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 gonads i.e steroid hormones and inhibin.

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

 

Stress

Stress, either physical, mental or emotional, can inhibit function of the hypothalamic pituitary ovarian axis. Menstrual cycle cease or become sporadic and menopausal symptoms can appear depending on the duration of the stress inducer. Stress causes certain neurons with cell bodies in the cerebral cortex of the brain to secrete increased amounts of inhibitory neurotransmitters such as norepinephrine and beta endorphin, an opioid peptide.

The inhibitory neurotransmitters either directly or indirectly act on GnRH secreting neurons in the hypothalamus to inhibit the secretion of GnRH. As a result, secretion of GnRH by hypothalamic neurons decreases. Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH.

Decreased secretion of FSH and LH results in lack of stimulation of ovarian follicular development and decreased secretion of estrogens, progestins and androgens. Administration of exogenous FSH will restore ovarian function.

 

Oophorectomy

 

Removal of the ovaries referred to as bilateral oophorectomy in a pre-menopausal sexually mature female results in removal of the principal sources of estradiol, progesterone, androgens and inhibin in the circulation. Menstrual cycle cease and menopausal symptoms appear. Reproductive tissues atrophy and bone mass decreases. The decline in estradiol and progesterone releases the pulse oscillator neurons of the hypothalamus from negative feedback.

As a result, secretion of GnRH by hypothalamic GnRH secreting neurons increases. Administration of exogenous estradiol or progesterone inhibits secretion of GnRH. Increased GnRH stimulates gonadotropes of the anterior pituitary gland to secrete increased amounts of FSH and LH. The decline in inhibin releases the gonadotropes from inhibition and the gonadotropes secrete increased amounts of FSH.

Administration of exogenous inhibin decrease secretion of FSH.

 

Hyperprolactinemia

 

Females who develop prolactin-secreting tumors of the anterior pituitary have elevated plasma levels of prolactin, or hyperprolactinemia. These patients have milk discharge from the breast referred to as galactorrhea, and secondary amenorrhea, or absence of menstruation, after history of normal menstruation. They have normally developed female genitalia and female secondary sex characteristics.

High levels of prolactin inhibit GnRH secretion by GnRH secreting neurons. The lactotrope tumors secrete elevated levels of prolactin. Prolactin secretion can be inhibited by administration of exogenous agonists of dopamine, the physiologic prolactin inhibiting factor. Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH.

Decreased secretion of FSH and LH results in lack of stimulation of ovarian follicular development and decreased secretion of estrogen, progestin's and androgens as well as decreased production of inhibin.

 

Kallman's Syndrome

 

In certain individuals carrying a genetic defect in a gene encoding a cellular adhesion protein in GnRH neurons, these neurons fail to migrate from the olfactory bulb to the hypothalamus during fetal development. These individuals do not have either normal GnRH secretion or a normal sense of smell referred to as anosmia.

These individuals fail to experience normal development of the internal reproductive tract, external genitalia and breast at the time of puberty. They have primary amenorrhea due to a failure of initial ovarian follicular development. The absence of GnRH secreting neurons in the hypothalamus prevents secretion of GnRH into the hypothalamic hypophyseal portal circulation.

Lack of GnrH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH. Decreased secretion of FSH and LH results in lack of stimulation of ovarian follicular development and decrease secretion of estrogens, progestin's and androgens. Administration of exogenous estrogen and progesterone results in growth of sex accessory organs.

 

FSH Receptor

 

Inactivating mutations of the FSH receptor prevents granulosa cells of ovarian follicles from responding to FSH. Since the granulosa cells, before and after luteinization, are principal sources of estrogen, progestin's and inhibin, an FSH receptor defect results in functional removal of the principal sources of estrogens, progestin's and inhibin but not androgens in the circulation.

These individuals lack development of the internal reproductive tract, external genitalia and breasts at the expected time of puberty and they have primary amenorrhea due to a failure of initial of ovarian follicular development. Lack of estrogen releases the hypothalamic pulse oscillator neurons from negative feedback. As a result, GnRH secretion by the GnRH secreting neurons increases.

Increased stimulation of the pituitary gonadotropes by GnRH causes increased secretion about LH and FSH. Lack of inhibin causes a further increase in FSH secretion. Follicles do not develop due to inability of granulosa cells to respond to FSH. As a result, only small amounts of estrogens and inhibin are synthesized and follicles do not ovulate.

Increased amounts of LH stimulate the theca cells of the follicle to secrete increased amounts of androgens.

 

LH Receptor Defect - Pre-Ovulation

 

Inactivating mutations of the LH receptor prevent granulosa cells of preovulatory ovarian follicles from responding to LH. Since ovulation is the result of the action of LH on follicular granulosa cells, an LH receptor defect results in a failure of developed follicles to ovulate. Consequently, these individuals do not develop corpora lutea and do not menstruate.

These individuals have primary amenorrhea. These individuals are presumed to have normal GnRH secretion due to production of estrogens by the developing follicles. These individuals are presumed also to have normal levels of gonadotropins. Follicles develop to the preovulatory stage but do not ovulate due to inability of granulosa cells to respond to LH.

Corpora lutea do not form and synthesize progesterone and estradiol.

 

FSHβ Subunit Defect

 

Individuals with an inactivating mutation in the gene encoding the beta subunit of FSH secrete little or no biologically active FSH. These individuals secrete GnRH but the lack of FSH in the circulation results in a lack of development of ovarian follicles. These individuals lack development of the internal reproductive tract, external genitalia and breasts at the expected time of puberty and primary amenorrhea due to a failure of initial ovarian follicular development.

Lack of estrogen releases the hypothalamic pulse oscillator neurons from negative feedback. As a result GnRH secretion by GnRH secreting neurons increases. The gonadotropes secrete an inactive form of the beta subunit of FSH. As a result the pituitary does not secrete active FSH into the circulation. Increased stimulation of the pituitary gonadotropes by GnRH causes increased secretion of biologically active LH.

Follicles do not develop due to the absence of biologically active FSH as a result only small amounts of estrogens and inhibit are synthesised and follicles do not ovulate. Increased amounts of LH stimulate the theca cells of the follicle to secrete increased amounts of androgens. Administration of exogenous FSH, but not GnRH will cause ovarian follicular development.

 

Primary Hypothyroidism

 

Female patients with chronic severe primary hypothyroidism due to an inability to produce thyroid hormones often experience amenorrhea or absence of menstrual cycles. Administration of thyroid hormones causes resumption of menstrual cycles. The thyroid gland is unable to synthesize the thyroid hormones T3 and T4. Lack of thyroid hormone releases the TRH secreting neurons of the hypothalamus from negative feedback inhibition.

As a result, TRH secretion increases. High levels of prolactin inhibit GnRH secretion by GnRH secreting neurons. High levels of TRH stimulate the thyrotropes of the anterior pituitary to secrete increased amounts of TSH. High levels of TRH also stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin.

Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion FSH and LH. Decreased secretion of FSH and LH results in lack of stimulation of ovarian follicular development and decrease secretion of estrogens, progestins and androgens as well as decreased production of inhibin.

There may also be direct effects of excess thyroid hormones on ovarian function.

 

Secondary Hypothyroidism

 

Female patients with chronic severe secondary hypoparathyroidism due to an inability to produce biologically active TSH often experience amenorrhea or absence of menstrual cycles. Administration of thyroid hormones causes resumption of menstrual cycles. Lack of thyroid hormone releases the TRH secreting neurons of the hypothalamus from negative feedback inhibition. As a result, TRH secretion increases.

High levels of prolactin inhibit GnRH secretion by GnRH secreting neurons. The thyrotropes of the anterior pituitary secrete little or no biologically active TSH. High levels of TRH stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin. Decreased secretion of GnRH results in decreased secretion of FSH and LH.

Administration of exogenous GnRH will stimulate secretion of FSH and LH. Low levels of TSH result in synthesis of low levels of thyroid hormones T3 and T4 by the thyroid gland. Decreased secretion of FSH and LH results in lack of stimulation of ovarian follicular development and decrease secretion of estrogens, progestins and androgens as well as decreased production of inhibin.

 

Secondary Hyperthyroidism

 

Female patients with chronic severe secondary hyperthyroidism due to excessive production of TRH by a TRH secreting hypothalamic tumor often experience amonorrhea or absence of menstrual cycles. Tumors in the TRH secreting neurons of the hypothalamus secrete high levels of TRH. High levels of prolactin inhibit GnRH secretion by GnRH secreting neurons.

High levels of TRH stimulate the thyrotropes of the anterior pituitary to secrete increased amounts of TSH. High levels of TRH also stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin. Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH.

High levels of TSH result in synthesis of high levels of thyroid hormones T3 and T4 by the thyroid gland. Decreased secretion of FSH and LH results in the lack of stimulation of ovarian follicular development and decreased secretion of estrogens, progestin's and androgens as well as decreased production of inhibin.

 

Normal and Disordered Feedback Mechanisms - Female (Animation)
-How do GnRH, inhibin and estradiol regulate the pituitary in  females?
-How do estradiol, progesterone and testosterone regulate the hypothalamus
 in females?
-What other hormonal, neurogenic and psychogenic factors regulate the
 hypothalamic-pituitary unit in females?
-How does ovariectomy affect plasma levels of testosterone and inhibin?
-How are ovulation, estradiol and progesterone production, and secretion of
 inhibin, GnRH, FSH and LH affected by:
   -Ovariectomy                                              -Kallman's syndrome
   -An FSH beta-subunit defect                         -Primary hypothyroidism
   -An inactivating mutation of the FSH receptor -Secondary hypothyroidism
   -High levels of prolactin (hyperprolactinemia) -Secondary hyperthyroidism due to
   -Hypothalamic oligospermia                           hypothalamic TRH-secreting tumor
-How is prolactin secretion affected by:
    -Primary hypothyroidism
    -TRH-secreting tumor
    -Secondary hypothyroidism
-How do interruptions in the above feedback mechansims manifest themselves in
 the hypothalamus, pituitary and ovaries?