|
Amenorrhea
The absence of cyclical menstruation,
amenorrhea, most frequently reflects an abnormality in
hypothalamic/pituitary and/or ovarian function. Central amenorrhea can
be caused by disease of the brain or pituitary gland. The former may be
rarely due to a genetic defect or more commonly to acquired disease
leading to a deficit in the production of GnRH, which controls the
secretion of pituitary gonadotropins. Changes in body mass, stress (both
physical and psychological), and drug abuse may cause hypothalamic
amenorrhea due to brain dysfunction. Pituitary causes of amenorrhea
include destructive lesions, radiation damage, or tumors that produce
prolactin. High levels of prolactin suppress hypothalamic GnRH
production. In all of these situations, ovarian estrogen production is
markedly diminished. The consequences of untreated hypoestrogenemic
amenorrhea include infertility, osteoporosis, cardiovascular disease,
and the failure to go through puberty if the disorder arises early in
life.
Using the knowledge generated in earlier
years that the secretion of pituitary gonadotropins is regulated by the
gonadotropin-releasing hormone (GnRH) neurons, spectacular advances have
been made in the neuroendocrine control of reproductive function in the
last decade. The major brain sites involved in regulating sexual
behavior and pituitary gonadotropin secretion have been identified, as
well as the multiple hormones that regulate those complex functions.
Significant work has been done on the localization and biology of the
receptors for sex steroids and neurotransmitters. Advances in molecular
biology have provided new insights into how the genes for
neurotransmitters, neurotransmitter transporters, and neurotransmitter
receptors are regulated. The use of gene knockout transgenic animals
(10-12) and antisense oligonucleotides have helped understand more
clearly the physiological role of specific genes in reproductive
function.
The applications of these fundamental
discoveries to the understanding and treatment of reproductive diseases
in women have been numerous. For example, it has been shown that the
deficiency of GnRH secretion in Kallmann's syndrome is frequently due to
the failure of embryonic GnRH neurons to migrate to their hypothalamic
destination due to a defect in a neural adhesion molecule. The
recognition of pulsatility in GnRH secretion and the subsequent
discovery that continuous GnRH desensitizes the pituitary has led to
treatments with pulsatile GnRH or long-acting GnRH analogs to either
stimulate or suppress reproductive function, respectively. The
recognition of the importance of secretion of growth factors by glial
cells and astrocytes that, in turn, regulates the maturation of the GnRH
neurons has led to important advances in understanding the process of
normal puberty and the malfunction in precocious puberty (13). Important
advances have been made in the understanding of the effect of stress and
infections through glucocorticoids, prolactin, corticotropin-releasing
hormone (CRH), and cytokines on the GnRH neurons (14) and reproductive
function. Furthermore, considerable progress has been made in
elucidating the relationship between nutritional status and
reproduction. For example, recent studies have demonstrated that the fat
cell hormone, leptin, is essential for normal reproductive function,
although the mechanisms by which it affects reproduction are unknown
(15).
Ovarian follicular development and the
process of ovulation and maintenance of the corpus luteum are under the
control of pituitary gonadotropins. Hypothalamic-pituitary failure is a
major cause of amenorrhea. The regulation of LH secretion is much more
tightly coupled with GnRH secretion than is FSH secretion (16, 17).
Research in the last decade has clearly established that in addition to
GnRH, inhibin, activin, follistatin, progesterone (through its
5-reduction), and glucocorticoids regulate FSH secretion. The regulation
of the preovulatory gonadotropin surge leading to ovulation has also
been studied extensively during the same time period and has revealed a
high degree of unexpected complexity. In addition to estradiol, ovarian
and adrenal progesterone have been shown to be essential for the
magnitude and duration of the preovulatory LH surge (18). These steroids
do not act directly on the GnRH neurons to induce the preovulatory LH
surge, but rather influence the release of neuropeptides and
neurotransmitters. Increasing LH secretion-stimulating (accelerating)
factors and decreasing inhibitory (braking) factors precipitate the LH
surge. The list of major accelerating signals for GnRH secretion has
expanded and now includes norepinephrine, neuropeptide Y, galanin, and
the excitatory amino acid, glutamate, working through N-methyl-D-aspartate
(NMDA) and non-NMDA receptors (19-21). Evidence is accumulating which
suggests that the novel gaseous transmitter nitric oxide acts to mediate
glutamate signals to the GnRH neuron (22). Major inhibitors of GnRH
secretion include opioids, GABA, and tackykinins. The enzyme glutamic
acid decarboxylase has been shown to be very important in altering the
balance between stimulatory (glutamate) and GABA (inhibitory) signals
around the time of the LH surge when glutamate levels increase and GABA
levels decrease (23).
The premature loss of follicles from the
ovary also robs a woman of female sex hormones. This may be the
consequence of genetic aberrations that lead to a reduced germ cell
population in the fetal ovaries (gonadal dysgenesis), inherited
metabolic disease that promotes follicular demise (galactosemia,
myotonic dystrophy), autoimmune disorders, and destruction of ovarian
tissue as a result of infection or toxic effects of radiation or
chemotherapy. Important recent advances include the discovery that the
orphan nuclear transcription factor, steroidogenic factor 1, is
essential for gonadal development and the demonstration in a Finnish
family that mutations in the FSH receptor cause ovarian failure. The
latter discovery raises significant questions regarding the role of FSH
in ovarian function, which may be addressed by recent animal experiments
in which the FSH gene and FSH receptor have been mutated.
Ovarian failure is frequently associated
with autoimmune disease affecting other endocrine glands (24). A genetic
component to this type of ovarian dysfunction is likely as animal
studies suggest the presence of susceptibility and resistance loci. A
locus on chromosome 21 has been linked to one form of autoimmune ovarian
failure in the Finnish population. However, the way in which these genes
interact and how they modify the expression of ovarian determinants and
immune cell responses is unknown at the present time.
|
|
|
