Perimenopause is the transitional phase leading up to menopause, when a woman’s body begins to shift away from regular menstrual cycles. This stage of life often presents complex challenges for many women, as hormone levels can fluctuate significantly. While it can begin anywhere from a woman’s 30s to her 50s, it is often accompanied by a wide range of symptoms, including changes in menstrual patterns, sleep disturbances, fatigue, digestive issues, and shifts in mood and libido. Notably, up to 70% of women experience mood-related and cognitive symptoms during this transition, such as irritability, low mood, and difficulty concentrating. The conventional medical model can often overlook these symptoms or wrongly attribute them to other conditions, while a holistic approach typically seeks to understand the root cause.
As these hormonal fluctuations occur, imbalances between estrogen and progesterone may develop. One commonly observed pattern is estrogen dominance, which refers to a relative excess of estrogen compared to progesterone. This can happen when progesterone levels decline while estrogen remains within a normal range, or when estrogen itself is elevated, even if progesterone is adequate. This is typically the result of the body making too much estrogen, an increased intake of estrogen from medication, or improper metabolism of estrogen in the body. While estrogen dominance may arise during perimenopause, it has also been associated with other factors, such as polycystic ovary syndrome (PCOS) or obesity.
A recent case report examined the effects of a 14-month personalized nutrition and nutraceutical program in a 44-year-old woman experiencing debilitating symptoms during perimenopause. At her initial visit, she reported a sudden onset of weight gain in the abdominal and breast regions, along with breast tenderness, digestive discomfort, fatigue, and difficulty sleeping, without a clear cause. She also described anxiety, depression, ADHD-related symptoms, inattentiveness, and reduced tolerance to exercise, which interfered with her ability to complete work tasks. At that time, her BMI was 27.8 kg/m², classifying her as overweight. Her medical history included celiac disease, Hashimoto’s thyroiditis, osteoarthritis, and mitral valve prolapse, along with uterine cysts and fibroids, as well as a history of childhood trauma. After limited improvement with conventional care, she decided to pursue a root-cause approach to better manage her symptoms.
Before beginning the program, the patient had been prescribed a natural desiccated thyroid medication, and was self-supplementing with products that included vitamin B6, selenium, zinc, licorice root, oregano oil (with ginger and fennel oils), a digestive enzyme blend (including betaine HCl, ox bile, and pancreatin), phosphatidylserine, and N-acetylcysteine (NAC), as well as bovine thyroid and liver extract. She also reported using castor oil packs as part of her routine.
At the start of the program, an initial 24-hour urinary hormone panel was completed. Results showed elevations in several key markers, including alpha-pregnanediol, beta-pregnanediol, estrone, estradiol, 2-hydroxy (2-OH) estrone, 4-hydroxy (4-OH) estrone, free DHEA, and DHEA-S. These lab readings indicated an estrogen dominant pattern, and suggested a possible insufficiency in phase I and phase II liver detoxification, in addition to possible adrenal hyperactivity, which may have been contributing to oxidative stress and histamine sensitivity.
Following this test, the patient was placed on a targeted functional protocol that included nutrition and nutraceutical interventions. This consisted of the previously prescribed natural desiccated thyroid medication, S-adenosylmethionine (SAMe) along with methylated B vitamins (including 5-methyltetrahydrofolate [5-MTHF], vitamin B6, and vitamin B12), and a comprehensive blend of nutrients and botanicals including calcium D-glucarate, chrysin, chaste tree extract, green tea extract, diindolylmethane (DIM), black cohosh, broccoli-derived compounds, and resveratrol to support estrogen metabolism, methylation, and detoxification pathways. While her previous self-supplementation was largely discontinued, her prescription medications remained unchanged.
As previously recommended by her physician, the patient continued a dairy and gluten-free diet, eating primarily whole foods and abstaining from alcohol and processed foods throughout the program. In addition, she incorporated daily walks before and after work to help manage stress, support mood, and regulate energy levels.
About three months into the protocol, diindolylmethane (DIM) supplementation, which had been included in the initial protocol, was increased to further support estrogen metabolism, following the onset of intermittent hives. One month later, the amount of calcium D-glucarate and broccoli-derived compounds, which had also been included in the initial protocol, were increased to further support estrogen detoxification. At approximately ten months, DAO enzymes were introduced to address ongoing digestive discomfort. Finally, at 12 months, her primary care provider initiated an iron support regimen due to persistent fatigue and low ferritin and iron saturation levels.
Following 12 months of supplementation, a 24-hour urinary hormone panel was performed at follow-up to assess changes in her hormone levels and detoxification pathways. The results indicated the restoration of several hormone metabolite markers, with many others trending in a favorable direction. Improvements observed in the follow-up test revealed:
Estrogen and progesterone metabolites:
Estrogen metabolism pathways:
Androgens and adrenal markers:
Stress hormones:
Methylation marker:
While her ADHD symptoms and brain fog persisted throughout the duration of the program, the patient reported symptom improvement in several areas. These included resolved breast tenderness, improved fatigue, reductions in self-reported anxiety and depression of roughly 80%, more manageable menstrual cycles, reduced bloating and gas by roughly 80%, improved food and exercise tolerance, and reduced insomnia with the patient reporting an additional hour of sleep per night on average. Overall, the patient reported greater control over health, reduced anxiety, steadier energy, improved digestive function, and greater work productivity. While ADHD symptoms and brain fog persisted, weight decreased by 10% and menstrual cycles became more manageable. At the time of writing, goals include addressing ADHD-related challenges that impact work performance and following up with the primary care provider regarding persistently low ferritin levels.
Clinical Pearls
These positive findings suggest that changes in estrogen metabolism and methylation capacity likely played a key role in the patient’s progress. As the authors note, follow-up testing showed a shift away from the more reactive 4-OH metabolites and toward the favorable 2-OH pathway, which is generally associated with less proliferative activity and more efficient estrogen metabolism. While total estrogen levels remained relatively stable, estradiol decreased toward the normal range, the 2-OH:4-OH ratio increased, and the 16-alpha-hydroxy pathway (16-OH) dropped below detectable levels, indicating a more balanced detoxification pattern. Progesterone metabolites also normalized, suggesting better overall hormone balance. Methylation capacity rose from low to within range, supporting the conversion of potentially harmful estrogen intermediates into less active, more easily excretable forms. Together, these shifts point to more efficient phase I and phase II detoxification pathways, likely explaining the changes in mood, menstrual symptoms, and overall functioning. In addition, the patient’s quick improvement in digestive symptoms following DAO supplementation suggests that impaired histamine clearance may have been a major contributor to her gastrointestinal and inflammatory symptoms.
This case illustrates the importance of taking a root cause approach when navigating perimenopause, as complex challenges can often arise. By supporting areas such as estrogen metabolism, detoxification, methylation, and histamine clearance, and using available testing to guide treatment, it may be possible to help attenuate many of the common symptoms associated with perimenopause. As with any single case report, these findings reflect an individual response and may not be generalizable. Further research is needed to better understand how supporting estrogen metabolism and methylation may influence outcomes across broader populations of women navigating this phase of life.
Learn more about perimenopause, hormone health, and detoxification:
Wellness Essentials: The Role of Key Nutrients in Women's Health at Every Stage
DIM to Promote Estrogen Homeostasis
Hormones: The Alchemists of Skin and Hair Health
By Jesse Martin, MS
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