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Menopause

Differential Diagnosis of Menopause

Genevieve Neal-Perry, MD, PhD 
Reviewed on July 22, 2024
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Introduction

The experience of symptoms during the menopause transition is a complex interplay involving true menopausal symptoms, aging-related symptoms and societal context. However, these factors lack clear definitions and often overlap.

Early onset of prolonged amenorrhea necessitates consideration of other diagnoses, such as polycystic ovary syndrome, secondary hypogonadotropic hypogonadism, hyperprolactinemia, thyroid disease, or uterine issues like Asherman syndrome. Severe depression or stress, along with significant weight loss, can also disrupt menstrual periods. Pregnancy should always be considered and tested for in cases of amenorrhea. All of these conditions can be associated with vasomotor symptoms (VMS), and mood changes, making specific laboratory testing based on clinical suspicion essential. Palpitations, heat intolerance, agitation, anxiety, sleep disturbances, weight loss and tremor can all be signs of hyperthyroidism, while fever or cough can point to an infection…

Introduction

The experience of symptoms during the menopause transition is a complex interplay involving true menopausal symptoms, aging-related symptoms and societal context. However, these factors lack clear definitions and often overlap.

Early onset of prolonged amenorrhea necessitates consideration of other diagnoses, such as polycystic ovary syndrome, secondary hypogonadotropic hypogonadism, hyperprolactinemia, thyroid disease, or uterine issues like Asherman syndrome. Severe depression or stress, along with significant weight loss, can also disrupt menstrual periods. Pregnancy should always be considered and tested for in cases of amenorrhea. All of these conditions can be associated with vasomotor symptoms (VMS), and mood changes, making specific laboratory testing based on clinical suspicion essential. Palpitations, heat intolerance, agitation, anxiety, sleep disturbances, weight loss and tremor can all be signs of hyperthyroidism, while fever or cough can point to an infection like tuberculosis.

It is crucial to differentiate perimenopausal depression from major depression and simple dysphoria. Major depression includes loss of interest in nearly all activities, while perimenopausal depression is usually accompanied by irritability and anxiety. Another distinguishing factor is the variability (lability) of mood in perimenopausal depression, setting it apart from the consistently low mood during major depression. Other potential diseases that can be mixed with perimenopausal depression include subsyndromal depression, adjustment disorder, psychological distress, bereavement, depressive episodes associated with bipolar disorder and various medical conditions that may contribute to depressive symptoms.

A variety of symptoms commonly associated with menopause may actually indicate autonomic disorders such as multiple sclerosis, tumors, such as pituitary tumors, prolactinoma, pheochromocytoma and carcinoid syndrome. Serotonin-producing carcinoid tumors may manifest with nocturnal diarrhea and episodic flushing without sweating. Phaeochromocytomas, which release adrenaline and noradrenaline, are characterized by persistent hypertension, flushing and profuse sweating, as well as episodic headaches and tachycardia. Therefore, regular cancer screening is crucial, as it could aid in the differential diagnosis of menopausal symptoms.

Diagnostic Tools for Menopause

To comprehensively assess a patient with menopausal symptoms, a thorough understanding of her past health history is crucial. This evaluation involves consideration of lifestyle, social status, current and previous treatments, previously and currently used medications, past operations and family health history. The patient's gynecological background and present problems must also be assessed. The physical examination is done by a healthcare provider. It includes visual inspection of the vulva, vagina, cervix and bimanual palpation of pelvic organs. In cases of abnormal discharge, immediate microscopic examination (a "wet smear") may be necessary.

While it is generally not recommended to conduct specific laboratory tests for menopause, there are cases where confirming ovarian failure is helpful. This is often done by checking for elevated Follicle-stimulating hormone (FSH) levels. The UK National Institute for Health and Care Excellence guideline suggests considering measuring FSH in symptomatic women aged 40 to 45 and in women under 40 years of age if menopause is suspected. However, the Choosing Wisely campaign by the American Board of Internal Medicine Foundation advises against measuring FSH concentrations in women in their 40s to identify the menopausal transition due to the variation in FSH levels throughout the menstrual cycle and between cycles. A potentially useful tool in predicting menopause timing is testing anti-Müllerian hormone levels. One cohort study of 50 women demonstrated that an anti-Müllerian hormone level below 0.05 ng/ml reliably predicted menopause within the following 5 years. Since inhibin B is the first hormone to decline in menopause, preceding a rise in FSH, testing its levels may be a useful way to indicate early menopause onset. Measuring estradiol during perimenopause isn't clinically useful, as its levels remain relatively stable until the late menopausal period. After the menopausal transition is over, consistently low estradiol levels and the absence of progesterone can indicate the completion of this stage.

Imaging measurements, such as antral follicle counts using transvaginal ultrasonography, recording of all follicles measuring ≤7 mm in diameter and assessing functional ovarian reserve, can provide insights into fertility status and ovarian aging. However, these methods are better predictors of fertility loss than menopause itself. Other proposed measurements, like total ovarian volume and stromal thickness, still lack the sensitivity and specificity required for clinical use. Osteoporosis is assessed by dual-energy X-ray absorptiometry (DXA). This type of screening is indicated for all women ≤65 years of age. Younger postmenopausal women should undergo DXA as well in the presence of osteoporosis risk factors.

Besides the traditional diagnostic tools, the gold standard for evaluating symptoms in menopause is the woman's self-report of her experience. All symptoms must be assessed, considering their intensity, location, temporal nature, frequency, affective impact and perceived threat. The individual woman's interpretation of her symptoms is crucial for determining management priorities and making shared decisions. Effective communication is essential for achieving positive outcomes. The Menopause Rating Scale II, a validated 11-item questionnaire that covers somatic, psychological and urogenital symptom clusters, is a valuable symptom assessment tool that facilitates diagnostics in clinical practice and research.

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