Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: 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.

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

Conception control by a single monthly injection.

PIP: 73 women of childbearing age and proven fertility were injected with dehydroxy-progesterone acetophenide, 150 mg and estradiol enanthate, 10 mg on Day 7, 8, or 9 of a new cycle and on Days 7-9 in succeeding cycles for a total of 929 cycles (1-24 cycles/patient). Patients missing 1 or more injections because of failure to menstruate were started as new patients and no patient was restarted more than 3 times. 69% received 1 series of injections; 24% received 2 series; and 7% received 3 series. There was a moderate prolongation of monthly bleeding. Cycles averaged 2 days shorter than before therapy. There was absolute pregnancy protection. Discontinuation was 45% for this study, most during the first 5 cycles, 1/2 of drug related discontinuation due to abnormal bleeding. Cytology smears, breast examinations and endometrial biopsies repeated before and during therapy were unremarkable.^ieng

Endometrial histology and parentereal estrogen-progestogen administration.

PIP: During the sixth, seventh, eighth, or ninth cycle of use, endometrial tissue was obtained through suction biopsy from 40 patients (mean age 26 years, mean number of pregnancies 3.5) receiving Deladroxate at the Hospital of the University of Pennsylvania Family Planning Clinic. Tissue was obtained from Day 1-29 after the most recent injection. Deladroxate is composed of 150 mg of 16-alpha, 17-alpha dihydroxyprogesterone acetophenide and 10 mg of estradiol enanthate in an oil vehicle. Injections were parenteral and administered on the seventh, eighth, or ninth day of each cycle. In the 36 specimens considered adequate for evaluation, the histologic features studied and scored were glandular morphology, stromal morphology, and vascular morphology. During the first 9 days of the cycle, the time interval before, during, and immediately after each injection, glandular activity attributable to estrogenic action was evident. After the first cycle, throughout each entire cycle, including the brief interval of estrogenic effect, glandular vacuolation and predecidual stromal reaction secondary to progestational effect were seen. The endometrial histologies may have been affected by variabilities in the absorption of the parenterally administered prepartion or by selective absorption of the estrogen or progestogen. In the discussion comparisons are made to typical sequential and combination preparations.^ieng

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.

Serum estrogens and ovulation return in chronic users of a once-a-month injectable contraceptive.

To determine whether the long-term exposure to a monthly injectable contraceptive, containing dihydroxyprogesterone acetophenide 150 mg and estradiol enanthate 10 mg, induces significant changes on the serum estrogens profile and ovulation return in women, a study in chronic users was undertaken. Ovarian function was assessed for 3 months following a single injection of the contraceptive agent in a group of women (n = 7) who have been on this formulation for an average period of 6.7 years and in a non-user control group (n = 7). The serum concentrations of 17 beta-estradiol, estrone and progesterone were measured in samples drawn at regular intervals throughout the entire study. The endometrial bleeding pattern was recorded in all subjects. The results indicated that the post-injection serum estradiol maximum levels (exogenous peak) occurred significantly earlier (p less than 0.05) in chronic users as compared with the non-user control group. Baseline serum estrone concentrations were slightly higher in chronic users than those observed in the control group, while the values of serum 17 beta-estradiol did not exhibit significant differences among the two groups. Ovulation was documented within 60-90 days after injection in all subjects from both groups. A similar length of the first bleeding-free period was observed in all participants. The overall data provide evidence of a moderate increase of estrone, one of the still active metabolic conversion products of 17 beta-estradiol, in the sera of chronic users of this combined contraceptive without affecting its pharmacodynamics.

PIP: The effects of longterm exposure to a monthly injectable contraceptive agent containing 150 mg of dihydroxy-progesterone acetophenide and 10 mg of estradiol enanthate on the serum estrogens profile and ovulation return were investigated in 7 women who had been taking this form of fertility control for an average of 6.7 years and 7 previous nonuser controls. Blood samples were taken immediately prior to injection and twice a week thereafter for a total of 3 months. Longterm users were injected 25-30 days after their previous injection, while the nonusers were injected during the early follicular phase of their menstrual cycle. Baseline serum estradiol concentrations were not significantly different between the 2 groups; immediately after injection, however, serum levels of estradiol increased rapidly to attain a maximum value of 314 in longterm users and 283 pg/ml in controls. The time required to reach maximum estradiol levels was significantly less in longterm users (4.2 days) compared with controls (6.3 days). Higher serum estrone levels were recorded at baseline in the chronically exposed women, although there were no significant differences between groups after 30 days. Ovulation was documented 60-90 days after injection in all subjects and endometrial bleeding patterns were the same in both groups. Overall, these data suggest that the slight increase in serum estrone levels associated with longterm use of this injectable contraceptive is not sufficient to produce prolonged ovarian and endometrial function impairment.

Efficacy, acceptability, and clinical effects of a low-dose injectable contraceptive combination of dihydroxyprogesterone acetophenide and estradiol enanthate.

A total of 1,904 women, aged 15-38, used an injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate, given once during each menstrual cycle between the 7th and 10th day, and preferably on the 8th day of the cycle, for a total of 17,576 cycles. Of these 1,904 women, 1,197 completed 12 cycles of use of the injectable combination. One subject became pregnant during the trial, resulting in a cumulative pregnancy rate of 0.07%. Principal reasons for discontinuation were personal, non-medical reasons, such as lost to follow-up, no longer wished to continue, protocol violation, desire to change to another contraceptive method, moved away, or other personal reasons. Mean weight of 1,901 subjects at admission to the trial was 53.5 +/- 0.2 kg and this increased to 54.3 +/- 0.3 kg after 12 cycles of use. Approximately 50% of subjects experienced menstrual bleeding similar to normal throughout the study period. The most frequent menstrual abnormality was irregular bleeding, experienced by approximately one-third of subjects.

[Clinical analysis and evaluation of various hematologic and metabolic constants with the use of monthly microdoses of parenteral contraceptives]. / Análisis clínico y valoración de algunas constantes hematologicas y metabólicas con el uso de un anticonceptivo parenteral mensual en microdósis.

PIP: 75 women of proven fertility were treated as a contraceptive measure with an injection of 75 mg. of duhydroxyprogesterone acetophenide, and of 5 mg. of estradiol enanthate. Doses were half of what regularly used, and were injected between the 7th and the 9th day of the cycle. Total number of cycles studied was 859. Most important side effects of the treatment was headache in 28.3% of patients, spotting in 15.5%, and emotional instability in 10.5%. Metabolic and hematologic data were unchanged, and vaginal cytology was negative. There were no pregnancies. It must be remembered that, in every contraceptive treatment, lower doses are always preferable when equally effective. (Summary in ENG).^ieng

[A ten year clinical investigation of injectable contraceptives]. / Investigacion clinica sobre diez anos de anticonceppion inyectable mensual.

PIP: The article describes the results obtained over a period of 10 years with contraception by monthly injection of 150 mg of dihydroxyprogesterone acetophenide, and 10 mg of estradiol enanthate. 100 fertile patients were observed, for a total of 8074 cycles. There were no pregnancies, and only minimal side effects. No changes were observed in blood profile, urine and hepatic function, and in blood coagulation; there were no instances of breast or uterine cancer. In 10 years only 15% of patients abandoned this method because of changes in the menstrual cycle, changes which were expected, but which had not been explained to the patients.^ieng

[Norethisterone enantate as a tricyclical contraceptive. Comparative study]. / Enantato de noretisterona como contraceptivo tricíclico. Estudio comparativo.

PIP: A clinical comparative study between treatment with norethisterone enanthate, and treatment with estradiol enanthate and dehydroxiprogesterone was done to study the differences in effectiveness, changes in menstrual cycle, and side effects of the 2 preparations. Duration of investigation was of 15 months, for a total of 824 cycles. Among the 35 patients treated with norethisterone enanthate there were no pregnancies, and the drug was well accepted. There were a few cases of amenorrhea and of spotting; both manifestations disappeared spontaneously. In 65% of patients the menstrual cycle was longer than usual. 25 patients were treated with the bihormonal preparation; there was 1 pregnancy. Cycles were very close together, and lasted about 6-8 days. There were a few cases of spotting. Side effects were similar with both treatments, and never serious.^ieng

Clinical trial of intramuscular injection as contraceptive compound.

PIP: 99 women of proven fertility received 778 intramuscular contraceptive injections. An injectable compound containing 150 mg dihy droxyprogesterone acetophenide and 10 mg of estradiol enanthate (Deladroxate) in castor oil was prepared in a 1-cc disposable syringe. The injections were administered intramuscularly in the upper outer glut eal region on Day 8 of each menstrual cycle. The study was initiated in September 1965 and was completed by February 1969, with all data being recorded on a computer for future analysis. No pregnancies occurred. No serious side effects were noted. There were improvements in cases of dysmenorrhea and premenstrual tension. Minor complaints were not a problem in the use of the contraceptive except for intermenstrual spotting, which prompted 8 patients to discontinue the method. It is concluded that the long-acting intramuscular injection of estrogen-progesterone given once a month is effective and useful in difficult contraceptive patients in a public health clinic.^ieng

Once-a-month estrogen/progestogen injectables.

PIP: About 8 million women use the long acting injectable contraceptive depot-medroxy-progesterone acetate (DMPA) and norethisterone enanthate (NET-EN). These progesterone only injectables are not dependent on sexual activity and are easy to administer. Yet they are not always well accepted since they can interfere with menstrual bleeding and often induce amenorrhea. Researchers find that adding estrogen to DMPA and NET-EN treats these irregularities. They must use esters with limited action to protect the endometrium from constant estrogens, however, which requires monthly injections. Thus bleeding occurs once a month just like the normal menstrual cycle. Clinical trials in China of Injectable No. 1 (250 mg 17-alpha-hydroxyprogesterone caproate and 5 mg estradiol valerate) show that it has few side effects and is acceptable. Other trials in China are evaluating monthly injectables with NET-EN or megestrol acetate. Numerous developing countries often as WHO's Special Programme of Research in Human Reproduction for effective, safe, and fully studied monthly injectables. WHO operates under a 2 part strategy: optimum improvement of HPR 102 (50 m NET-EN and 5 mg estradiol valerate) and Cyclofem (25 mg DMPA and 5 mg estradiol cypionate) resulting in a reduction of the dose of at least 1 of the hormones and results of a study of the efficacy and side effects of these 2 injectables. It hopes the study provides the impetus to introduce them into national family planning programs. It demonstrates that they are indeed efficacious, effect fewer changes in the menstrual cycle than the progesterone only injectables, and are well accepted, even though women must go to a clinic every 27-33 days for an injection. Other studies are determining their effects on lipid and glucose metabolism, coagulation, and fibrinolysis. They are also looking at the time needed for ovulation to return. 1 study shows that menstruation returned in all women by the 3rd cycle.^ieng

Long-acting injectable contraceptives.

PIP: 3 injectable preparations of progestogens for female contraception are reviewed: medroxyprogesterone acetate, algestone acetophenide-estradiol enanthate combination, and norethisterone enanthate. Information is presented concerning the absorption, fate and distribution of the preparations, its use as a contraceptive, biochemical and metabolic effects, return of ovarian function and fertility following discontinuance, and current status. Further information is presented for medroxyprogesterone acetate because of its wider use. These topics concern its effect on the mammary gland and other regimens of use.^ieng