Resistance to
dopamine agonists can be defined with respect to failure to normalize PRL levels and failure to decrease
tumor size by > or = 50%. Using these definitions, failure to normalize PRL levels is seen in 24% of those treated with
bromocriptine, 13% of those treated with
pergolide and 11% of those treated with
cabergoline. Failure to achieve at least a 50% reduction in
tumor size occurs in about one-third of those treated with
bromocriptine and 10-15% of those treated with
pergolide or
cabergoline. Studies of in vitro cell preparations show that the D2 receptors of resistant
tumors are decreased in number but have normal affinity. Treatment approaches for resistant patients include switching to another
dopamine agonist and raising the dose of the drug as long as there is continued response to the dose increases and no adverse effects. Transsphenoidal surgery can also be done. If fertility is desired,
clomiphene,
gonadotropins, and
GnRH are also options. If fertility is not desired,
estrogen replacement may be used unless there is a macroadenoma, in which case control of
tumor growth is also an issue and
dopamine agonists are generally necessary. However, in many cases modest or even no reduction may be acceptable long-term as long as there is not
tumor growth.
Hormone replacement (estrogen or
testosterone) may cause a decrease in efficacy of the
dopamine agonist so that it must be carried out cautiously. Reduction of endogenous
estrogen, use of
selective estrogen receptor modulators, and
aromatase inhibitors are potential experimental approaches.