Elevated beta human chorionic gonadotropin (hCG) in postmenopausal women is an important finding, which frequently brings diagnostic uncertainty.
Whereas beta hCG has been historically associated with pregnancy, relatively low elevations are not uncommon for women who have undergone menopause.
With this community, pregnancy is essentially ruled out and the differential diagnosis includes physiological, analytical and pathologic reasons.
A detailed knowledge of these mechanisms is required to prevent undue anxiety, inappropriate tests and potentially erroneous diagnoses from being made.
Most common, clinically relevant etiology of mildly elevated beta hCG in postmenopausal women occurs through pituitary secretion.
Decreased levels of oestrogen and progesterone in the postmenopausal years displace the normative negative feedback of the hypothalamic–pituitary axis.
That leads to increased release of gonadotropins, especially luteinising hormone (LH) and follicle-stimulating hormone (FSH).
Because LH and hCG share a common structure, the pituitary gland is capable of also producing small amounts of hCG.
While this is physiological, it is a benign phenomenon.
Therefore, pituitary hCG tends to be low (generally less than 14 IU/L) and related to augmented FSH levels (often being greater than 30-40 IU/L).
These values are often stable on repeat measurements and can be more convincingly confirmed by suppression following short-term oestrogen therapy.
This mechanism is the most likely explanation among asymptomatic postmenopausal females who exhibit low and stable levels of beta hCG.
False readings
Another consideration is analytical error, the presence of assay interference, often called “phantom hCG.”
This is because heterophile antibodies present in patients’ serum disrupt the immunoassay (a laboratory technique designed to identify or measure specific substances, known as analytes, within a sample) to give falsely high beta hCG levels.
When these antibodies bind nonspecifically to the components of the assay, it can lead to misleading readings.
Clinically, this should be suspected when serum and urine results are inconsistent – usually a positive serum beta hCG with a negative urine test.
Furthermore, values can be very irregularly low for lack of clear association with the clinical signs.
As heterophile antibodies are not excreted in urine, urine beta hCG testing is a useful confirmatory step.
Additional confirmation is possible with a diluted assay/assay with different platforms.
Knowing this reason is important because not being aware can cause unnecessary imaging (and/or invasive practice) for each patient.
Possible tumour
Neoplastic causes, although not usually discussed, require attention, especially where the clinical picture is atypical.
These consist of both trophoblastic and non-trophoblastic neoplasms (abnormal growth of cells).
Gestational trophoblastic disease (GTD), including invasive mole or choriocarcinoma, is extremely rare among postmenopausal women but is an important differential diagnosis.
In these cases, beta hCG levels are usually significantly elevated and show an increasing trend over time.
Patients may also suffer from symptoms like vaginal bleeding.
The extent of elevation is generally well above one experienced in benign pituitary secretion, thus keeping the distinction clinically pertinent.
Moreover, non-trophoblastic malignancies can also produce beta hCG ectopically.
Lung tumours, tumours of the gastrointestinal tract, kidneys and breast have all been associated with it.
In these instances, beta hCG readings are usually mild to moderately high and may be accompanied by systemic symptoms such as weight loss, fatigue or other unusual clinical presentations.
Although a rare cause, it has clinically severe consequences and needs to be taken into account, especially if laboratory studies are not as benign as intended or if other relevant features are observed.
Other triggers
Exogenous sources of beta hCG could also be a trigger, particularly within the modern medical and wellness system.
Beta hCG may be taken as part of weight loss regimens, anti-ageing treatments or, at a later date, in fertility.
Fertility-related use is not common in women in the postmenopausal period, but it is still necessary to have an extensive medication and supplement history.
In settings where integrative or longevity medicine is utilised, this causation relates more than ever and it should not be left unnoticed.
The presence of small changes in beta hCG concentration may also be due to renal impairment.
Low renal clearance may contribute to accumulation of the hormone, especially in elderly patients with decreasing kidney function.
Though not a main reason, this can make low-level elevated levels more significant and therefore should be contemplated when no other explanation is evident.
Evaluation of renal function may be a fairly routine part of the whole process.
The clinically applicable interpretation of beta hCG in postmenopausal women should be based on three main aspects, which would be the absolute level, temporal trend and overall clinical setting.
A typical benign phenotype will be beta hCG 14 IU/L, a growing trend toward serial testing, the presence of vaginal bleeding or pelvic complaints, unexplained weight loss, or abnormal imaging findings.
In such instances, additional imaging (ultrasound or computed tomography) and referral to specialist may be indicated to rule out malignancy or other life-threatening pathology.
A modest increase in beta hCG in postmenopausal women is, if not rare, a benign and physiological finding, most frequently attributed to pituitary secretion.
A more organised and methodical approach is necessary to differentiate between assay interference and more significant pathological causes.
By utilising laboratory results, the clinical context, and relevant follow-up, healthcare professionals can arrive at an accurate diagnosis that incorporates both laboratory findings and clinical insights.
Additionally, thorough documentation and effective communication with patients are crucial for ensuring safe clinical practice and providing medico-legal protection, while also helping to prevent unnecessary interventions.
Datuk Dr Nor Ashikin Mokhtar is a consultant obstetrician and gynaecologist, and a functional medicine practitioner. For further information, email starhealth@thestar.com.my. The information provided is for educational and communication purposes only, and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star does not give any warranty on accuracy, completeness, functionality, usefulness or other assurances as to the content appearing in this column. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.
