ORAL CONTRACEPTION: MECHANISM

OF ACTION

RICHARD A. BRONSON, MD
North Shore University Hospital

Manhasset, New York

The combination of steroid hormones in oral contraceptives acts both centrally

and peripherally to alter normal reproductive function. Ovulation is inhibited

through suppression of gonadotropin release. Follicular maturation is impaired,

although there is evidence that follicular atresia continues.

The incidence of ovulation in women taking oral contraceptives is less than

2 % . As the number of missed days of oral contraceptive use increases, the risk of

ovulation rises. However, even in the face of occasional ovulation, the

peripheral changes that occur secondary to chronic exposure to the progestin

component of the oral contraceptive make both fertilization and implantation

unlikely events. Hence, while the risk of ovulation increases with the use of

formulations that contain progesterone only, and in the newer low dose

contraceptives, the risk of pregnancy does not increase markedly.

CENTRAL MECHANISMS OF CONTRACEPTIVE ACTION

During the spontaneous ovulatory cycle, under the influence of follicle

stimulating hormone (FSH), granulosa cells aromatize thecal androgens to

estrone and estradiol (22). lntrafollicular estrogen stimulates the continued

proliferation of granulosa cells, creating a follicular microenvironment that

supports the normal development of the ovum and insures adequate numbers

of granulosa cells to provide sufficient luteal progesterone secretion for

maintenance of pregnancy ( 2 0 ) . During follicular maturation, rising concentra­

tions of plasma estradiol signal the brain that the follicle is ready for ovulation.

A subsequent luteinizing hormone (LH) surge triggers intraovarian events,

leading to release of a fertilizable ovum. During the luteal phase, ovarian

secretion of a combination of estrogen and progesterone leads to suppression of

pituitary gonadotropins. In the absence of the chorionic gonadotropin signal

from the conceptus, the corpus luteum is not maintained, but undergoes

luteolysis. With a fall in steroid hormones, menstruation occurs and FSH levels

begin to rise, reinitiating follicular growth.

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

& Row, Publishers, Inc. 0009-9201/81/0901-0869$0100.

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

where contraceptive steroids exert most of their gonadotropin-inhibiting action

has yet to be clearly defined. Kastin et al. administered gonadotropin-releasing

hormone (GNRH) to females following short-term use of oral contraceptives

(16 ). They found a rise in FSH and LH that did not differ significantly from that

of control subjects. As the pituitary response to the hypothalamic GNRH was

normal, these early studies suggested that contraceptive steroids suppressed

gonadotropins at the level of the hypothalamus or higher in the central nervous

system. Other investigators, however, have reported that the administration of

GNRH to women who had been ingesting oral contraceptives containing

combinations of estrogens and progestins for longer periods resulted in a

significantly lower release of both LH and FSH, when compared with controls

(21, 2 5 ) .

EFFECT OF ESTROGEN AND PROGESTERONE ALONE AND IN

COMBINATION ON THE HYPOTHALAMUS AND PITUITARY

HYPOTHALAMUS

Although the action of the sex steroids on target cells within the central

nervous system had been assumed to be primarily through classic mechanisms,

whereby effects were mediated by translocation of the hormone bound to a

cytosol receptor to the nucleus and followed by its interaction with chromatin, it

is now known that multiple interactions of great complexity exist between

catecholestrogens, catecholamines, and the endorphins in the regulation of

neurosecretion of GNRH and other hypophysiotropic neurohormones.

Catecholestrogens, naturally occurring metabolites of estradiol (that are

hydroxylated in the 2 or 4 position of the A ring of the steroid nucleus), share a

common structure with the catecholamines dopamine and norepinephrine and

on this basis interact with catecholamine receptors within the central nervous

system as well as with cytoplasmic estrogen receptors. The differing neural

metabolites of estradiol have divergent actions. 2-Hydroxyestrone appears to

be a physiologic inhibitor of prolactin release in normal women (9). 2­

Hydroxyestradiol stimulates prolactin but not gonadotropin release. 2­

Hydroxyestrone has also been shown to decrease gonadotropin secretion in

estrogen-primed hypogonadal women ( 1 ) . The effects of the catecholestrogens

on hypothalamic-pituitary function may be mediated not only through

catecholamine receptor binding but also by alteration in CNS catecholamine

concentrations. 2-Hydroxyestrone inhibits tyrosine hydroxylase as well as

catechol-0-methyltransferase, enzymes involved in the synthesis and deg­

radation of dopamine and norepinephrine.

Endogenous opiate receptor agonists, the endorphins, also appear to play a

role in anterior pituitary function, including gonadotropin release (26).

Endorphin levels are elevated in hypophyseal portal blood compared with

peripheral blood, suggesting their possible direct effect on the pituitary.

Estrogens influence endorphin levels within the central nervous system, and

endorphins in turn alter the activity of neural enzymes (such as estradiol-2­

hydroxylase) that play a role in the synthesis of catechol estrogens within the

central nervous system (9). This complex process of interactions appears to

 ORAL C O N T R A C E P T I O N : MECHANISM OF ACTION 871

regulate the hypothalamic neurosecretion of GNRH into the pituitary portal

circulation ( 2 3 ) .

Alterations in pituitary sensitivity to GNRH following exposure to the sex

steroids are mediated in part by changes in GNRH receptor content of the

gonadotrophs. Gonadotropin-releasing hormone can also potentiate the

response of the gonadotrophs to subsequent injections of the releasing

hormone (self-priming) ( 3 1 ) . Hence, the effects of the gonadal sex steroids on

the hypothalamus and pituitary can result not only from a direct action at the

level of the gonadotroph, as will be documented next, but also subsequent to an

augmented secretion of hypothalamic GNRH into the portal circulation.

PITUITARY

Several studies, using dispersed rat anterior pituitary cells as well as superfused

hemipituitaries, have documented a direct effect of estrogen and progesterone

on the pituitary gonadotrophs (2, 17). Estradiol augments both LH and FSH

release in vitro in response to G N R H . The effect of progesterone on GNRH­

stimulated LH release by anterior pituitary cells in culture is time dependent.

There is an increased response after short periods of exposure to progesterone,

followed by inhibition thereafter. The effect of progesterone on GNRH­

stimulated FSH secretion is exclusively stimulatory.

Apflebaum and Taleisnik (2) have found that the concentration of both LH

and FSH within superfused rat hemipituitaries is increased in a dose-dependent

manner in response to estradiol. In contrast, there is no acute effect of

progesterone on pituitary cell content of FSH and LH, indicating that

progesterone's stimulatory effect is due to a change in pituitary sensitivity to

GNRH rather than to de novo synthesis of the gonadotropins. Hseuh et al. have

also documented an increased sensitivity of rat pituicytes in culture to GNRH

following estradiol exposure ( 1 3 ) . In their study, progesterone alone did not

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

of Apflebaum and Taleisnik, the intracellular content of LH was not affected by

either estradiol or progesterone.

Ferin and co-workers have shown that estradiol benzoate induces an FSH/LH

surge when given to rhesus monkeys immediately after pituitary stalk section

(7). In this instance, it is presumed that any communication between the

hypothalamus and the pituitary has been destroyed, implying a direct

stimulatory effect of estrogen on the pituitary gonadotrophs.

Young and Jaffe (32) have studied, in humans, the influence of estrogen on

gonadotropin release in response to GNRH. Doses of estradiol benzoate were

administered to normal women on an every 12-hour basis for 6 days, beginning

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

of estradiol benzoate on pituitary response to GNRH was both concentration

and duration dependent.

At early follicular phase levels of estradiol (40-60 pg/ml), no augmentation in

LH release was noted in response to GNRH, despite 132 hours' exposure. At

circulating levels comparable to those of the late follicular phase, a suppressive

effect of estradiol benzoate was demonstrated when the duration of exposure to

estradiol benzoate was less than 60 hours. With longer exposure, LH release in
872 BRONSON

response to GNRH was markedly augmented. Activation of positive feedback

with spontaneous LH surges in response to exogenous estrogen was noted

when levels of serum estradiol greater than 200 pg/ ml were achieved for over 50

hours.

Other recent studies ( 1 9 ) in humans suggest that progesterone may play a

role in regulating the periovulatory gonadotropin surge. In oophorectomized

subjects given various treatment regimens of estrogen and progesterone, an

FSH surge accompanied by an augmented LH surge was seen if progesterone

were administered after an increase in serum estradiol had occurred. No FSH

surge was seen in response to estradiol alone. In the absence of estrogen

priming, there was no change in basal gonadotropin levels in response to

progesterone. If estradiol benzoate and progesterone were administered

concomitantly, FSH but not LH was acutely suppressed. While progestins

administered alone to oophorectomized humans are poorly effective in sup­

pressing LH and FSH, they do suppress these hormones when administered in

large doses to normal menstruating females by acting synergistically with

endogenous estrogen.

It is now generally accepted that inhibition of pituitary gonadotropin

secretion is the most important mode of action of oral contraceptives. Early

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

gonadotropins was not inhibited in oral contraceptive users. Preparations that

contain sufficiently large amounts of estrogen-progestin suppress basal LH and

FSH concentrations (11). No ovulatory gonadotropin surge occurs to cause

ovulation. The FSH fails to rise to normal follicular phase levels and follicular

development is inhibited. As a result, endogenous estradiol concentrations

remain low.

The extent of hypothalamic-pituitary suppression appears to be dose related.

Spellacy et al. showed, by sequential pituitary stimulation with GNRH, that oral

contraceptives containing 50 g or more of ethinyl estradiol suppress gona­

dotropin release to a greater extent than the lower dose formulations ( 2 7 ) . In

women using oral contraceptives containing 35 µg of ethinyl estradiol, basal

FSH/LH levels were unchanged from controls and there was no suppression of

FSH response to GNRH stimulation. Suppression of LH response was seen only

to maximal GNRH stimulation.

Mishell et al. have provided evidence in humans that the combined use of

estrogens and progestins has a direct suppressive effect on pituitary gona­

dotropins in the majority of oral contraceptive users (21). While prolactin

release was stimulated, there was inhibition of gonadotropin release in response

to GNRH.

Long-term suppression of GNRH in itself may result in an impaired response

of the pituitary gonadotrophs to the releasing hormone, which is corrected

following repeated GNRH stimulation. In a single subject in whom no LH or

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

FSH/LH release, suggesting that the contraceptive steroids had a direct

inhibitory effect on pituitary gonadotropin release. A larger study group of

contraceptive users will have to be tested, however, before this question can be

answered with surety.

 ORAL C O N T R A C E P T I O N : M E C H A N I S M OF A C T I O N 873

PERIPHERAL EFFECTS OF ORAL CONTRACEPTIVES

OVARY

A threshold level of serum FSH is necessary for follicular development beyond

the early primary follicle stage. Ovarian biopsies in a group of women with

hypothalamic, hypogonadotropic hypogonadism secondary to olfactogenital

dysplasia have revealed only primordial and early primary follicles but no

secondary follicles ( 10 ) . There was marked inhibition of initiation and progres­

sion of follicular growth, although atresia of immature follicles persisted.

Ovulation could be induced with exogenous gonadotropins in these women.

Hence, gonadotropin deficiency prevented follicular maturation, but atresia

persisted in these ovaries.

Basal pituitary gonadotropin levels, although suppressed in oral contracep­

tive users, are sufficient to allow early follicular development and atresia to

continue, but complete follicular maturation is not common. During long-term

treatment with oral contraceptives, ovaries are grossly reduced in size and

present a quiescent picture. The number of primordial follicles varies con­

siderably between women and is dependent primarily on the age of the

individual, with no correlation with duration of oral contraceptive use. In the

majority of oral contraceptive users, normal numbers of primary follicles are

present in all stages of development. Although later follicular growth is

impaired, secondary follicles and even mature graafian follicles may be

occasionally seen after long-term treatment. In one study, a large number of

atretic follicles was seen, when compared with ovaries from women not using

contraceptive steroids ( 1 8 ) . This observation has not been confirmed in other

studies (28), in which normal numbers of atretic follicles were seen. These

findings are consistent with the clinical observation that menopause is neither

postponed nor accelerated by long-term continuous use of oral contraceptives.

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

number of cervical crypts colonized by sperm, have been quantitated following

treatment with ethinyl estradiol and medroxyprogesterone acetate. Proges­

terone counteracts the stimulatory effect of estrogen on penetrability of

cervical mucus, and there is a marked diminution in the number of sperm

entering the cervix.

OVIDUCT

Sperm transport into the distal ampulla, the site of fertilization, may also be

dependent on the sex steroids. The epithelium of the subhuman primate

oviduct, particularly that of the rhesus monkey, is dependent on estrogen to

maintain a normal state of cellular differentiation. Both ciliated and secretory

cells atrophy and dedifferentiate after ovariectomy. After subsequent treat-

874 BRONSON

ment with estrogen, a hypertrophied ciliated oviductal epithelium is found.

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

regenerated cyclically (30). Estrogen appears to stimulate ciliogenesis, while

cilia regress in progesterone-dominant states, both during the luteal phase and

postpartum. Subsequent postpartum treatment with estrogen results in

increased proliferation of ciliated epithelium. These observations suggest that

progesterone antagonizes the cilia-maintaining effect of estrogen.

The isthmus of the human fallopian tube may be analogous to the cervix in its

ability to secrete mucus ( 1 5 ) and regulate sperm transport. Under conditions of

low estrogen exposure, ciliated cells are sparse and luminal mucus secretion is

minimal. During the midfollicular phase of the normal menstrual cycle,

secretion of mucus becomes evident, between microvilli and filling mucosal

folds. At the time of preovulatory estradiol peak, large areas of tubal mucosa

covered with mucus and the cilia are now relatively inconspicuous. Mucus

secretion diminishes following ovulation. As mucus secretion is no longer

evident in the midluteal phase, under the influence of rising progesterone

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

administration as well as local application of progesterone to the oviduct alters

sperm transport and increases the rate of polyspermic fertilization (14). Tubal

transport of eggs into the uterus is also accelerated.

In addition, circumstantial evidence has been presented that the contra­

ceptive progestins may have a direct effect on capacitation of sperm in addition

to their action on tubal transport of gametes. Fertilization rates were impaired

following oviductal insemination of progestin-treated rabbits despite the direct

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

vitro fertilization rates in mice.

Embryo transfers at varying times after ovulation (4) indicate that an

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

Embden-Meyerhof pathway of anaerobic glycolysis, which are needed for

utilization of glucose and glycogen, the major energy sources for the embryo

during nidation. These enzymes are not present until the morula stage ( 3 ) .

Alterations in tubal embryo transport in response to the use of oral contra­

ceptive steroids could then diminish the likelihood of successful implantation.

ENDOMETRIUM

The endometrium becomes receptive to attachment and penetration of the

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

receptivity to the invasiveness of the trophoblast is crucially dependent on

proper hormonal priming through a programmed sequence of exposures to

 ORAL C O N T R A C E P TI O N : M E C H A N I S M OF ACTION 875

estrogen and progesterone. These requirements have been carefully studied in

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

progesterone-dominant uterine environment, murine blastocysts undergo a

delay in implantation. Metabolic processes, as reflected in oxygen uptake and

carbon dioxide production, diminish markedly ( 2 9 ) . There is evidence, again in

rodents, that metabolic inhibitors may be secreted by the progestational

endometrium until the time of nidatory estrogen surge.

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

trophoblast (24). Blastocysts transferred to the uterus of castrate mice

maintained on exogenous progesterone fail to implant and remained trapped

within the zona pellucida. Following administration of exogenous estrogen, the

zona dissolves, freeing the embryo, and surface alterations occur in the

trophoblast, allowing its attachment to the endometrial epithelium. In addition,

changes also occur in the endometrial epithelium that allow the trophoblast to

broach this potential barrier to invasion ( 8 ) .

While mechanisms of implantation vary markedly between species, making

extrapolation difficult, the extensive glandular secretion seen in the mid­

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

maternal endometrial vascular system.

Once the endometrium has decidualized, trophoblast invasion is impaired and

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

observations must be extrapolated to humans with caution, especially in light of

the apparent invasiveness of the human trophoblast and its ability to implant in

numerous extra uterine locations (a phenomenon not observed in other species),

it would not be unreasonable to assume that the glandular atrophy and stromal

decidualization that occur following chronic exposure to contraceptive steroids

result in an endometrial environment hostile to implantation and further

growth of the embryo.

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