Differentiating Perimenopause: Avoiding Diagnostic Pitfalls – Thara Vayali, ND

The Perimenopause Problem: Navigating the Transition and Its Challenges

Thara Vayali, ND

Exploring the complexities of perimenopause, its clinical challenges, and how naturopathic physicians can differentiate symptoms and address root causes.

This article delves into the nuances of perimenopause, outlining its stages, associated symptoms, and the importance of differential diagnosis. It highlights how naturopathic physicians can offer holistic, patient-centered care to address the root causes of symptoms often misattributed to perimenopause.

Each year in the United States, more than 2 million women enter menopause.1,2 Statistics reported through reputable and commonly referenced sources vary. Still, according to the 2020 US Census data and the number of women reaching the average age of menopause annually, the estimate is closer to 5600 women per day.1,2 Versions of this staggering statistic have influenced a frenzy of education, advocacy, and solutions for women between the ages of 35-60. The rise in awareness has broadened beyond menopause into discussions about the menopausal transition, or perimenopause, with a rallying cry for a preventative approach to managing the symptoms of perimenopause with hormone therapy and antidepressants. 

The clinical challenge of this attention is that perimenopause has a gold standard, scientifically accepted definition within research,3 as awareness grows, even within research, the nomenclature varies.4 This has left media sources to broaden the definition as it suits their narrative. Coupled with the fact that perimenopause does not have a pathognomonic biomarker, there is a risk of overdiagnosis when female patients above age 35 present with symptoms.5-8 This I refer to as the ‘Perimenopause Problem.’ As the term perimenopause is now coming into the office from patients themselves, it becomes increasingly important for clinicians to have a keen knowledge of the definitions related to the reproductive stages and their differential diagnoses.

Defining Reproductive Stages

The gold standard in defining menopause and related stages was developed at the Stages of Reproductive Aging Workshop (STRAW) in 2001 with experts from 5 countries evaluating the best evidence available, and it was later expanded on in 2011.3 The STRAW 10+ updates describe female reproductive life in three broad phases: Reproductive, Menopausal Transition, and Postmenopause. These phases are divided into specific stages, providing a comprehensive framework for understanding women’s reproductive aging progression.

The stages orient around the day of confirmation of menopause, which could be considered Stage 0: the date a woman has not had an ovulatory cycle for 12 consecutive months after age 45, also called the final menstrual period (FMP).3,6-9. Before age 45, this length of time with non-ovulatory cycles would be considered premature ovarian insufficiency (POI) or amenorrhea.8 Because perimenopause includes all stages from Stage 3b to Stage -1 with wide variations in symptoms and signs, it is critical to know which stage your patient is in to validate symptoms if appropriate and trigger further investigation if symptoms have a mismatch with reported ovarian function. 

Below, I outline the relevant stages and their signs and symptoms, as defined by the STRAW 10+ updates and The Study of Women’s Health Across the Nation (SWAN).3,6 The terms menopausal transition and perimenopause are interchangeable terms:

Late Reproductive Stage (Stage -3):

• Subdivided into Stages -3b and -3a
• Stage 3b: Regular menstrual cycles, normal Follicle Stimulating Hormone (FSH), a potential decrease in Anti-Mullerian Hormone (AMH) and Antral Follicle Count (AFC)
• Stage -3a: Subtle changes in cycle length (1-2 days), increased early follicular phase FSH

Early Menopausal Transition/Perimenopause (Stage -2) 

• Menstrual cycles begin to shift by up to 7 days for some cycles
• Higher FSH only on extended cycles
• Estradiol remains relatively stable
• Few noticeable symptoms
• This stage, on average, occurs approximately four years before the FMP. The distribution expands to 7.5 years in 2.5% of the studied population.

Late Menopausal Transition/Perimenopause  (Stage -1)

• Ovulatory cycles missed for 60 days or more
• FSH level fluctuations between the reproductive range and menopausal range
• The sudden drop in estradiol levels correlates with common documented symptoms.
• This stage, on average, occurs approximately two years before the FMP. The distribution expands to 4 years in 2.5% of the studied population.

Menopause

• Ovulatory cycles have ceased for 12 months
• FSH levels rise, estradiol levels remain low

Early Postmenopause (Stage +1):

• Subdivided into Stages +1a, +1b, and +1c
• Reflects continued changes in FSH and estradiol levels for approximately two to ten years after the final menstrual period10 

The longitudinal SWAN data set has shown that the clinical and research assumptions that the menopausal transition only occurred in the 12 months before the FMP were misguided.6 The data shows that 2 years before the FMP, we saw a drastic drop and surge in estradiol and FSH, respectively.6 This is consistent across race, ethnicity, and BMI.6 

The criteria to note here is that the strong and compelling data on the symptoms of menopause and perimenopause are related explicitly to Stage -1 (late perimenopause), which occurs on average in the 2 years before menopause. It is critical to understand that therapies, such as estrogenic herbs and hormone replacement therapy (HRT), which may be appropriate for late perimenopause and menopause, should not be first-line treatments during the late reproductive and early perimenopausal years. Despite commonly referenced sources frequently citing the incorrect statistic that symptoms of perimenopause can start 10 years before menopause, there is no substantial evidence to support this claim.3,6-9 However, because there are many overlapping symptoms in late perimenopause to other common female-related conditions,11 the 10-year span validates and identifies that women from age 35 up until late perimenopause are indeed suffering. As naturopathic physicians, we can do the detective work required to treat the cause rather than assume perimenopause. 

Symptoms and Risk Factors of Perimenopause

Common Symptoms of Late Perimenopause

• Vasomotor symptoms are defined as hot flashes and night sweats12-14
• Sleep disturbances12-14
• Cognitive and short-term memory concerns15-18
• Depression and anxiety18-23
• Musculoskeletal pain syndromes24 

Risk Factors Associated with Estradiol Declines

• 2.6 fold increased risk for CVD when estradiol levels reach menopausal levels,25-28
• Significantly increased risk for osteoporosis due to increased osteoclastic activity in the 5-10 years post menopause29

An important caveat is that the above definitions and symptoms have a population to whom these definitions may not suit due to their masking of ovulatory symptoms. Individuals with POI, chronic illness with irregular menstrual bleeding, endocrine disorders such as polycystic ovarian syndrome (PCOS) or endometriosis, and long-term hormonal contraceptive use.30-33

The Importance of Differential Diagnosis

Conditions Mimicking Perimenopause Symptoms

Given the variability in symptoms during the late reproductive stage into the menopausal transition (ages 35-60), our task as naturopathic physicians is to differentiate perimenopause from other conditions within the nutritional, endocrine, and immune systems. 

The six conditions that may be presenting as a perimenopausal picture are mild dehydration, iron deficiency, long covid or similar chronic post-viral illnesses, autoimmune/inflammatory conditions, hypercortisolism, and hypothyroidism.

The symptoms of fatigue, weakness, and brain fog cross all six diagnoses. In addition, long covid, autoimmune conditions, hypercortisolism, and hypothyroidism, which occur primarily in women 34-40, may affect menstrual cycles and cause weight gain, joint inflammation, cognitive concerns, and mood changes.41-52 The cross-talk between these conditions and estradiol is emerging, where these symptoms have been shown to worsen during the low estradiol phases of the menstrual cycle. 53-55 

Emerging Research on Estradiol and Chronic Illness

Recent research suggests that COVID-19 and autoimmune conditions like systemic lupus erythematosus, myalgic encephalomyelitis/chronic fatigue syndrome, and rheumatoid arthritis may trigger early menopause.56-58 While the mechanism is unclear between any of these associations, these emerging associations put clinicians in a position to differentiate new mechanisms and the best routes to care. 

The Perimenopause Problem arrives with a triad of patient demand, lack of a laboratory diagnosis, and a clinical focus on declining or oscillating estrogen as the main culprit of symptoms. While pharmaceutical or herbal estrogen augmentation may improve symptomatology, they may mask underlying issues that deserve attention.

Core Principles of Perimenopausal Care

Foundational Clinical Assessments

In a clinic, when a patient presents with typical perimenopausal symptoms, the differential diagnosis begins with clinical assessments that naturopathic physicians are best suited to.  

An astute naturopathic approach to addressing these interwoven conditions is to start at the foundations of neuroendocrine health and work systematically toward downstream outcomes. 

1. Ensure adequate hydration, not simply water intake, but water absorption through scientifically balanced oral rehydration solutions 
2. Assess for micromineral deficiencies of iron, zinc, selenium, iodine
3. Rule out thyroid issues that can mimic perimenopause symptoms
4. Fat-soluble vitamin (Vitamins A, D, E, and K) assessment and support
5. Support methyl donors
6. Regulate cortisol secretions
7. Address inflammation
8. Assess ovulatory hormone patterns

The ‘Peri-Panel’: Comprehensive Baseline Lab Work

• A complete blood count (CBC)
• Iron studies (Ferritin, Total Iron, TIBC) with B12
• Thyroid panel (TSH, T4, T3, Anti-TPO, Tg-Ab)
• Vitamin D
• High-sensitivity C-reactive Protein (hs-CRP)
• Anti-nuclear Antibodies  and Rheumatoid Factor (ANA and RF)
• Salivary Diurnal Cortisol
• Day 3 Serum FSH and Luteinizing Hormone –  Between the ages of 30-45, these tests are often less helpful as cycles may be variable or affected by hormonal contraception. Aside from fertility, this test should only be performed in suspected PCOS, late perimenopause, or premature menopause due to known risk factors59.
• Salivary Progesterone and Estradiol 10 days before the predicted menstruation date. Similar to serum FSH and LH markers, these results should not be relied on as a diagnostic for perimenopause and instead be used in suspected luteal phase deficiency, endometriosis, or estrogen dominance60.

Conclusion

The Perimenopause Problem is characterized by increasing awareness and misinformation, leading to potential misdiagnoses and an over-reliance on hormonal therapies to address common presenting symptoms in this age range. This presents a significant challenge for both women and healthcare providers. The lack of a universally used definition in messaging and the absence of specific biomarkers for perimenopause complicate the clinical landscape, making it essential for practitioners to differentiate between perimenopause and other health conditions that may mimic its symptoms. The STRAW 10+ framework offers a structured approach to identifying the various stages of reproductive aging, emphasizing the importance of differentiating symptoms, signs, and timing of early versus late perimenopause. Naturopathic physicians are well-equipped to investigate underlying health issues that may contribute to symptoms often attributed to this phase, such as chronic illnesses, autoimmune conditions, and nutrient imbalances. By employing a comprehensive assessment strategy, including a Peri-Panel of relevant tests, clinicians can tailor interventions that alleviate symptoms and address root causes. Ultimately, a holistic approach that considers the interplay between hormonal health, lifestyle factors, and individual patient needs will ensure that women receive appropriate care during this demanding period and empower them with body literacy and personalized solutions before falling prey to narrow perspective solutions presented by the burgeoning interest in women’s health. 

References

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