What are the treatment options for a woman with elevated testosterone levels and fertility issues, potentially due to polycystic ovary syndrome (PCOS)?

Treatment of Elevated Testosterone and Fertility Issues in Women

For women with elevated testosterone and fertility issues, particularly those with PCOS, first-line treatment should be lifestyle modification targeting 5% weight loss combined with metformin (500-2000mg daily) to improve insulin sensitivity, followed by clomiphene citrate (50-150mg daily for 5 days starting cycle day 5) for ovulation induction if pregnancy is desired. 1, 2, 3

Initial Diagnostic Workup

Before initiating treatment, confirm the diagnosis and exclude other causes:

• Measure total testosterone or free testosterone using LC-MS/MS (liquid chromatography-tandem mass spectrometry), which shows superior specificity (92%) compared to direct immunoassays (78%) 1
• Obtain TSH to exclude thyroid disease as a cause of menstrual irregularity 1
• Measure prolactin using morning resting serum levels to exclude hyperprolactinemia, with levels >20 μg/L considered abnormal 1
• Perform 2-hour oral glucose tolerance test with 75g glucose load to screen for glucose intolerance and type 2 diabetes 2
• Obtain fasting lipid panel including total cholesterol, LDL, HDL, and triglycerides, as insulin resistance drives dyslipidemia 2
• Measure mid-luteal phase progesterone (cycle day 21-23) to confirm anovulation, with levels <6 nmol/L indicating anovulation 1

Important caveat: Total testosterone is abnormal in only 70% of women with confirmed PCOS, meaning 30% have normal testosterone levels despite having the condition 1. If clinical suspicion remains high despite normal testosterone, measure androstenedione and DHEAS as second-line tests 1.

First-Line Treatment: Lifestyle Modification

Initiate multicomponent lifestyle intervention before or concurrent with any pharmacologic therapy, as this is the foundation of treatment 2:

• Target weight loss of just 5% of initial body weight, which improves metabolic parameters, ovulation rates, and pregnancy outcomes 2
• Implement diet, exercise, and behavioral strategies together rather than any single component 2
• Screen every PCOS patient for metabolic dysfunction regardless of body weight, as insulin resistance occurs independent of BMI 2

Second-Line Treatment: Metformin for Metabolic Management

Use metformin as the preferred insulin-sensitizing agent when pharmacologic intervention is warranted 2:

• Metformin decreases circulating androgen levels through improved insulin sensitivity 2
• Metformin improves ovulation rates and metabolic outcomes 2
• Metformin tends to decrease weight, unlike thiazolidinediones which increase weight 2
• Typical dosing starts at 500mg daily and titrates up to 1500-2000mg daily in divided doses 2

Critical pitfall to avoid: Do not use thiazolidinediones as first-line agents given their tendency to increase weight and variable risk-benefit profiles compared to metformin 2.

Third-Line Treatment: Ovulation Induction for Fertility

For women actively seeking pregnancy, clomiphene citrate is FDA-approved and indicated for ovulatory dysfunction in women desiring pregnancy 3:

• Clomiphene is specifically indicated for patients with polycystic ovary syndrome 3
• Start each course on or about cycle day 5, with properly timed coitus in relationship to ovulation 3
• Initial dosing is 50mg daily for 5 days, which can be increased if ovulation does not occur 3
• Patients with PCOS should be started on the lowest recommended dose due to unusual sensitivity to gonadotropin and risk of exaggerated response 3
• Long-term cyclic therapy is not recommended beyond about six cycles (including three ovulatory cycles) 3

Critical Safety Considerations with Clomiphene

Monitor carefully for ovarian hyperstimulation syndrome (OHSS), which can progress rapidly and become serious 3:

• Early warning signs include abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain 3
• If ovarian enlargement occurs, additional clomiphene therapy should not be given until ovaries return to pretreatment size 3
• Use the lowest dose consistent with expected clinical results to minimize risk 3
• Pelvic examination is necessary prior to the first and each subsequent course of treatment 3

Discontinue treatment immediately if visual symptoms occur, as visual disturbances including blurring, scotomata, and phosphenes have been reported 3.

Understanding the Pathophysiology

The mechanism by which elevated testosterone impairs fertility extends beyond anovulation 4, 5:

• Elevated testosterone causes extensive luminal accumulations of secretions and cell debris in the fallopian tube, resulting in ciliary clumping and luminal blockage 4
• Testosterone exposure alters cilia gene expression and decreases ciliary beating frequency, impairing gamete transport 5
• In the isthmus, complete luminal collapse can occur, further obstructing the reproductive tract 4

This explains why some women with PCOS remain subfertile even after achieving ovulation, as tubal function may be compromised 4, 5.

When to Suspect Alternative Diagnoses

Very high testosterone levels (>2-3 SD above normal reference range) warrant urgent investigation for androgen-secreting tumors 1, 6:

• Rapid onset of symptoms, severe hirsutism, or very high testosterone levels suggest possible ovarian or adrenal tumor 1
• If laboratory values seem discordant with clinical presentation, consider laboratory interference and request diethyl ether extraction prior to immunoassay 6
• Ovarian steroid cell tumors are rare but clinically malignant in 25-43% of cases 6

Monitoring and Follow-Up

Track ovulation with basal body temperature charting or mid-luteal progesterone levels to determine if treatment is effective 3. Reassess metabolic parameters every 6-12 months, including weight changes, blood pressure, and lipid profile 1.