Progesterone is a hormone produced principally by the ovary after ovulation. Progesterone serves many purposes, but its principal function is to prepare the lining of the uterus (the endometrium) to allow a fertilized egg to implant and grow. Progesterone is sometimes not produced in adequate amounts or its effect on the lining of the uterus is inadequate. This problem is called luteal deficiency. It is more common in older women and in women with abnormal ovulation. An abnormal lining of the uterus is also more common in women receiving clomiphene (Serophene or Clomid). 

Several different methods have been used to evaluate the adequacy of the endometrium. An ultrasound scan performed midcycle can measure the consistency of the endometrium and its thickness. A progesterone blood test drawn approximately one week after ovulation may also indicate the progesterone output from the ovary. A single progesterone level, however, is only a rough estimate; since progesterone is released in pulses that range widely even within a span of 24 hours. The endometrial biopsy is the best test to evaluate the adequacy of the endometrium.

Progesterone has been used widely in an attempt to improve implantation and fertility. Progesterone therapy has been used in the treatment of luteal phase deficiency, for the treatment of recurrent miscarriages, and in women undergoing in vitro fertilization and related procedures.

INDICATIONS

It is difficult to know in many cases whether progesterone is necessary or helpful. Progesterone is not approved by the FDA for use in women who are attempting to become pregnant or who are not pregnant. The drug is available as an injectable, oral preparation, and a vaginal cream. To date, there is no convincing evidence that progesterone causes birth defects. This seems to make sense, since progesterone is a natural hormone and is identical in structure to the progesterone which is produced during the menstrual cycle and during pregnancy.

RISKS AND BENEFITS

The potential benefit from using the progesterone must therefore be balanced with potential risk. While long-term adverse consequences of progesterone therapy have not been identified in humans and appear unlikely, the safety of this or any drug cannot be absolutely guaranteed. The FDA requires inclusion of a package insert regarding synthetic progestins with each progesterone prescription. These drugs have some progestational effects but also have other effects which progesterone does not have, including male hormone effects. Synthetic progestins may not be safe in pregnancy.

DOSAGE

Progesterone is available in several forms. Injection of progesterone produces the highest blood levels. Natural progesterone is dissolved in an oil for injection. Because of the body’s rapid metabolism of progesterone, the shot should be given daily to maintain adequate blood progesterone levels.

Progesterone suppositories or creams have also been used, but the absorption of progesterone through the vagina is more variable. Blood levels are less predictable but progesterone may exert a direct local effect when absorbed through genital tissue.

The oral progesterone capsule is a relatively new way to take progesterone. This avoids the possible complications of pain and abscess formation associated with injections. Oral progesterone is rapidly absorbed into the circulation. For best blood levels, this should be taken twice a day. The oral progesterone has not been used clinically as long as the suppositories or the intramuscular preparations. On a theoretical basis, the metabolism of progesterone given orally could be different from the way progesterone is broken down when it is given either vaginally or intramuscularly. Some of the breakdown products of progesterone may therefore form in different amounts with different routes of administration.

SIDE EFFECTS

The side effects of progesterone injection are mainly related to local irritation caused by injection. Suppositories are messy and sometimes give vaginal irritation, itching, burning, or yeast infection. The oral progesterone is well tolerated with side-effects in some women of dizziness or sleepiness. This can be minimized by taking the highest dose of progesterone at night. Care must nevertheless be exercised when taking oral progesterone, especially for the first three days, to avoid complications related to drowsiness.

CLINICAL EXPERIENCE

Progesterone has been used in many women who are at risk for miscarriage. There is good evidence that progesterone is usually not helpful in this setting, unless an abnormal uterine contour or a luteal phase defect had been diagnosed previously and progesterone supplementation is started before implantation.

Progesterone is used routinely in most in vitro fertilization programs after egg retrieval to support the lining of the uterus. The theoretical basis for progesterone use rests on the assumption that a high level of estrogen requires more progesterone to create an adequate uterine environment, and some of the progesterone producing potential of the ovary may be diminished after oocyte retrieval. In an early study on in vitro fertilization, pregnancy rates improved once progesterone was utilized. Although it is not known which patients require progesterone therapy during in vitro fertilization, most programs continue to use this medication for support of implantation.

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