Using Progestins in Clinical Practice

Using Progestins in Clinical Practice

Barbara S. Apgar

Progestational agents have many important functions, including regulation of the menstrual cycle, treatment of dysfunctional uterine bleeding, prevention of endometrial cancer and hyperplastic precursor lesions, and contraception. Because of the reported side effects of synthetic analogs called “progestins,” there has been interest in replicating the natural hormone for clinical use. Natural progesterone is obtained primarily from plant sources and is currently available in injectable, intravaginal and oral formulations. An oral micronized progesterone preparation has improved bioavailability and fewer reported side effects compared with synthetic progestins. Adolescents and perimenopausal women may require progestational agents for the treatment of dysfunctional uterine bleeding resulting from anovulatory cycles. These agents may also be used in women at risk for endometrial hyperplasia because of chronic unopposed estrogen stimulation. Progestin-only contraceptives can be used in women with contraindications to estrogen; however, efficacy requires rigorous compliance. New progestins for use in combination oral contraceptive pills were specifically developed to reduce androgenic symptoms. It is unclear whether these progestins increase the risk of venous thromboembolic disease. Progestin-only emergency contraception offers a regimen that is more effective than combination oral contraceptive pills, with fewer reported side effects. (Am Fam Physician 2000;62:1839-46,1849-50.)

Progesterone is a naturally occurring steroid hormone. In nonpregnant women, the main sites of progesterone biosynthesis are the ovaries and the adrenal cortices.(1) Despite the extensive protein binding of serum progesterone, its half-life is only about five minutes. Because of the poor oral absorption of progesterone and its susceptibility to rapid first-pass metabolism in the liver, a variety of oral, injectable and implantable synthetic analogs, called “progestins,” have been developed.(2) Progestational agents have many important clinical functions, including regulation of the menstrual cycle, prevention of endometrial hyperplasia, treatment of abnormal uterine bleeding and contraception.

Physiologic Functions of Progesterone

Progesterone plays an important role in postovulatory regulation of the menstrual cycle. Under the influence of luteinizing hormone, the corpus luteum secretes progesterone, which stimulates the endometrium to develop secretory glands. The corpus luteum produces progesterone for approximately 10 to 12 days of the cycle. If a fertilized ovum is not implanted, progesterone and estrogen levels decline sharply, resulting in menstrual bleeding.(3) If fertilization occurs, progesterone supports implantation of the ovum and maintains the pregnancy.(4)

Progesterone controls the estrogen-primed endometrial glands by decreasing the number of estrogen receptors, thus preventing endometrial cancer. Progesterone also regulates mitosis in fully differentiated endometrial cells.(5) It now appears that severely atypical endometrial lesions and early well-differentiated endometrial cancer can be reversed with high-dose progestin therapy in women of reproductive age.(6)

Types of Progestational Agents

NATURAL PROGESTERONE

Natural progesterone is obtained from compounds derived from soybeans and Mexican yam roots, and occasionally from animal ovaries.(7) The hormone is not available from any natural source without extraction and synthesis.

Oral Micronized Progesterone. Micronizing is a process designed to increase the half-life of progesterone and reduce its destruction in the gastrointestinal tract. Micronization decreases particle size and enhances the dissolution of progesterone.

Maximal serum concentrations are achieved more rapidly with orally administered micronized progesterone (Prometrium) than with injected progesterone. Absorption of micronized progesterone is enhanced twofold when the hormone is taken with food.(8)

Unlike synthetic progestins, micronized progesterone has not been shown to affect mood,9 decrease high-density lipoprotein (HDL) cholesterol levels(10,11) or adversely affect pregnancy outcome.12 The most commonly reported side effects are fatigue and sedation.

Transvaginal Progesterone. Transvaginal progesterone delivery is the most practical nonoral route of administration. A new progesterone vaginal gel (Crinone) has sustained-release properties that were not available in the original intravaginal preparations. Intravaginal administration produces uterine effects with minimal systemic side effects.(13) In one study,(14) both 4 percent and 8 percent progesterone vaginal gel formulations induced secretory changes in the endometrium and prevented hyperplasia in women of reproductive age who were receiving estrogen therapy for secondary amenorrhea or premature ovarian failure.

SYNTHETIC PROGESTINS

The pharmacologic effects of synthetic progestins differ from those of natural progesterone. Reported androgenic effects of synthetic progestins include fluid retention, reduction of HDL cholesterol levels, headaches and mood disturbance. Consequently, there has been interest in synthesizing progestins that better mimic the natural hormone.

The classification of progestins has caused confusion. The designation of first-, second- or third-generation progestin is based on time since market introduction and not on structural and physiologic differences or efficacy. Another classification scheme, presented in Table 1, is based on structural derivation and divides progestins into estranes, gonanes and pregnanes.(15)

Some of the progestins derived from 19-nortestosterone are considered to be strongly androgenic and capable of producing side effects such as hirsutism and acne. Attempts have been made to alter the progestins to reduce the relative androgenicity.(16)

The side effects of various progestational agents are listed in Table 2. Many of these reported effects are based on limited data.(17) One of the most comprehensive placebo-controlled studies comparing hormone replacement regimens in postmenopausal women demonstrated that progestin-containing regimens did not result in weight gain, increased anxiety or cognitive and affective symptoms.(18) Commonly used progestational agents are summarized in Table 3.

Using Progestational Agents in Clinical Practice

INDUCTION OF WITHDRAWAL BLEEDING IN SECONDARY AMENORRHEA

Progestational agents have been used successfully to induce withdrawal bleeding in women with oligomenorrhea or secondary amenorrhea. The progestin most commonly used for this purpose has been medroxyprogesterone acetate (Provera). This agent produces predictable withdrawal bleeding of an estrogen-primed endometrium. Short courses of orally administered medroxyprogesterone acetate (5 mg twice daily for five days) have produced withdrawal bleeding in 93 percent of amenorrheic women.(19)

One study found that oral micronized progesterone (300 mg per day) produced withdrawal bleeding in 90 percent of women with oligomenorrhea or amenorrhea.(20) Side effects were similar to those for placebo. Another study found that progesterone vaginal gel was successful in inducing withdrawal bleeding in women with secondary amenorrhea.(14) Withdrawal bleeding occurred in 81 percent of the women who used the 4 percent formulation and 82 percent of the women who used the 8 percent formulation.

TREATMENT OF DYSFUNCTIONAL UTERINE BLEEDING

“Dysfunctional uterine bleeding” is defined as a variety of manifestations of uterine bleeding occurring in the absence of pathology or medical illness. This bleeding usually results from anovulation and occurs at the extremes of life. Most instances of anovulatory bleeding are examples of estrogen withdrawal or estrogen-progestin breakthrough bleeding.(21)

In most situations, dysfunctional uterine bleeding can be managed without surgical intervention. Progestational agents, singly or in combination with estrogen, are often used to correct the bleeding. Although progestins cannot eliminate the cause of anovulatory cycles, they are effective in alleviating the consequences on a monthly basis.(22) If hormone administration does not correct the bleeding, the diagnosis of dysfunctional uterine bleeding is excluded, and a search for other causes should be initiated.

Adolescents. Immaturity of the hypothalamic-pituitary-ovarian axis predisposes up to one third of adolescents to dysfunctional uterine bleeding.(23) In most adolescents, the bleeding can be controlled with cyclic progestins (medroxyprogesterone acetate, 5 to 10 mg per day for 10 to 12 days of the month) or low-dose oral contraceptive pills (with the added advantage of contraception). It is important to administer therapy for short periods (three to six months) and then reevaluate the patient. As many as 93 percent of adolescents with dysfunctional uterine bleeding respond to medical therapy.(23)

Perimenopausal Women. Dysfunctional uterine bleeding in perimenopausal women is generally related to declining b-estradiol levels. In this age group, it is particularly important to rule out endometrial atypia and cancer before initiating therapy. However, patient age is not as important as duration of exposure to unopposed estrogens.(24)

Although endometrial hyperplasia is a benign finding, atypical endometrial hyperplasia is a true precursor to adenocarcinoma and has a significant tendency to progress if it is not treated with progestational agents. The potential for progression to adenocarcinoma in women with atypical endometrial hyperplasia ranges from 8 to 29 percent.(25) A diagnosis must be obtained by endometrial sampling.

Because the majority of hyperplasias in women of reproductive age result from chronic anovulation, most benign hyperplasias regress without progestin therapy if spontaneous ovulation occurs. If anovulation recurs on a regular basis, progestins are generally administered for seven days (minimum duration for the prevention of hyperplasia) to 12 days of each cycle.

In a study comparing the effects of micronized progesterone (300 mg per day) and the progestin norethisterone (15 mg per day) in premenopausal women, menstrual cycles were well controlled with either agent, but cessation of dysfunctional uterine bleeding was achieved more frequently in the women who took progesterone.(22) Once treatment with either agent was discontinued, endometrial hyperplasia often recurred. Recurrences were reported in 24 percent of women after the discontinuation of progestin and in 10 percent of women after the discontinuation of micronized progesterone. Therefore, progestational therapy should be continued on a long-term basis in perimenopausal women with chronic anovulation. Repeat endometrial sampling may be required.

Postmenopausal Women. Endometrial hyperstimulation resulting from unopposed estrogen administration can be reduced by adding a progestin in postmenopausal women. Therapy with a progestin for 12 or more days each month can prevent new cases of endometrial hyperplasia and significantly reduce the risk of endometrial carcinoma.(10) The reported incidence of endometrial cancer in postmenopausal women treated with estrogen and a progestational agent is lower than that observed in the general population.(26)

Unwanted uterine bleeding is one of the most frequent factors in a postmenopausal woman’s decision to discontinue hormone replacement therapy. It has been shown that complete secretory gland maturation and subsequent withdrawal bleeding are not required for the prevention of endometrial hyperplasia. The appropriate dose and duration of progesterone therapy are those that reduce secretory gland mitoses to a very low rate with marginal secretory gland transformation and that induce a high incidence of amenorrhea without irregular bleeding. Continuously administered hormone replacement therapy can provide the same endometrial protection as sequential therapy, yet avoid withdrawal bleeding.(27)

Although continuous medroxyprogesterone acetate therapy achieves amenorrhea in more than 90 percent of women, it can lead to severe endometrial atrophy with resultant irregular bleeding. A regimen consisting of low-dose micronized progesterone (100 mg per day) and micronized estradiol (Estrace; 1.5 mg per day) for 25 days each month controls endometrial proliferation but does not fully suppress mitotic activity.(27) Consequently, amenorrhea is induced without irregular spotting. This regimen avoids the cyclic bleeding linked to a simulated endometrial cycle and reduces the bleeding associated with severe atrophy.

Progestins and Contraception

Because the estrogen component of oral contraceptive pills has remained at 30 to 35 [micro]g per day over much of the past decade, attention has been focused on the progestin component. Most of the antiovulatory effects of oral contraceptive pills derive from the action of the progestin component. The estrogen doses in these pills are not sufficient to produce a consistent antiovulatory effect. The estrogenic component of oral contraceptive pills potentiates the action of the progestin and stabilizes the endometrium so that breakthrough bleeding is minimized.(15)

The progestin-only methods of contraception work by a similar mechanism. Progesterone suppresses gonadotropin-releasing hormone, thereby inhibiting the release of follicle-stimulating hormone and luteinizing hormone. This action prevents ovulation. The atrophic endometrium that results from prolonged exposure to progestins minimizes the likelihood of implantation. By promoting the development of a thick cervical mucus, progestin-only contraceptives also make sperm penetration less likely.

The breakthrough bleeding that occurs with progestin-only contraceptives is usually worse during the first few months of use and relates more to changes occurring in the endometrium than to fluctuating endogenous hormones.(28) Adding estrogen after prolonged progestin-only contraceptive use may promote epithelial repair and reduce unscheduled bleeding.

LONG-ACTING PROGESTIN CONTRACEPTION

Injectable medroxyprogesterone acetate in crystalline form (Depo-Provera) is a highly effective contraceptive that can be administered at any time as long as there is verification of a negative pregnancy test. The standard dose of 150 mg is injected intramuscularly every three months. Women who are breast-feeding can receive injectable medroxyprogesterone acetate postpartum once lactation has been established. If this form of contraception is not initiated while menses is occurring, a backup method of contraception should be employed for at least seven days.(15) Amenorrhea and delayed return to fertility are common side effects.

The subdermal contraceptive implant system (Norplant) consists of six flexible capsules, with each capsule containing 36 mg of levonorgestrel. These implants are inserted surgically in the upper arm and can be left in place as long as five years. In adolescents, this contraceptive method has been shown to have greater efficacy than oral contraceptive pills.(29) Breakthrough bleeding is common initially, and surgical removal can be challenging if the implants were not placed correctly at the time of insertion.

PROGESTIN-ONLY ORAL CONTRACEPTIVE PILLS

The currently available progestin-only oral contraceptive pills (“mini-pills”) include norethindrone (Micronor, with each pill containing 0.35 mg of norethindrone) and norgestrel (Ovrette, with each pill containing 0.075 mg of norgestrel). Lactating women are good candidates for this contraceptive method.

No increase in the risk for cerebral thromboembolic events has been reported for progestin-only oral contraceptive pills.(30) In fact, the World Health Organization (WHO) has deemed this contraceptive method to be acceptable for use in women with a history of venous thrombosis, pulmonary embolus, diabetes, obesity or hypertension. Vascular disease is no longer considered a contraindication to use.(15)

For retention of efficacy, progestin-only oral contraceptive pills must be taken at the same time each day. If a pill is taken more than three hours late, a backup method of contraception should be used for at least the next 48 hours.

COMBINATION ORAL CONTRACEPTIVE PILLS

The association between progestins and venous thromboembolism remains a subject of great controversy. Some studies have shown an increased risk of thromboembolism in women taking oral contraceptive pills containing second- and third-generation progestins,(31) whereas other studies have not demonstrated an increased risk.(32) No clear mechanism for increased risk has been established, and a meta-analysis of 17 studies showed no difference in the hemostatic effects of oral contraceptive pills containing second- and third-generation progestins.(33) progestin-only emergency contraception Postcoital contraception, or emergency contraception, has been found to reduce the rates of unwanted pregnancy after unprotected sexual intercourse, with no significant adverse outcomes. It is estimated that postcoital contraception can prevent about 75 percent of pregnancies that would occur without treatment.(34) The only WHO contraindication to the use of emergency contraception is pregnancy. Contraindications from the U.S. Food and Drug Administration (FDA) include coronary artery disease, clotting disorders and a history of venous thromboembolism.

The Yuzpe regimen of emergency contraception involves the administration of combined oral contraceptive pills to provide 100 [micro]g of ethinyl estradiol and 0.5 mg of levonorgestrel in two doses given 12 hours apart. Because of the high strogen doses, nausea, vomiting, dizziness and fatigue are common side effects.

Compared with the Yuzpe method, a progestin-only method has been found to have lower rates of side effects and greater efficacy (85 percent pregnancy prevention rate for the progestin-only method versus 57 percent pregnancy prevention rate for the Yuzpe method).35 Until recently in the United States, the progestin dose needed for emergency contraception could only be obtained by taking 20 0.075-mg norgestrel tablets. The FDA has now labeled Plan B (800-330-1271), which consists of two 0.75-mg levonorgestrel tablets. One tablet is taken as soon as possible but no later than 72 hours after unprotected sexual intercourse; the second tablet is taken 12 hours after the first dose.

REFERENCES

(1.) Chakmakjian ZH, Zachariah NY. Bioavailability of progesterone with different modes of administration. J Reprod Med 1987;32:443-8.

(2.) Simon JA. Micronized progesterone: vaginal and oral uses. Clin Obstet Gynecol 1995;38:902-14.

(3.) Fraser IS. Regulating menstrual bleeding. A prime function of progesterone. J Reprod Med 1999;44(2 suppl):158-64.

(4.) Giudice LC. Genes associated with embryonic attachment and implantation and the role of progesterone. J Reprod Med 1999;44(2 suppl):165-71.

(5.) Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progesterone-treated endometrial hyperplasia. Am J Obstet Gynecol 1989;160: 126-31.

(6.) Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434-40.

(7.) Peterson CM. Progestogens, progesterone antagonists, progesterone, and androgens: synthesis, classification, and uses. Clin Obstet Gynecol 1995;38: 813-20.

(8.) Simon JA, Robinson DE, Andrews MC, Hildebrand JR 3d, Rocci ML, Blake RE, et al. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril 1993;60:26-33.

(9.) Sherwin BB. The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women. J Clin Endocrinol Metab 1991;72:336-43.

(10.) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995;273:199-208 [Published erratum appears in JAMA 1995;274:1676].

(11.) Ottosson UB, Johansson BG, von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985;151:746-50.

(12.) Cornet D, Alvarez S, Antoine JM, Tibi C, Mandelbaum J, Plachot M, et al. Pregnancies following ovum donation in gonadal dysgenesis. Hum Reprod 1990;5:291-3.

(13.) Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396-401.

(14.) Warren MP, Biller BM, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999;180:42-8.

(15.) Speroff L, Glass RH, Kase NG. Oral contraception. In: Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins, 1999:867-945.

(16.) Collins DC. Sex hormone receptor binding, progestin selectivity, and the new oral contraceptives. Am J Obstet Gynecol 1994;170:1508-13.

(17.) Prior JC, Alojado N, McKay DW, Vigna YM. No adverse effects of medroxyprogesterone treatment without estrogen in postmenopausal women: double-blind, placebo-controlled, crossover trial. Obstet Gynecol 1994;83:24-8.

(18.) Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92: 982-8.

(19.) Battino S, Ben-Ami M, Geslevich Y, Weiner E, Shalev E. Factors associated with withdrawal bleeding after administration of oral dydrogesterone or medroxyprogesterone acetate in women with secondary amenorrhea. Gynecol Obstet Invest 1996;42:113-6.

(20.) Shangold MM, Tomai TP, Cook JD, Jacobs SL, Zinaman MJ, Chin SY, et al. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea. Fertil Steril 1991;56:1040-7.

(21.) Speroff L, Glass RH, Kase NG. Dysfunctional uterine bleeding. In: Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins, 1999:575-93.

(22.) Saarikoski S, Yliskoski M, Penttila I. Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 1990; 12:89-97.

(23.) Falcone T, Desjardins C, Bourque J, Granger L, Hemmings R, Quiros E. Dysfunctional uterine bleeding in adolescents. J Reprod Med 1994;39: 761-4.

(24.) Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990;75: 59S-76S.

(25.) Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403-12.

(26.) Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-13.

(27.) Gillet JY, Andre G, Faguer B, Erny R, Buvat-Herbaut M, Domin MA, et al. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. Maturitas 1994;19:103-15.

(28.) Fraser IS, Hickey M, Song JY. A comparison of mechanisms underlying disturbances of bleeding caused by spontaneous dysfunctional uterine bleeding or hormonal contraception. Hum Reprod 1996;11(suppl 2):165-78.

(29.) Polaneczky M, Slap G, Forke C, Rappaport A, Sondheimer S. The use of levonorgestrel implants (Norplant) for contraception in adolescent mothers. N Engl J Med 1994;331:1201-6.

(30.) Lidegaard O. Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study. BMJ 1993;306:956-63.

(31.) Bloemenkamp KW, Rosendaal FR, Buller HR, Helmerhorst FM, Colly LP, Vandenbroucke JP. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med 1999; 159:65-70.

(32.) Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol 1999;180:241-9.

(33.) Winkler UH. Effects on hemostatic variables of desogestrel- and gestodene-containing oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: a review. Am J Obstet Gynecol 1998;179:S51-61.

(34.) Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428-33.

(35.) Trussell J, Ellertson C, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plann Perspect 1996;28:58-64,87 [Published erratum appears in Fam Plann Perspect 1997;29:60].

Members of various medical faculties develop articles for “Practical Therapeutics.” This article is one in a series coordinated by the Department of Family Medicine at the University of Michigan Medical School, Ann Arbor. Guest editor of the series is Barbara S. Apgar, M.D., M.S., who is also an associate editor of AFP.

The Authors

BARBARA S. APGAR, M.D., M.S., is clinical professor in the Department of Family Medicine at the University of Michigan Medical School, Ann Arbor. She received her medical degree from Texas Tech University Health Science Center School of Medicine, Lubbock, where she also completed a family practice residency. In addition, Dr. Apgar completed a faculty development fellowship at Michigan State University College of Human Medicine, East Lansing, and earned a master’s degree in anatomy at the University of Michigan Medical School.

GRANT GREENBERG, M.D., M.A., is clinical instructor in the Department of Family Medicine at the University of Michigan Medical School, where he earned his medical degree and completed a family practice residency. Dr. Greenberg also earned a master’s degree in ecology and evolutionary biology at Indiana University, Bloomington.

Address correspondence to Barbara S. Apgar, M.D., M.S., 883 Sciomeadow Dr., Ann Arbor, MI 48103 (e-mail: bapgar@umich.edu). Reprints are not available from the authors.

BARBARA S. APGAR, M.D., M.S., and GRANT GREENBERG, M.D., M.A. University of Michigan Medical School, Ann Arbor, Michigan

TABLE 1

Classification of Synthetic Progestins

Usual classification by generation[*]

Classification

by structure First Second

Estranes Ethynodiol diacetate —

(with ethinyl

estradiol: Demulen)

Norethindrone

(Micronor)

Norethindrone

acetate (Aygestin)

Gonanes Norgestrel (Ovrette) Levonorgestrel

(Norplant; with

ethinyl estradiol:

Alesse, Nordette)

Pregnanes Medroxyprogesterone —

acetate (Provera)

Classification

by structure Third

Estranes —

Gonanes Desogestrel (with

ethinyl estradiol:

Desogen)

Gestodene[]

Norgestimate (with

ethinyl estradiol:

Ortho-Cyclen,

Ortho Tri-Cyclen)

Pregnanes —

[*]–The traditional classification is based on time since

market introduction and not on structural and physiologic

differences or efficacy.

[]– Not available in the United States.

TABLE 2

Reported Side Effects of Progestational Agents

Natural (micronized) progesterone

Fatigue

Somnolence

Synthetic progestins

Edema

Abdominal bloating

Anxiety

Irritability

Depression

Myalgia

TABLE 3

Progestational Agents

Active ingredient Brand name Formulation Strength

Medroxy- Provera Tablet 2.5, 5 and

progesterone 10 mg

acetate

Cycrin Tablet 2.5, 5 and

10 mg

Amen Scored tablet 10 mg

Depo-Provera Vial or prefilled 150 mg

syringe, for per mL

IM injection

Norethindrone Aygestin Scored tablet 5 mg

acetate

Norethindrone Micronor Tablet 0.35 mg

Nor-Q-D Tablet 0.35 mg

Norgestrel Ovrette Tablet 0.075 mg

Micronized Prometrium Capsule, in 100 and

progesterone peanut oil[] 200 mg

Crinone Vaginal gel, 4 and

prefilled 8 percent

applicators

containing

mineral oil

Active ingredient Brand name Dosing patterns

Medroxy- Provera Daily

progesterone 5 or 10 mg daily for 12 days

acetate per month starting on

day 1 or day 16

5 or 10 mg daily for 5 to

10 days

5 or 10 mg daily for 5 to

10 days starting on day 16

or day 21 of 28-day cycle

10 mg daily for 10 days per

month

Cycrin Same as above

Amen Same as above

Depo-Provera 150 mg IM every 3 months

Norethindrone Aygestin Once daily

acetate 2.5 to 10 mg daily for 5 to

10 days of 28-day cycle

Norethindrone Micronor Once daily

Nor-Q-D Once daily

Norgestrel Ovrette Once daily

Micronized Prometrium 200 mg once daily in the

progesterone evening for 12 sequential

days each month

100 mg once daily

400 mg daily in the evening

for 10 sequential days

Crinone One full applicator of 4

percent gel in vagina every

other day for up to six

doses; if no response,

repeat regimen using 8

percent gel

Active ingredient Brand name Comments[*]

Medroxy- Provera Continuous HRT

progesterone Cyclic HRT

acetate

Amenorrhea

Dysfunctional uterine

bleeding

Induction of secretory

endometrium

Cycrin Same as above

Amen Same as above

Depo-Provera Contraception

Norethindrone Aygestin Continuous HRT

acetate Secondary amenorrhea

Norethindrone Micronor Contraceptive mini-pill

Nor-Q-D Contraceptive mini-pill

Norgestrel Ovrette Contraceptive mini-pill

Micronized Prometrium Cyclic HRT

progesterone

Continuous HRT

Secondary amenorrhea

Crinone Secondary amenorrhea

Cost for brand

Brand name Dosing patterns name drug (generic)[]

Provera Daily $15.93 (6.60 to 8.95)

5 or 10 mg daily for 12 days 9.48 (2.64 to 5.40)

per month starting on

day 1 or day 16

5 or 10 mg daily for 5 to 3.95 (1.10 to 2.25)

10 days

5 or 10 mg daily for 5 to 3.95 (1.10 to 2.25)

10 days starting on day 16

or day 21 of 28-day cycle

10 mg daily for 10 days per 9.90 (2.10 to 4.68)

month

Cycrin Same as above 8.70 (6.60 to 8.95)

Amen Same as above 9.00 (13.80 to 14.00)

Depo-Provera 150 mg IM every 3 months 48.10 for a 150-mg vial

Aygestin Once daily 39.73

2.5 to 10 mg daily for 5 to 6.62

10 days of 28-day cycle

Micronor Once daily 34.82 for one pack

Nor-Q-D Once daily 31.92 for one pack

Ovrette Once daily 30.85

Prometrium 200 mg once daily in the 14.4

evening for 12 sequential

days each month

100 mg once daily 18.9

400 mg daily in the evening 24

for 10 sequential days

Crinone One full applicator of 4 30.00 for six tubes of

percent gel in vagina every 4 percent gel

other day for up to six 60.00 for six tubes of

doses; if no response, 8 percent gel

repeat regimen using 8

percent gel

HRT = hormone replacement therapy; IM = intramuscular.

[*]–Pregnancy categories: micronized progesterone, category B;

all progestins, category X.

[]–Unless otherwise noted, estimated cost to the pharmacist based

on average wholesale prices for 30 tablets in the lowest strength

listed, as given in Red Book. Montvale, N.J.: Medical Economics

Data, 1999. Cost to the patient will be higher, depending on

prescription filling fee.

[]–Do not use in patients with peanut allergy.

COPYRIGHT 2000 American Academy of Family Physicians

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