Elevated Total Testosterone During Early Pregnancy
Elevated total testosterone in early pregnancy should be evaluated by confirming the elevation with repeat measurement, assessing for underlying hyperandrogenic conditions (particularly PCOS), and monitoring for pregnancy complications—especially preeclampsia—while recognizing that mild elevations alone do not predict adverse outcomes in most cases.
Understanding Normal vs. Elevated Testosterone in Pregnancy
Physiological Changes
- Total testosterone normally increases during pregnancy due to elevated sex hormone-binding globulin (SHBG), which binds testosterone and reduces free (bioavailable) hormone 1.
- Women with polycystic ovary syndrome (PCOS) have significantly higher total testosterone (median 1.94 nmol/L vs. 1.41 nmol/L) and free androgen index (0.25 vs. 0.18) during the second trimester compared to women without PCOS matched for BMI 2.
Defining "Elevated" Testosterone
- In non-pregnant women with reproductive endocrine disorders, testosterone >2.5 nmol/L is considered abnormal 1.
- During pregnancy, reference ranges shift upward, and the clinical significance of elevation depends on the degree of increase and associated conditions 2, 3.
Diagnostic Evaluation
Initial Assessment
- Confirm the elevation with repeat measurement, as single values can be misleading due to assay variability 1.
- Measure free testosterone or calculate the free androgen index (total testosterone ÷ SHBG × 100) to assess bioavailable androgen, especially when SHBG is elevated in pregnancy 1.
- Obtain androstenedione and DHEAS if testosterone is markedly elevated (>10.0 nmol/L for androstenedione or age-adjusted thresholds for DHEAS) to rule out adrenal or ovarian tumors 1.
Assess for Underlying Conditions
- Screen for PCOS if not previously diagnosed: PCOS affects 4–6% of the general population but 10–25% of women with temporal lobe epilepsy, and is characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries on ultrasound 1.
- Evaluate for non-classical congenital adrenal hyperplasia if DHEAS is elevated, as this can cause modest testosterone elevation 1.
- Consider medication-induced elevation: valproate (an antiepileptic drug) is a common cause of elevated testosterone and PCOS-like features 1.
Imaging When Indicated
- Pelvic ultrasound (transvaginal or transabdominal, performed between cycle days 3–9 in non-pregnant women) can identify polycystic ovaries (>10 peripheral cysts, 2–8 mm diameter, with thickened ovarian stroma) 1.
- MRI is the preferred second-line imaging modality during pregnancy for characterizing indeterminate adnexal masses, as it avoids ionizing radiation 1.
- Ultrasound by an expert is the first-line imaging procedure for adnexal masses diagnosed during pregnancy 1.
Clinical Significance and Pregnancy Outcomes
Association with Gestational Diabetes Mellitus (GDM)
- First-trimester total testosterone levels are higher in women who subsequently develop GDM (mean not specified, but a cutoff of 0.45 ng/mL predicts GDM with 63.6% sensitivity and 62.7% specificity) 3.
- However, testosterone alone has low predictive power and cannot be used as a standalone screening marker for GDM; it may have a role in combination with other markers 3.
- Age, total testosterone, and BMI are independent predictors of GDM development 3.
Association with Preeclampsia
- Women with PCOS who have the highest tertile of testosterone levels in the early second trimester have a significantly increased risk of preeclampsia (adjusted OR 6.16,95% CI 1.82–20.91) 2.
- This finding is driven by a limited number of cases and should be interpreted with caution, but it suggests that very high testosterone in PCOS pregnancies warrants closer surveillance for preeclampsia 2.
No Association with Miscarriage
- Early pregnancy testosterone levels do not predict pregnancy outcome in terms of miscarriage risk 4.
- There is no difference in total testosterone between women with ongoing pregnancies (mean 3.6 ± 2.6 nmol/L) and those with first-trimester miscarriages (mean 3.6 ± 2.4 nmol/L), regardless of PCOS status 4.
- This calls into question the role of testosterone in causing miscarriage in women with PCOS 4.
Ovarian Stimulation and Testosterone
- Ovarian stimulation for assisted reproduction increases early pregnancy testosterone levels compared to spontaneous conceptions 5, 6.
- In IVF patients, early pregnancy testosterone correlates linearly with the number of oocytes retrieved 5.
- However, elevations in early pregnancy testosterone after ovarian stimulation do not appear to be associated with adverse pregnancy outcomes, including preterm delivery, hypertensive disorders, low birth weight, or cesarean delivery 5.
Management Algorithm
Step 1: Confirm and Characterize the Elevation
- Repeat total testosterone measurement to confirm elevation 1.
- Calculate free androgen index or measure free testosterone by equilibrium dialysis 1.
- Obtain androstenedione and DHEAS if testosterone is markedly elevated 1.
Step 2: Identify Underlying Cause
- Assess for PCOS (clinical features: hirsutism, menstrual irregularity, obesity; biochemical: LH/FSH ratio >2, elevated testosterone) 1.
- Review medications (especially valproate) 1.
- Consider non-classical congenital adrenal hyperplasia if DHEAS is elevated 1.
- Perform pelvic ultrasound or MRI if an adnexal mass is suspected 1.
Step 3: Monitor for Pregnancy Complications
- If testosterone is in the highest tertile (especially in PCOS pregnancies), increase surveillance for preeclampsia with serial blood pressure monitoring, urine protein assessment, and symptom education 2.
- Screen for GDM at 24–28 weeks as per standard guidelines, recognizing that elevated first-trimester testosterone is an independent risk factor 3.
- Reassure the patient that mild-to-moderate elevations in early pregnancy testosterone do not predict miscarriage or other adverse outcomes in most cases 4, 5.
Step 4: Address Underlying Conditions
- For women with PCOS, optimize metabolic health (weight management, insulin resistance treatment) to reduce long-term cardiovascular and metabolic risks 1.
- For women on valproate, consider alternative antiepileptic drugs in consultation with neurology if hyperandrogenism is problematic 1.
Common Pitfalls and Caveats
Do Not Over-Interpret Mild Elevations
- Testosterone naturally increases during pregnancy due to elevated SHBG; mild elevations without clinical hyperandrogenism or PCOS do not require intervention 1, 2.
- Avoid unnecessary anxiety by explaining that testosterone elevation after ovarian stimulation is expected and not associated with adverse outcomes 5, 6.
Do Not Rely on Testosterone Alone for GDM Screening
- First-trimester testosterone has low sensitivity and specificity for predicting GDM and should not replace standard glucose tolerance testing 3.
Do Not Assume Testosterone Causes Miscarriage
- Despite historical concerns, early pregnancy testosterone levels do not predict miscarriage risk, even in women with PCOS 4.
Do Not Miss Rare but Serious Causes
- Markedly elevated testosterone (>10.0 nmol/L for androstenedione or very high DHEAS) should prompt evaluation for adrenal or ovarian tumors 1.
Key Takeaways
- Elevated testosterone in early pregnancy is most commonly associated with PCOS or ovarian stimulation and does not predict miscarriage 2, 4, 5.
- Very high testosterone levels in PCOS pregnancies are associated with increased preeclampsia risk, warranting closer surveillance 2.
- First-trimester testosterone is an independent risk factor for GDM but has low predictive power as a standalone marker 3.
- Repeat measurement, assess for underlying hyperandrogenic conditions, and monitor for pregnancy complications rather than treating the testosterone elevation itself 1, 2, 3.