyses, which takes into account decades of research.

NHP: In your book you state that a deficiency of serotonin is the reigning theory about the biological cause of depression. Does estrogen have an effect on serotonin levels, and if so what are they?

KJM & SAR: Estrogen appears to have a significant effect on serotonin levels. In the brains of those who are depressed, there is a lack of serotonin, which can occur due to reduced serotonin production and release, over-activity of receptors that remove serotonin, and/or over-activity of the chemicals that break serotonin down. Estrogen naturally affects each of these levels of serotonin functioning, which is why estrogen may serve as a natural anti-depressant. The following is a short list of the ways estrogen influences serotonin:

• Serotonin Creation: Estrogen displaces tryptophan, one of the building blocks of serotonin, from its binding sites, which increases its availability for creating more serotonin
• Serotonin Breakdown: To prevent too much breakdown of serotonin, estrogen interferes with enzymes that deconstruct serotonin.
• Serotonin Uptake: Estrogen increases the retrieval of serotonin by increasing the density of binding sites and receptors that are friendly to serotonin, particularly in areas that control mood.

Put simply, this list shows how estrogen makes more of the raw elements necessary for creating serotonin, removes the materials that interfere with making it, and provides more containers for it to be gathered. Therefore, the rise and fall of estrogen alters the neurotransmitter landscape in a way that directly influences a woman’s vulnerability to depression.