Progesterone is naturally secreted by the ovary
in the second two weeks of the menstrual cycle in
reproductive age ovulating women. Progesterone or
progesterone-like substances called progestogens or
progestins are also ingested by women in birth control
pills, menopausal hormone replacement therapy, or
just sometimes to induce a menstrual period or regulate
abnormal bleeding problems if menses are skipping
or bleeding is irregular or prolonged. Progesterone
has been used also as therapy for PMS syndrome and
for women with infertility or frequent pregnancy loss.
Many magazine articles have described the benefits
and hazards of estrogens in women, but progesterone
effects are much less known. A recent symposium, Fraser
IS, Lobo R (eds and cochairs):Update on progestogen
therapy. J Reprod Med 1999;44:139-232. brought together
much of the current knowledge about progesterone administration
for different purposes and helps answer some questions
that many women may be interested in.
What is the difference between progesterone and progestogens
(synthetic progesterones)?
Progesterone has the identical chemical structure
to the substance made in a woman's body by the ovarian
corpus luteum (gland formed after an egg is ovulated
each month). Actually the progesterone is now synthetically
made but it behaves as best we know, just like the
body's natural progesterone once it is absorbed into
the blood stream. This is to be distinguished from
synthetic progesterone-like chemicals called progestogens
which bind to the body's progesterone receptors and
function for the most part, just like progesterone.
Because they are chemically different than natural
progesterone, they sometimes have side effects or
actions that are different than progesterone.
Progestogens were originally developed because they
were capable of being absorbed into the blood when
ingested in pill form, whereas progesterone itself
was not orally absorbed. Recently, however, it has
been found that micronization of progesterone (making
very tiny crystals of the progesterone) enhances absorption
from the gastrointestinal tract. Thus micronized progesterone
is now sometimes being used for menopausal hormone
replacement therapy instead of progestogens. Birth
control pills still have progestogens as the active
progesterone-like component.
In contrast to some of the progestogens such as medroxyprogesterone
acetate (Provera®, Cycrin®) natural progesterone
does not seem to suppress good cholesterol (HDL),
has no effect on blood pressure or mood, and shows
less of a tendency to cause increased male-hormone-like
effects such as facial hair growth. Each synthetic
progestogen may have a somewhat different side-effect
profile so it is not easy to generalize.
Is it better to take progesterone as a pill, a shot,
a vaginal suppository or a cream?
All of the above forms of progesterone and progestogens
have been used. The method of administration is best
determined by availability, convenience of use and
price. Absorption and duration of action will vary
by the form of progesterone used:
pills - peak absorption is about 1-4 hours and is
cleared by 24 hours. Taking the pills with food enhances
absorption.
shots - usually given in the form of progesterone
in oil, doses peak at about 12 hours after administration
and take at least 48 hours or more to clear. There
are depot forms of medroxyprogesterone acetate (Depo-Provera®)
that last at least 12 weeks which gives it its contraceptive
effect.
vaginal suppositories, cream - absorbed to peak in
4 hours and cleared by 24 hours. Sometimes mixed in
cocoa butter or propylene glycol as the carrying agent.
A cream is also commercially available (Crinone®).
skin creams - creams tend not to absorb through the
skin very well but alcohol-based gels are effective
with a once a day application. A 10% alcohol and propylene
glycol base also seems to be quite effective and clears
by 24 hours.
What are the effects of too little or too much progesterone?
Progesterone acts to stabilize the tissue lining of
the uterus (endometrium) so if it is absent, such
as with ovarian anovulation, irregular and heavy menstrual
bleeding often occurs after a period without any menstrual
bleeding. Thus progesterone is used to prevent this
irregularity of bleeding if it is given continuously.
If, on the other hand, a onetime bolus of progesterone
is given such as with a shot or with only 5 days of
oral pills, then the falling progesterone levels will
actually cause an estrogen-primed endometrium to slough
and therefore start a menses.
Too much progesterone often causes tiredness and
even sedation. This side effect can be beneficial
in a women who has epilepsy or even uterine irritability
causing preterm labor because progesterone in high
doses can decrease seizure activity and uterine contractions.
Progesterone tends to promote vaginal dryness by
counteracting the effect on lubrication of estrogens
and it can also decrease the amount of menstruation
or block it entirely by reversing estrogen effect
on the growth of the uterine lining. If a woman has
stopped having menses on a birth control pill, the
progestogen component needs to be decreased if menstrual
bleeding is desirable.
How is progesterone used to regulate abnormal bleeding?
There are two ways that progesterone can be effective
to regulate abnormal menses or bleeding. If given
continuously such as in birth control pills or with
postmenopausal hormone replacement therapy, progesterone
will prevent menstrual sloughing as long as there
is a small amount of estrogen present. If birth control
pills are taken continuously so that a woman skips
the week of the "placebo" or inactive pills
and immediately begins a new pill pack, then she will
not have any menses at all. This is the pill regimen
used for endometriosis to suppress endometrial growth
and thus inactivate endometriosis. If progesterone
doses are too small without any estrogen around, such
as with the "mini" birth control pill, breakthrough
bleeding often occurs because estrogen is needed to
stabilize the blood vessels in the base layer of the
endometrium. Such bleeding would be called atrophic
bleeding since the tissue is very bare down to its
basal layer.
The second way in which progesterone is used to control
abnormal menstrual bleeding is to induce a menses
by giving a bolus of progesterone and then discontinuing
it. This could be by a shot of progesterone in oil
or by taking 5-10 days of progesterone or progestogen
by pill. The rule-of-thumb has been that if a woman
is not pregnant and estrogen had previously stimulated
even a small amount of endometrial growth, then a
menstrual-like bleed would result within about 10
days of stopping the progesterone. Unfortunately,
this regimen only works 70-95% of the time with the
shots being less effective and the progestogens (Provera®,
dydrogesterone) being 90-95% successful. Common doses
used to induce withdrawal bleeding would be:
medroxyprogesterone acetate (Provera®) 5 mg twice
a day or 10 mg once a day for 5 days
micronized progesterone 200 - 300 mg for 10 days
progesterone in oil shots intramuscularly, 100-200
mg for one dose
oral contraceptive pills (most monophasic pills with
all the same dose of estrogen and progestogen), one
pill each day for 4-5 days (for example using pills
out of a pill pack or using the emergency contraceptive
regimen but taking one pill each day for 4 days instead
of all at once.
Sometimes if the bleeding has been quite heavy or
prolonged, the progestogens will be given longer than
5-10 days just to allow a woman's recovery from the
constant bleeding and blood loss.
Does progesterone block or lessen the beneficial
effect of estrogen on heart disease and osteoporosis
prevention?
The effect of various estrogen and progestogen/progesterone
combinations have been looked at extensively in the
Postmenopausal Estrogen/Progestin Interventions (PEPI)
trial, Writing Group for the PEPI Trial: Effects of
estrogen or estrogen/progestin regimens on heart disease
risk factors in postmenopausal women: the postmenopausal
estrogen/progestin interventions (PEPI) trial. JAMA
1995;273:199-208. . Some of the following generalizations
can be drawn:
high density lipoproteins - basically progestogens
such as Provera® lessen some of the estrogen effect
of raising HDL (good cholesterol) but in combination
with estrogen, the net effect is still to raise HDL
a small amount. Natural progesterone does not blunt
this response and when used with estrogen, HDLs rise
more than when Prover® is used.
low density lipoproteins - all of the hormone regimen
combinations lowered the bad cholesterol (LDL)
blood pressure - there were no effects of estrogen
alone or any of the combinations with progestogens
or progesterone on either systolic or diastolic blood
pressure.
weight and abdominal girth - interestingly, all women,
even those who had no estrogen or progesterone, gained
weight and increased abdominal girth during this menopausal
study. The women who took any hormonal therapy gained
LESS weight and had LESS increase in abdominal girth.
Blood sugar - all hormonal regimens resulted in a
lower fasting blood sugar. However,the estrogen with
medroxyprogesterone acetate (Provera®) raised
the 2-hour post glucose blood sugar implying that
the progestogen may worsen a diabetic tendency.
Does progesterone cause mood changes?
The brain has both estrogen and progesterone receptors.
In women who have epilepsy, seizures are known to
occur more frequently during times of high estrogen
(late follicular phase and ovulation) and they are
decreased when progesterone is high. In this sense,
progesterone acts a a brain anesthetic to some degree.
High doses of progesterone can be very sedating.
Women who have depression, have lower brain levels
of serotonin, thus the success of medications that
block the body's degradation of serotonin and allow
brain levels to remain higher. Estrogens are known
to block one of the enzymes (monoamine oxidase - MAO)
which degrades serotonin with the result of elevating
mood. Progestogens, probably more so than natural
progesterone, increase MAO concentration thus producing
depression and irritability. Pure progestogen treatment
without estrogen, such as DepoProvera® is know
to worsen depression in women who already have a tendency
toward or clinical signs of depression. The combination
of estrogen plus progestogens such as used in birth
control pills and menopausal hormonal replacement
therapy does not tend to worsen mood because the compounds
are neutralizing each other. There are some women
who are more sensitive to certain hormones so their
doses may need to be adjusted.
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