Normal

 

Regulation of the hypothalamic-pituitary unit is a complex process involving both negative and positive feedback mechanisms in the female. It should be remembered that the hormones of the hypothalamic-pituitary unit i.e GnRH, FSH and LH exist in a dynamic equilibrium with the hormones of the gonads i.e steroid hormones and inhibin.

In the female increasing concentrations of estradiol as ovarian follicles grow progressively sensitize the pituitary to GnRH so that just before ovulation a burst of LH and FSH is released in response to GnRH. This amplification by estradiol of the gonadotropin response to GnRH Is termed positive feedback and is what causes the female to be cyclical in contrast to the male, which does not have this positive feedback mechanism and is acyclical.

 

Hypothalamus

GnRH

 

GnRH is secreted in a pulsatile manner by neurons with cell bodies in the hypothalamus. GnRH stimulates synthesis and glycosylation of beta subunits of FSH and LH.

 

 

Pituitary

FSH

 

FSH stimulates the synthesis of estradiol in ovarian granulosa cells by enhancing synthesis of the P450 aromatase enzyme. FSH also increases lactic acid production, synthesis of inhibin, activin and insulin like growth factor 1, production of proteoglycans, and general synthesis of DNA, RNA and protein. FSH induces synthesis of LH receptors in granulosa cells, resulting in a progressive increase in LH responsiveness prior to ovulation.

 

LH

 

Prolactin

Gonadotropin secretion is inhibited by high concentrations of prolactin termed hyperprolactinemia. Prolactin appears to act directly on GnRH secretory neurons to block either synthesis or secretion of GnRH. Although the inhibition occurs at the level of the hypothalamic-pituitary unit the mechanisms are not well-understood. Individuals with primary or secondary hypothyroidism or with secondary hyperthyroidism due to a TRH secreting hypothalamic tumor also have decreased gonadotropin secretion that is thought to be mediated via increased prolactin due to increased TRH secretion.

TRH has been shown to stimulate prolactin secretion by pituitary lactotropes.

 

Ovary

Inhibin

nhibit acts on the pituitary gonadotropes to suppress the synthesis and release of FSH but not of LH. This modulatory effect of inhibn is termed negative feedback.

 

Estradiol

Progesterone

 

Progesterone along with estradiol acts on unidentified hypothalamic pulse oscillator neurons which in turn act on GnRH secreting neurons to inhibit GnRH secretion. Negative modulation of GnRH secretion results in diminished FSH and LH secretion with a greater inhibition of LH secretion. The effect of progesterone on the GnRH pulse oscillator neurons appears to be to decrease GnRH pulse frequency which results in decreased LH and FSH pulse frequency.

This effect predominates in the luteal phase of the menstrual cycle. The apparently increased gonadotropin pulse amplitude during the luteal phase appears to be due to the release of accumulated gonadotropin during the longer interpulse interval.

 

CNS Inhibitors

 

GnRH secretion is inhibited by a variety of neurogenic factors including. Stress. Beta endorphin, a stress related opioid peptide. Morphine. Alpha adrenergic blockers and dopaminergic blockers.