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Luteinizing
hormone I/' 1 1
Follicle-Stimulating
Hormone r
Bslradiol . _
Progesterone
^ _
Leptin
1 ---
Childhood Puberty Reproductive Maturity Menooause
Figure 3. Hormonal changes and periods of increased vulnerability to mood disturbances and autoimmune disorders during a woman's life
span. The increasing activity of the reproductive axis during puberty and the decreasing activity of the same axis during the first stages of menopause are
associated with changes in Ihe activity of the stress system, represented here by changes in hypothalamic corticotropin-releasing hormone {CRH) secretion. The
monthly concurrent fluctuation of ovarian estradioi and hypothalamic CRH secretion is also shown (see Figure 4 for details).
anocortin neurons that inhibit gonadotropin-releas- flow, leptin is thought to provide the peripheral
ing hormone and, hence, follicle-stimulating hor- signal to a central mechanism regulating the size of
mone and luteinizing hormone secretion. Evidence body fat stores (33). Leptin suppresses the hypo-
from studies in nonhuman primates suggests that in thalamic-pituitary-adrenal axis by inhibiting hypo-
the period immediately before ovulation, a decrease thalamic CRH and adrenocortical cortisol secretion
in estradiol levels leads to reduced hypothalamic (34, 35) while it stimulates gonadai function by po-
CRH secretion. This effectively disinhibits the gona- tentiating the activity of the gonadotropin-releasing
dotropin-releasing hormone (GnRH) neuron and hormone neuron (36). Thus, increasing leptin may
possibly participates in the generation of the ovula- be involved in the control of the onset of puberty, a
tory luteinizing hormone surge (27). This takes phenomenon long known to be temporally related
place simultaneously with a delayed estrogen-in- to the acquisition of a certain fat mass (36-38).
duced central noradrenergic surge that has an ad- Low leptin levels may be involved in the adaptive
ditional positive effect on the gonadotropin-releas- activation of the hypothalamic-pituitary-adrenal
ing hormone neuron (24). axis and the inhibition of gonadai function that
Estradiol also downregulates glucocorticoid re- takes place in starvation and anorexia nervosa (39-
eeptor binding in the anterior pituitary, hypothala- 41). Some of the effects of leptin on the central
mus, and hippocampus: this tends to increase hypo- nervous system are mediated by inhibition of the
thalamie-pituitary-adrenal axis activity by interfering potent orexogen neuropeptide Y, which normally
with glucocorticoid negative feedback, whereas pro- stimulates the CRH neuron and inhibits the locus
gesterone opposes these effects (28). It is not known ceruleus-norepinephrine system (42-44).
whether the changes induced by estrogen in neuro-
nal CRH and glucocorticoid receptor activities are
mechanistically related, but they do alter the system Central and Peripheral Roles of
in the same direction. One should also keep in mind Corticotropin-Releasing Hormone
the regulatory feedback loops and adaptations that
take place over time as new equilibria are estab- Dr. George P. Chrousos: The marked changes
lished in the relation shown in Figure 1 (29, 30). that take place in a woman's reproductive system
The newly discovered adipocyte-derived peptide during her life are bound to affect the functioning
hormone leptin interacts directly and indirectly with of the stress system. The first of these changes takes
both the adrenal and gonadai axes, and its levels are place at puberty, when gonadarche is slowly estab-
higher in women than in men (31, 32) (Figure 2). lished with increasing ovarian follicle growth and
By promoting satiety and sympathetic system out- circulating estradiol levels first and then the estab-
232 1 August 1998 • Annals of Internal Medicme • Volume 129 • Number 3
lishment of ovulatory menstrual cycles within the characteristic "hot flashes" and so-called climacteric
next 2 to 3 years (Figure 3). During this time, the depression (Table 2).
stress system receives increasing intermittent posi- "Reproductive" CRH has been identifled in var-
tive input from estradiol. Puberty is a period of ious reproductive tissues and can, accordingly, be
increasing vulnerability to disorders or states char- ovarian, testicular, endometrial, or placental. It is a
acterized by disturbances or changes in hypotha- form of "tissue" corticotropin-releasing factor
lamic CRH secretion (3, 45), such as melancholic (CRH found in peripheral tissues) and is analogous
and atypical depression, eating disorders, chronic to the "immune" CRH found in immune organs
active alcoholism or other addictions, and chronic and inflammatory sites (48). The functions of im-
active athleticism, as well as seasonal affective dis- mune CRH may shed light on those of reproductive
order, the chronic fatigue and fibromyalgia syndromes, CRH and are briefly discussed below.
and several autoimmune disorders (Table 2). Inflammatory sites examined by immunohisto-
Once established, the monthly fluctuations of es- chemistry and extraction-chromatography contain
tradiol that accompany menstrual cycles are ex- large amounts of immune CRH, which is identical
pected to influence the secretion of central nervous to hypothalamic CRH (48). Endothelial cells, mac-
system CRH and catecholamines until menopause rophages, and tissue fibroblasts all have CRH in
(Figure 4). Decreased secretion of CRH in the late their cytoplasm. Immune neutralization and CRH
luteal and menstruation phases would be expected antagonist experiments have demonstrated marked
and might help explain the presence of luteal dys- inhibition of inflammation indices, such as the vol-
phoric mood disorder (the premenstrual tension ume of the inflammatory exudate and its leukocyte
syndrome) and the increased incidence of suicides concentration (48-51). Immune CRH is present at
and enhanced vulnerability to autoimmune and al- high levels in many sites of experimental inflamma-
lergic inflammatory phenomena seen during these tion in the rat and mouse and in all natural inflam-
periods (7, 8, 46, 47) (Table 2). Finally, during the matory sites examined thus far in humans. The lat-
perimcnopausal period and early menopause, there ter include the inflamed joints of patients with
is a progressive, intermittent decrease in estradiol rheumatoid arthritis and osteoarthritis and the thy-
levels that would be expected to be associated with roid glands of patients with Hashimoto thyroiditis
decreased activity of the CRH and locus ceruleus- (52, 53). The exact mechanisms by which immune
norepinephrine systems and naight help explain the CRH exerts its proinflammatory actions are not
known, but one mechanism is the degranulation of
mast cells (54). Indeed, CRH causes vasodilation,
Table 2. Potential Pathogenic Effects of Central and increases vascular permeability, and allows extravasa-
Peripheral Corticotropin-Releasing Hormone
in Women* tion of plasma through the capillary vessel walls (48).
In inflammatory sites, CRH is not only generated
Changes States
by immune system cells but is also secreted from
Central CRH the terminals of sympathetic postganglionic nerves
Increased secretion Psychiatric hypercortisolism and primary afferent nerves, whose cell bodies in
Melancholic depression
Eating disorders the sympathetic and dorsal root ganglia contain
Chronic active alcoholism large amounts of CRH (48). Secretion of immune
Chronic active exercise
Somatic sequelae CRH is suppressed by glucocorticoids and soma-
Osteoporosis tostatin. Female rats have greater inflammatory re-
Viscera! obesity
infertility
sponses and produce more immune CRH in inflam-
Decreased secretion Atypical depression matory sites than male rats do, and the presence of
Seasonal affective disorder
Chronic fatigue and fibromyalgia
estrogen seems to cause the difference. Despite high
syndromes local produetion of immune CRH in inflammatory
Rheumatoid arthritis
Postpartum biues, depression, and
sites, concurrent plasma concentrations are ex-
autoimmunlty tremely low, probably as a result of rapid clearance
Premenstrual tension syndrome
Climacteric depression
mechanisms.
Peripheral CRH Corticotropin-releasing hormone and its recep-
Increased secretion of immune CRH Inflammatory disorders
Increased secretion of placental CRH Premature labor tors are also present in rat and human ovaries (Ta-
Decreased secretion of placental CRH Delayed labor ble 3). Ovarian CRH is primarily found in the theca
Decreased secretion of ovarian CRH Ovarian dysfunction
Anovulation and stroma and also in the cytoplasm of the ovum
Defective corpus luteum function itself (55, 56). Corticotropin-releasing hormone re-
Increased secretion of ovarian CRH Early menopause
Decreased secretion of endometrial ceptors, which are type 1 (similar to those of the
CRH Infertility anterior pituitary), are also found primarily in the
Early spontaneous abortion
stroma and theca and in the cumulus oophorus,
CRH = conicottopin-teleasing hormone. whereas the foflicular fluid contains CRH as well.
1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3 233
Ovulaiion
Luteinizing
Hormone
FoJJicle-.Stimulating
Honnonc
Estradiol
Progesterone
Figure 4. Hormonal changes and period of increased vulnerability to mood disorders and autoimmune phenomena during the menstrual
cycle. The decreased activity of the reprodurtive axis in the late luteal and early follicular phases is associated with concurrent changes in the activity of the
5tress system, represented here by changes in hypothalamic corticotropin-reieasing hormone (CRH) secretion.
The findings suggest that CRH may participate in The latter half of human pregnancy is associated
the communication between the ovum and the cumu- with hypercortisolism (Figure 5). Indeed, the levels
lus oophorus and may influence ovarian steroid bio- of free plasma cortisol and 24-hour urinary free
synthesis. Incubation of granulosa-lutein cells with cortisol excretion in pregnancy overlap with levels in
CRH suppresses estradiol and progesterone secretion patients with mild Cushing syndrome (64). In the
in a dose-dependent, interleukin-1-mediated manner same vein, dexamethasone cannot properly suppress
(57, 58). In this sense, ovarian CRH has antirepro- cortisol in late pregnancy, just as it cannot in the
ductive actions that might be related to the earlier Cushing syndrome. Placental CRH causes this hy-
menopausal failure of ovaries in women exposed to percortisolism of human pregnancy (Table 3). By 28
high psychosociai stress (59). We believe that a to 30 weeks" gestation, CRH levels in plasma are
major physiologic function of ovarian CRH is its similar to those in the portal system, whereas the
participation in the "aseptic" inflammatory phenom- levels of CRH-binding protein are similar to those
ena of the ovary, including ovulation and luteolysis. in nonpregnant women and normal men (65, 66). At
The human endometrium also contains CRH 34 to 35 weeks' gestation, CRH-binding protein
(Table 3). In fact, the endometrial glands are full of concentrations decrease by two thirds, whereas total
CRH during both the proliferative and the secretory and free CRH levels are markedly increased in
phases of the cycle (60). In the luteal phase, CRH is plasma during labor and return to undetectable
probably secreted into the lumen of the uterus, amounts within hours after delivery.
where it may participate in the inflammatory phe-
nomena of blastocyst implantation and (later in the In the early 1980s, several groups demonstrated
cycle) of menstruation. Compared with interimplan- that placental CRH was produced by the syncy-
tation sites, implantation sites in rat endometrium tiotrophoblast, chorion, amnion, and decidua and
show local extravasation of plasma and contain in- that it was the product of the same gene that pro-
creased amounts of CRH messenger RNA and duces hypothalamic CRH (65, 67). Incubation of
CRH (61). We found CRH expression in human human placental tissue with CRH caused secretion
decidualized endometrial stroma, and other re- of j8-endorphin and a-melanocyte-stimulating hor-
searchers demonstrated that CRH itself decidual- mone in a dose-dependent manner (68). In addi-
ized endometrial stroma cells synergistically with tion, CRH caused stimulation of prostaglandin-Es
progesterone (60, 62). It is interesting that the effect and prostaglandin-Foo:, both of which have a role in
of estradiol on CRH transcription in immortalized labor and delivery; in contrast, CRH receptors were
human uterine epithehal cells seems to be inhibitory shown in the myometrium, where CRH had a con-
rather than stimulatory; this may explain, to some strictive effect in synergy with oxytocin (69-71). In
extent, the contraceptive properties of the "day af- addition, CRH was found to stimulate nitric oxide
ter" pill, which contains high doses of estrogen (63). production by the endothelium of placental vessels
234 1 August 1998 • Annals of Internal Medicine * Volume 129 • Number 3
and to cause the dilation of these vessels, thus fa- Table 3. Reproductive Corticotropin-Releasing Hormone
cilitating fetoplacental circulation (72). and Its Potential Physiologic Functions*
To determine whether placental CRH was se- Site of Production Function
creted in a pulsatile or circadian fashion in the third
trimester of pregnancy and whether there were any Ovarian CRH (theca, stroma, ovum) Suppression of ovarian
correlations over time between placental CRH and steroidogenesis
Inflammatory phenomena
the hypothalamic-pituitary-adrenal axis hormones, Ovulation
we studied normal pregnant women in the 34th Luteolysis
Endometrial CRH {endometrial glands,
week of pregnancy (Figure 6). We found CRH, decidua) Inflammatory phenomena
ACTH, and cortisol pulsations but, in contrast to Decidualisation
Implantation
ACTH and cortisol (which were secreted in a cir- Menstruation
cadian fashion), plasma CRH did not have a circa- Placental CRH (cytotrophoblast,
syncytiotriophobla5t, amnion,
dian rhythm (73). In the time cross-correlation anal- chorion) Maternal hypercortisolism
yses, CRH levels correlated positively with those of Fetoplacental circulation
Fetal adrenal function
ACTH and cortisol, which means that either CRH Timing of labor
causes secretion of ACTH and cortisol or cortisol Labor and delivery
stimulates placental CRH secretion, or both. In- * CRH = corticotropin-releasing hormone. ..... . . . .
deed, glucocorticoids stimulate placental CRH se-
cretion in cultured human placental cells (74). Thus, circadian rhythm of ACTH and cortisol (75). The
in the last trimester of pregnancy, the placenta se- persistent elevation of plasma ACTH and a-mela-
cretes CRH, which seems to be under the positive nocyte-stimulating hormone levels then may cause
influence of cortisol. Circulating placental CRH some hypertrophy of the adrenal cortices in normal
then causes ACTH secretion, in synergy with portal pregnant women.
parvicellular arginine-vasopressin, which thus seems Thus, placental CRH seems to be responsible for
to be responsible for generating the pulsations and the maternal hypercortisolism of pregnancy; for
Progesterone
Estradiol
CRH-
Binding Protein
CRH
ACTH
J_J_
Conisol
12 24 38 Day 1 3 6 12
Weeks Weeks
Figure 5. Hormonal changes and period of increased vulnerability to mood disorders and autoimmune phenomena during pregnancy and
the postpartum period. The increasing levels of corticotropin-releasing hormone [CRH) in the last trimester, aiong with the decreasing levels of CRH-binding
protein, may participate in the initiation and progression of labor. The decreased secretion of estradiol and hypothalamic CRH in the postpartum penod is
associated with changes in the activity of the stress system, represented here by decreased CRH secretion. ACTH = adrenocorticotropic hormone.
ACTH
C
/ if
\1 II ^
' ' ACTH
\ I
Ponal
AVP
M M Portal
AVP
Portal
AVP
Plasma
M M
Plasma Plasma
ACTH
^ ACTH ACTH
t\
'lasma Plasma ^lasma
Cortisol Corlisol !]ottisol