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A breakthrough study by the School of Life Sciences and the Gerald Choa Neuroscience Institute at The Chinese University of Hong Kong (CUHK) has revealed for the first time that hormonal imbalance during women’s perimenopausal period affects brain cell energy metabolism, significantly increasing the risk of Alzheimer’s disease (AD). The research shows that when levels of oestradiol[1] (E2) remain chronically higher than those of progesterone[2] (P4), it disrupts the cholesterol metabolism and energy production systems of neurons, rendering brain cells more susceptible to damage. This discovery offers a new direction for the early prevention of neurodegeneration in women. The findings have been published in the international journal Nature Communications.

Beyond reproduction, hormonal balance impacts brain health

E2 and P4 are female hormones with critical functions for physiological systems. In the brain, E2 promotes neuronal activity, aiding learning and memory; P4 modulates the excitatory effects of E2, helping to improve sleep quality and relieve anxiety. During the luteal phase[3] of the menstrual cycle, the secretion of P4 in the female body can surge to 1,400% above baseline levels, far exceeding the 220% rise in E2. This high level of P4 is maintained for up to 10 days during the cycle, highlighting its critical role in balancing E2.

However, as women enter perimenopause, hormones begin to fluctuate, often leading to a state where E2 remains relatively too high while P4 is insufficient, a condition known as oestrogen dominance. Perimenopause can last from six to nine years. According to previous reports, in women aged 40 to 58, this state of oestrogen dominance can persist for up to one-third of the perimenopausal period. Being in a state of imbalance for a prolonged period could increase the chance of epilepsy and stroke, and might potentially raise the risk of developing AD and related neurodegenerative conditions.

Women face higher risk of Alzheimer’s disease

The scientific community has long recognised that women are at a greater risk of developing AD than men, with the risk increasing significantly after they enter menopause. However, the specific mechanisms behind this have not been fully understood.

The CUHK team used mouse models to simulate the hormonal fluctuations of female perimenopause, combined with analysis of human brain data. The research results revealed that P4 guides E2 in regulating cholesterol synthesis within neurons. Cholesterol is not just a structural component of cells but also a key signal that activates the mitochondria, cells’ energy production line. Oestrogen dominance not only weakens the energy production efficiency of neurons but also exacerbates brain cell energy imbalance. This can trigger toxic reactions from neuronal over-excitation, leading to the collapse of energy metabolism and apoptosis, or cell death, ultimately increasing the risk of pathological features associated with AD.

Hormone replacement therapy: the importance of progesterone supplementation

The impact of hormonal imbalance on the brain begins during perimenopause. Restoring balance through P4 supplementation at this stage can help protect neurons and prevent neurodegeneration. This study provides key scientific evidence that can help to optimise the timing and composition of hormone replacement therapy (HRT). Combined with results from various international studies and surveys, it confirms that the use of natural or highly stable synthetic P4, along with early intervention measures, contributes to the maintenance of brain health.

• The Women’s Health Initiative Memory Study (WHIMS) previously reported that combined E2 and progestin therapy increased the risk of neurodegeneration. However, the study used early synthetic progestins rather than the body’s natural P4. Many early synthetic progestins can convert into oestrogens or androgens in the body, exacerbating the imbalance. Additionally, the study subjects included only post-menopausal women aged 65 and older, making it difficult to reverse neuronal damage caused by hormonal changes that occurred years earlier, during perimenopause.
• The French E3N Study, which tracked over 80,000 post-menopausal women for an average of more than eight years, found that oestrogen-only therapy increased breast cancer risk by 29%, while oestrogen combined with those early synthetic progestins increased the risk by 69%. In contrast, treatment combining oestrogen with natural micronised P4 did not significantly increase the risk of breast cancer.
• In a recent randomised controlled trial, daily oral administration of natural P4 significantly reduced night sweats and hot flashes in perimenopausal women, while improving sleep quality and helping to stabilise mood.

E2 and P4: potential for identification of high-risk groups

Corresponding author Professor Kim Chow Hei-man, Associate Professor in the School of Life Sciences at CUHK, expressed hope that by revealing the synergistic work of P4 and E2 – including the regulation of cholesterol metabolism, mitochondrial function and neuronal stability – this research will reawaken public attention to P4 and brain health.

Professor Chow added that plasma E2:P4 ratio could potentially serve as biomarkers to help identify perimenopausal female groups at higher risk of cognitive decline. The research team also hopes that future studies of women’s health will further explore the interactions between E2 and novel synthetic progestins, as well as their impact on neuronal health. This will assist in optimising HRT strategies and better grasping the optimal timing for using natural P4.

For the full research, please visit: https://www.nature.com/articles/s41467-025-66726-4

[1] Oestradiol is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as the estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female pattern of fat distribution.

[2] Progesterone is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy and embryogenesis of humans and other species. It is the major example in the body of a group of steroid hormones called the progestogens.

[3] The luteal phase refers to the latter half of the menstrual cycle.