1. Steroid Hormones

 Figure 1A shows the role of the steroid hormones, estrogens and progesterone, in controlling gonadotrophin secretion. These effects were clearly established by experiments in many mammalian species that demonstrated that removal of the gonads leads to increased GnRH, LH, and FSH. In humans failure to synthesize estrogens, due to aromatase deficiency for example, has the same consequences. Both estradiol and progesterone exert negative feedback inhibition on GnRH secretion by the hypothalamus as well as by direct inhibition of gonadotrophin secretion at the pituitary. The latter involves alterations in the expression of the genes for all three of the subunits required for LH and FSH synthesis as well as modulation of the sensitivity of pituitary gonadotrophs to GnRH. The negative feedback effect of estrogen predominates during the follicular phase of the reproductive cycle and that of progesterone, synthesized in large amounts by the corpus luteum, predominates during the luteal phase.

Fig1. The Hypothalamic-Pituitary-Ovarian Axis. A. Under the influence of Kiss1 peptide from the arcuate nucleus (ARC) or the anteroventral periventricular nucleus (AVPV), hypothalamic neurons in the median eminence release GnRH in a pulsatile fashion. GnRH stimulates pituitary gonadotrophs to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Prior to ovulation, the target cells for LH are the thecal cells of the follicle and those of FSH are the granulosa cells. these two components of the follicle collaborate to synthesize estrogen. After ovulation (the luteal phase of the cycle) LH stimulates the production of progesterone and estrogen by the corpus luteum. These steroids exert negative feedback inhibition on LH and FSH release at the level of the pituitary and on GnRH secretion, primarily at the arcuate nucleus by inhibiting Kiss-1 secretion. Just prior to ovulation, estrogen has a positive (green dashed line) feedback effect on GnRH secretion, through Kiss-1 secretion by the AVPV and at the pituitary. Inhibin B, secreted by the follicle and inhibin A, secreted by the corpus luteum, exert negative feedback on FSH secretion by the pituitary. B. FSH secretion is under local control by activin which stimulates its secretion and follistatin which binds to and blocks the effect of activin. As shown in part A, ovarian inhibins inhibit FSH secretion by blocking activin binding to its receptor.

It is currently thought that the primary feedback effects of the steroid hormones on GnRH secretion are exerted at the level of kisspeptin-1 secretion although direct effects on the GnRH neurons have not been definitively ruled out. The current model is depicted in Figure 1A with the negative feedback effects of estradiol and progesterone being mediated by the Kiss-1 neurons in the arcuate nucleus.

The midcycle positive effect of estradiol on GnRH and LH secretion is mediated by a group of Kiss-1 neurons in the anteroventral periventrinuclear nucleus (AVPV). These cells respond to the rapid rise in estro gens produced by the maturing follicle with increased Kiss-1 secretion and stimulation of GnRH secretion that drives the midcycle LH-surge. The positive feedback of estrogen on LH (and FSH) secretion is also exerted at the pituitary gland and involves enhancement of the sensitivity to GnRH. The relative role of the pituitary, as opposed to changes in GnRH secretion, in mediating the midcycle LH surge varies with species. In primates, including humans, the pituitary appears to be the predominant site of this regulatory event. The molecular mechanism of the switch from negative to positive feedback by estrogen is not understood.

2. Activins, Inhibins, and Follistatin

Although all three of these peptides are produced throughout the body, the focus in this section will be on their presence in the pituitary gland and their role in the regulation of FSH secretion. All are involved in the GnRH-independent regulation of FSH secretion from the gonadotrophs in the pituitary, as depicted in Figure 13-10B. The synthesis of the FSHβ subunit is very sensitive to locally produced activin. Activins also participate in maintaining and increasing the number of GnRH receptors, and thus pituitary sensitivity to GnRH. Follistatin is a monomer of around 300 amino acids (several isoforms exist) which binds to and inhibits the function of activins in the pituitary. Inhibins A and B, which show little difference in their activities, bind to activin receptors, blocking their ability to increase FSH secretion. Thus, whereas LH secretion from gonadotrophs is largely responsive to GnRH, FSH secretion is also modulated by the interactions of these three peptide hormones, the locally produced activin and follistatin and the inhibins from the gonads. Similar interactions between activins, inhibins, and follistatin occur in many tissues outside the pituitary in the control of cell growth and function.

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مواضيع ذات صلة

Uterine Effects of Estrogen and Progesterone

Menopause

Control of the Ovary by the Hypothalamus and Pituitary

Synthesis of Progesterone and Estrogens

Female Steroid Hormones

The Androgen Receptor

Hypothalamic-Pituitary-Testis Axis: Feedback Control

Causes of Destructive (Low RAIU) Thyrotoxicosis

Causes of Hyperthyroidism

Hypothalamic-Pituitary-Testes Axis: Hormonal Control of the Testis

Sex Hormone-binding Globulin

Modification of Testosterone in Target Tissues