Gene/Protein Disease Symptom Drug Enzyme Compound
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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

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 X 80 mg p.o. or MPA 2 X 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.
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PMID:A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer. 214 91

This study reports on 56 women who volunteered for consultation at a gynaecological hospital for their climacteric symptoms. The stability of their low oestradiol and high gonadotrophin plasma levels was controlled first. Afterwards they were treated for 3 mth with natural oestradiol (percutaneously). Once the plasma oestradiol levels were proved to be stable during the treatment, natural progesterone was also administered (orally) the last 10 days of treatment. As observed with all steroid administration, the same therapeutic regimen induced different individual plasma levels of the natural steroids. The relationship between mood and plasma levels was as follows. Moderate depressive symptoms were correlated to the lowest plasma oestradiol level, before and after treatment. Only when a moderate increase in oestradiol level was induced did the oestradiol treatment itself lead to a pleasant feeling of well-being. When an excessive increase was induced by the treatment, most of the women complained of unpleasant side effects, mostly irritability and aggressiveness. Progesterone had very few psychological effects if oestradiol levels were low or slightly increased. When plasma oestradiol was high, a moderate elevation of plasma progesterone induced a pleasant tranquillizing effect. A massive elevation of plasma progesterone levels immediately induced an inadequate hypnotic effect, sometimes with dizziness. Therefore, therapeutic administrations of natural steroids appear to strongly influence the mood and behaviour of post-menopausal women. However, the expected pleasant effect could not be successfully achieved without a careful adaptation of the correct dosage to each individual patient.
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PMID:Differential effects of exogenous oestradiol and progesterone on mood in post-menopausal women: individual dose/effect relationship. 709 5

In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.
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PMID:[Phase II study of NK 622 (toremifene citrate) in advanced breast cancer, a multicentral cooperative dose finding study]. 842 89

The US Food and Drug Administration finally approved the injectable contraceptive Depo-Provera (DMPA) in October 1992, 25 years after its introduction. Women return to a health facility every 90 days for an intramuscular injection of 150 mg DMPA, which provides them 99% effective contraception. Menstrual changes and spotting are the leading reasons for DMPA discontinuation. Eventually, more than 50% of DMPA users develop amenorrhea. During the first year, women gain about 2 kg and weight increases as time passes. Weight gain is the second leading reason for DMPA discontinuation. DMPA may adversely affect glucose tolerance in women at risk for diabetes, but it does not affect cardiovascular or metabolic functions. It may increase the risk of osteoporosis. A rare side effect is convulsions. 1-10% of DMPA users have other central nervous system effects, such as headaches, dizziness, and depression. Itching and rashes may develop. Fertility returns within 1 year after discontinuation. DMPA is linked to low birth weight. It apparently does not harm breast-fed infants or hinder lactation. A World Health Organization study shows that DMPA users less than 35 years old experience a slight increase in breast cancer but a reduced incidence of endometrial cancer. Nurses are instrumental in guiding women as they choose DMPA and in informing them about its potential side effects, including breast cancer risk. They must screen women for pregnancy and evaluate their risk of breast cancer. They must determine whether women are able to return every 3 months for DMPA injections. Women who select DMPA must use other contraception, e.g., barrier protection, within the first 24 hours after initial injection. Nurses should counsel them about the likely menstrual changes to reduce the likelihood of dissatisfaction. They should recommend a daily dose of 1200 mg of elemental calcium and daily exercise of long bones to minimize the risk of developing osteoporosis.
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PMID:Depo-Provera. 849 47

Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when used for hormone replacement than typically encountered with progestins and oral progesterone. Uses in patients with infertility and hypoestrogenism and secondary amenorrhea are reviewed.
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PMID:Uses of progesterone in clinical practice. 1033 67

The use of depo-medroxyprogesterone acetate (DMPA), or Depo Provera, has been debated for the 20 years since it became available in 1967. The US Food and Drug Administration (FDA) refused to approve Depo Provera on the basis that it caused breast tumors in a controlled study of Beagle dogs and Rhesus monkeys conducted by Upjohn, the manufacturer. Depo Provera has been approved in over 60 other countries and is in use in 30 or 40 others with an estimated total of almost 5 million users. A natural hormone, progesterone, DMPA is injected intramuscularly and absorbed slowly. Common dosage is 150 mg every 3 months and usually is administered during the 1st week of the menstrual cycle. The pregnancy rate with Depo Provera is .44 pregnancies/100 women years for women receiving 100 mg every 3 months. No pregnancies were recorded in recent studies for women receiving 150 mg. Possible side effects include amenorrhea, weight gain, dizziness and headaches. The median time for contraception after the presumed duration of one's last injection is 5-1/2 months. Some countries only permit women who already have 1 child to use Depo Provera. The FDA in the US approves the use of Depo Provera for treatment of endometrial and renal cancer but accuses it of causing cancer in Beagles and Rhesus monkeys. The studies were conducted over 7 and 10-year periods, respectively, with extremely negative results including the death of 3 dogs due to "drug-induced diabetes," atrophication of adrenal glands, and malignant tumors. There were similar results for the monkey study. In the UK, the Committee for Safety in Medicine supports Upjohn's view that Beagles are unsuitable for comparison testing because "all dogs are acutely sensitive to progesterone." Groups such as the National Women's Health Network, the institute for Food and Development Policy, and "Mother Jones" have used the media to generate opposition to Depo Provera, citing a double standard for rich and poor women, developed and less developed countries. The proponents of Depo Provera criticize health activists for imposing their own standards on women in developing countries. Regarding concerns about greater risk of Acquired Immune Deficiency Syndrome (AIDS), Depo Provera can be injected with disposable needles. In response to the controversy, Upjohn withdrew its application to the FDA in September 1986 but intends to resubmit with new information from a World Health Organization report, which showed no evidence of an increased risk of cancers of the endometrium, liver, or breast.
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PMID:Depo Provera: still controversial. 1217 73

A study of intramuscular injections of depo medroxyprogesterone acetate (Depo Provera) as a postpartum contraceptive was undertaken in an attempt to determine the following: 1) the continuation rates for this contraceptive method in a postpartum family planning program; 2) to compare the continuation rates of Depo Provera given as a postpartum contraceptive with other postpartum contraceptive methods, as reported elsewhere; 3) the use-effectiveness of Depo Provera as a postpartum contraceptive method; 4) the side effects of postpartum injections; and 5) the reasons for discontinuation of this method. Between April 1969 and May 31, 1972 there were a total of 325 acceptors at the Family Planning Department of McCormick Hospital in Chiang Mai, Thailand. 217 of the women were acceptors of 3-month injections and 108 women were acceptors of 6-month injections. Of all acceptors, 94.2% received their 1st injection within 5 days of delivery. Cases continuing beyond 12 months were too few in number for significant statistical analysis. There were no known method failure pregnancies. Of the 325 postpartum acceptors of the 3-month and 6-month Depo Provera injections, 152 had discontinued the method by May 31, 1972. Of these, 47 were lost to follow up. The reasons for the discontinuation of the 105 remaining cases were bleeding problems (amenorrhea, prolonged, frequent or heavy bleeding, and irregular periods), other medical reasons (palpitation and dizziness, abdominal pain, pain at injection site, and melasma), and personal reasons.
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PMID:Use of a long-acting injectable contraceptive in a postpartum family planning program. 1226 37

The Workshop was attended by over 50 representatives from 11 countries, including Bangladesh, India, Indonesia, the Philippines, Sri Lanka, and Thailand, who were able to meet 10 of the women from Thailand who had used Depo-Provera continuously for over 10 years with no serious side effects or any unwanted pregnancies. Reported data on the Depo-Provera users indicated that return of fertility with Depo-Provera was comparable to that with oral contraceptives or IUDs, and that over a 3-year period, 981 women out of every 1000 were protected from unwanted pregnancy. Figures on congenital abnormalities suggested a possible protective effect, while less serious side effects included headache, dizziness, and menstrual disturbances. 1 session was devoted to consideration of cost and sources of supply of injectable contraceptives, concluding that cost might be reduced by increased worldwide usage, and competition among manufacturers. While recognizing the need for continued scientific monitoring of side effects, the Workshop agreed that on the grounds of safety, exceptional use-effectiveness, and acceptability, injectable contraceptives have a valuable role to play in family planning.
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PMID:First Asian Workshop on Injectable Contraceptives. 1230 36

FDA has approved medroxyprogesterone acetate as Depo Provera Contraceptive Injection, effective for 3 months in preventing pregnancy in women. In clinical studies, the drug's failure rate was less than 1%. However, physicians must ensure that patients receive injections on schedule to prevent pregnancy. The recommended dose is 150 mg administered every 3 months by deep, intramuscular injection in the gluteal or deltoid muscle. Most women in clinical studies of Depo Provera experienced menstrual irregularities. As use continued, amenorrhea became common, reported by 57% of the women by the end of a year of treatment. Other side effects included weight gain, headache, nervousness, abdominal pain or discomfort, dizziness, and asthenia. Physicians should administer the drug only to women found not to be pregnant, because fetal exposure may lead to low birth weight and other problems. Recent data have demonstrated that longterm use may contribute to osteoporosis, and the drug's manufacturer, the Upjohn Company of Kalamazoo, Michigan, will conduct additional research to study this possible side effect. Contraindications are similar to those for other contraceptives and include undiagnosed vaginal bleeding, known or suspected malignancy of breast, thromboembolic disorders, cerebral vascular disease, and liver dysfunction. Depo Provera was developed in the 1960s and has been approved for contraception in many other countries. When FDA first reviewed data on the drug in the 1970s, animal studies raised questions about its potential to cause breast cancer. Since then, longterm controlled clinical studies in other countries have shown a risk of breast cancer comparable to oral contraceptives, and no increased risk for ovarian, liver, or cervical cancer. The studies also showed that the contraceptive injection reduced the risk of endometrial cancer. FDA approved the drug October 29, 1992.
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PMID:3-month contraceptive injection approved. 1231 15


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