Gene/Protein Disease Symptom Drug Enzyme Compound
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The most effective, convenient, reversible method of birth control is considered to be long-acting progestogen injections. Used by over 90 countries, Depot medroxy-progesterone acetate (DMPA, Depo-Provera, Upjohn) has yet to be approved by the U.S. Food and Drug Administration. The reluctance of the FDA to approve DMPA and much of the controversy surrounding this method revolve around the results of testing done on animals who were given large doses of the progestogen over a long period of time and developed tumors. However, the large body of research and records on this method that have been compiled over the past 30 years is positive. The injectable method works like oral contraceptives, inhibiting ovulation. Changes in menstruation have been the chief complaint of women who use this method; however, the duration and frequency of spotting and bleeding diminish over time. Other side effects of DMPA and Norethindrone enanthate (NET EN, Noristerat, Schering) are discussed. Also discussed is the history of development and testing for the 2 methods and subdermal implants, specifically Norplant.
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PMID:Injectable contraception. 252 77

Histological changes were studied in the ovary and uterus of rats receiving different doses of Depo-Provera (DMPA) and Noristerat (NET-EN) for varying duration. The effect of DMPA on ovarian and uterine tissues was strongly progestational. The whole morphological alteration in the ovary after DMPA therapy appeared to be the atresia of the follicular apparatus with degeneration of the growing follicles. Uterine histology reflected that endometrial tissues gradually became inactive and with prolonged treatment at high doses, atrophy of the endometrium was noted. In NET-EN-treated rats, absence of mature follicles and recent corpora lutea reflected the blockade of ovulation. There was no extreme atrophy of the ovary or endometrium as found with DMPA treatment. With higher doses of NET-EN, endometrial growth was arrested.
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PMID:Histological changes in the ovary and uterus of rat after injectable contraceptive therapy. 297 Mar 68

Depot-medroxyprogesterone acetate (DMPA) in a dose of 1-2 g per injection has been administered up to 3 times a week i.m. since the early 1960s for the prevention of miscarriage, but this therapy has proven unsuccessful. However, its use for contraception proved effective. Depot-norethindrone enanthate (NET-EN) was combined with DMPA in the late 1960s. NET-EN was injected every two months. In Germany, DMPA preparations made by the Upjohn Co. (Depot-Clinovir) and NET-EN made by the Schering Co. (Noristerat) are available for contraceptive purposes. Injectable gestagens are used in more than 80 countries worldwide, except for the US, because in studies on beagle dogs breast tumors developed. Injectables occupy a high share of contraceptives in developing countries: 8% in Kenya, 12% in Thailand, and almost 20% in Jamaica, while in central Europe the three-month injectable represents only 1% of contraceptive agents. In terms of pharmacokinetics, the maximum concentration of NET-EN is reached after an injection of 1 mg/kg i.m., averaging 2-5 ng/ml, which is over the 1 ng/ml dose required for contraceptive effectiveness. The bioavailability is 100% when so applied, while the elimination half-time is 15-20 days. A 1977 WHO study revealed a continuation rate of 70-75% after 12 months. About 10% complained of bleeding disorders. Within the first 6 months of DMPA use amenorrhea sets in in one-third of the cases; it occurs in over 60% of cases after 1-1.5 years of use. Bleeding disorders often cause discontinuation, which can be treated with estrogen-gestagen combination preparations. Dihydroxyprogesterone acetophenid is combined with estradiol enanthate (E2-EN), MPA with estradiol cypionate (E2-Cyp), NET-EN with estradiol valerate (E2-Val), and 17-alpha-hydroxyprogesterone caproate with E2-Val. The rate of continuation with the DMPA/estrogen combination was more than 60%, while it varied between 26.5% and 44.1% with NET-EN plus E2-Val after 1 year of use.
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PMID:[Depot gestagens]. 857 39

Norethisterone enanthate (NET-En), an established intramuscular long-acting contraceptive agent, has previously been shown to be effective in inhibiting fertility in two rodent species even 4 days after oral ingestion. Pharmacokinetics of NET and NET-En were studied after oral and intramuscular doses in two animal species and a few women. The results suggest that the NET-En was absorbed within a day in all the species after oral dose. The estimates of relative bioavailability ranged from 13 to 51% in rabbits, monkeys, and women. The elimination half-life was 5-10 days. The presence of the active component, NET, in the circulation over the experimental period of 15 days suggests that NET-En could be useful as a long-acting oral pill. The suppression of progesterone levels during the luteal phase of menstrual cycle in women also supports this finding.
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PMID:Pharmacokinetics of orally administered norethisterone enanthate in rabbit, monkey, and women. 926 34

Progestin-only injectables are among the most effective and safe of all contraceptives, yet they are not widely used in many countries. This limited use is in part due to a lack of accurate information about health concerns, inadequate counseling for users about managing side effects, and their limited availability. Where they are available, progestin-only injectables rapidly become one of the preferred methods. Depot-medroxyprogesterone acetate (DMPA) and norethindrone enanthate (NET-EN) are the two progestin-only injectables in use worldwide. The former drug is sold under the brand name Depo-Provera, and the latter as Noristerat. DMPA is delivered in a water-based, crystalline suspension and absorbed gradually by the body. The normal injection of 150 mg is intended to be administered every three months, but contraceptive protection continues for an additional two weeks to provide a grace period for women who are late receiving their next injection. NET-EN is an oily solution which requires a larger needle than DMPA for injection. A 200 mg injection of NET-EN is usually administered every two months. Both of these safe, highly effective drugs are injected in either the upper arm or buttocks. DMPA and NET-EN can be distributed easily in nonclinical settings where nonphysicians can provide them to clients. The main disadvantage of the method is the disruption of the menstrual cycle, but that is generally not a serious medical problem. Focusing mainly upon DMPA, this article includes discussion of menstrual irregularity, the reduced risk of endometrial cancer among DMPA users, and method availability.
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PMID:Progestin-only injectables offer many advantages. 1228 28

New injectable and implantable contraceptives that provide a slow, steady dose of hormone over long periods of time promise convenient, trouble-free contraception not related to intercourse. Like oral progestagen-only contraceptives, they prevent fertilization by impeding sperm penetration through the cervical mucus, and, also like oral progestagens, their major side effects are menstrual disorders. Injectable contraceptives have the advantage that they can be administered by trained health workers and the disadvantage that they cannot be removed. New 90-day injectables that do not release initial high levels of progestagens are being developed. Family Health International is conducting Phase III clinical trials of the NET 90-day injectable, which releases .66 mg progestagen a day. Other 90-day injectables include a levonorgestrel and a progesterone injectable being developed by Stolle, a norgestimate injectable being tested by Ortho Pharmaceutical, and steroid ester injectables being developed by the World Health Organization and the US National Institute of Child Health and Human Development. Combined estrogen-progesterone monthly injectables are used by millions of women in Mexico, Latin America, and China; and 2 monthly combined injectables, HRP112 and HRP102, are being tested by the World Health Organization. 2 injectables, Upjohn's Depo-Provera and Schering's Noristerat, have been available for over a decade. Both are extremely effective, with pregnancy rates of less than 2/100 woman-years of use. Depo-Provera has been approved for use in the UK and West Germany but not in the US, due to the development of breast and endometrial tumors in experimental animals. The longest acting steroid contraceptives are the implantables. Family Health International is conducting Phase III clinical trials of the biodegradable NET pellets, containing 85% norethindrone and 15% cholesterol, developed by Endocon, Inc. Capronor, a biodegradable capsule containing levonorgestrel, developed by the Research Triangle Institute, is currently being tested in animals. The Population Council's Norplant consists of 36 mg levonorgestrel in 6 silicon elastomer capsules, which are not biodegradable. Norplant is effective for 5 years, after which the capsules must be removed. Norplant is highly effective, with a pregnancy rate of less than 1/100 woman-years of use. Its advantages are the lack of estrogen-related side effects and a swift return to fertility. Disadvantages are a higher initial cost and the need for insertion and removal by trained personnel.
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PMID:Long-acting steroids provide new options. 1231 56

Depot medroxyprogesterone acetate (DMPA, Depo-Provera) is used for contraception by 8-9 million women in more than 90 countries, including the US, as of January 1993. Pharmacologically active levels of DMPA persist for 3-4 months following injection. A 150 mg dose is used most often for high contraceptive efficacy every 3 months. Norethindrone enanthate (NET-EN, Noristerat) is somewhat less widely used and is not marketed in the US. Injectables act primarily by inhibiting ovulation, lowering the levels of follicle-stimulating hormone and luteinizing hormone. Approximately 50% of women using DMPA for 1 year report amenorrhea whose occurrence is less frequent with NET-EN. Menstrual changes are the most frequent causes of discontinuation of injectables. In cases of heavy bleeding it is appropriate to undergo gynecological examination to rule out unrelated conditions, such as vaginitis, cervicitis, or cervical lesions. The use of conjugated estrogen (12.5-2.5 mg daily) for 10-21 days will minimize bleeding. Some women using injectables experience headache, dizziness, bloating of the abdomen or breast, and mood changes. Long-term use of DMPA or NET-EN can often result in 1-3 kg weight gain. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives was launched in 1979 to examine cancer risks with the use of DMPA in Thailand, Mexico, and Kenya. The relative risk of breast cancer was 1.21, which was statistically not significant. In women diagnosed with breast cancer under age 35, short-term exposure to DMPA was associated with a slightly increased breast cancer risk, which, however, was not associated with duration of use. DMPA dramatically lowers the risk of endometrial cancer for at least eight years following discontinuation of its use. DMPA did not alter the risk of cervical cancer. Fertility returns in 70% of former users within 12 months; it is suitable for postpartum and lactating women, and provides other noncontraceptive benefits.
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PMID:Injectable contraception: the USA perspective. 1234 20

Norethisterone enanthate (NET-EN) and depot-medroxyprogesterone acetate (DMPA) are two forms of injectable progestin used for contraception. Whereas clinical research indicates that women using DMPA are more susceptible to HIV and other genital pathogens, causal relationships have not been determined. Providing an underlying mechanism for this connection, however, is recent work that showed DMPA weakens genital mucosal barrier function in mice and humans and respectively promotes susceptibility of wild-type and humanized mice to genital infection with HSV type 2 and HIV type 1. However, analogous effects of NET-EN treatment on antivirus immunity and host susceptibility to genital infection are much less explored. In this study, we show that compared with mice in estrus, treatment of mice with DMPA or NET-EN significantly decreased genital levels of the cell-cell adhesion molecule desmoglein-1 and increased genital mucosal permeability. These effects, however, were more pronounced in DMPA- versus NET-EN-treated mice. Likewise, we detected comparable mortality rates in DMPA- and NET-EN-treated wild-type and humanized mice after intravaginal infection with HSV type 2 or cell-associated HIV type 1, respectively, but NET-EN treatment was associated with slower onset of HSV-induced genital pathology and lower burden of systemic HIV disease. These findings reveal DMPA and NET-EN treatment of mice significantly reduces genital desmoglein-1 levels and increases genital mucosal permeability and susceptibility to genital pathogens while also implying that NET-EN generates less compromise of genital mucosal barrier function than DMPA.
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PMID:Norethisterone Enanthate Increases Mouse Susceptibility to Genital Infection with Herpes Simplex Virus Type 2 and HIV Type 1. 3204 94