Can You Take Enclomiphene and Anastrozole Together?
Yes, you can safely take enclomiphene (or clomiphene) and anastrozole together, and this combination is actually more effective than either agent alone for treating male hypogonadism and infertility. This recommendation is based on multiple studies demonstrating safety and efficacy in the male fertility context, though it's critical to understand that this differs completely from breast cancer treatment where such combinations are contraindicated.
Context Matters: Male Fertility vs. Breast Cancer
The safety and appropriateness of combining these medications depends entirely on the clinical indication:
For Male Hypogonadism and Infertility (Safe and Effective)
The combination of clomiphene citrate and anastrozole is both safe and effective for hypoandrogenic subfertile men. 1
Combination therapy produces superior outcomes compared to monotherapy, with 43% of men achieving normozoospermia versus only 25% with anastrozole alone 2
Total motile sperm count improves significantly more with combination therapy (11.3 million vs. 2.1 million with anastrozole monotherapy, P=0.03) 2
The combination maintains therapeutic testosterone levels while normalizing estradiol levels and testosterone-to-estradiol ratios, which neither agent achieves optimally alone 1
Clomiphene citrate increases testosterone significantly (mean increase to 571 ng/dL), but also raises estradiol levels 3
Anastrozole alone increases testosterone modestly (mean increase to 408 ng/dL) but effectively lowers estradiol and improves testosterone-to-estradiol ratio 3
By combining both agents, you achieve the testosterone-boosting effects of clomiphene while using anastrozole to control the estradiol elevation, creating an optimal hormonal profile 1
For Breast Cancer Treatment (Contraindicated)
Never combine anastrozole with selective estrogen receptor modulators (SERMs) like tamoxifen or clomiphene in breast cancer treatment. 4
The National Comprehensive Cancer Network explicitly recommends avoiding this combination due to antagonistic effects 4
Patients receiving combined tamoxifen and anastrozole gained no benefit over tamoxifen alone in the ATAC trial, suggesting the SERM's weak estrogenic activity counteracts anastrozole's estrogen-depleting action 5, 4
The mechanism of antagonism occurs because SERMs (including clomiphene) have partial estrogen agonist activity that interferes with the complete estrogen suppression desired from aromatase inhibitors 4
Safety Profile of the Combination
The combination therapy demonstrates an acceptable safety profile in male fertility treatment. 1
Side effects occurred in 11 of 51 patients (22%) and included: anxiety/irritability (n=5), decreased libido (n=4), and elevated hematocrit >54% (n=2) 1
No significant prostatic or hematologic safety concerns emerged after 6 months of combination therapy 1
The side effect profile is manageable and does not differ substantially from monotherapy with either agent 1
Practical Implementation
Start with clomiphene citrate 25 mg daily, then add anastrozole 1 mg daily if estradiol exceeds 50 pg/mL or testosterone-to-estradiol ratio falls below 10. 1
Monitor total testosterone, bioavailable testosterone, estradiol, and testosterone-to-estradiol ratio at baseline, 6 weeks, and 12 weeks 3
Check semen analysis at baseline and after at least 3 months of combination therapy 2, 1
Monitor hematocrit and PSA at 6 months to assess safety 1
Typical follow-up duration is 91 days (range 64-117 days) before assessing response 2
Common Pitfalls to Avoid
Do not confuse the male fertility indication with breast cancer treatment—the same drug combination has opposite recommendations depending on context 4
Do not use this combination in women with breast cancer or for breast cancer risk reduction, as it provides no benefit and may be harmful 5, 4
Do not assume monotherapy is sufficient—combination therapy produces significantly better improvements in total motile sperm count and normozoospermia rates 2
Do not neglect monitoring estradiol levels—the primary rationale for adding anastrozole is to control estradiol elevation that occurs with clomiphene alone 1