Bio-Identical Compounded Hormones and the FDA Regulations

  1. What is “compounding”? In general, compounding is a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.
  2. Is combining two or more drugs considered compounding? Yes, compounding includes the combining of two or more drugs. 
  3. Why do some patients need compounded drugs? Sometimes, the health needs of a patient cannot be met by an FDA-approved medication. For example:
    if a patient has an allergy and needs a medication to be made without a certain dye; or

b) if an elderly patient or a child can’t swallow a pill and needs a medicine in a liquid form that is not otherwise available.


4.     Are compounded drugs approved by the FDA?Compounded drugs are not FDA-approved. This means that FDA does not verify the safety, or effectiveness of compounded drugs. Consumers and health professionals rely on the drug approval process to ensure that drugs are safe and effective and made in accordance with Federal quality standards. Compounded drugs also lack an FDA finding of manufacturing quality before such drugs are marketed. 

Generally, state boards of pharmacy will continue to have primary responsibility for the day-to-day oversight of state-licensed pharmacies that compound drugs in accordance with the conditions of section 503A of the FDCA, although FDA retains some authority over their operations. However, outsourcing facilities that register under section 503B are regulated by FDA and must comply with CGMP requirements and will be inspected by FDA according to a risk-based schedule. 


5.     What are the risks associated with compounded drugs? There can be health risks associated with compounded drugs that do not meet federal quality standards.  Compounded drugs made using poor quality practices may be sub- or super‑potent, contaminated, or otherwise adulterated. Additional health risks include the possibility that patients will use ineffective compounded drugs instead of FDA-approved drugs that have been shown to be safe and effective.  

6.     Who regulates and inspects facilities that compound drugs? Generally, state boards of pharmacy will continue to have primary responsibility for the day-to-day oversight of state-licensed pharmacies that compound drugs in accordance with the conditions of section 503A of the FDCA, although FDA retains some authority over their operations. For example, the adulteration or misbranding of drugs compounded under section 503A, or false or misleading statements in the labeling or advertising of such drugs, may result in violations of Federal law. Firms that register with FDA as “outsourcing facilities” under section 503B will be regulated by FDA and inspected by FDA according to a risk-based schedule. 


Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.