Estrogens and selective estrogen receptor modulators in acromegaly

The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.

Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. These compounds were initially called "antiestrogens," but it was subsequently recognized that this inadequately described their spectrum of activities. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. This review will explore the preclinical and clinical pharmacology of raloxifene, and compare it to other SERMs currently available for clinical use.