GnRH, a larger prohormone, undergoes modification during processing to a decapeptide. This modification includes cyclized glutamine (pyro-Glu) at its N-terminus and an amidated C-terminus (Fig. 41.14). The release of GnRH occurs in a pulsatile manner, and both the pulsatile secretion and frequency of pulses have significant effects on the gonadotrope. Continuous infusion of GnRH downregulates the GnRH receptor, resulting in decreased secretion of FSH and LH. On the other hand, pulsatile secretion does not desensitize the gonadotrope to GnRH, maintaining normal secretion of FSH and LH. When the frequency of one pulse per hour is maintained, GnRH preferentially increases LH secretion (Fig. 41.16). At a slower frequency of one pulse per 3 hours, GnRH preferentially increases FSH secretion. Gonadotropins promote sex steroid synthesis, and in men, testosterone and estrogen negatively regulate the pituitary and hypothalamus. The release of GnRH at the median eminence occurs in response to various inputs such as puberty, CNS, opioids, stress, and prolactin. It stimulates the synthesis and secretion of LH and FSH, which in turn act on the gonadotrope via PKA, inhibin, and other pathways. GnRH receptors, FSH receptors, and LH receptors are present in the pituitary gonadotrope, which interact with various gonadal cell types involved in steroidogenesis and gametogenesis. The hypothalamic-pituitary-gonadal axis plays a crucial role in regulating the reproductive system. Exogenous progesterone inhibits gonadotropin function in men and has been considered as a potential component of male contraception. Inhibin selectively provides negative feedback on FSH secretion in both men and women. In women, progesterone and testosterone negatively regulate gonadotropic function at the hypothalamus and pituitary level. Estrogen, at low doses, also exerts negative feedback on FSH and LH secretion. However, high estrogen levels maintained for 3 days lead to a surge in LH and, to a lesser extent, FSH secretion. This positive feedback is crucial for promoting ovulation and is observed at the hypothalamus and pituitary, where GnRH pulse amplitude and frequency increase. High estrogen levels also increase the sensitivity of the gonadotrope to GnRH by enhancing both GnRH receptor levels and postreceptor signaling (see Fig. 41.14). The somatotrope, part of the hypothalamic-pituitary-liver axis (Fig. 41.17), produces GH (somatotropin). GH primarily acts on the liver to stimulate the production of insulin-like growth factor (IGF)-I. GH is a 191–amino acid protein that shares similarities with PRL and human placental lactogen (hPL), leading to some overlap in their activities. Various forms of GH exist, and their secretion is regulated by multiple factors.
Fig. 41.14 ). GnRH is produced as a larger prohormone and, as part of its processing to a decapeptide, is modified with a cyclized glutamine (pyro-Glu) at its N-terminus and an amidated C-terminus.
GnRH is released in a pulsatile manner (
Fig. 41.15 ), and both the pulsatile secretion and the frequency of the pulses have important effects on the gonadotrope. Continuous infusion of GnRH downregulates the GnRH receptor, thereby resulting in a decrease in FSH and LH secretion. In contrast, pulsatile secretion does not desensitize the gonadotrope to GnRH, and FSH and LH secretion is normal. At a frequency of one pulse per hour, GnRH preferentially increases LH secretion (
Fig. 41.16 ). At a slower frequency of one pulse per 3 hours, GnRH preferentially increases FSH secretion. Gonadotropins increase sex steroid synthesis (see
Fig. 41.14 ). In men, testosterone and estrogen negatively feed back at the level of the pituitary and the hypothalamus.
Ca++, PKC, other pathways? SlowFast GnRH (+) pulses GnRH pulses LH synthesis and secretion FSH synthesis and secretion FSHLH PKA Inhibin Pulsatile release of GnRH at median eminence PubertyCNS Opioids Stress Prolactin (−)Sex steroids GnRH neurons inputs (+) (−) (−) GnRH Sex steroids GnRH receptor FSH receptorLH receptor Pituitary gonadotrope Gonadal cell types Steroidogenesis Gametogenesis •Fig. 41.14 Hypothalamic-pituitary-gonadalaxis.FSH,follicle-stimulatinghormone;GnRH,gonadotropin-releasinghormone;LH,luteinizinghormone.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine
Physiology. 3rded.Philadelphia:Mosby;2007.)
Exogenous progesterone also inhibits gonadotropin function in men and has been considered as a possible component of a male contraceptive pill. Additionally, inhibin negatively feeds back selectively on FSH secretion in men and women. In women, progesterone and testosterone negatively feed back on gonadotropic function at the level of the hypothalamus and pituitary. At low doses, estrogen also exerts negative feedback on FSH and LH secretion. However, high estrogen levels maintained for 3 days cause a surge in LH and to a lesser extent FSH secretion. This positive feedback, which is critical in promoting ovulation, is observed at the hypothalamus and pituitary. At the hypothalamus, GnRH pulse amplitude and frequency increase. At the pituitary, high estrogen levels greatly increase the sensitivity of the gonadotrope to GnRH, both by increasing GnRH receptor levels and by enhancing postreceptor signaling (see
The Somatotrope
The somatotrope produces GH (somatotropin) and is part of the hypothalamic-pituitary-liver axis (
Fig. 41.17 ). A major target of GH is the liver, where it stimulates production of insulinlike growth factor (IGF)-I. GH is a 191–amino acid protein that is similar to PRL and human placental lactogen (hPL); accordingly there is some overlap in activity among these hormones. Multiple forms of GH 746 SECTION8Berne & Levy Physiology 1.8 1.2 0.6 0 12 10 8 6 1200 1300 1400 1500 1600 Hours GnRH(pg/10 min) LH(ng/mL)