Edited by Joel GottesfeldFollicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an ␣ subunit, also present in luteinizing hormone, and a unique  subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSH ( Gonadotrope cells in the anterior pituitary synthesize and secrete luteinizing hormone (LH) 2 and follicle-stimulating hormone (FSH) in response to pulses of hypothalamic gonadotropin-releasing hormone 1 (GNRH), which can be modulated by activin/inhibin and steroid feedback from the gonads. Gonadotropin hormones are heterodimers of a common ␣ subunit and a unique  subunit. Gonadotropin levels fluctuate 3-4-fold throughout the menstrual or estrous cycle, preceded by changes in the  subunit transcription (1, 2). Dysregulation of the tightly controlled gonadotropin levels leads to reproductive pathophysiology. Low levels of gonadotropin hormones lead to infertility; low LH leads to hypogonadism and anovulation, whereas low FSH causes follicular growth arrest (3-5). High levels also lead to reproductive pathologies, particularly in females, such as polycystic ovary syndrome, characterized by an increase specifically in LH (6 -8), and premature ovarian failure or primary ovarian insufficiency, which is associated with an increase in FSH (9, 10). Recently, it was determined that increased levels of FSH in the circulation, due to retrafficking of FSH to the GNRH-regulated secretory pathway, resulted in 5-fold more corpora lutea in the ovaries, implicating higher FSH levels in greater follicle recruitment (11). Furthermore, polymorphism in the FSHB promoter in women, which regulates  subunit expression, increases the level of FSH and has been associated with early menarche and menopause (12). Another genomewide association study reported that polymorphism 5Ј of the FSHB gene, which causes a higher level of FSH in the circulation, is also associated with premature puberty, early natural menopause, and dizygotic twinning (13).Normal reproductive function requires pulsatile secretion of GNRH into the hypophysial portal system, whereas long term tonic exposure to GNRH adversely affects the hypothalamicpituitary-gonadal axis (14 -16). GNRH receptors lack the Cterminal tail that normally mediates desensitization through -arrestin association and encapsulation into clathrin-coated vesicles, rendering the receptor resistant to this regulatory mechanism. Thus, the receptor does not internalize as rapidly as other GPCRs (17). Given that GNRH receptors do not internalize within the frequency of the pulse, due to the lack of a cytoplasmic tail, other feedback mechanisms must exist within the gonadotrope to shut off the signal and maintain gonadotropin expression within the narrow physiological range. This ...