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Young female Black rat (Rattus rattus), were administered monthly long acting steroid contraceptive to induce hypertriglyceridemia. It was observed that by 3 weeks of the second injection of estrogen containing mixed type of contraceptive, female rats developed consistent and frank hyperglyceridemia . TG in the treated rats was 195.8 ± 7.44 mg /100 ml as compared to 91.5 ± 6.27 mg/100ml in plasma of the control group.

This study aimed at evaluating the availability of the primate Sapajus libidinosus as an animal model for research assessing the physiological effects of the continuous use of combined hormonal contraceptives. In order to do this, six reproductively active female S. libidinosus from the Primate Research Center of the University of Brasília were selected to take part in this experiment. Every 21 days or so, each female received a single dose of combined hormonal contraceptive (algestone acetophenide and 17-enanthate estradiol) in a total of five doses throughout the experiment. The physiological parameters were accessed by means of 13 blood samples from each female, whereas three were gathered during the baseline and 10 samples were collected during the treatment phase. The results showed that the contraceptive use provoked changes in hematological coagulation factors such as an increase in the amount of platelets (p=0.039) and a reduction in both prothrombin (p<0.001) and thromboplastin coagulation time (p<0.001). These results are similar to what has been observed in human patients; thus, it is concluded that S. libidinosus can be successfully used in studies about the physiological impact of hormonal contraceptives.

Perlutal® (other names: Topasel®, Perlutan®) is a once-a-month injectable contraceptive that contains 10 mg estradiol enanthate and 150 mg dihydroxyprogesterone acetophenide. A prospective trial was conducted in 216 women in Medellin, Colombia, over five years (5,462 woman-months) to establish the rates of the different vaginal bleeding patterns during the use of Perlutal, and to assess their relation with discontinuation of the Perlutal regimen. It was found that with the use of Perlutal, the duration of menstrual bleeding decreased from 3.9 to 2.7 days (p

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.

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 17β-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.

Long-acting contraception by monthly intramuscular injection is an attractive method for family planning which fills a gap in birth control technology. The main advantage of this approach over long-acting (2-6 months) progestin injectables is much better cycle control. To achieve this goal, an estrogen had to be included in the formulation with significant reduction in the progestin dose. Until 1976, there were only three monthly injectables available (Injectable No. 1, Cycloprovera and Deladroxate), but they were faced with logistic, toxicological or clinical problems. It took over 15 years to resolve many of these problems and add a new product (Mesigyna = 50 mg norethisterone enantate plus 5 mg estradiol valerate in an oily solution). Cycloprovera, at a lower dose, received the new name of Cyclofem and Deladroxate was manufactured under the trade names of Perlutal or Topasel. The latter requires in-depth re-evaluation of its toxicological hazards. There are many other formulations currently being developed with incomplete data so far on safety and efficacy.The major advantage of once-a-month combined injectable contraceptives over long-acting progestin injectables is a considerably improved cycle control. Researchers added an estrogen while greatly reducing the progestin dose to achieve better cycle control. The only 3 monthly injectables available up to 1976 (Cycloprovera, Deladroxate, and Injectable No. 1) had logistical, toxicological, or clinical problems. Some of the toxicological problems for Deladroxate, for instance, included pituitary hyperplasia development in rats, a carry-over effect, and estradiol accumulation. Researchers resolved many of these problems over more than 15 years. Pharmacologists reduced the dose of Cycloprovera, which was then remarketed under the new name of Cyclofem. Since the original manufacturer withdrew Deladroxate from the market, other manufacturers now market it as Perlutal and Topasel. Researchers need to conduct a detailed reevaluation of the toxicological hazards of Deladroxate before it is approved for general use or is banned for its toxicity in humans. A new once-a-month combined injectable contraceptive has also been added, Mesigyna (50 mg norethisterone enanthate + 5 mg estradiol valerate in an oily solution consisting of castor oil and benzyl benzoate at a ratio of 6:4). Mesigyna performance is similar to that of Cyclofem. Monthly combined injectables with limited clinical experience include the trade names of Unimens and Lutofollin and 4 with various new combinations (e.g., 50 mg NET-EN and 5 mg estradiol unducelate). Four other products are at an early development stage.

The metabolic effect of the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enanthate (EEn) 10 mg was compared to that of other regularly used contraceptive methods (pills containing: ethinylestradiol (EE) 0.050 mg + levonorgestrel (LNG) 0.250 mg, EE 0.030 mg + LNG 0.150 mg; EE 0.030/0.040/0.030 mg + LNG 0.050/0.075/0.0125 mg; norethisterone enanthate (NEE) 200 mg i.m.; non-hormonal methods). Serum triglycerides, HDL/LDL-cholesterol, copper, ceruloplasmin, total and free cortisol, CBG, total and free testosterone and SHBG in chronic users were determined. A total of 237 women took part in this study. Taking users of non-hormonal methods as control, triglyceride levels were higher, and total and free testosterone levels were lower in women using DHPA 150 mg + EEn 10 mg and in those taking contraceptive pills (p less than 0.05 - 0.01). Such modifications were slightly less in the group using the injectable. The effects of DHPA 150 mg + EEn 10 mg on HDL/LDL-cholesterol copper, ceruloplasmin, CBG, total and free cortisol and SHBG were rare or non-existent. Nevertheless, the contraceptive pills (even the low-dose formulations) correlate with modifications of all those variables, which were highly significant in comparison with the injectable (p less than 0.01) and with non-hormonal methods (p less than 0.01); there were no differences between the last two methods. The results suggest that the metabolic effect of DHPA 150 mg + EEn 10 mg is not higher than that of the commonly used oral contraceptives. On the other hand, they do not suggest that the dose contained in this injectable is exaggerated. There is no evidence that it produces accumulation of effects in the organism. These findings should be taken into account when referring to the long-term safety of this injectable.

Introduction This study compared two regimens of a monthly injectable contraceptive containing dihydroxyprogesterone acetophenide 150 mg and estradiol enanthate 10 mg (Perlutan®) over 12 cycles of use. Methods Three hundred sixty-five adolescents were randomized into two groups. The patients in Group 1 received an initial injection of Perlutan® on the 1st–5th day of their menstrual cycle and subsequent injections every 30±3 days, whereas those in Group 2 followed the traditional schedule of administration in which the first injection is administered between Days 7 and 10 of their menstrual cycle and subsequent injections 7–10 days after Day 1 of withdrawal bleeding. This schedule may result in an irregularity in the timing of injections. Results No significant difference was found between the two groups regarding tolerability or pregnancy (two in Group 1 and three in Group 2). Conclusion Monthly administration limits the annual number of injections to a maximum of 12, thus frequently reducing the total annual dose while maintaining efficacy and tolerability similar to those obtained with the traditional regimen.

Texto completo: acesso restrito. p. 277–280 Submitted by Suelen Reis (suelen_suzane@hotmail.com) on 2013-01-16T11:28:26Z No. of bitstreams: 1 coutinho.pdf: 195605 bytes, checksum: 98465cdf654de2776a9b68a35d0bf153 (MD5) Made available in DSpace on 2013-01-16T11:28:26Z (GMT). No. of bitstreams: 1 coutinho.pdf: 195605 bytes, checksum: 98465cdf654de2776a9b68a35d0bf153 (MD5) Previous issue date: 2000 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.

Perlutal (other names: Topasel, Perlutan) is a once-a-month injectable contraceptive that contains 10 mg estradiol enanthate and 150 mg dihydroxyprogesterone acetophenide. A prospective trial was conducted in 216 women in Medellín, Colombia, over five years (5,462 woman-months) to establish the rates of the different vaginal bleeding patterns during the use of Perlutal, and to assess their relation with discontinuation of the Perlutal regimen. It was found that with the use of Perlutal, the duration of menstrual bleeding decreased from 3.9 to 2.7 days (p0.01), and that the incidence of dysmenorrhea decreased from 31% to 1.6% (p0.01). At one year of follow-up, the incidence of altered bleeding patterns was 5.1%. The discontinuation rate due to an altered bleeding pattern was 3.9%. It is concluded that the low incidence of altered bleeding patterns observed with the use of Perlutal leads to a low discontinuation rate among users.

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.

Once-a-month combined injectable preparations draw their contraceptive efficacy from continuous ovulation suppression. When their use is discontinued, ovulation resumes within a few weeks or a few months, depending on the formulation. After use of the dihydroxyprogesterone acetophenide 150 mg/estradiol enanthate 5 mg combination for one to two years, ovulation returns in most subjects 3-4 months after discontinuation of treatment. Similarly, recent data show that after 2-year use of the depot-medroxyprogesterone acetate 25 mg/estradiol cypionate 5 mg or the norethisterone enanthate 50 mg/estradiol valerate 5 mg combination, approximately 70% women have resumed ovulation by the third month post-treatment. This is shorter than the time for return of ovulation experienced by ex-users of progestogen-only injectable contraceptives.This paper reviews the progress made in the determination of ovulation and specifically addresses the effects of returning ovulation after discontinuance of once-a-month injectable contraceptive preparations. Correlation between ovulation and the hormones estrogen, progesterone, and luteinizing hormone (LH) is well documented. It has served as the basis for many studies on determining ovulation mid-point and in evaluating the efficacy, safety, and time of returned ovulation when using various contraceptive methods and preparations. Current monthly injectable contraceptive formulations are discussed and used as comparison for the new generation injectables. New generation contraceptives in this study are preparations (combinations) of several compounds. The depot microcrystalline form of medroxyprogesterone acetate (DMPA) in combination with estradiol cypionate (E2-Cy) was studied. The authors conclude that these initial studies on the new generation combination monthly injectables indicate that these new contraceptives are highly effective in inhibiting ovulation, as well as allowing for predictable return of ovulation.

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.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.

4 progestational contraceptive formulations were tested for their effects and effectiveness as contraceptives during postpartum lactation. 100 women were enrolled in the study and were divided into 4 groups: Group 1 monthly injections of 300 mg of Depo-Provera intramuscularly; Group 2 monthly intramuscular injections of 150 mg of Deladroxone (dihydroxyprogesterone acetophenide); Group 3 daily per oral administration of .5 mg of chlormadinone acetate; and Group 4 daily per oral administration of quingestanol acetate. Milk samples were collected on the 3rd 5th and 7th days and then monthly until the end of the 12th month for biochemical assays. Initiation of lactation was not affected by using any of the 4 progestogens. Milk yield was lowest in Group 3 but was basically comparable in all groups. Lipid content of milk showed no significant difference among groups receiving medication and between medicated groups and controls during the 1st month. Later drops were demonstrated. Lactose content showed a rise during the 3rd and 5th days postpartum in all groups as compared to controls and later it dropped. Body weights of infants in medicated groups and controls fell within established percentiles; however male and female infants of Groups 1 and 3 showed the greatest increment increase. No pregnancies occurred. Menstrual patterns are shown figuratively. Menstrual disturbances were however the main complaint and side effect of this postpartum contraception. Abdominal distension occurred in 12% of the Depo-Provera users and in 4% of the chlormadinone acetate group. 2% of Deladroxone users reported loss of hair. Depo-Provera showed the best results followed by Deladroxone quingestanol acetate and chlormadinone acetate.

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.

The effect of monthly injectios of 300 mg Depo-Provera or 150 mg Deladroxone and of daily oral administration of .5 mg chlormadinone acetate or .3 mg quingestanol acetate on lactation was studied in Egyptian women during the 1st year of lactation. Women receiving Depo-Provera had the highest milk yield followed by those taking Deladroxone and quingestanol acetate. The milk yields while taking these hormonal preparations were higher than in untreated controls. However those women taking chlormadinone acetate had lower milk yields than untreated controls. The increased milk yield is probably due to the progestagenic activity and minimal estrogenicity of these drugs.

Eleven steroidal compounds were tested for their ability to induce in vitro maturation of Heteropneustes fossilis oocytes. C 18 estrogenic steroids (estradiol-17α and -17β) were totally ineffective in inducing oocyte maturation, while androgenic steroids (19-nortestosterone and 11-ketotestosterone) were only marginally effective. Significant maturational ability was confined to C 21 steroids; the most potent among them were 11-deoxycortisol, 11-deoxycorticosterone, and 21-deoxycortisol.

The clinical use of monthly injectable contraceptive preparations is reviewed. The preparations include estrogen-progestogen combinations progestogen only and estrogen only. Clinical trials of monthly injectables were done with: 1) Deladroxate - 150 mg dihydroxyprogesterone (Algestone) acetophenide (DHPA) + 10 mg estradiol enanthate (EE) in 1 ml oil: 2) Cycle-Provera - depot medroxyprogesterone acetophenide + 10 mg estradiol-3- Benzoate 17beta butyrate; acetate (DMPA) + estradiol cypionate; 3) Unimens - 150 mg 16-17 dihydroxyprogesterone 4) Gravibinon - 250 mg 17alpha-OH progesterone (250 mg) caproate + 5 mg estradiol valerate; 5) 50-70 norethisterone enanthate (Net En) and 5-10 mg estradiol unducelate; 6) 25 mg norgestrel and 5 mg estradiol hexahydrobenzoate; 7) Czechoslovakian injectables; 8) progestogen-only preparations; and 9) estrogen only. The rate of continuation with the use of injectable contraceptives compares favorably with that of IUDs and pills. Most studies show a carryover cumulative effect to subsequent cycles. There is a tendency toward a significant dropout rate following 12 months of use and a delay in return to fertility. The main advantage of monthly injectables is a better cycle control that with the ones used for longer periods.

Tixocortol pivalate is a corticosteroid with topical anti-inflammatory activity equal to that of hydrocortisone. It was evaluated in a group of 18 normal subjects to determine whether it exerted any systemic glucocorticoid activity after single oral or intrarectal doses and after short-term dosing by the intranasal route. Effects of tixocortol pivalate were compared to those of oral dexamethasone and intrarectal betamethasone 21-phosphate. By the three routes, tixocortol pivalate does not induce any changes in plasma Cortisol, leukocyte counts (neutrophils, lymphocytes, monocytes, eosinophils), blood glucose, or 24-hr urinary excretion of sodium and potassium, whereas there were changes after dexamethasone and betamethasone. Tixocortol pivalate, however, increased urinary free cortisol-like substances. It is concluded that tixocortol pivalate given for short periods by nonparenteral routes does not induce a measurable systemic glucocorticoid effect. Clinical Pharmacology and Therapeutics (1983) 33, 343–350; doi:10.1038/clpt.1983.43

Erythrocyte ghosts were loaded with pancreatic DNase I and fused with Y-1 adrenal tumor cells to test the possibility that this enzyme might inhibit the steroidogenic responses of the cells to ACTH and cyclic AMP. Fusion of erythrocyte ghosts loaded with DNase I, but not those containing albumin, ovalbumin, boiled DNase I, or DNase I with excess G-actin, inhibited the increase in production of 20 alpha-dihydroprogesterone produced by ACTH and dibutyryl cyclic AMP; inhibition was concentration-dependent with 50% inhibition by 3 X 10(7) molecules of DNase I per cell. It was found that inhibition by DNase I was exerted at the step in the steroidogenic pathway at which cholesterol is transported to mitochondria where steroidogenesis begins. This was shown by measuring transport of cholesterol into the inner mitochondrial membrane, by measuring the production of pregnenolone by isolated mitochondria and by demonstrating that DNase I was without effect on the conversion of pregnenolone to 20 alpha-dihydroprogesterone (an end-product of steroid synthesis). The actin content of Y-1 cells was measured by two methods based upon inhibition of DNase I and by SDS gels following centrifugation. The cells were found to contain 2-3 X 10(7) molecules of actin per cell of which two-thirds is present as G-actin. Since DNase I is known to bind to G-actin to give a one to one complex, these and other findings suggest that at least some of the G-actin in the cells may be necessary for the steroidogenic responses to ACTH and cyclic AMP.

The effect of administration of various contraceptive tablets, namely, Lyndiol 2.5, Lyndiol 1.0, and lynestrenol 0.5 mg., and Deladroxate injection on milk composition was investigated. A diminution was observed in milk proteins and milk fat which was statistically significant in all cases, compared to a control (placebo) group. Narrow variations were observed in milk lactose which were, however, statistically insignificant. The milk inorganic constituents, namely, sodium, potassium, calcium, and magnesium, were significantly decreased. The total inorganic phosphorus showed no change except in the lynestrenol 0.5 mg. and Deladroxate groups, in which it was diminished. The above findings speak strongly in favor of an adverse effect of these steroids on milk composition. The possible role played by these drugs in this concern is discussed.

Thirty-one patients who completed 24 monthly injections with a long-acting injectable estrogen-progestogen contraceptive were followed with basal body temperature and regular urinary pregnanediol determinations until return of ovulatory function was established. Selected patients were studied for plasma gonadotropin patterns and for pituitary reserve by Metopirone tests. Sixteen patients who had received 24 consecutive montly injections required from 12 to 42 weeks to establish spontaneous ovulation. Three patients who received clomiphene citrate after 20 weeks of anovulation promptly ovulated and subsequently maintained regular ovulation. Six patients who discontinued the injections prior to 2 years demonstrated a correlation between the number of injections and the length of posttreatment anovulation. Six patients who received their injections bimonthly during the last 6 months of treatment returned to ovulatory cycles within 8 to 16 weeks. These patients had unacceptable irregularity of their withdrawal flow while taking injections bimonthly. Serial determinations of FSH and LH by radioimmunoassay on selected patients showed depression of FSH and lack of an LH peak during the period of anovulation, but normal patterns once ovulation recurred. All patients studied showed normal response to Metopirone tests after discontinuation of the drug. All patients ultimately returned to normal ovulatory cycles.

Thirty-eight women were treated over 353 menstrual cycles with an intramuscular contraceptive preparation of 150 mg of dihydroxyprogesterone acetophenide in combination with 10 mg of estradiol enanthate. Treatment consisted of one injection “monthly”. This compound proved to be an effective antifertility agent. Persistent menstrual irregularities of varying degree, was seen in every subject followed for more than 5 cycles, and was severe enough in 26% of the study group to cause cessation of therapy. The subject acceptance of this preparation was not enthusiastic, and it seems unlikely that it will supplant other contraceptive modes for the majority of the populace.

Summary 1. Cortisol gives a more intense and stable reaction with an acetic acid containing fluorescence reagent than with a conventional ethanol containing reagent. Other steroids, and the non-corticosteroid fluorogens, give less strong responses. 2. The non-corticosteroid serum fluorogens can be estimated by measuring the fluorescence with excitation wavelengths shorter than used for cortisol. A simple correction can be applied to estimate corticosteroids in the presence of other fluorogens. 3. Methods are described for carrying out the whole procedure on 0.5 ml or less of serum. Very close correlation with a competitive protein binding assay was achieved.

130 women received injections of 150 mg dihydroxyprogesterone acetophenide combined with 10 mg estradiol enanthate once a month. The first 6 cycles after beginning injections were shortened; return to normal length occurred after the eighteenth injectionW After the twenty-fourth injection cycle length increased to 33.5-39 days. Duration and amount of flow and dysmenorrhea increased initially. Side effects included gastrointestinal symptoms headache mild blood pressure changes allergic reactions and weight changes. Ovulation returned in 18 patients 6 to 14 weeks after cessation of therapy; 9 women became pregnant 5 to 9 months after the last injection.

One hundred and fifty milligrams of a synthetic injectable progestational compound, dihydroxyprogesterone acetophenide, combined with 10 mg. of estradiol enanthate (Deladroxate 150-10), injected intramuscularly to normal females on the seventh to ninth days of the cycle gave the most satisfactory cyclic uterine bleeding as compared to a number of other combinations of the progestagen and estrogen. The mean cycle length from this combination after the first cycle varied between 26.3 and 28.3 days. Only 16 per cent of the cycles deviated from the pretreatment mean of the individual patients' cycles by more than ± 2 days. When the medication was discontinued after four consecutive cycles ovulatory cycles returned within 5 to 13 weeks. There was a minimum of side effects and patient acceptance was excellent.

16-alpha 17-alpha-dihydroxyprogesterone acetophenide and estradiol enanthate were employed in combination as an intramuscular injectable "once-a-cycle" contraceptive agent (Deladroxate). 127 patients participated in the study for a total of 605 cycles. The injection date was as close to Cycle Day 8 as possible. Urinary pregnanediol determinations were preformed by the method of Klopper during Days 19-23. 73% of the 127 patients found this method of contraception acceptable. 3 of the Deladroxate dosages studied (100:20 150:5 and 150:15) produced a 79% acceptability rate. This method has proven of special value to patients with psychiatric problems who had found or believed other methods unsatisfactory. No pregnancies occurred and side effects occurred in only a few cycles. In a small group of cases there was evidence that the first posttreatment cycle was anovulatory since pregnanediol excretion was .2-1.3 mg/24 hours in 11 cycles nonsecretory endometrium occurred in 7 and no pregnancies occurred despite a missed injection in 33 cycles. Observations that protection against pregnancy may be extended into at least 1 cycle beyond the "treatment cycle" suggest the possibility that the frequency of injection might be reduced to every other cycle instead of once a cycle. It appeared that this method provides some margin of safety for the poorly motivated patient who may fail to keep her appointments with absolute regularity.(AUTHORS MODIFIED)

This report is concerned with the endometrial response to once-a-month injectable dihydroprogesterone acetaphenone and estradiol enanthate as a contraceptive agent. Fifty-eight representative endometrial biopsies were obtained at various times during the cycle from 189 women observed through 1,255 drug-induced cycles. A distinctive carry-over effect on the endometrium was noted from one cycle into the next. This characteristic effect, observed after flow has begun and prior to the next injection, consists of the presence of subnuclear secretory-like cytoplasmic vacuolation of the glands in a basically proliferative endometrium with a loose stroma. Following injection on the eighth day of a cycle the endometrium exhibits a progression to incompletely developed secretory glands with minimal deciduoid reaction, followed by gradual atrophy and breakdown terminating in menstrual flow. Histologic atypia was not observed. Discontinuance of the drug was followed by a lag of several months before the endometrium was totally established as normal. No pregnancies were observed in less than 3 months subsequent to cessation of therapy.

Cock testes incubated with labeled pregnenolone or progesterone as substrates produced testosterone as the main compound. The formation of 17α-hydroxyprogesterone was greater with progesterone as precursor, but the production of radioactive 20β-dihydroprogesterone and androstenedione was similar with either substrate. Testes from 1-, 21-, and 40-day-old chicks incubated with progesterone as a substrate had a very low testosterone: androstenedione production ratio (0.05). In mature animals, however, more testosterone than androstenedione was produced from radioactive progesterone and the production ratio testosterone: androstenedione was 24.

A study was planned on the effect of contraceptive steroids on milk yield and composition in goats after established lactation. The goats were classified into six groups: Group I received no medication and was considered as a control group. Group II was given Deladroxate injections. Groups III and IV received Lyndiol 2.5 and Lyndiol 1.0, respectively. Group V received lynestrenol 0.5 mg. alone and Group VI, mestranol 0.1 mg. alone. The milk yield per 24 hours was found to decrease in all groups, the drop amounting to 42 per cent in the control group, 71.6 per cent in Group II, 60 per cent in Group III, 52 per cent in Group IV, 55.6 per cent in Group V, and 56 per cent in Group VI. The growth rate of the kids in Groups II, III, and IV was lower than that in the control group. The milk fat and proteins dropped gradually. This was most marked in medicated groups. Milk lactose showed minor variations, while the changes in the inorganic constitutents were inconsistent, varying between increment and decrement. These results confirm the previous findings in women, that gestagens exert an adverse effect on the quantity and quality of milk when they are orally or parenterally administered during lactation.

Liver function during treatment with an intramuscular progestagen-estrogen combination was assessed in 191 patients. Serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels did not change significantly. Thymol turbidity determinations and total protein albumin globulin alkaline phosphatase and serum bilirubin levels were all within normal limits. Only 2 patients had deviations from the norm in more than 1 of the battery of liver function studies. Return to normal levels was demonstrated in those individuals with alterations prior to medication. It is concluded however that further long-term follow-up studies of protein fractions and carbohydrate alterations in regard to hepatic changes are warranted.

The results of a clinical investigation on 22 fertile women treated cyclically with a total of 341 injections of Deladroxate, an injectable, long-acting oestrogen-progestogen are presented. The injections were administered on the 8th (7th–9th) day of each cycle. Before treatment, the patients were observed through 2 cycles for cycle length as well as duration and amount of flow. In some cases the dose was increased because of a shortening of the cycle. The over all mean cycle length during the treatment was 25.3 days, though with fairly marked variations. The mean cycle length before treatment was 28.4 days. The duration of flow ranged from 1–30 days. About 72% of 320 withdrawal bleedings lasted for 4–8 days. Of the flows 60% were of normal amounts, while the majority of the remaining flows were scantier than the normal pre-treatment flows of the subjects. Side effects during treatment were recorded in one or more cycles in 17 of the 22 subjects and were in most cases slight and transient. The most common complaints were breast tenderness, oedema, and irregularities of bleeding. No pregnancy occurred during treatment. After discontinuation of the injections, bleedings and cycles normalized spontaneously in 11 women. In 1 woman curettage was performed because of profuse flow, and 2 women were treated with oral oestrogen-progestogens because of persistent bleeding. Eight women started oral contraception before the cycles became regular.

The metabolic fate of 6, 7-3H-estradiol enanthate (3H-EEn) and 4-14C -dihydroxyprogesterone acetophenide (14C-DHPA) has been studied in 4 normal women. Two women received a mixture of 3H-EEn and non-radioactive dihydroxyprogesterone acetophenide by the i.m. route whereas two other women received 14C-DHPA and non-radioactive estrogen. A similar experiment was repeated after 4 to 6 menstrual cycles during which the four subjects were treated with non-radioactive Deladroxate (10 mg estradiol enanthate and 150 mg dihydroxyprogesterone acetophenide). A higher excretion in feces was noted for the progestogen in contrast to the estrogen, which was preferentially excreted in urine. Almost 55% of the 3H-material in urine was conjugated mainly with glucuronic acid and to a lesser extent with sulfuric acid. Unconverted estradiol enanthate, 2-methoxy-estrone and estrone were identified in the urine as the main metabolic conversion products. No significant differences of the metabolic fate were found after chronic treatment with Deladroxate.

Progestagens used as antifertility agents in oral contraceptive agent (OCA) preparations are reviewed. The history of their development is briefly presented and the following groups of progestagens are revie wed with regard to structure and production: 1)the 19-norprogestagens; 2 ) 17 alpha-acetoxyprogesterone; 3)the 6-methylated progestagens; 4)chlor madinone acetate; 5)algestone acetophenide quinestanol acetate and norgestrel; and 6)other progestagens examined as contraceptive agents. Structural formulas of the various compounds accompany the discussions. Biologic activity classifies progestagens as: 1)progestagens without estrogenic and androgenic effects; 2)progestagens without estrogenic androgenic and antiandrogenic effects; 3)progestagens with slight androgenicity 4)progestagens with some androgenicity; 5)progestagens with some estrogenic and slight androgenic properties; and 6)estrogens with some progestational but no androgenic activity.

The author reports the results of a clinical study on 17 fertile women treated through a total of 120 cycles with Deladroxate, an injectable, long-acting oestrogen-progestogen. The injections were administered on the 8th (7th–9th) day of each cycle. Before treatment was started, the patients were observed through 2 cycles with regard to cycle length as well as duration and amount of flow. Moreover, ovulation was assessed by means of daily recording of basal body temperature (BBT), pregnanediol analyses, total pituitary gonadotrophin analyses, and endometrial biopsies. In some cases the dosage had to be increased because of a shortening of the cycle. The mean cycle length during the treatment was 24.2 days, though with fairly marked variations (mean cycle length before institution of treatment: 28.2 days). Duration of flow ranged from 3–35 days. About 84% of 108 withdrawal bleedings lasted for 4–8 days. Of the flows 56 % were of normal amount, while the majority of the remaining 44 % were scantier than in the patients with normal periods. The ovulation-inhibiting effect of Deladroxate was assessed by daily recording of BBT, pregnanediol and pituitary gonadotrophin assays, and endometrial biopsies. Five of the 41 BBT curves (41 cycles) were biphasic. Four out of 34 endometrial biopsies, obtained on the 23rd day of the cycle, showed a secretory phase. Forty out of 41 cycles were anovulatory, as assessed by the pregnanediol excretion, while in 1 cycle the excretion pattern was not characteristic. In 20 out of 37 cycles there was a definite depression of gonadotrophin excretion, while in 17 cycles the excretion pattern was not characteristic. The effect of Deladroxate on the adrenal cortex was studied by means of 17-ketogenic steroid and 17-ketosteroid excretion. With both groups of steroids there seemed to be a tendency to a reduced excretion during treatment. No changes in the fibrinogen, prothrombin, GO-transaminase, bilirubin, or thymol values were observed during treatment. Side effects during treatment, recorded in 11 of the 17 subjects, were in most cases slight and transient. The most common complaints were breast tenderness, oedema, and irregularities of bleeding. No pregnancy occurred during treatment.

Concentrations of fibrinogen and plasminogen as well as plasma euglobulin fibrinolytic activities were determined in blood from women receiving oral or parenteral contraceptives. The orally active preparations consisted of mixtures of different progestins and estrogens. The two parenteral preparations contained progestin alone or a combination of progestin and estrogen. Fibrinogen concentrations remained normal in all groups. Plasminogen concentrations were elevated in women receiving oral preparations but not in those receiving the parenteral preparations. Plasma euglobulin fibrinolytic activity increased after oral contraceptives, was normal after the parenteral preparation containing estrogen and progestin, and decreased after the preparation consisting solely of a progestin.

Rates of entry of estrone ( E1, estradiol (E2), progesterone (P), 20αdihydroprogesterone (20αDHP), estrone sulfate (E1S) and estradiol-3-sulfate (E2S) from buffer solutions into slices of human endometrium were measured in multiple-tracer continuous-flow incubations of the tissue. The fraction of perfused P entering the cells was found to be similar to that of E1 and E2. Increases in the concentrations of E2 in the medium to 5 μg/ml did not alter the fraction of perfused E1 and E2 going into cells. Estrone sulfate and E2S entered readily into endometrial cells and were completely converted to E1 and E2. Rates of interconversion between ElS-E2S, E1-E2 and P-20αDHP were measured. The conversion of E1 to E2 was relatively increased by the addition of E2 to the medium. A large fraction of E1 and P entering the tissue was released to the medium while E2 and 20αDHP left the cells only after being converted to the corresponding ketonic steroids. Consequently, the net uptake of E2 and 20αDHP was larger than the n...

To assess the effects of injectable Deladroxate (150 mg of 16-alpha 17-alpha dihydroxyprogesterone acetophenide and 10 mg of estradiol enanthate) on the endometrium and on the exfoliated vaginal cells a group of 50 women who had used this once-a-month injectable contraceptive for 1250 consecutive cycles were studied. 18 of these women were studied for a length of 30 consecutive cycles. Endometrial biopses and vaginal smears taken during treatment showed the changes in the endometrium and in the exfoliated vaginal cells reflected a high estrogen response during the first year of use. The endometrial glands showed late proliferation and hyperplasia. The karyopyknotic index was high with a peak level around the twentieth day of the cycle. During the second year the endometrium was atrophic proliferative and the smears showed low estrogen response with a rather flat curve. Secondary amenorrhea developed in 3 cases of the group which used the contraceptive for 30 months. It was either associated with atrophic proliferative or cystic hyperplastic endometrium. No secretory changes were reported in the endometrium. The vaginal smears did not show any abnormal cells even after 30 successive cycles.

The article reports a study of the length and characteristics of menstrual cycles induced by a single monthly injection of 150 mg of dihydroxprogesterone acetophenide with 10 mg of estradiol ethanate (Deladroxate) administered to 60 regularly ovulating women for a total of 198 cycles. Cycle lengths are analyzed at length and the results are comparatively discussed in relation to the time of injection and cycle duration. The duration and extent of menstrual flow is reported through 6 cycles. The occurence of side-effects and the return to normal cycles are presented and discussed. It is noted that the characteristics of artificially induced cycles were indistinguishable from normal cycles. Recommendations for the most effective use of Deladroxate are given and further studies of the method are encouraged.

A parenteral estrogen-progestogen preparation administered intramuscularly at monthly intervals has been studied in 385 patients during 4512 cycles. No pregnancies were established during the use of the medication. The discontinuation rate over the course of 25 months was 43.6%. Thirty-three pregnancies are known to have occurred within 1 to 20 months of discontinuation. Cervical cytology, endometrial histology, and liver function, investigated during the program, were not adversely affected. The most frequent associated effect was prolonged or excessive vaginal bleeding. The preparation and mode of contraception were well tolerated and readily accepted.

A new progestational steroid, the acetophenone derivative of 16α,17α;- dihydroxyprogesterone, was compared with several progestogens for masculinizing effects on the offspring of rats treated during pregnancy. The results were similar to those obtained with progesterone and 17α-hydroxyprogesterone caproate: this new steroid did not alter the normal male:female sex ratio and did not virilize the internal or external sex structures of the newborn. The present results confirm those of others in finding that 6α-methyl-17α-hydroxyprogesterone acetate, 17α-ethinyl-19-nortestosterone and 17aethinyl- 19-nortestosterone acetate increased the number of male and intersex offspring, as determined by ano-genital measurements and masculinization of internal and external sex organs.

Steroid hormone content and steroid synthesis in vitro were studied in a clinically and morphologically typical luteoma of pregnancy. The only Δ 4 -3-ketosteroid present was tentatively identified by paper and thin-layer chromatography as Δ 4 -androstene-3,17-dione. Net synthesis (μg) of this androgen was augmented in vitro by HCG. No radioactive steroid formation from acetate-1- 14 C could be established after analysis by reverse isotope dilution. The biochemical and histologic data suggest that the luteoma of pregnancy originates from the ovarian stroma. The augmentation of steroidogenesis by HCG in vitro in this study and the clinical observation of postpartum regression in other studies are compatible with the concept that the placental gonadotropin plays some role in development and maintenance of this specific ovarian lesion.

The effects of progestational steroids on the chemical composition of milk during the 1st year of lactation are described. The milk samples were analyzed for total protein lipid and lactose content. When compared with a group of nonmedicated women chlormadinone acetate Depo-Provera and Deladroxone all caused a marked increase in protein co ntent in the early stages of lactation while quingestanol acetate had little overall effect. The average protein content in gm% over the period was as follows: chlormadinone acetate 1.07 Depo-Provera 1.04 Deladroxone .96 quingestanol acetate .86 and controls .83. Lipid and lactose content showed irregular changes in the medicated groups as compared with the controls. The general trend towards an increase in milk protein with all 4 progestagens may be explained by the direct stimulating effect of their estrogenic metabolites on mammary tissue.

The effect of monthly injectios of 300 mg Depo-Provera or 150 mg Deladroxone, and of daily oral administration of .5 mg chlormadinone acetate or .3 mg quingestanol acetate on lactation was studied in Egyptian women during the 1st year of lactation. Women receiving Depo-Provera had the highest milk yield, followed by those taking Deladroxone and quingestanol acetate. The milk yields while taking these hormonal preparations were higher than in untreated controls. However, those women taking chlormadinone acetate had lower milk yields than untreated controls. The increased milk yield is probably due to the progestagenic activity, and minimal estrogenicity, of these drugs.