Depo-Provera in adolescents: effects of early second injection or prior oral contraception.

PURPOSE: To examine the effects of an early second injection or prior use of oral contraceptive pills (OCP) on side effects of Depo-Provera during the early months of use in adolescents. METHODS: Thirty-six girls, gynecologic age 4.2 +/- 0.3 years, and body mass index (BMI) 23.2 +/- 0.8, received the currently recommended injection of 150 mg every three months. Twenty-seven girls (gynecologic age 3.9 +/- 0.5 years, BMI 24.0 +/- 0.8) received the second injection six weeks after the first injection. Fifteen girls (gynecologic age 5.0 +/- 0.5, BMI 25.4 +/- 1.3) switched directly from an OCP to Depo-Provera. The patients were periodically assessed by their care providers. RESULTS: Early administration of the second injection of Depo-Provera did not alter the bleeding episodes, onset of bleeding, or total days of bleeding (14.3 +/- 3.7 vs. 17.1 +/- 4.0, p = 0.62) during the three months interval following injection, compared with the standard second injection interval. Moreover, an excessive BMI gain (BMI increase 0.99 +/- 0.22 vs. 0.40 +/- 0.14, p = 0.03) was observed in these girls. Girls who switched directly from OCP showed no difference in the rate of BMI gain when compared to those not previously on OCP (BMI increase 0.38 +/- 0.3). Bleeding duration of these girls, however, was markedly reduced; the total number of days of bleeding was 5.7 +/- 1.9 (p = 0.0003) during the first three month interval, and 5.7 +/- 2.3 (p = 0.019) during the three month period following the second injection. This reduction did not persist beyond the first six months. CONCLUSIONS: Early second Depo-Provera injection does not alter the experience of menstrual abnormalities, and predisposes to greater weight gain; OCP use prior to Depo-Provera results in a decrease in the duration of bleeding with no change in the weight gain rate.

PIP: The capability of an early second injection or prior use of oral contraceptives (OCs) to improve satisfaction and long-term continuation of Depo-Provera in adolescents was investigated in a clinical trial involving 78 females 12-20 years of age (average, 15.9 years) recruited from a hospital-based adolescent health clinic. 36 subjects received injection of 150 mg of Depo-Provera every three months (Group 1), 27 received the second injection after only six weeks (Group 2), and 15 switched directly from OCs to the standard Depo-Provera regimen (Group 3). There was no difference between Groups 1 and 2 in terms of duration or frequency of menstrual bleeding; however, prior OC users experienced a significant reduction in the duration and intensity of bleeding in the first six months of Depo-Provera use (when estrogen was still present in the women's systems). Overall, 64% of study subjects reported less dysmenorrhea while on Depo-Provera. A slightly greater change in body mass index was observed among girls in Group 2 than in Groups 1 and 3; moreover, 70% of those in the early injection group reported increased appetite and weight gain compared to 39% of those on the standard schedule. The most commonly reported side effects included initial pain and soreness at the injection site (27%), decreased libido (56%), mood changes (31%), depression (26%), frequent headache (25%), fatigue (24%), and increase in acne (15%); there were no significant differences by group. 17 adolescents (22%) discontinued Depo-Provera, generally after two injections and due to bleeding irregularities or weight gain. 87% of adolescents who were prior OC users, 52% of those on the regular schedule, and 39% of those who received an early injection stated they were very satisfied with Depo-Provera. These findings indicate that early second Depo-Provera injection offers no advantages; use of OCs immediately prior to Depo-Provera should be further investigated, however, given its potential to minimize bleeding problems.

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.

A comparative study of the metabolic effects of injectable and oral contraceptives.

The metabolic effects of an injectable contraceptive, Depo-provera (medroxyprogesterone acetate), an oral contraceptive pill containing 50 micrograms ethinyl estradiol and 500 micrograms norgestrel and a control group (not on contraceptives) were compared in 3 groups, each comprising 32 women. The subjects were matched for race, age and parity. Mean duration of treatment was 41.7 +/- 18.3 months for Depo-provera and 59.6 +/- 29.0 months for the pill group. Glucose tolerance was impaired in both treatment groups. The combination pill showed more changes in both glucose tolerance and insulin response. Lipid levels remained unchanged in both treatment groups.

Depo-Provera highly effective as injectable contraceptive.

PIP: Ignorance of the law is 1 of the reasons that more family planning practitioners do not use Depo-Provera, an excellent hormonal preparation and a highly effective contraceptive (99+%). If the Food and Drug Administration (FDA) approves a drug for use in the US, physicians may prescribe that drug for any use they feel is medically justified. The FDA can give its opinion about the drug's safety, but it cannot tell doctors how to use it. The FDA has approved Depo-Provera for use in the US to treat endometriosis and endometrial carcinoma. Thus, physicians who do not use Depo-Provera as a contraceptive have 1 of 2 reasons: either they have not formed an opinion on Depo-Provera's safety and effectiveness as a contraceptive; or they are tacitly admitting that the FDA has more jurisdiction over their practices than it actually does. Some basic information is required if a physician decides to provide Depo-Provera to his/her patients. Depo-Provera should be administered (150 mg intramuscularly) every 90 days for contraception. Women whould be warned in advance to expect erratic bleeding. After 2-3 injections, their periods should decrease or disappear and remain that way as long as they take the injections. Some women will gain weight with Depo-Provera, but the gain rarely exceeds 10 pounds. Others will lose weight. Occasionally, a woman will bleed excessively. In that case, she should contact the clinic and begin receiving daily ethinyl estradiol for 10 days. That will control the bleeding unless she has an underlying pathology. When a woman wants to discontinue Depo-Provera use, she simply does not get her next injection. Her period may not return for 6-10 months. No evidence indicates that Depo-Provera decreases fertility after discontinuation.^ieng

Medroxyprogesterone acetate and homozygous sickle-cell disease.

The haematological and clinical effects of medroxyprogesterone acetate in homozygous sickle-cell (SS) disease were assessed in a 2-year controlled crossover trial completed by 23 patients. Haematological indices remained steady during the placebo phase, but during the medroxyprogesterone-acetate phase fetal haemoglobin, total haemoglobin, red-cell mass, and red-cell survival rose significantly, and reticulocytes, irreversibly-sickled-cell counts, and total bilirubin fell significantly. Painful crises were significantly less frequent during the medroxyprogesterone-acetate than the placebo phase. These results are compatible with an inhibition of in-vivo sickling in patients with SS disease during medroxyprogesterone-acetate treatment. The mechanisms of such an effect require further study.

Depo provera in perspective.

PIP: In this discussion of Depo-Provera (DMPA) attention is directed to the following: pharmacology and mode of action; clinical considerations; cervical dysplasia; breast cancer; and endometrial carcinoma. DMPA, a microcrystalline suspension of medroxy-progesterone acetate, is used widely around the world as a contraceptive, particularly in developing countries. MPA (medroxy-progesterone acetate) is a synthetic progesterone which in its mycrocrystalline depot form can be delivered by simple intramuscular injection or jet injector to that depending on the dose administered plateau contraceptive blood levels will be maintained for 90-180 days when doses of 150 mg and 300 mg respectively are used. The effect of DMPA in suppressing ovulation is at the hypothalmic level where it inhibits the gonadotrophic release responsible for the midcycle surge in luteinizing hormone responsible for ovulation. When 150 mg is administered every 3 months pregnancy rates range from 0.0-1.2/100 women years. The pregnancy rates range from 0.0-3.8/100 women years when 300 mg is administered every 6 months. The drug is usually administered initially in the first 7 days of the menstrual cycle to avoid possible effects on an established pregnancy. Menstrual disturbances are the major reason for discontinuation of DMPA. The usual side effects are amenorrhea, irregular but infrequent bleeding, and a few instances of prolonged or heavy bleeding. There is no evidence to suggest that DMPA increases the risk of invasive cancer of the cervix, but the evidence regarding the incidence of cervical dysplasia is ambiguous. There have not been any cases of breast cancer that can be related to DMPA use, but DMPA toxicology studies on beagle bitches revealed an increased incidence of benign and malignant breast tumors. It is well established that in adenocarcinoma of the endometrium DMPA is effective in causing regression and preventing recurrence of this tumor.^ieng

Progestin therapy for advanced ovarian cancer: a phase II Eastern Cooperative Oncology Group trial.

PIP: This is the report of results from a phase 2 trial of high-dose progestin therapy for treatment of ovarian cancer. 19 women received 1000 mg of Depo Provera (medroxyprogesterone acetate) weekly by intramuscular injection for at least 8 weeks and longer if there was no evidence of tumor progression. None of the women in the study was responding any longer to surgery, radiation therapy, or conventional cytotoxic chemotherapy. Response was measured as: 1) regression if there was at least a 50% decrease in the area of measurable lesion; or 2) disease progression as at least a 25% increase over the original measurements or the appearance of new lesions. Based on these criteria, there were no responses in the 19 women. Only 1 patient remained stable (3 months). Median survival time was 2 months with 75% of the patients dying within 4 months. 1 patient suffered severe vomiting and another experienced bleeding; there was no other toxicity. It is concluded that progestin therapy does not have a beneficial effect and its use in ovarian cancer patients should be limited to those with endometrioid histology.^ieng

Reply to Dr. Edwin B. McDaniel. Exaggerated claims of depo-provera safety.

PIP: This reply to a letter criticizing the author's article on Depo-Provera use which appeared in the same publication argues that proponents of Depo-Provera have misled the public about its suitability for wide use. Because many Thai women have already used Depo-Provera for a decade or more, because it takes 10 times as much Depo-Provera to produce the same blood level in monkeys as in humans, and because tribal women in Thailand weighing less than 45 kg routinely received 6 month doses of 450 mg, 3 times the 3 month dose, any difference between the doses given experimental monkeys and village women is marginal. The study by McDaniel and Potts of women with endometrial cancer hospitalized in Chiang Mai and Lumpoon Provinces which examined Depo-Provera use among them had too small a sample to detect less than a 20-fold relative risk; moreover, very few cases of endometrial cancer actually came in for treatment. Depot medroxyprogesterone acetate (DMPA) and norgesterone produce a situation similar to early menopause in which the uterus is atrophic because ovulation has ceased, but estrogen production continues and the endometrium is stimulated. Menopausal women are at high risk of developing endometrial cancer. Research literature suggests that the reproductive systems of breastfed infants are vulnerable to longterm action of DMPA in milk. Babies exposed in utero may be at risk of vaginal adenosis or cardiovascular malformations. Giving Depo-Provera to mothers of nursing babies violates the restrictions on use of children in medical experiments evolved after the Nuremburg trials. The hostility of population control activists to critics concerned about cancer evidence may prevent abnormal conditions from being looked for. It is suggested that DMPA experimenters experiment on themselves for 10 years while a moratorium on use of Depo-Provera is observed until the results are available.^ieng

Pharmacokinetic study of different doses of Depo Provera.

Doses of DepoProvera of 25, 50, 100 and 150mg were administered to four groups of women. The mean time for the return of follicular and luteal activity increased with increasing dose of DepoProvera. Luteal activity was suppressed for a longer period than follicular activity. None of the women receiving the two higher doses of DepoProvera showed a return of luteal function within 100 days of injection. The period for which medroxyprogesterone acetate (MPA) was detectable in serum increased with increasing dose but the values for the 100 and 150mg doses were not significantly different. There was a significant correlation between the concentration of MPA in blood and the return of follicular and luteal function. It is suggested that in the population studied, 100mg DepoProvera would be as effective as the usual 150mg dose and that injection of 50mg DepoProvera would provide a contraceptive effect for two months. The dose of MPA in the monthly injectable CycloProvera could be substantially reduced without loss of effectiveness.

PIP: Various doses of Depo-Provera (25, 50, 100, and 150 mg) were administered to Thai women volunteers to comparatively determine the effect of these doses on ovulation suppression and on menstruation; clinical effects were correlated with levels of medroxyprogesterone acetate (MPA) in serum. The women were randomly divided into 4 groups. In terms of effect of Depo-Provera on ovarian function, the mean time for the return of follicular function increased with increasing doses of Depo-Provera and varied from 41.2 (25 mg), 59.6 (50 mg), 77 (100 mg), and 110 days (150 mg); these differences were significant. None of the women who received the 2 higher doses of Depo-Provera showed return of luteal function within 100 days of injection. MPA was detectable in serum for increasing periods based on increased dosages; however, the values for the 100 and 150 mg doses were not significantly different. No significant correlation between MPA concentration in serum and return of follicular and luteal function was found. For this population, 100 mg is as effective as 150 mg of Depo-Provera (the usual dose), and 50 mg of Depo-Provera is sufficient to provide 2 months of contraception; therefore, the monthly dose in a Cyclo-Provera program could be reduced considerably without losing contraceptive effectiveness.

Extracts from the report on the Joint IGCC/IFRP East and South East Asia Seminar on Regional Fertility Research.

PIP: The attempt is made to provide some answers on the use of Depo Provera. In the use of Depo Provera, the standard procedure is to give an injection of 150 mgs in 1 ml in an arm or hip muscle every 12 weeks, beginning soon after delivery or miscarriage or early in the menstrual cycle in the case of menstruating women. The outstanding attraction of the long-acting contraceptive injection in the minds of the 81,034 Chiang Mai acceptors is what can be described as the freedom from the fear of forgetting. The acceptors also enjoyed the ease and convenience of administration and the high effectiveness of the method. Of 142 women using this method for a year, on an average, only one woman will have an unexpected pregnancy. Depo Provera has a lower failure rate then IUDs, condoms, foams, jellies, or the "safe period," and it does not produce pelvic infection and inflammation wometimes seen with IUDs. It also does not effect breast milk in nursing mothers. The drawbacks to the use of the injectable contraceptive include amenorrhea, irregular menstrual periods, spotting, and sometimes heavy periods. Depo Provera also has other uses which include use in instances of threatened and habitual miscarriage and use in the treatment of endometriosis. Depo Provera is a safe method. Among the estimated 1 million or so users, there has not been a death caused by Depo Provera. Depo Provera has been approved for use in 10 European countries. The World Health Organization and the International Planned Parenthood Federation have approved the use of Depo Provera.^ieng

Use of depo-provera in the treatment of aggressive sexual offenders: preliminary report of three cases.

PIP: A preliminary report of the use of Depo-Provera (medroxyprogesterone acetate) in the treatment of 3 aggressive sexual offenders is presented. The 3 males, ages 20, 30, and 16, were treated with 300 mg of Depo-Provera every 10 days; after 1 month of treatment their plasma testosterone levels dropped from 461, 810, and 760 to 28, 110, and 207 ngs%, respectively. The 2 married men initially reported loss of energy but this complaint left them within a few weeks. They were able to continue sexual relations with their spouses to a satisfactory degree. The 16-year-old claimed that he had no interest in sex and no longer masturbated. All 3 were quite pleased with the results of the treatment, both with regard to the defusing of their destructive sexual energy and the concomitant mellowing of their temperaments. It is concluded that this new therapeutic opportunity must be promulgated so that families, judges, and others who were previously without hope may extend that hope to the smallggroup of now treatable patients.^ieng

A field study of Depo-Provera: its use as a contraceptive method by women in a rural town in West Malaysia from February 1968 to December 1969.

PIP: To determine the acceptability, practicability, and popularity of Depo-Provera as an additional contraceptive method to be offered by the National Family Planning Board NFPB of Malaysia, 550 patients of Sungai Besar, Malaysia, who accepted the Depo-Provera injection method from the start of the injection program, February 23, 1968, until the cutoff date of December 31, 1969, were studied. At the cutoff date, 318 (58%) were still receiving regular injections at 3-month intervals. The remaining 232 women discontinued use of the injection. Of those who discontinued use, 176 (32%) were interviewed, while the other 56 women were lost to follow-up, due mainly to migration. Assuming that 1 injection would protect a woman from getting pregnant for a 3-month period, the retention rates at the end of 12 and 24 months were 63% and 41%. These continuation rates were fairly high and were as good as those for the oral pill, which is the main contraceptive method provided since the beginning of the operational service program of the NFPB in May 1967. Except for a small number of Indian women with a high rate of discontinuation there was not much difference in continuing the method between the Malays (60%) and the Chinese (56%). The younger age group of women seemed to have a higher proportion of discontinuation. The findings showed that amenorrhea (35%)most bothered the women who discontinued the injection method. Irregular bleeding (20%) and other medical side effects (11%) were the other main complaints that caused women to discontinue using the injection as a contraceptive method. It was concluded that Depo-Provera (150 mg) injected once every 3 months appears to be simple, acceptable, popular, and effective as a contraceptive method among women in a rural town in Malaysia.^ieng

[Experience with contraceptive effect of Depo-Provera, 300mg and 450mg, administered in 6-month intervals]. / Zkusenosti s antikoncepcní úcinností Depo-Provery v dávce 300 mg a 450 mg podaných v intervalech 6 mesícu.

PIP: The application of Depo-Provera in doses of 300 mg over a 6.7-month period and 450 mg over a 4.7-month period was studied. No failures were observed. The major complication was bleeding, although amenorrhea and weight gain were also noted. The percentage of discontinuation was 4.4% for 300 mg and 8.9% for 450 mg. 75% experienced irregularities and difficulties in bleeding.^ieng

Progestogen treatment of recurrent endometrial carcinoma.

PIP: Postmenopausal women with recurrent or metastatic adenocarcinoma of the endometrium were treated with Delalutin (17-alpha-hydroxyprogesterone caproate), Depo-Provera (6-methyl-17-alpha-hydroxyprogesterone acetate), or Colprone (6,17-dimethyl-6-dehydroprogesterone). Numbers of patients on each medication were 20, 25, and 30, respectively. The regimens of these progestogens were .5-1.0 gm of Delalutin intramuscularly twice (in 1 case thrice) a week; Depo-Provera intramuscularly 100 mg/day for 10-14 days, then 100 mg 3 times a week for 6 weeks, finally 200 mg/month; and Colprone orally at 100 mg/day for Week 1, 200 mg/day for Week 2, 400 mg/day for Week 3, 800 mg/day for Week 4 on, and, with an objective or equivocal response, 400 mg/day as a maintenance dose. 3 months was considered an adequate trial period. Responses were considered objectively present (positive response), equivocal, or absent. Objective responses were 5 with Delalutin, 6 with Depo-Provera, and 7 with Colprone. Responses were absent in 11 Delalutin, 17 Depo-Provera, and 17 Colprone patients. Objective responses occurred with 3 of 39 pelvic masses, 8 of 22 abdominal masses, 6 of 23 vaginal lesions, and 9 of 21 pulmonary metastatic problems. None of the 5 osseous or central nervous system lesions responded to therapy. Results were especially good in patients who had recurrences 3 or more years after primary (nonprogestogen) therapy, patients with low-grade lesions, and those who had pulmonary metastasis. The progestogens produced an objective response rate of 24%. Use of progestogens is recommended after other measures have failed. In an added discussion, 2 physicians report findings similar to the ones in the main article.^ieng