2005 Literature Review Proposes Serotonin Mediates the Effects of Estrogen

The authors argue that the serotonergic mediation of estrogen has important clinical implications and warrants further investigation.


PSR has been publishing articles on the often-overlooked concept of women and psychedelics. One article from December 2019, Female Hormones, 5-HT2A Receptors, and Psychedelics, summarized several scientific studies investigating this concept. This article is a more detailed look into one of those studies.

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology.

The authors of a 2005 review article in BMC Women’s Health integrated information from studies in the disciplines of endocrinology, molecular biology, neuroscience, and epidemiology.1 The author’s analysis indicated that serotonin might mediate the effects of estrogen in a variety of ways. They stated,

We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution.

The paper summarizes the literature of the time, focusing on the effects of serotonin and estrogen on four physiological systems: central nervous, skeletal, vascular, and immune, and breast cancer. The authors confined their analysis of the effects of estrogen to the known functions of serotonin and its receptors. The overall intent of their review was to propose a shift in strategic thinking for researchers:

We hypothesize that considering how estrogen’s actions might be mediated by serotonin explains findings that would not be predicted by either action alone and suggests possible treatment strategies that have not yet been considered.

A Note on Serotonin Receptors and the Psychedelic Effect

Serotonin and its receptors have a myriad of functions in the body. Among them is the psychedelic effect, which is attributed to the 5-HT2A receptor, although others are likely involved. Psychedelic Science Review has published articles on the serotonin receptors such as The Serotonin Receptors: An Overview and Their Importance in Psychedelic Research.

Modulation of the psychedelic effect is just one aspect of female hormones and the serotonin system. The selected examples below capture the complexity of the effects and body systems that are involved. This drives home how profound and far-reaching the impact of these hormonal interactions are.

Effects of Estrogen and Serotonin on the Central Nervous System

In terms of the central nervous system (CNS), the authors of the review point out from their analysis that estrogen influences the transmission of pain, dizziness, headaches, nausea, and depression. And, these effects are known to be a consequence of serotonin signaling. As a result, the interaction and modulating effects of estrogen and serotonin may account (and suggest treatments) for conditions including headaches, night sweats, fibromyalgia, and depression in women.

Outside the CNS, estrogen influences bone density, vascular function, and self-recognition by the immune system. These are also effects that are consistent with those of serotonin. From this, the authors propose that a better understanding of the interactions between serotonin and estrogen may reveal novel and critical information for treating diseases like multiple sclerosis, lupus, osteoporosis, and blood clots (and the resulting heart attacks and strokes).

Effects of Estrogen and Serotonin on Breast Cancer Risk in Obese Women

The integration of serotonin and estrogen research results also shed light on some mechanisms related to breast cancer. The researchers suggested that the effect of serotonin mediation on estrogen may account for the difference in breast cancer risk due to obesity before and after menopause.

When thought of solely in terms of the cumulative exposure to estrogen over time, obesity (which increases estrogen) would be expected to increase breast cancer risk regardless of a woman is pre- or postmenopausal. However, breast cancer risk in obese women is less before menopause than following. The authors applied what was known about serotonin and its receptors to this mystery and proposed an explanation. The explanation centers around another female hormone, progesterone, and a physiological process called apoptosis.

Apoptosis is basically the programmed death of a cell. It is a normal process that occurs are part of regular cell turnover. It is also crucial in fetal development, such as during the formation of fingers and toes. If apoptosis is suppressed, it can result in uncontrolled cell proliferation, which may result in cancer. Too much apoptosis causes disease and tissue damage, among other issues. Clearly, apoptosis must be tightly controlled by the body. Also crucial to the author’s explanation is that the activation of 5-HT2A receptors promotes apoptosis. Conversely, activating 5-HT1A receptors suppresses apoptosis.

The researchers proposed that in obese women, increased estrogen in the presence of progesterone increases the activation of serotonin 5-HT2A receptors. However, increased estrogen without progesterone increases the activation of 5-HT1A receptors. This explanation makes sense considering progesterone levels are higher in premenopausal women and decrease as a woman enters perimenopause and then menopause. Therefore, they contend, progesterone has a protective effect against breast cancer in premenopausal women.

The Entourage Effect is Unique in Women

In concluding, the authors stated:

Altering specific aspects of the serotonergic system, rather than simply increasing E2, could allow clinicians to target treatments in particular tissues or towards particular receptor types, alleviating undesirable side effects of E2 administration.

Whether today or in 2005, it isn’t earth-shattering news that female hormones make women unique. The new ideas explained in detail in this review paper, however, integrate the science of estrogen with serotonin. Instead of focusing solely on the effects of the female hormones, these scientists observed relationships suggesting that serotonin modulates the effects of estrogen. In other words, an entourage effect.

More research is needed to understand the entourage effect in women. With the current explosion of interest in psychedelic research, this is a critical concept to understand and master. More knowledge in this area will lead to formulations containing precise amounts of specific compounds.

Barb Bauer Headshot

Barb is the former Editor and one of the founders of Psychedelic Science Review. She is currently a contributing writer. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.


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