Progesterone - Its Uses and Effects
Frederick R. Jelovsek MD
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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