Effect of anovulatory drugs on the human urinary tract and urinary tract infections.

PIP: Over a 1-year period, 44 women using either Demulen, Deladroxate or the Lippes loop were studied at the University of Pennsylvania for urinary tract disorders. Monthly catheterized urine specimens were cultured and examined cytologically. Excretory urograms and serum creatinine examinations were performed 1 month prior to and 6 and 12 months after contraceptive initiation. No effect on the urinary tract was observed by X-ray studies. All serum creatinines remained normal. Urine sediments showed cytologic patterns consistent with phase of cycle. Incidence of asymptomatic bacteriuria was 6.8% initially and 11% during the course of study. Only 1 Demulen patient developed asymptomatic tract infection. Urographic abnormalities were found in a certain percentage of women of reproductive age irrespective of contraceptive use. Study results, are confirmed by urograms of family planning clinic patients, indicate that estrogen-progestogen contraceptives appear to have little significant effect on human tract anatomy or infection rate.^ieng

Present status of injectable contraceptives: results of seven-years study.

PIP: 2 experimental contraceptive injection programs are reported. 1 method provides for administration of a combined long-acting estrogen-progestogen product once a month, the other uses a long acting progestogen alone once every 90 days. In the once-a-month injection program in Los Angeles 615 patients representing 871 admissions were studied; treatment data are for both 1st and all admissions. Age distribution was 21-25 years. Patients received 150 mg of progestogen/10 mg estrogen injection. 88.1% reported cycles of 22-30 days/on admission. Some results are: For 1st and all admissions average duration of flow was 6.6 days; for 1st admission group complaints consisted of breast tenderness, 46% dysmenorrhea, 61.8%, weakness or dizziness, 42.8%, local reaction to injection, 37.4%. For all admissions, complaints were: breast tenderness, 43.3%, dysmenorrhea, 59.6%, weakness, 40.2%, local reaction, 33%. Reasons for dropout for both groups included rigidity of protocol, about 52%, moved away, 4.5%, extraneous illness, 1.5%; 64.4% of all admissions discontinued treatment due to unrelated reasons. No pregnancies were reported. The once every 90 day injection of medroxyprogesterone acetate given in doses of 150 mg were given to 243 women, of whom 57% were aged 20-29. Some results are: 1) number of days of bleeding ranged from 6-20 days, 2) 4.6% reported nervousness, 3.4% nausea, 2.1% headaches, 3) main reasons for dropouts were moving away, 11.8%, bleeding, 4.6%, and 4) 1/3 resumed ovulation within 1/2 year. Both methods are found to be extremely effective.^ieng

Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive.

The pharmacodynamics of the combination of dihydroxyprogesterone acetophenide (DHPA) and estradiol enanthate (E2-EN) following its intramuscular administration at two doses were studied in 16 healthy women of reproductive age. Subjects were randomly allocated in two groups: group I (n = 9) received the combination DHPA 150 mg + E2-EN 10 mg on three consecutive monthly injections, while group II (n = 7) received half-dose of the same formulation. Ovarian function and endometrial bleeding patterns were investigated in all participants for one pre-treatment cycle, three treatment intervals and two post-treatment cycles. The results disclosed that ovulation was inhibited for at least 30 days following DHPA/E2-EN administration in all participants from both groups. The circulating estradiol levels 30 days after last injection were slightly elevated as compared with those observed in normal early follicular phase. Return to ovulatory cycles was documented within 90 days after treatment. The length of the bleeding-free intervals during treatment was shortened in both groups, particularly in group II. No significant changes in HDL-cholesterol levels were observed throughout the study. It is envisaged however, that large modification of the formulation and additional long-term safety studies will be required prior to its recommendation.

PIP: The pharmacodynamics of the combination of dihyroxyprogesterone acetophenide (DHPA) and estradiol enanthate (E2-EN) following its intramuscular administration at 2 doses were studied in 16 healthy women of reproductive age attending the Family Planning Clinic at General Hospital in Mexico City. Subjects were randomly allocated in 2 groups: group I (n=9) received the combination DHPA 150 milligrams and E2-EN 10 milligrams on 3 consecutive monthly injections, while group II (n=7) received 1/2 dose of the same formulation. Ovarian function and endometrial bleeding patterns were investigated in all participants for 1 pretreatment cycle, 3 treatment intervals and 2 post-treatment cycles. The results disclosed that ovulation was inhibited for at least 30 days following DHPA/E2-EN administration in all participants from both groups. The circulating estradiol levels 30 days after last injection were slightly elevated as compared with those observed in normal early follicular phase. Return to ovulatory cycles was documented within 90 days after treatment. The length of the bleeding-free intervals during treatment was shortened in both groups, particularly group II. No significant changes in HDL-cholesterol levels were observed throughout the study. It is envisaged however, that large modification of the formulation and additional long-term safety studies will be required prior to its recommendation.

Metabolic effects of once-a-month combined injectable contraceptives. The World Health Organization Task Force on Long-Acting Systemic Agents for Fertility Regulation, Geneva, Switzerland.

The results of metabolic studies on once-a-month combined injectable contraceptives are summarized, focusing on four preparations: dihydroxyprogesterone acetophenide 150 mg/estradiol enanthate 10 mg; depot-medroxyprogesterone acetate 25 mg/estradiol cypionate 5 mg; norethisterone enanthate 50 mg/estradiol valerate 5 mg; and 17 beta-hydroxyprogesterone caproate 250 mg/estradiol valerate 5 mg. Their effects on carbohydrate metabolism, lipid metabolism, hemostasis, serum prolactin, cortisol, binding globulins and liver functions are reviewed. Areas requiring further research are identified.

Once-a-month injectable contraceptives: efficacy and reasons for discontinuation.

Reports of the phase III clinical trials on four combined progestogen-estrogen once-a-month injectable contraceptives, Deladroxate, Cyclofem, Mesigyna and Chinese Injectable No. 1, are reviewed focussing on efficacy and reasons for discontinuation. Deladroxate, currently used in many Latin American countries has proved to be highly effective and well accepted. However, this combination was withdrawn by the original manufacturer because the progestogen component of this drug induced a high number of breast cancers in dogs and very curious pituitary hyperplasia in rats. Cyclofem and Mesigyna were found to be highly effective and highly acceptable drugs. Side-effects were minimal and were of minor importance. The Chinese Injectable No. 1 had unacceptably high failure rates with a monthly injection schedule. After doubling the dose in the first month of use, the efficacy was satisfactory. It was found that all monthly injectable contraceptives provided better cycle control than the every 3 months depot-medroxyprogesterone acetate, although abnormal bleeding was still the main drug-related complaint and reason for discontinuation. Missed appointment is another reason for discontinuation which might reflect the problem of frequent injection schedule, thus indicating the need for proper selection of the users and good counselling.

PIP: This literature review examines the efficacy and reasons for discontinuation of 4 combined progestogen-estrogen, once-a-month injectable contraceptives: Deladroxate, Cyclofem, Mesigyna, and Chinese injectable No. 1. Deladroxate is used mainly in Latin America, while the Chinese injectable No. 1 is largely limited to China. Among 18 studies, no pregnancies occurred in the 3017 women using Deladroxate (32,857 woman-months). It was well accepted, but the manufacturer withdrew it from the market after studies showed that the progestogen (dihydroxyprogesterone acetophenide) caused dogs to develop breast cancer and rats to develop an odd pituitary hyperplasia. Of the 4 once-a-month injectables, Cyclofem and Mesigyna provide the most promise. They are very effective at preventing pregnancy (0-0.23/100 women-years of use and 0.08-0.48/100 women-years of use, respectively). Acceptance of Cyclofem and Mesigyna was high. Side effects were limited and had minimal importance. An advantage of Cyclofem and Mesigyna is their much better cycle control than the once-every-3 months injectable Depo-Provera. The failure rate of the Chinese Injectable No. 1 on the once-a-month injection schedule was too high (10.35/100 women-years of use). When researchers doubled the dose in the 1st month of use, however, efficacy was satisfactory (0.8/100 women-years of use). The main drug-related complaint and reason for discontinuation of all once-a-month injectables was abnormal bleeding. Another key reason for discontinuation was missed appointment, suggesting that a frequent injection schedule poses a problem. Good planning and health workers properly selecting users and providing them good counseling may overcome this problem. Frequent visits would increase the staff work load.

Multicenter, double-blind, comparative clinical study on the efficacy and acceptability of a monthly injectable contraceptive combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate compared to a monthly injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate.

Healthy, regularly menstruating women, aged 14-38 years, were enrolled in a comparative, double-blind, phase III, clinical trial to evaluate the contraceptive efficacy and acceptability of a combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate compared to the commercially available contraceptive combination of 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol enanthate. Subjects received the contraceptive combination intramuscularly, between the 7th and 10th day of each menstrual cycle, during 12 consecutive menstrual cycles. Approximately 60% of the subjects in both groups completed the study. Principal reasons for discontinuation were personal, nonmedical reasons. Principal medical reasons for discontinuation were menstrual-related, irregular bleeding being the most frequent. Differences in menstrual patterns between the two groups did not lead to differences in discontinuation rates. Three contraceptive failures occurred during the trial, one in Group A (90/6 mg) and two in Group B (150/10 mg), indicating that the lower dose formulation is at least as efficient as the higher dose.

Pharmacodynamic effects of once-a-month combined injectable contraceptives.

The pharmacology and clinical assessment of existing first generation once-a-month combined injectable contraceptives, mainly Deladroxate and Chinese Injectable No. 1, are reviewed. Although these two types of monthly injectables have been used in some million women in China and Latin America, Deladroxate needs indepth re-evaluation of its long-term toxicity and possible accumulation. For injectable No. 1, its disadvantage of being administered on an erratic schedule will cause significant confusion in family planning practice. When used in a strict once-a-month schedule, it is not sufficiently effective for contraception. In order to attain predictable menstrual cycle control as well as high efficacy with a 30-day injection schedule, two improved once-a-month injectable formulations, Cyclofem and Mesigyna, were developed. Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna. Also, it is important to note that the second part of the injection cycle is dominated by the progestogen component of both monthly formulations. A longitudinal study indicated that there is no accumulation of norethisterone after 12 months of treatment with NET-EN 50 mg and estradiol valerate 5 mg.

PIP: About 1 million women in Latin America and China have used the 1st generation once-a-month combined injectable contraceptives Deladroxate and Chinese Injectable No. 1. Animal toxicity studies of Deladroxate found pituitary hyperplasia in rats, breast tumors in beagles, and accumulation of estradiol enanthate in the body. Thus, long-term toxicity and accumulation of Deladroxate need to be reevaluated. The erratic schedule of the Injectable No. 1 (initially administered on day 5 with 2 ampoules or 1 dose on day 5 and 1 dose on day 12; subsequent administration on the 10-12th day of the cycles) will confuse acceptors and family planning providers. Yet, a strict once-a-month cycle of Injectable No. 1 does not adequately protect against conception. Researchers have developed 2 improved once-a-month injectable formulations, Cyclofem and Mesigyna, to achieve good menstrual cycle control and high efficacy. The estrogen components of both formulations (estradiol valerate and cypionate) sufficiently elevate plasma estrogen levels for 7-11 days. One injection of both formulations inhibits follicle maturation for about 30 days and ovulation and corpus luteum formation for about 60 days. The doses of Cyclofem (25 mg depot-medroxyprogesterone acetate + 5 mg estradiol cypionate) and Mesigyna (50 mg norethindrone acetate + estradiol valerate) have been found to be optimal for use in large scale clinical trials. Not only are the absolute amounts of the progestogen and estrogen important, but also the progestogen/estrogen ratio. A lower estrogen dose in both Cyclofem and Mesigyna effects breakthrough ovulation. The progestogen component predominates the 2nd part of the injection cycle in both formulations. Norethindrone does not accumulate in the body after 12 months of treatment with Mesigyna.

Monthly injectable steroid contraceptives and cervical carcinoma.

The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives is a large multinational hospital-based case-control study of steroid contraceptives and gynecologic, hepatobiliary, and mammary neoplasms. Monthly injectable steroid contraceptives which contained the long-acting progestogen dihydroxyprogesterone acetofenide plus a shorter-acting estrogen (usually estradiol enanthate) were used by women in two of the countries (Chile and Mexico) from which data were collected. In preliminary analyses of data from Chile (1979-1983), a strong association was observed between use of these products and invasive cervical cancer. Therefore, three additional data sets from these two countries were analyzed in further detail for this report. Analyses of additional data from Chile on invasive cervical cancer (1983-1985) and cervical carcinoma in situ (1979-1986) and of data on invasive cervical cancer from Mexico (1979-1986) failed to confirm the initially observed association. The original finding was probably due to chance, but a causal interpretation cannot be confidently ruled out, and additional studies are warranted.

Dihydroxyprogesterone acetophenide 150 mg + estradiol enantate 10 mg as monthly injectable contraceptives.

A survey among users and health personnel participating in the Salvadorian Social Security Institute (ISSS) Family Planning Program revealed interest in including a monthly preparation for injection as a contraceptive method offered by this Institution. The formulation containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enantate (E2EN) 10 mg was chosen for conducting an open and prospective study of efficacy and tolerability. Between January 1992 and March 1994, 7054 women were treated with this product for a total of 60010 months. A sample composed of 4505 women treated at this Institution confirmed that average users are young, have one or two children, do not show a particular geographical distribution and choose the monthly injection instead of oral contraceptives as the first contraceptive method or for the puerperium. The study formulation showed a high efficacy (Pearl Index: 0.018) and tolerability (general withdrawal rate throughout the study: 27.09%). The most frequent adverse events included bleeding disorders, headache and mastalgia; their incidence decreased spontaneously from the sixth month (3.9%), reaching 0% after two years. Treatment was discontinued due to adverse events in 3.47% of women. No significant bodyweight or systolic and diastolic blood pressure alterations were observed. Based on these results, the monthly injectable contraceptive was included in the basic product list at ISSS.

Nuevas aportaciones acerca de la potencia estrogénica de un anticonceptivo inyectable mensual / New contributions on the estrogenic potency of a monthly injectable anticonceptive

Se presentan los resultados mexicanos de un Estudio Multicéntrico Internacional destinado a evaluar los efectos metabólicos y a través de ellos la potencia estrogénica del anticonceptivo inyectable mensual constituido por Dihidroxiprogesterona Acetofénido (DHPA) 150 mg + Estradiol Enantato (EEn) 10 mg. Una serie de análisis bioquímicos realizados en usuarias crónicas de varios métodos de planificación familiar permite constatar que los niveles séricos de cobre, ceruloplasmina y transcortina (CBG) son significativamente más altos en las mujeres que emplean diferentes píldoras con etinilestradiol y levonorgestrel, inclusive microdosificadas, que en las que utilizan la técnica inyectable o métodos no hormonales (p > 0.05 - 0.01). Por el contrario, al comparar a las usuarias del inyectable con las de métodos no hormonales, no se observaron diferencias. El hecho de que el empleo prolongado de DHPA 150 mg + EEn 10 mg no induzca modificaciones en los parámetros mencionados sugiere que su potencia estrogénica no es mayor, sino quizá menor que la de los anticonceptivos orales de uso habitual. No se encontraron indicios de acumulación de efectos hormonales en el organismo. Dado que la potencia estrogénica y los efectos colaterales de los anticonceptivos hormonales se correlacionan de manera directa, se considera que estos resultados preliminares abogan en favor de la seguridad a largo plazo del inyectable estudiado.