Post-Menopausal women see us for many reasons and many symptoms. In the initial consultation, when we sit down and discuss the challenges these women may be facing, one symptom that many women report is that they are more “forgetful,” or can’t remember simple things, such as “where did I just put my keys.” For some women, this of course would be a cause of great concern.
But being forgetful or suffering from “brain fog” is usually not the only problem these women are facing. Memory problems are just one challenge. Depleted hormone levels and cardiovascular risks are others and all three have been tied together.
The issue of cognitive health in women is complex
Helping patients with cognitive dysfunction can be complex as there are many factors to consider. One problem is the controversies surrounding the benefits or risks of synthetic estrogen therapy. Let’s recall that the famous hormone study of 2004, which we will discuss below, concluded that synthetic hormone therapy – Premarin was associated with increased risk for dementia and reduced cognitive function.
A June 2020 paper (1) outlined some of these complexities and risks.
“Estrogens play a crucial physiological function in the brain; however, debates exist concerning the role of estrogens in Alzheimer’s disease. Women during pre-, peri-, or menopause periods are more susceptible for developing Alzheimer’s disease, suggesting the connection of sex factors and a decreased estrogen signaling in Alzheimer’s disease pathogenesis (development). Yet, the underlying mechanism of estrogen-mediated neuroprotection is unclarified and is complicated by the existence of estrogen-related factors. Consequently, a deeper analysis of estrogen receptor (ER) expression and estrogen-metabolizing enzymes could interpret the importance of estrogen in age-linked cognitive alterations.
Previous studies propose that hormone replacement therapy may attenuate (reduce) Alzheimer’s disease onset in postmenopausal women, demonstrating that estrogen signaling (disrupted or bad cellular communications when a women is in a “disease” not healthy state) is important for the development and progression of Alzheimer’s disease.”
Because of the 2004 Woman’s Health Initiative findings, synthetic Hormone Replacement therapy (HRT) is usually not prescribed for memory disorders. It is prescribed for common menopausal symptoms. It however became clear to some researchers that hormone replacement therapy was helping some women with cognitive dysfunction.
This line of research was expanded on in a May 2021 study (2) which suggested: “women approaching menopause suffered from altered functions in brain regions related to cognitive function, working memory, the results also revealed a direct association between levels of E2 and brain functions in perimenopausal women.”
So why not use estrogen to help problems of memory?
A December 2018 paper (3) led by researchers at Nova Southeastern University and Georgetown University, issued a paper: “A Heartfelt Message, Estrogen Replacement Therapy: Use It or Lose It”
Here is a summary as it impacts cardiovascular and cognitive health in postmenopausal women:”
“The issue of cardiovascular and cognitive health in women is complex. During the premenopausal phase of life, women have healthy blood pressure levels that are lower than those of age-matched men, and they have less cardiovascular disease. However, in the postmenopausal stage of life, blood pressure in women increases, and they are increasingly susceptible to cardiovascular disease, cognitive impairments, and dementia, exceeding the incidence in men.
The major difference between pre- and postmenopausal women is the loss of estrogen.
Thus, it seemed logical that postmenopausal estrogen replacement therapy, with or without progestin, generally referred to as menopausal hormone treatment, would prevent these adverse (symptoms and conditions).
However, despite initially promising results, a major randomized clinical trial refuted the benefits of menopausal hormone treatment, leading to its falling from favor.”
The study that these researchers are talking about is the famous 2004 study (3) “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.” which, because of the concerns of using equine (horse) estrogen in women led to the recommendation that hormone replacement not be used therapeutically for the prevention of cardiovascular disease. The results of this study led to the recommendation that menopausal hormone therapy for the prevention of cardiovascular disease be halted in almost all patients. The 2018 study above questions this line of thinking as well as a September 2018 study in the journal Brain Sciences (4).
In this paper the researchers noted:
While the evidence supporting a link between estrogen depletion and risk for Alzheimer’s disease appears relatively consistent, the influence of hormone therapies containing estrogen to enhance cognition (e.g., during menopause) or reduce Alzheimer’s disease risk is controversial and the results are inconsistent.
The Women’s Health Initiative Memory Study (WHIMS), an ancillary study of the Women’s Health Initiative (WHI) hormone therapy trials, (the 2004 study) was conducted a decade ago and concluded that Premarin (estrogen plus a synthetic progestin) was associated with increased risk for dementia and reduced cognitive functioning.
However, the initial interpretation of the Women’s Health Initiative Memory Study findings have since been criticized based on a number of issues. These include the idea of a healthy cell bias, which suggests estrogens will be neuroprotective in a healthy environment but not in a disease environment. The WHIMS study included participants that had health disorders, and several studies have since suggested that the efficacy of hormonal therapy may be contingent on the health status of individuals, whereby the estrogen’s neuroprotective effects may depend on having healthy neurons. A second area of critique relates to the ‘critical window’ or ‘timing’ hypothesis, which proposes that hormone therapy is only effective when initiated early in menopause or just prior to menopause (the women in the WHIMS study averaged 15 years post-menopause).
The type of hormone therapy is also considered relevant to the potential for cognitive benefits and/or risks. The hormone therapy in the Women’s Health Initiative Memory Study was Premarin which is approximately 50% sulphated estrone and 1% estradiol, plus a synthetic progesterone. This is relevant as 17β-estradiol has positive effects on cognition, whereas estrone has been associated with negative effects on cognition.
Now what does this mean?
The debate as to whether estrogen or hormone therapy will be beneficial or harmful centers around the use of the controversial synthetic estrogen and progesterone (Premarin ) which is derived from pregnant horses. These estrogens have been shown to have a negative impact on cardiovasuclar disease, Alzheimer’s disease and memory and cognitive problems among other concerns.
Hormone therapy does not work the same way for every woman
Jumping to a January 2021 (5) paper, the study’s authors wrote: “Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer’s disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy where possible benefits include a delay in the onset of dementia-yet findings are inconsistent.” In other words, estrogen therapy may help some, not others, there is also still the concern with side-effects of the synthetic hormones. Let’s emphasize again that this is a discussion of synthetic hormone therapy. However the researchers did find: “Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of hormone therapy modifies the relation between Body Mass Index and brain volume positively.”
Hormone therapy could positively impact memory loss and memory loss impacted by obesity.
The role of oxidative stress
A September 2021 study (6) from doctors at the University of North Texas Health Science Center found “Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50-70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex (gender) is also an important risk factor. Sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions.
Simply, sex hormones are NOT neuroprotective in high oxidative stress conditions. If you have issues with chronic inflammation, hormone therapy will likely not protect you from cognitive dysfunction.
Hormone Replacement Therapy
Since the publication of the Women’s Health Initiative (WHI) hormone therapy trials 16 years ago, many women have been denied or have discontinued Hormone Replacement Therapy because of the risks associated with synthetic hormones. The research we have cited above from 2018 – 2020 shows that doctors are now questioning parts of this study because of the evidence that estrogen could help protect against memory problems and Alzheimer’s disease by addressing other health concerns in the patient including cardiovascular disease.
At the Magaziner Center for Wellness, we treat many women, with bio-identical hormones (BHRT). Bio-identical hormones are different than synthetic hormones because they are structurally and chemically the same as the three estrogens naturally produced by the body – Estriol, Estradiol and Estrone and natural progesterone, testosterone and others. Synthetic hormones – namely conjugated estrogens feature a manipulated form of the three estrogens. In our expereince we have found the body responds to and metabolizes synthetic hormones differently than bio-identical hormones. Bio-identical hormones are far safer and more effective than synthetics and, therefore, have grown in use. At the Magaziner Center for Wellness, we have been treating patients for more than 30 years with BHRT.
Is bio-identical hormones right for you? This is best answered in a consultation with your physician and following appropriate lab work.
1 Uddin MS, Rahman MM, Jakaria M, et al. Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia. Mol Neurobiol. 2020;57(6):2654-2670. doi:10.1007/s12035-020-01911-8
2 He L, Guo W, Qiu J, An X, Lu W. Altered Spontaneous Brain Activity in Women During Menopause Transition and Its Association With Cognitive Function and Serum Estradiol Level. Frontiers in endocrinology. 2021 May 11;12:548.
3 Speth RC, D’Ambra M, Ji H, Sandberg K. A heartfelt message, estrogen replacement therapy: use it or lose it. Am J Physiol Heart Circ Physiol. 2018;315(6):H1765-H1778. doi:10.1152/ajpheart.00041.2018
4 Anderson GL, LimacherUddin MS, Rahman MM, Jakaria M, et al. Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia. Mol Neurobiol. 2020;57(6):2654-2670. doi:10.1007/s12035-020-01911-8 M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701‐1712. doi:10.1001/jama.291.14.1701
5 Gurvich C, Hoy K, Thomas N, Kulkarni J. Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process. Brain Sci. 2018 Aug 28;8(9):163. doi: 10.3390/brainsci8090163. PMID: 30154388; PMCID: PMC6162653.
6 Sumien N, Cunningham JT, Davis DL, Engelland R, Fadeyibi O, Farmer GE, Mabry S, Mensah-Kane P, Trinh OTP, Vann PH, Wilson EN, Cunningham RL. Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress. Endocrinology. 2021 Sep 1:bqab185. doi: 10.1210/endocr/bqab185. Epub ahead of print. PMID: 34467976.
7 Boyle CP, Raji CA, Erickson KI, Lopez OL, Becker JT, Gach HM, Kuller LH, Longstreth Jr W, Carmichael OT, Riedel BC, Thompson PM. Estrogen, brain structure, and cognition in p ostmenopausal women. Human brain mapping. 2021 Jan;42(1):24-35.