Starting Dose for Compounded Combination Estrogen/Progesterone/Testosterone Cream
For compounded combination hormone creams, I strongly recommend against their routine use due to significant quality control concerns and lack of standardized dosing; instead, prescribe FDA-approved transdermal estradiol 50 mcg/24-hour patches twice weekly plus oral micronized progesterone 200 mg for 12-14 days monthly, with testosterone added separately only if clinically indicated after documented deficiency. 1, 2
Critical Problems with Compounded Hormone Creams
Quality Control and Safety Concerns
Compounded preparations show alarming variability in actual hormone content, with measured estradiol levels ranging from 0.433 to 0.55 mg/g (up to 27% variation) and progesterone levels from 93 to 118 mg/g (up to 27% variation) across different pharmacies, even when the same dose was prescribed. 3
Manufacturing quality is not ensured, and unspecific harm from compounding has occurred on large scales, including deaths from infected products. 2
The North American Menopause Society, American College of Obstetricians and Gynecologists, and FDA have all issued statements outlining concerns regarding risks from variability in compounded hormone preparations. 3
Pharmacokinetic Inadequacy
Commonly used compounded estrogen creams (Bi-est 80:20 formulations) at doses of 2.0-3.0 mg yield consistently lower serum estrogen levels compared to standard-dose estradiol patches, with the 2.0 mg dose producing an AUC-estradiol of only 181 versus 956 for the patch (p<0.001). 4
Estriol levels remain low in all compounded formulations, questioning the rationale for its inclusion in Bi-est preparations. 4
Transdermal progesterone cream at 40 mg daily produces only sub-luteal plasma progesterone levels (median 2.5 nmol/l), which is insufficient for adequate endometrial protection. 5
Recommended Evidence-Based Alternative Regimen
Estrogen Component
Start with transdermal estradiol 50 mcg/24-hour patches applied twice weekly (every 3-4 days) to clean, dry skin on the lower abdomen, buttocks, or upper outer arm, rotating sites to minimize irritation. 1
If symptoms persist after 2-3 months, increase to 100 mcg/24-hour patches applied twice weekly, with maximum maintenance dosing of 100-200 mcg/day for optimal symptom control. 1
Transdermal administration has a neutral effect on venous thromboembolism risk (OR 0.9) compared to oral estradiol which significantly increases VTE risk (OR 4.2), representing a nearly 5-fold difference in thrombotic risk. 1, 6
Progesterone Component for Endometrial Protection
Women with an intact uterus must receive oral micronized progesterone 200 mg daily for 12-14 days every 28 days in a sequential regimen to prevent endometrial hyperplasia and cancer. 1, 7
Natural progesterone is devoid of androgenic and glucocorticoid activities, is slightly hypotensive due to antimineralocorticoid activity, and appears optimal in terms of cardiovascular effects, blood pressure, VTE risk, and possibly breast cancer risk compared to synthetic progestogens. 7
Continuous combined regimens can be used to avoid withdrawal bleeding in later postmenopause, but sequential regimens provide insufficient endometrial protection in the mid to long term. 7
Testosterone Component (If Clinically Indicated)
Testosterone should only be added as a separate prescription after documenting deficiency and establishing clear clinical indication for androgen replacement, not routinely included in combination preparations. 2
Custom compounding is only seldom legitimate, such as in cases of documented allergy or when prescribing components not approved by regulatory authorities despite being scientifically acceptable. 2
Common Pitfalls to Avoid
Never assume compounded creams deliver the prescribed dose—pharmacokinetic studies demonstrate they consistently underdeliver estrogen and fail to achieve adequate progesterone levels for endometrial protection. 5, 4
Avoid using compounded preparations when FDA-approved registered preparations exist for the same purpose, as these provide assured quality control and standardized dosing. 2, 7
Do not use oral estrogens when transdermal options are available, as oral administration increases VTE risk, gallbladder disease, and possibly stroke—all preventable with transdermal delivery. 7
Never use ethinyl estradiol for hormone replacement therapy, as this synthetic estrogen carries significantly higher thrombotic risk than bioidentical 17β-estradiol. 1