Progesterone

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When we hear the term "female hormone," estrogen is usually the first word that comes to mind. Yet progesterone is as essential to the reproductive process as estrogen is. In fact, the word's Latin roots mean "supports pregnancy." A woman's native progesterone maintains menstruation and pregnancy; in addition, progesterone taken as a drug can have a pivotal role in hormone replacement therapy.
Native progesterone

Progesterone, a chemical compound that is secreted by the ovaries and to a lesser extent by the adrenal glands, circulates throughout the body like other hormones. Progesterone's effects are registered in the uterus, breast, cardiovascular system, and central nervous system. These tissues contain progesterone receptors - molecules that latch on to progesterone. When a receptor links with progesterone, it twists into a position that enables it to lock into the cell's DNA, triggering the production of a protein. The process is comparable to turning the key in the ignition to start a car.

The number of progesterone receptors in a cell may vary from time to time. For example, high levels of estrogen stimulate cells of the endometrium, or uterine lining, to produce more progesterone receptors; when progesterone levels in the uterus rise, the number of progesterone receptors in the endometrium falls.

Progesterone plays a role in the following:

* Menstruation. Estrogen and progesterone play complementary roles in orchestrating the menstrual cycle. In the follicular phase of the menstrual cycle - so named because an egg is just developing within a follicle - the ovaries steadily increase production of estrogen. Estrogen reaches peak levels at ovulation, as an egg is released from the follicle. Thereafter, the empty follicle, or corpus luteum, excretes progesterone. Progesterone levels mount steadily during the last, or luteal, phase of the cycle. As levels of progesterone and estrogen increase, so does the thickness of the endometrium; when production of both hormones declines, the endometrium shrinks and is shed during menstruation.
* PMS. The week or so before menstruation - the late luteal phase - is also the point at which women are most likely to have symptoms of PMS. Increased levels of progesterone, which occur not only in the uterus but throughout the body, are thought to be at least partly responsible for many of the symptoms that characterize PMS, such as bloating, breast tenderness, headache, fatigue, and mood swings.

As progesterone circulates throughout the body, it is subject to chemical reactions that produce a variety of slightly different compounds, called metabolites. Although research has failed to find higher progesterone levels among women who suffer from PMS, there is evidence that levels of different progesterone metabolites vary widely from woman to woman and may be different in PMS sufferers and in those who don't experience PMS. Thus, the way that progesterone is metabolized, rather than the amount of progesterone in circulation, may determine who develops PMS. Some progesterone metabolites appear to make membranes more permeable, allowing fluid to seep into the tissues. Others may have a sedative effect, producing drowsiness and fatigue.

Progesterone also increases levels of monoamine oxidase - an enzyme that breaks down serotonin, the brain chemical associated with mood elevation. Progesterone's depressive effects are probably responsible for the dark moods associated with PMS, which may be alleviated with selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Zoloft, and Luvox.

• Pregnancy. Progesterone affects genes for growth factors that maintain the endometrium. It regulates endometrial growth to enable an embryo to become implanted in the uterus.
Progesterone as drug

Progesterone's chemical structure has been identified, synthesized in the laboratory, and incorporated into a variety of pharmaceuticals that act much like the body's progesterone. These substances, called progestogens, include both micronized plant-derived progesterone, which is chemically identical to the body's hormone, and progestins, synthetic versions that may have slightly different effects. Progestogens are used for the following:

• Birth control. The estrogen/progestogen combinations in oral contraceptives turn off gonadotropins - hormones that influence the release of estrogen and progesterone. As a result, ovulation doesn't occur and the endometrium isn't hospitable to implantation of an embryo. Progestogen-only contraceptives are thought to prevent conception by reducing the likelihood of implantation and affecting cervical mucus.

A variety of progestins are used in contraceptive pills, including desogestrel, ethinodiol diacetate, norethindrone, norgestimate, norgestrel , and levonorgestrel.

The newest of these, desogestrel (Desogen and Ortho-Cept) and norgestimate (Ortho Cyclen and Ortho Tri-Cyclen), are less likely than the others to cause such as weight gain, bloating, and acne. They have also been demonstrated to have a beneficial effect on blood lipids: They cause a slight drop in LDL (bad) cholesterol and a slight increase in HDL (good) cholesterol. Unfortunately, desogestrel has also been linked with an increased risk of blood clotting.

Individual responses to progestins vary dramatically. For that reason, finding the right birth control pill usually requires considering one's tolerance for known side effects and one's personal risk for blood clots. It often necessitates trying a few pills before settling on one.

* Treating secondary amenorrhea. The absence of periods in women who once menstruated is known as secondary amenorrhea. For several decades, progestogens have been used to treat women who had missed periods but were not pregnant and whose irregular cycles were thought to be due to hormone imbalances. The progestogens appear to transform the endometrium from the proliferative phase - in which it builds up - to the secretory phase, during which it breaks down. Bleeding usually begins 3-5 days after a 5-10-day treatment with progestogens.
* In hormone-replacement therapy. Amid growing evidence linking postmenopausal estrogen with endometrial cancer, researchers called on earlier experience with progestogens in treating secondary amenorrhea. They began to incorporate them into HRT to curtail endometrial development. Although the dosage was different - 10-14 days of progestogen treatment - the results were comparable: withdrawal from progestogens caused the endometrium to break down and bleed. Subsequent studies indicated that women on the combined estrogen/progestogen regimen had no greater risk of endometrial cancer than did those who weren't on HRT. In the last decade, a continuous progestogen HRT regimen in which both estrogen and progestogen are taken daily has been developed. The constant dose of progestogen prevents endometrial proliferation with little or no bleeding.

Progesterone's other effects

Although progesterone may trigger the proliferation of breast tissue during the luteal phase of the menstrual cycle, there is little evidence that progestogens in either birth control pills or HRT cause breast cancer.

Progestogens do appear to dampen estrogen's beneficial effects on serum lipid levels. In the Postmenopausal Estrogen/Progestins Intervention (PEPI) trial, women who took estrogen alone had better lipid profiles than did those who took estrogen with a progestogen. However, all had more favorable lipid results than did women who didn't take estrogen.

Despite popular books and articles that promote progestogens for preventing bone loss, there is no evidence that they decrease the risk of fractures. In studies in which women took progestogens alone, the hormones had little effect on bone density. Nor did women who took HRT that included progestogens have greater bone density than those who took estrogen alone.
Progestogens of the future

Selective progesterone receptor modulators, which activate progesterone receptors in some parts of the body but block receptors in other parts, are on the horizon. Such "designer progesterones" may preserve progesterone's protective effects on the endometrium but do away with the bloating, mood swings, and other PMS-like effects that have given the hormone a bad name.
FDA-Approved Progesterone-only products

Legend for chart:

A - Generic Name
B - Trade Name
C - Type
D - Use

A B
C
D

Micronized progesterone Prometrium, Crinone, Progestasert

Natural progesterone

Prometrium: capsules for HRT,
secondary amenorrhea
Crinone: vaginal gel for HRT,
secondary amenorrhea
Progestasert: IUD for contraception

Levonorgestrel Norplant

Progestin

Implantable contraceptive

Medroxyprogesterone Amen, Cycrin, Provera, Depo-Provera
acetate (MPA)
Progestin

Depo-Provera: injectable
contraceptive, endometriosis
therapy
Others: capsules for HRT,
secondary amenorrhea

Norethindrone Aygestin, Micronor, Nor-QD

Progestin

Aygestin: capsules for HRT,
secondary amenorrhea
Others: oral contraceptives

Norgestrel Orvette

Progestin

Oral contraceptive

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