Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
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Medroxyprogesterone (Depo-Provera), a progesterone used as an injection for 1) treating cancer of the uterus, and 2) an injectable contraceptive, is approved by 69 countries, manufactured in at least 6 countries, and is distributed to 42 countries by the International Planned Parenthood Federation. However, long-term safety studies revealed by 1970 that it caused benign and malignant mammary tumors in dogs. FDA therefore withdrew oral products containing this drug and required a warning for injection labeling. FDA denied approval to the Upjohn Company in March 1978 to manufacture medroxyprogesterone for contraception for the following reasons: 1) safety questions are unresolved; 2) safer contraceptive alternatives are available; 3) irregular bleeding caused by the drug, then treated by estrogen administration imposes an added risk factor and decreases the benefits of a progesterone-only contraceptive; and 4) possible exposure of the fetus poses a risk of congenital malformations, enhanced by prolonged activity of the drug. However, treatment by the drug for uterine cancer is still available.
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PMID:DES and breast cancer. 63 66

The US Food and Drug Administration (FDA) has not approved any injectable contraceptives, but, in December 1990, it approved Norplant, an implantable contraceptive. Family planning providers insert 6 capsules, each with 36 mg levonorgestrel, in a fan shape under the dermis of the upper arm. Norplant protects against pregnancy for at least 5 years . Fecundity returns within 2 weeks after capsules' removal. The steady low levels of levonorgestrel keep down both luteinizing hormone and follicle stimulating hormone levels. It suppresses ovulation and thickens the cervical mucus. Contraindications of Norplant are active thromboembolism, undiagnosed genital bleeding, acute liver disease, liver tumors, and breast cancer. Phenytoin and other drugs which speed up liver metabolism reduce Norplant's efficacy. The leading side effect of Norplant is irregular bleeding patterns. Some less common side effects include headaches, nervousness, dizziness, and acne. First year continuation rates range from 76 to 99% and 25 to 78% for 5 years of use. More than 85% of Norplant users are satisfied. Both continuation and satisfaction are associated with patient counseling. Research and development of biodegradable and other nonbiodegradable implants is ongoing. The most common injectable contraceptive in the world is Depo-Provera. 150 mg of Depo-Provera every 3 months suppresses ovulation, deteriorates the endometrium, thickens cervical mucus, and reduces motility of the tubes, thereby providing adequate protection against pregnancy. Some research shows Depo-Provera use significantly increases the low-density lipoprotein to high-density lipoprotein ratio, thereby increasing the risk for atherogenesis. Effectiveness rates match those of Norplant. Norethindrone enanthate was the first injectable contraceptive. Even though 40 countries approve it, the US does not. Animal studies of injectable microspheres or microcapsules with either progestogen or progestogen and estrogen are in progress.
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PMID:Injectable and implantable contraceptives. 138 11

A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.
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PMID:Long-acting hormonal contraceptives for women. 195 67

In a retrospective study the case histories of 70 users of Depo-Provera (containing depo medroxyprogesterone acetate) were reviewed during April-June 1987 at the Family Planning Association of Victoria's Richmond Clinic in Australia to ascertain their socioeconomic status, obstetric and contraceptive history, and side effects of Depo-Provera use. 47 (67%) were employed; 20 (29%) were health care card holders (8 were unemployed and 6 were supporting mothers); 2 were wards of state referred from adolescent institutions; and 3 women (4%) had intellectual disability. 37 (53%) had been pregnant with the total number of pregnancies of 65; 16 women had a total of 25 terminations of pregnancy; and 1 woman had a history of 4 therapeutic abortions. 53 women (76%) had started using contraception before the age of 20; 47% had used more than 1 type of contraception, 46% had used oral contraceptives only, 23% had used the condom, and 5% had used nothing. Age range at start of Depo Provera use was 14-40 years. The reasons given for commencing Depo-Provera included a combination of problems with other methods, forgetting OCs, and side effects of OCs. 47 (67%) had requested the use of Depo-Provera, of whom 13 (18%) had used it previously. 43 (61%) used Depo-Provera for 1 year or less, and only 1 patient had used it for 6 years. Among 52 women (74%) who had more than 1 dose of the injectable, the major side effects related to menstrual disturbances; 31 (41%) had amenorrhea. 2 of these women had breakthrough bleeding during the 1st dose. 17 women (24%) had either irregular bleeding or breakthrough bleeding, while 1 patient continued to have regular periods. 7 women (10%) had other side effects including depression; 4 women (6%) complained of weight gain; and 2 (3%) had breast soreness. 41 women (59%) were smokers, and 40% of them smoked 15 or more cigarettes per day. 35% of the women continued with the method beyond the study period, while the proportion of women within the clinic who continued using Depo-Provera was about 0.5%.
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PMID:Depo Provera: a profile of current users. 214 Jun 75

Medroxyprogesterone acetate injections (Depo-Provera) were given to 625 women at 3 monthly intervals involving 693 episodes. Ages at entry to the study ranged from 15-51 years with the majority in their 20s and a mean age of 30. Length of exposure ranged from 3-168 cycles. 4 women have received more than 160 continuous cycles of DMPA. Of the medication-induced reasons for discontinuing DMPA, bleeding was the most common with an incidence of 10.5% followed by depression (1.4%), weight gain (1.4%), and loss of libido (1.6%). No patient ceased treatment because of headaches, recurrent vaginal infections, mastalgia, nausea, chloasma, hypertension, or other vascular illnesses. The 59 women who move away or were lost to follow-up accounted for 405 cycles of treatment. The solitary unplanned pregnancy occurred in a 28-year-old obese woman who had previously had other method failures, once with an IUD and once with oral contraceptives (OCs). No association was found with carcinoma of the cervix. Of 80 women ceasing treatment to become pregnant, only 1 women has required the assistance of chlomiphene and conceived 2 years after ceasing DMPA. Amenorrhea was the side effect most appreciated by the women using DMPA. Due to the problem of irregular bleeding, it is wise to warn prospective patients about the lack of bleeding control that they have 1 chance in 10 of having relative menorrhagia. Women using OC subject to frequent vaginal moniliasis had a marked reduction in episodes after switching to DMPA. Chloasma, 1 of the minor stigmas of OC, was not induced in any of the patients. DMPA is a safe and efficient reversible method of contraception for women who have various gynecological conditions or problems associated with using OCs.
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PMID:Medroxyprogesterone acetate as an injectable contraceptive. 296 70

A table lists the commonly used methods of reversible contraception, their mechanism of action, and some adverse effects -- oral contraceptives (OCs), combined and progestin only; IUDs; the condom; diaphragm with spermicide; cervical cap with spermicide; sponge with spermicide; spermicide; periodic abstinence; and medroxyprogesterone acetate. The progestin-only OCs have a higher failure rate than the combined OCs and may cause irregular bleeding. Their principal indication is for nursing mothers who want to use an OC. To minimize the risk of cardiovascular adverse effects, OCs containing 35 mcg of estrogen or less and a low dose of a progestin are preferred. Most studies have found no overall increase in the incidence of breast cancer in women using OCs, but the possibility remains that the incidence may be increased in some subgroups. The 2 IUDs now marketed in the US -- the Progestasert and the Copper T380A both have a T shape and are medicated. The increased risk of pelvic inflammatory disease associated with IUDs was limited to the 1st few months after insertion in 1 study of 472 women using IUDs other than the Dalkon Shield. The increased risk of ectopic pregnancy appears to be lower with copper-containing devices than with the Progestasert. The advantages of condom use include safety and protection against sexually transmitted diseases, including Acquired Immune Deficiency Syndrome (AIDS). Diaphragms, which also offer some increased protection against sexually transmitted diseases, have been associated with an increased risk of urinary tract infection. The cervical cap, a smaller device than the diaphragm, can be left in place for 48 hours without adding more spermicide and is less messy to use than the diaphragm. The vaginal contraceptive sponge can protect during multiple acts of coitus over a 24-hour period. Nonoxynol-9, the most common spermicide used in the US, is a chemical surfactant that destroys the cell walls of sperm and offers some protection against sexually transmitted diseases. Women with irregular menstrual periods have the greatest risk of failure with periodic abstinence. Medroxyprogesterone acetate is not approved by the US Food and Drug Administration for contraceptive use.
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PMID:Choice of contraceptives. 297 98

The current use of oral contraceptives and intrauterine devices for population control is reviewed including the mechanism of their antifertility actions and the use-effectiveness of each method. The use-effectiveness of the IUD has been calculated as 1.5-3.0 pregnancies per 100 woman-years of exposure. The IUD has a high continuation rate (70% after 2 years) and is excellent for poorly motivated population groups. The most serious common side-effect--pelvic infection--can be controlled by more careful screening and modern antibiotic therapy. Other side-effects include irregular bleeding and uterine perforation, but not at significantly high levels. Oral contraceptives have been found to be virtually 100% effective, even in the new lower dose preparations containing around .5 mg progesterone and .05-.15 mg estrogen per tablet. New hormonal contraceptive approaches include pills which progesterone only, high postcoital estrogen administration, and long-acting injectable progestogen (Depo-Provera). All of these methods are highly effective but have some undesirable side-effects and require further study. Careful examination of the recent research reports connecting oral contraceptive use with increased risk of thromboembolism indicate that whatever the danger in oral contraceptive use, the direct physical hazards of pregnancy after contraceptive failure are much higher and more serious. Though a 100% safe contraceptive is a desirable ideal, the safety of current oral contraceptives and IUDs is higher than most other aspects of modern life.
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PMID:Use of drugs and intrauterine devices for birth control. 418 Jul 10

The risks and benefits of Depo-Provera, the controversial contraceptive, are examined. In April 1983 Upjohn Limited, the American manufacturers of Depo-Provera, presented evidence about its product before a government appointed panel at a hearing held in public. This was the 1st time this had happened in Britain. The panel also read submissions from the Coordinating Group on Depo-Provera, a group of women who argue that a longterm license should not be granted. A 150 mg dose of Depo-Provera, a synthetic progestogen (medroxyprogesterone), injected into the muscle is slowly released into the body over a 3-month period and inhibits ovulation by suppressing the pituitary hormones which cause release of a mature egg. It was initially licensed in the UK in 1973 for treatment of endometriosis. In 1978 it was approved for short term contraception in limited circumstances. At present it is only recommended for women who have been immunized against German measles to provide contraceptive cover during the active period of the virus and for those whose partners have had a vasectomy but whose sperm count is not yet negative. In 1981 it was licensed for use as a treatment for endometrial, renal, and breast cancer. The UK Committee on Safety of Medicines (CSM) now recommends that Depo-Provera should be used in the longterm but only as a last resort when all other contraceptive methods are unsatisfactory. It also wanted 4 warnings to be entered on the data sheet to which doctors refer: that Depo-Provera could be secreted in breast milk; that doctors should ensure their patients are not already pregnant; that tumors have developed in monkeys given 50 times the human dose; and that a few cases of breast cancer have been reported but no causal relationship with Depo-Provera has been established. The licensing authority considered that the potential risk associated with Depo-Provera use appeared to outweigh the benefits, and it rejected the CSM's advice. Kenneth Clarke was particularly concerned that the drug might be given to women without their informed consent, a concern raised by the women's group. Upjohn maintains that Depo-Provera is a safe, efficient contraceptive which has had no known death attributed to it and that its failure rate is lower than with other methods. It is recognized, in Upjohn data, that Depo-Provera frequently disrupts the menstrual cycle and that there may be irregular bleeding or spotting. After 1 year of taking the drug many women suffer amenorrhea, and a woman may not regain her fertility for up to 18 months after stopping the injections. Upjohn argues that excessive bleeding is rare, but the women's group submits numerous experiences from women who have suffered heavy bleeding long after the effects of the drug would be expected to have worn off.
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PMID:A case for concern? 622 88

A scanning and transmission electron microscopy study was undertaken of the effect of the progesterone releasing intrauterine device (Progestasert, Alza Corporation, USA) on the uterine endometrium and fallopian tube epithelium. Small erosions of surface epithelium and microthrombosis of stromal capillaries were found in the endometrium below the inert part of the device. A reduction of ciliated cells and shortened cilia were seen in the endometrium below the active part of the device and large dilated venules were present in the underlying stroma. Fallopian tubes from IUD patients contained fewer ciliated cells than those of the controls. The morphological changes described are likely to be major factors responsible for the irregular bleeding which occurs with Progestasert IUDs and the possible increase in tubal pregnancy.
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PMID:The effect of the progesterone-releasing intrauterine device on uterine endometrium and fallopian tube epithelium. 695 5

In a double-blind clinical trial the effect on the bleeding pattern disrupted by progesterone-only injectable contraception of quinestrol, an estrogen which is stored in body fat and is slowly released over days, was studied in 236 Thai women giving informed consent and having irregular or nonexistent bleeding patterns since the start of Depo-Provera contraception. In all 214 women participated in the complete trial, receiving 3 monthly injections of depot-medroxyprogesterone acetate. The bleeding pattern showed no statistical significance between the quinestrol-treated group and placebo group in terms of the overall effects on the following definitions: acceptable bleeding, amenorrhea, irregular bleeding and prolonged bleeding. However, there was an apparent increase in amenorrhea in the placebo group after the second injection of progestin as well as a fall in irregular bleeding. Prolonged bleeding was seen most frequently after the first injection, and declined during the later injection study periods. Acceptable bleeding occurred in only 6 of 78 subjects in the fourth injection group. Hence, the use of quinestrol in this trial did not significantly change the bleeding pattern of depot-medroxyprogesterone acetate users.
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PMID:The use of quinesterol for the control of vaginal bleeding irregularities caused by DMPA. 741 3


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