What does it mean if a woman not taking hormonal medications has normal progesterone levels in blood work but elevated levels in urinary metabolites?

Discordance Between Normal Serum and Elevated Urinary Progesterone Metabolites

This pattern most commonly indicates either inadequate adrenal suppression in undiagnosed congenital adrenal hyperplasia (CAH), topical progesterone contamination, or normal physiologic variation in metabolite excretion timing—and requires repeat testing with urinary steroid profiling to distinguish between these possibilities.

Understanding the Discordance

The disconnect between serum progesterone and urinary metabolites reflects several key physiologic principles:

• Urinary metabolites lag behind serum levels by 1-2 days, meaning elevated urinary pregnanediol-3-glucuronide (PdG) may reflect progesterone production from 24-48 hours earlier that is no longer detectable in serum 1
• Day-to-day variability in urinary metabolites is substantial, and the National Kidney Foundation recommends repeating measurements on 2-3 separate occasions before concluding that elevation is persistent 2
• Topical progesterone absorption creates a unique pattern where salivary and tissue levels rise significantly while serum levels remain unchanged or minimally elevated, potentially leading to elevated urinary metabolites without corresponding serum elevation 3

Most Likely Clinical Scenarios

Scenario 1: Undiagnosed Congenital Adrenal Hyperplasia

This is the most clinically significant possibility requiring immediate evaluation:

• Women with CAH due to 21-hydroxylase deficiency can have non-suppressible progesterone of adrenal origin that manifests as elevated urinary progesterone metabolites even when serum progesterone appears controlled 4
• Characteristic urinary steroid profiles by gas chromatography-mass spectrometry best distinguish this subgroup, showing specific progesterone metabolite patterns that indicate adrenal rather than ovarian production 4
• This pattern associates with menstrual disturbance, primary amenorrhea, and infertility due to failure of endometrial thickening from chronic progesterone excess 4

Scenario 2: Topical Progesterone Contamination

Even if the patient denies taking hormonal medications, inadvertent exposure must be considered:

• Topical progesterone creams are absorbed and produce elevated salivary and urinary metabolites without raising serum levels in the first 3 hours after application 3
• Ask specifically about skin creams, cosmetics, or supplements that may contain "natural" or micronized progesterone, as patients often don't consider these "medications" 3

Scenario 3: Timing and Physiologic Variation

Normal menstrual cycle dynamics can create apparent discordance:

• Urinary PdG profiles lag 1-2 days behind serum progesterone, so elevated urinary metabolites may reflect recent ovulation while current serum levels have already declined 1
• The timing of sample collection matters critically—if serum was drawn in early follicular phase but urine reflects late luteal phase excretion, discordance is expected 1

Diagnostic Algorithm

Step 1: Repeat and Confirm

• Obtain first morning urine specimens on 2-3 separate occasions to reduce variability and confirm persistent elevation 2
• Simultaneously measure serum progesterone on the same days to assess whether discordance persists 1

Step 2: Comprehensive Steroid Profiling

• Order urinary steroid profile by gas chromatography-mass spectrometry to identify specific metabolite patterns that distinguish adrenal from ovarian progesterone production 4
• This is the definitive test to identify CAH-related progesterone excess versus other causes 4

Step 3: Rule Out Exogenous Sources

• Explicitly ask about all topical products, including over-the-counter creams, cosmetics, and supplements containing progesterone or "wild yam extract" 3
• Consider avoiding all potential hormone-containing products for 72 hours before repeat testing 2

Step 4: Assess for Low Energy Availability If the patient is an athlete or has restrictive eating patterns:

• Low energy availability causes decreased progesterone as part of functional hypothalamic amenorrhea, making elevated metabolites less likely but worth considering in the differential 5

Critical Pitfalls to Avoid

• Don't dismiss elevated urinary metabolites as "lab error" without comprehensive steroid profiling, as this may miss undiagnosed CAH with serious reproductive consequences 4
• Don't assume "not taking hormonal medications" means no hormone exposure—topical progesterone in cosmetics is common and often not recognized by patients as medication 3
• Don't compare single-timepoint measurements without accounting for the 1-2 day lag between serum and urinary values 1
• Don't use creatinine-adjusted values alone for progesterone metabolites without also examining absolute concentrations, as creatinine indexing is more beneficial for estrogen metabolites 1

When to Refer to Endocrinology

Immediate referral is warranted if:

• Urinary steroid profiling confirms adrenal progesterone production patterns 4
• Patient has menstrual irregularities, primary amenorrhea, or infertility alongside this finding 4
• Repeat testing confirms persistent discordance after excluding exogenous sources 2