Information from the Nurses' Health Study indicated that the combination of estrogen and androgen used to treat hypoandrogenism could increase breast cancer risk. However, other studies indicated androgens may decrease breast cancer risk. Follow-up studies on the Women's Health Initiative found women who received estrogen and no progestogen showed a significant decrease in cardiovascular disease (CVD) and breast cancer. This has caused a reconsideration of androgens added to estrogens. Still, the FDA requires demonstration of CVD and breast cancer safety for any product containing androgens or estrogen plus an androgen; that has not been done.
There is considerable controversy over the earliest age at which it is clinically, morally, and legally safe to use GnRH analogues, and for how long. The sixth edition of the World Professional Association for Transgender Health 's Standards of Care permit it from Tanner stage 2 but do not allow the addition of hormones until age 16, which could be five or more years later. Sex steroids have important functions in addition to their role in puberty, and some skeletal changes (such as increased height) that may be considered masculine are not hindered by GnRH analogues.