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OF ACTION
RICHARD A. BRONSON, MD
North Shore University Hospital
2 % . As the number of missed days of oral contraceptive use increases, the risk of
unlikely events. Hence, while the risk of ovulation increases with the use of
formulations that contain progesterone only, and in the newer low dose
supports the normal development of the ovum and insures adequate numbers
tions of plasma estradiol signal the brain that the follicle is ready for ovulation.
from the conceptus, the corpus luteum is not maintained, but undergoes
luteolysis. With a fall in steroid hormones, menstruation occurs and FSH levels
It has been known for many years that long-term treatment with oral
Clinical Obstetrics and Gynecology, Vol. 24, No. 3 , S e p t e m b e r 1 9 8 1 . Copyright° 1981 by Harper
869
870 BRONSON
contraceptives not only causes an abolition of the midcycle surge of both FSH
and LH but also suppresses basal levels of LH and FSH ( 1 1 ) . The site of action
(16 ). They found a rise in FSH and LH that did not differ significantly from that
significantly lower release of both LH and FSH, when compared with controls
(21, 2 5 ) .
HYPOTHALAMUS
Although the action of the sex steroids on target cells within the central
cytosol receptor to the nucleus and followed by its interaction with chromatin, it
on this basis interact with catecholamine receptors within the central nervous
Estrogens influence endorphin levels within the central nervous system, and
hydroxylase) that play a role in the synthesis of catechol estrogens within the
circulation ( 2 3 ) .
the hypothalamus and pituitary can result not only from a direct action at the
PITUITARY
Several studies, using dispersed rat anterior pituitary cells as well as superfused
on the pituitary gonadotrophs (2, 17). Estradiol augments both LH and FSH
Apflebaum and Taleisnik (2) have found that the concentration of both LH
GNRH rather than to de novo synthesis of the gonadotropins. Hseuh et al. have
affect the LH response to GNRH, but when given in combination with estrogen,
the sensitizing effect of the estradiol was antagonized. In contrast to the study
Ferin and co-workers have shown that estradiol benzoate induces an FSH/LH
surge when given to rhesus monkeys immediately after pituitary stalk section
Young and Jaffe (32) have studied, in humans, the influence of estrogen on
in the early follicular phase. A single bolus challenge of 100 g GNRH was given
intravenously, 12 hours following the last dose of estradiol benzoate. The effect
estradiol benzoate was less than 60 hours. With longer exposure, LH release in
872 BRONSON
when levels of serum estradiol greater than 200 pg/ ml were achieved for over 50
hours.
endogenous estrogen.
observations demonstrated that the effect of these sex steroids was not a direct
one on the ovary and that the ovarian response to administration of exogenous
ovulation. The FSH fails to rise to normal follicular phase levels and follicular
remain low.
Spellacy et al. showed, by sequential pituitary stimulation with GNRH, that oral
FSH/LH levels were unchanged from controls and there was no suppression of
Mishell et al. have provided evidence in humans that the combined use of
to GNRH.
FSH elevation occurred following a single bolus of GNRH, daily infusions of the
releasing hormone administered for 5 days again did not result in an increase in
contraceptive users will have to be tested, however, before this question can be
OVARY
the early primary follicle stage. Ovarian biopsies in a group of women with
dysplasia have revealed only primordial and early primary follicles but no
tive users, are sufficient to allow early follicular development and atresia to
treatment with oral contraceptives, ovaries are grossly reduced in size and
atretic follicles was seen, when compared with ovaries from women not using
studies (28), in which normal numbers of atretic follicles were seen. These
findings are consistent with the clinical observation that menopause is neither
CERVIX
The cervical mucus is maximally penetrable to sperm during the late follicular
phase, when serum estradiol concentration is maximal. During the luteal phase,
and also during oral contraceptive use, the mucus becomes thick, cellular, and
impenetrable to sperm. Sperm numbers within the cervical canal, as well as the
OVIDUCT
Sperm transport into the distal ampulla, the site of fertilization, may also be
With the addition of progesterone, the epithelium deciliates and secretory cells
predominate. During the late luteal phase of a normal ovulatory cycle, ciliated
cells atrophy.
Studies of the human oviduct also indicate that cilia are lost and are
cilia regress in progesterone-dominant states, both during the luteal phase and
The isthmus of the human fallopian tube may be analogous to the cervix in its
low estrogen exposure, ciliated cells are sparse and luminal mucus secretion is
folds. At the time of preovulatory estradiol peak, large areas of tubal mucosa
covered with mucus and the cilia are now relatively inconspicuous. Mucus
levels, it is not unlikely that the combined daily exposure to progesterone and
estrogen, in the oral contraceptive formulations currently used, would alter the
normal sequence of mucus production within the fallopian tube and influence of
sperm transport. It has been shown in nonprimate species that the systemic
sperm transport and increases the rate of polyspermic fertilization (14). Tubal
proximity of sperm with eggs ( 5 ) . Norgestrel has also been found to inhibit in
vitro fertilization of hamster eggs by hamster sperm (12). These effects appear
to be species dependent, as sex steroids have not been found to alter in vivo or in
optimum time of entry of the embryo into the uterus exists that favors
successful nidation. The early cleaving embryo lacks the initial enzymes of the
utilization of glucose and glycogen, the major energy sources for the embryo
during nidation. These enzymes are not present until the morula stage ( 3 ) .
ENDOMETRIUM
blastocyst (the implanting embryo) for only a short time during the menstrual
cycle and is hostile to its growth at other times (6). This acquisition of
rodents (8). Two peaks of plasma estradiol are noted, one occurring in the
preovulatory period and the other preceding nidation. In the absence of the
second nidatory estradiol surge, the blastocyst fails to implant. Indeed, in the
The uterine secretions, under the influence of nidatory estrogen, play a role
in lysis of the zona pellucida and altering the surface properties of the
zona dissolves, freeing the embryo, and surface alterations occur in the
changes also occur in the endometrial epithelium that allow the trophoblast to
secretory human endometrium may also provide similar factors leading to zona
lysis and favoring the early stages of nidation. Stromal edema, maximal on the
seventh postovulatory day (the time of implantation) would also aid trophoblast
penetration of the endometrium, allowing rapid contact of the embryo with the
embryos fail to implant. There is evidence, again in rodents, that the decidua
may play a role in regulating trophoblast outgrowth (6, 8). While these
the apparent invasiveness of the human trophoblast and its ability to implant in
it would not be unreasonable to assume that the glandular atrophy and stromal
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