Norplant implants: the mechanism of contraceptive action.

OBJECTIVE: To determine if fertilization occurs unnoticed among Norplant users who are ovulatory. DESIGN: Serial blood samples were obtained during 1 month from sexually active Norplant users experiencing regular menstrual bleeding patterns and a control group of noncontracepting women trying to conceive. The sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG). SETTING: All samples were obtained from women receiving contraceptive service and health care at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. Assays for hCG were performed at the Department of Biomedical Sciences, University of Tampere, Finland. PATIENTS, PARTICIPANTS: A total of 32 women using Norplant implants were enrolled in the treatment group, and 20 women of proven fertility who were attempting to conceive served as a control group. INTERVENTIONS: Duration of Norplant use was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th year, 3 in the 5th year, and 1 in the 7th year. MAIN OUTCOME MEASURE: The determination of pregnancy was based on the presence of hCG in the luteal phase, using a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days after ovulation. RESULTS: Nine pregnancies were detected. All were in the control group trying to conceive. Six of these advanced to clinical pregnancies, and three did not proceed beyond the next expected menses. None of the Norplant users had evidence of hCG production, whether the observed cycles were anovulatory or ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1 in 50 and 1 in 150,000. The null hypothesis that Norplant users conceive at a natural rate can be rejected at the 0.05 level. CONCLUSION: Interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

PIP: This study sought to determine if fertilization can occur unnoticed among Norplant users who are ovulatory. Serial blood samples were obtained during a 1-month period from women receiving contraceptive service and healthcare at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. These women were all sexually active Norplant users who experienced regular menstrual bleeding patterns, and their sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG) at the Department of Biomedical Sciences at the University of Tampere, Finland. There was also a control group of 20 noncontracepting women included who were trying to conceive. Duration of Norplant was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th, 3 in the 5th year, and 1 in the 7th year. Pregnancy determination was based on the presence of hCG in the luteal phase by use of a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days postovulation. 9 pregnancies were detected, all in the control group who were trying to conceive. 6 of these advanced to clinical pregnancies and 3 terminated spontaneously at the next menstrual period. None of the Norplant users evidenced and hCG production, whether or not the observed cycles were ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1/50 and 1/150,00. The null hypotheses that Norplant users conceive at a natural rate can be rejected at the 0.05 level. Thus, interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants.

OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.

PIP: The study sought to examine the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. This observational, prospective, case-controlled, comparative study occurred at the Family Planning Clinic of PROFAMILIA in Santo Domingo, Dominican Republic. 31 subjects agreed to receive Norplant contraceptive implants between 13-77 months prior to this study and there were 12 nonhormonal contraceptors who also volunteered to participate. Follicle stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for 1 menstrual cycle, and almost 1/2 of the cycles of norplant acceptors were anovulatory: the remainder (55%) had some form of dysfunction such as diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from controls. Anovulation is clearly 1 of the main mechanisms of Norplant action, but even in presumptive ovulatory cycles, the dysfunctions described could have contributed to the high contraceptive effectiveness of Norplant.

The menstrual cycle in women using an intrauterine device.

The duration and hormonal characteristics of the menstrual cycles of women using Copper T intrauterine devices (IUDs) were studied. Daily load samples were obtained during both the pre- and postovulatory phases of 30 IUD-associated cycles and the hormone values were compared with those of 15 normally menstruating women not using contraception. The ovulation rate and peak levels of 17 beta-estradiol and luteinizing hormone (LH) were not significantly different between the two groups. The average number of days from the 1st day of menstrual bleeding to the LH peak (the proliferative phase) was longer in the IUD users. The number of days from the LH peak to the onset of menstrual bleeding (the luteal phase) was shorter in the IUD users. Because of the compensating nature of these statistically significant differences, the total cycle length appeared to be unchanged. At the time of menstruation, the plasma levels of both progesterone and 17 beta-estradiol were significantly higher among IUD users. It is concluded that the presence of an IUD does not influence ovarian function, but that ovarian steroid production and endometrial events become asynchronous.

PIP: The duration and hormonal characteristics of the menstrual cycles of women using the Copper T IUD were studied. Daily blood samples were obtained during the pre- and postovulatory phases of 30 IUD-associated cycles and the hormone values were compared with those of 15 normally menstruating women not using contraception. The ovulation rate and peak levels of 17 beta-estradiol and (LH) luteinizing hormone were not significantly different between the 2 groups. The average number of days from the 1st day of menstrual bleeding to the LH peak (proliferative phase) was longer in IUD users. The number of days from the LH peak to onset of the menstrual bleeding (luteal phase) was shorter in the IUD users. Because of the compensating nature of these statistically significant differences, the total cycle length appeared to be unchanged. At the time of menstruation, the plasma levels of both progesterone and 17 beta-estradiol were significantly higher among IUD users. It is concluded that the presence of an IUD does not influence ovarian function, but the ovarian steroid production and endometrial events do become asynchronous.

Pituitary-ovarian function after tubal ligation.

Pituitary-ovarian function was evaluated by measurement of daily serum levels of luteinizing hormone (LH), 17 beta-estradiol, and progesterone in women with a previous history of tubal ligation. Normally menstruating women served as controls. The duration of the proliferative and luteal phase was similar for both groups. The midluteal progesterone level averages did not differ between the two groups. Preovulatory LH and 17 beta-estradiol peaks were significantly lower in the tubal ligation group; average midluteal LH and 17 beta-estradiol levels were also lower. These results reveal that pituitary-ovarian function can be altered following surgical sterilization.

PIP: Menstrual disorders have been reported following tubal surgery. This study investigates luteinizing hormone (LH), 17beta-estradiol, and progesterone levels in 30 women (age range, 24-38 years; average age, 32 years), who had had elective tubal ligation for fertility control. Elective surgical sterilization was performed between 1 month and 8 years previously. The controls consisted of 15 normally menstruating women (aged 20-32 years; average age, 24), seeking to become pregnant who had not used either oral contraceptives or IUDs for at least 1 month before the study. Daily blood samples were collected starting from day 10 of the menstrual cycle until the onset of the next menstruation. Case selection and specimen collections were done in Santo Domingo, Dominican Republic. Hormone determinations by radioimmunoassays were done on a double-blind basis at the Population Council in New York. Progesterone and 17-b estradiol were determined by radioimmunoassay according to the method of Thorneycroft and Stone, while human luteinizing hormone (hLH) was measured by the double antibody technique of Vaitukaitis et.al. Average duration of the proliferative and luteal phase were 14.4 + or - 3.0 and 13.3 + or - 2.9 days, respectively, for the control group and 13.5 and 2.4 and 14.2 + or - 1.7 days for the women with tubal ligation. The total length of the cycle, 27.7 days, is the same for both groups. The midluteal progesterone level averages did not differ between the 2 groups, although when the controls were compared with tubal ligated women 30 years of age or younger, the difference was significant. Preovulatory LH and 17beta-estradiol peaks were significantly lower in the tubal ligation group, as were the average midluteal LH and 17beta-estradiol levels. These results suggest that surgical sterilization can result in subtle changes in ovarian function, even though ovulation itself is not affected. Bleeding irregularities following tubal ligation may in part be due to the fact that different surgical procedures may have different effects on ovarian blood supply. Further research should be done to compare specific effects of different sterilization procedures on ovarian function.

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg of medroxyprogesterone acetate and 5 mg of E(2)-cypionate: effects on ovarian function.

OBJECTIVE: To assess whether women who were administered the first injection of DMPA+E(2)C on day 7 of their menstrual cycle (delayed injection) exhibit the same degree of ovarian suppression as women who receive it on day 5 of their menstrual cycle. DESIGN: Multicenter, randomized controlled trial. SETTING: Reproductive health clinics. PATIENT(S): Women aged between 18 and 38 years (inclusive) willing to use DMPA+E(2)C as their method of contraception. INTERVENTION(S): Participants received a DMPA+E(2)C injection on day 5 (control group, n = 41) or day 7 (delayed-injection group, n = 117) of their menstrual cycle. MAIN OUTCOME MEASURE(S): Ovarian activity and follicular development determined by serial serum progesterone levels and vaginal ultrasound. RESULT(S): Participants who received DMPA+E(2)C on day 5 of their menstrual cycle (control group) exhibited no more than limited follicular growth (no follicle >16 mm). Of those women who received DMPA+E(2)C on day 7 of their menstrual cycle (delayed-injection group), 21 (18%) showed some follicular growth, of whom 4 (3%) ovulated. CONCLUSION(S): The first injection of DMPA+E(2)C given on day 7 of a menstrual cycle does not provide the same inhibition of ovarian activity as that observed when it is administered on day 5 of the menstrual cycle.

Absence of chorionic gonadotropin in sera of women who use intrauterine devices.

A controlled study was undertaken to determine whether unnoticed pregnancies routinely occur in users of the intrauterine contraceptive device (IUD). Starting on day 10 of the menstrual cycle and continuing through the onset of menstruation or until the diagnosis of pregnancy, we collected daily blood samples from three groups of normally menstruating young women. The study groups were (A) IUD users (n = 30), (B) women with tubal ligation (n = 30), and (C) women trying to become pregnant (n = 15). The sequential serum samples were analyzed by radioimmunoassay for progesterone (P), human luteinizing hormone (hLH), and human chorionic gonadotropin (hCG). No positive hCG assays in luteal phase blood sera of IUD users were observed. The only positive hCG determinations of IUD users coincided with the preovulatory surge of hLH. Two subjects who became pregnant, as judged by progressive increases in hCG and P levels in the luteal phase, belonged to the group planning pregnancy. The finding of two pregnancies in 15 months of exposure is consistent with the assumption of natural fertility. The probability of no pregnancies in 30 months at risk, as observed among the IUD users, is between 1 in 200 and 1 in 100,000, depending on the assumption made for natural fertility. The study demonstrates that IUD users do not retain their natural fertility, and that IUDs do not exert their antifertility effect as abortifacient agents. If a confirmed pregnancy is detected in an IUD user, it may be assumed to represent an isolated case of contraceptive failure.

PIP: A controlled study was undertaken to determine whether unnoticed pregnancies routinely occur in users of the IUD. Beginning on day 10 of the menstrual cycle and continuing through the onset of menstruation or until the diagnosis of pregnancy, the authors collected daily blood samples from 3 groups of normally menstruating young women. The study groups were: a) IUD users (n=30); b) women with tubal ligation (n=30); and c) women trying to become pregnant (n=15). The sequential serum samples were analyzed by radioimmunoassay for progesterone (P), human luteinizing hormone (hLH), and human chorionic gonadotropin (hCG). No positive hCG assays in luteal phase blood sera of IUD users were observed. The only positive hCG determinations of IUD users coincided with the preovulatory surge of hLH. 2 subjects who become pregnant as judged by progressive increases in hCG and P levels in the luteal phase belonged to the group planning pregnancy. The finding of 2 pregnancies in 15 months of exposure is consistent with the assumption of natural fertility. The probability of no pregnancies in 30 months at risk, as observed among the IUD users, is between 1 in 200 and 1 in 100,000, depending on the assumption made for natural fertility. The study demonstrates that IUD users do not retain their natural fertility, and that IUDs do not exert their antifertility effect as abortifacient agents. If a confirmed pregnancy is detected in an IUD user, it may be assumed to represent an isolated case of contraceptive failure.

Progestin-only contraceptive rings.

Several progestin-only long acting contraceptives are currently available in the form of implants or injectables. Vaginal rings are another contraceptive option in the final stages of development. These steroid-containing polymer rings are placed in the vagina, providing relatively constant drug release, thus allowing for lower effective doses. Vaginal rings have the advantage of being user-controlled and non-provider dependent, and their use is non-coital related. The first clinical study with medroxyprogesterone acetate vaginal rings was published in 1970. Since then numerous clinical trials testing different steroids and doses have followed. A large Phase III multicenter clinical trial with a levonorgestrel ring, releasing 20 microg/day, was coordinated and sponsored by WHO. The cumulative one-year pregnancy rate was 4. 5%. The principal reasons for discontinuation were menstrual disturbances (17.2%), followed by frequent expulsion of the ring (7. 1%), and vaginal symptoms (6.0%). The finding of erythematous lesions in the vagina in some women has led to the development of a more flexible device. Collaboration with industry should facilitate the manufacture of a redesigned levonorgestrel ring with a higher release rate. The Population Council is also developing a vaginal ring containing Nestorone for 6 months of continuous use. Ovulation inhibition was achieved in over 97% of the segments studied, with rings releasing either 50, 75, or 100 microg/day. No pregnancies occurred in women using the low-dose ring, while one pregnancy each occurred in the intermediate- and high-dose ring groups for a 6-month cumulative pregnancy rate of 0.0, 1.9, and 2.1%. Bleeding irregularities were common. Nestorone is orally inactive; therefore this ring is also excellent for use in lactating women.

Estradiol delivery by vaginal rings: potential for hormone replacement therapy.

OBJECTIVES: To determine if delivery of estradiol from elastomeric vaginal rings gives estradiol blood levels in the range associated with effective estrogen replacement therapy and to determine the relation between in vitro estradiol release from the rings and blood levels in vivo. Secondary objectives related to changes in lipoprotein cholesterol, changes in climacteric symptoms, and evaluation of acceptability to users. METHODS: Three ring variants releasing approximately 100, 150 and 200 micrograms/day of estradiol in vitro were used through 22 days in 21 postmenopausal women, 7 on each dose levels. Blood samples for measurement of estradiol were taken at 3-4 day intervals. Lipoprotein cholesterol was measured before and at the end of treatment. Women were questioned about climacteric symptoms and about their satisfaction with the ring. RESULTS: Mean serum estradiol levels for the three groups of rings were 63 +/- 6, 94 +/- 5 and 136 +/- 13 pg/ml for the 100, 150 and 200 micrograms/day rings, respectively. FSH levels declined during ring use and the maturation values of cells collected on vaginal swabs markedly increased. Total and LDL cholesterol were significantly reduced and HDL cholesterol was not significantly changed. All women reported relief of postmenopausal symptoms. Vaginal discomfort during the first 3 days of use was reported by 12 women but overall satisfaction with the method was high. CONCLUSIONS: Women using the vaginal rings attained estradiol blood levels compatible with control of climacteric symptoms and bone loss. The relation between in vitro estradiol release and blood levels in vivo was essentially identical for all 3 doses. The use of vaginal rings to deliver estradiol for hormone replacement therapy is judged to merit further evaluation.

Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control and lipid profiles.

Four different models of contraceptive vaginal rings were tested during three cycles for luteal activity, bleeding control, plasma lipoproteins and serum levels of the contraceptive steroids. Two progestins, levonorgestrel acetate (LNGA) and ST 1435, alone or in combination with ethynyl-estradiol (EE) were tested. The rings released 100 ug/day of the progestins and 30 ug/day of EE. Luteal activity was detected among users of the progestin-only rings: 4 of 8 cycles with ST 1435 and 2 of 10 with LNGA. Only one of the 18 cycles studied with the two combined rings showed luteal activity, but the measurement of contraceptive steroid in plasma suggested that this subject delayed reinsertion of the ring for about one week in that particular cycle. Breakthrough bleeding was observed in 12 of 30 cycles of use of the progestin-only rings, and in only 2 of 27 cycles with the combined models. No significant changes in total cholesterol or its HDL-fraction were observed. However, the only reduction observed in HDL-cholesterol was among users of the LNGA-only ring. It is concluded that the two combined CVR models offer good possibilities of high effectiveness and bleeding control and merit further development.

PIP: Researchers analyzed data on 20 18-38 year old volunteers from the family planning clinic of PROFAMILIA in Santo Domingo, Dominican Republic, who had earlier undergone female sterilization to evaluate 4 different models of contraceptive vaginal rings during 3 cycles so as to identify which models would be the most likely to be an acceptable, safe, and effective family planning method. Women who used either of the 2 combined rings (ethinyl estradiol [EE] and either levonorgestrel acetate [LNGA] or ST 1435) had higher mean total serum levonorgestrel levels than those using the progestin-only rings (LNGA or ST 1435) (most were significant at .005). Luteal activity which marked ovulation was basically limited to users of the progestin-only rings (50% of cycles with ST 1435 and 20% of LNGA). It occurred in 1 of 18 cycles (5.6%) of users of combined rings (LNGA + EE). It probably occurred because of delayed insertion. The combined rings caused fewer incidents of breakthrough bleeding than did the progestin-only rings (7.4% vs. 40%). Neither the progestin-only nor the combined vaginal rings significantly altered total cholesterol or high density lipoprotein (HDL) levels. Users of the LNGA-only ring did experience an insignificant reduction in HDL, however. Further, triglycerides increased among users of the combined vaginal rings, but the increase was only significant with the LNGA + EE ring (25.4 mg/dl increase; p .05). Moreover, they fell significantly among users of the LNGA only ring (45.5 mg/dl decrease; p .05). The researchers concluded that the 2 combined rings hold the most promise due to good bleeding control and high effectiveness and therefore deserve further development.

The effect of levonorgestrel and estrone rods on male reproductive function.

The effect on spermatogenesis of the implantation of six rods containing levonorgestrel and three estrone rods was studied in seven volunteers aged 32-40, with normal pre-treatment spermiogram. None of the subjects achieved azoospermia. The lowest sperm count was below 1 million/ml in three subjects and below 12 million/ml in the other four. Plasma FSH and testosterone were severely depressed during the study, but LH was only transiently depressed for the first two months. Four subjects recovered pre-treatment sperm counts in spite of the FSH levels below 1.5 mIU/ml and testosterone levels below 1 ng/ml, which is contradictory to the current concept on hormonal regulation of spermatogenesis.

Comparative prolactin profiles in IUD users and non-IUD users.

Starting from the 10th day of the menstrual cycle through onset of the subsequent menstrual bleeding, daily blood samples were collected from 14 women using Copper T IUDs and 10 normal control women. The serum samples were analysed by radioimmunoassay (RIA) for human prolactin (hPRL) and human luteinizing hormone (hLH). hPRL values were subjected to statistics. Episodic patterns of hPRL were observed for all subjects. IUD users show generally lower daily levels of hPRL than non-IUD users, but the apparent differences were statistically insignificant.

Ovarian endocrine function through five years of continuous treatment with NORPLANT subdermal contraceptive implants.

Ovarian endocrine function was assessed in 88 women using NORPLANT subdermal implants during different periods of use and in a control group of 15 women using non-hormonal contraception. Blood samples for estradiol (E2) and progesterone (P) assays were obtained twice a week for five consecutive weeks. Three distinct E2 patterns were observed: one was characterized by fluctuating levels within a normal range (20 to 400 pg/ml), a second pattern corresponded to continuous low E2 levels (below 75 pg/ml in the 10 samples) and the third was characterized by high broad estradiol peaks reaching over 400 pg/ml. The proportion of sampling runs characterized by normal fluctuating levels increased from 38% in the first two years of use to 80% during the fifth year of use. Low E2 profile was only observed during the first two years of use (27%) and in only 1 case at the beginning of the third year of use (5%). The percentage of cycles with high broad estradiol peaks remained between 20-40% without a clear tendency to change in either direction with duration of use. Thirty-three percent of the observed sampling runs had luteal activity (P above 3 ng/ml). The proportion of runs with luteal activity increased from 14% during the first two years of use to 40% during the third and fourth, and 60% during the fifth year of use. All control subjects had luteal activity. The mean highest progesterone level was lower in the NORPLANT runs (8.7 +/- 3.9 ng/ml) as compared to the controls (11.3 +/- 3.8 ng/ml). NORPLANT sampling runs with luteal activity had normal fluctuating E2 levels with only one exception. However, not all cycles with normal E2 levels showed luteal activity. On the other hand, all runs with low E2 levels or high broad E2 peaks were without luteal activity. In summary, women using continuous low-dose levonorgestrel contraception through NORPLANT subdermal implants, have a variable degree of ovarian activity as compared with the more complete depression of ovarian function observed among pill or injectables' users. Ovarian activity becomes closer to normal during the third through fifth year of use.

PIP: Ovarian endocrine function was assessed in 88 women using NORPLANT subdermal implants during different periods of use and in a control group of 15 women using non-hormonal contraception. Blood samples for estradiol (E) and progesterone (P) assays were obtained twice a week for 5 consecutive weeks. 3 distinct E patterns were observed; one was characterized by fluctuating levels within a normal range (20 to 400 pg/ml), a 2nd pattern corresponded to continuous low E levels (below 75 pg/ml in the 10 samples) and the 3rd was characterized by high broad estradiol peaks reaching over 400 pg/ml. The proportion of sampling runs characterized by normal fluctuating levels increased from 38% in the first 2 years of use to 80% during the 5th year of use. Low E profile was only observed during the first 2 years of use (27%) and in only 1 case at the beginning of the 3rd year of use (5%). The % of cycles with high broad estradiol peaks remained between 20-40% without a clear tendency to change in either direction with duration of use. 33% of the observed sampling runs had luteal activity (p 3 ng/ml). The proportion of runs with luteal activity increased from 14% during the first 2 years of use to 40% during the 3rd and 4th, and 60% during the 5th year of use. All control subjects had luteal activity. The mean highest progesterone level was lower in the NORPLANT runs (8.7 + or - 3.9 ng/ml) as compared to the controls (11.3 + or - 3.8 ng/ml). NORPLANT sampling runs with luteal activity had normal fluctuating E levels with only 1 exception. However, not all cycles with normal E levels showed luteal activity. On the other hand, all runs with low E levels or high broad E peaks were without luteal activity. In summary, women using continuous low-dose levonorgestrel contraception through NORPLANT subdermal implants, have a variable degree of ovarian activity as compared with the more complete depression of ovarian function observed among pill or injectables' users. Ovarian activity becomes closer to normal during the 3rd through 5th year of use. (Author's).

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg medroxyprogesterone acetate and 5 mg estradiol-cypionate: effects on cervical mucus.

The objectives of this study were to assess whether women who were administered the first injection of the once-a-month contraceptive containing estradiol cypionate and 25 mg depot-medroxyprogesterone acetate (MPA+E(2)C) on Day 7 of their menstrual cycle (delayed injection) exhibit the same degree of cervical mucus changes as women who receive it on Day 5 of their menstrual cycle. This was a multicenter, randomized, controlled clinical trial. A total of 158 women, aged between 18 and 38 years (inclusive), who, were willing to use MPA+E(2)C as their contraceptive method participated in the trial. Participants received a MPA+E(2)C injection on Day 5 (control group, n = 41) or Day 7 (delayed-injection group, n = 117) of their menstrual cycle. Participants who received MPA+E(2)C on Day 5 of their menstrual cycle (control group) exhibited fair or poor mucus quality and poor sperm penetration. Of those women who received MPA+E(2)C on Day 7 of their menstrual cycle (delayed-injection group), 3 (3%) showed good mucus or good sperm penetration at some time point during follow-up. It is possible to conclude that the first injection of MPA+E(2)C given on Day 7 of a menstrual cycle does not provide the same degree of inhibition of mucus quality and sperm penetration as that observed if it is administered on Day 5. However, the theoretical risk of pregnancy after receiving MPA+E(2)C on Day 7 would be expected to be low.

Contraception with long-acting subdermal implants. A five-year clinical trial with Silastic covered rod implants containing levonorgestrel. The International Committee for Contraception Research (ICCR) of the Population Council.

A total of 189 women volunteered to accept subdermal implants for contraception. The implants were "covered rods", consisting of a core rod containing equal parts by weight of levonorgestrel and polydimethylsiloxane and sealed inside a thin-walled tube of Silastic tubing with medical adhesive. In one study 78 women used 4 3cm rods (study 07) and in the other 111 women used 6 3cm rods. In 5 years of use there were no pregnancies in either group. Terminations because of menstrual problems were twice as frequent among the 4-rod users than among users of the 6 rods. Menstrual pattern analysis is presented for the two rod regimens and compared with the previously reported patterns for the 6-capsule regimen (NORPLANT). Long--term in vivo release rates are also presented.

Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies of a potential male contraceptive method, monthly depot medroxyprogesterone acetate and testosterone esters.

A potential male contraceptive approach was evaluated in clinical trials involving monthly injections of depot medroxyprogesterone acetate and either subdermal implants of testosterone propionate or monthly injections of testosterone enanthate. Pregnancies occurred in partners of 9 men with recent sperm counts of 10 million/ml or below. In 5 of the 9 instances, the sperm counts were less than 1 million/ml. It appears that male contraceptive methods involving spermatogenic suppression may require attainment and maintenance of azoospermia. The pregnancy rate cannot be calculated, because the extent of other contraceptive use is uncertain. There were no spontaneous abortions. 6 pregnancies were carried to term, and all progeny were normal, based on physical examination at birth or 3 months after birth.

PIP: A potential male contraceptive approach was evaluated in clinical trials involving monthly injections of depot medroxyprogesterone acetate and either subdermal implants of testosterone propionate or monthly injections of testosterone enanthate. Pregnancies occurred in partners of 9 men with recent sperm counts of 10 million/ml or below. In 5 of the 9 instances, the sperm counts were less than 2 million/ml. It appears that male contraceptive methods involving spermatogenic suppression may require attainment and maintenance of azoospermia. The pregnancy rate cannot be calculated because the extent of other contraceptive use is uncertain. There were no spontaneous abortions. 6 pregnancies were carried to term, and all progeny were normal, based on physical examination at birth or 3 months after.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. II-Subjective and objective measures of effects. An international comparative trial.

Comparative clinical trials of 2 sizes of contraceptive vaginal rings and of an oral contraceptive were undertaken at 8 investigational sites (9 clinics). More than 500 women enrolled on each of the 3 study regimens. Side effects of the rings and of Nordette, the oral contraceptive, were evaluated by noting spontaneous complaints, by recording medications taken and by physical examination. Inquiries about changes in the frequency of specific conditions were made at the end of the subjects participation in the first year of the study. The incidence of spontaneous complaints was similar among users of the 2 different-sized rings and of the pill.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. III-Menstrual patterns. An international comparative trial.

Menstrual events among users of contraceptive vaginal rings (CVRs), releasing levonorgestrel and estradiol, were studied in comparison with a combined oral contraceptive, Nordette, in multicentered trials. CVRs were made with outside diameters of 50 and 58 mm and released about 250 micrograms and 290 microgram of levonorgestrel and 150 microgram and 180 microgram of estradiol per day, respectively. The CVRs were used continuously for 3 weeks and then removed for 1 week. Both the CVRs and Nordette were perceived to reduce menstrual flow and days of menstrual bleeding. Twenty to 25% of CVR users perceived increased intermenstrual bleeding or spotting. Diaries indicate, however, that on average, CVR users experienced about 1 day per month of bleeding or spotting with the ring in place. CVRs and Nordette produced approximately the same total number of bleeding and spotting days during 6 cycles of use, 27-29, but the small (50-mm OD) ring was associated with somewhat more spotting. This ring was also associated with somewhat more prolonged bleeding and spotting runs and with more prolonged nonbleeding intervals than reported by users of the larger (58-mm OD) ring or of Nordette. Differences among regimens, however, tended to be small even when statistically significant. Evidence from menstrual diaries indicates that these CVRs, and in particular 58-mm ring, provide control over the menstrual cycle comparable to the Nordette.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. I-Use effectiveness. An international comparative trial.

PIP: Contraceptive vaginal rings (CVRs), with approximate daily release rates of 250-290 mcg of levonorgestrel and 150-180 mcg of estradiol and manufactured in a shell design, were studied for effectiveness and acceptability in multicentered trials involving 1103 ring users in Brazil, Chile, Dominican Republic, Sweden, U.S., Denmark/Finland, and Nigeria. A comparison group of 533 women used the oral contraceptive Nordette. Both 1st and all segment 1 year gross pregnancy rates among CVR users were less than 3/100, rates similar to Nordette users. Continuation at 1 year was 50/100 users of the ring (all segments) and 38/100 among Nordette users, more of whom were lost to follow-up. Gross 1 year rates of termination for medical reasons ranged from 25-29/100. Ring users were more likely to terminate for vaginal problems and pill users for headache, nausea, and associated reasons. These trials indicate that CVRs of this design are as effective and have continuation rates equal to and possibly superior to Nordette under the same study conditions.^ieng

Sperm migration at different stages of the menstrual cycle.

Sperm migration to the upper genital tract was studied in 15 volunteers who were to be surgically sterilized to see if sperm migration to the upper genital tract is consistent during different stages of the menstrual cycle. Five subjects underwent surgery during the midproliferative phase, five during the periovulatory period and five during the secretory phase. The stage of the cycle was determined by endometrial and ovarian biopsy at the time of surgery. Volunteers had a single coitus 5-12 h before surgery, confirmed by Sims-Huhner test. Sperm were found in the uterus and at least one oviduct in all five subjects studied during the periovulatory phase, and only in two of the five cases undergoing surgery during either of the other phases. A good correlation was also observed between presence and number of sperm in the upper genital tract and quality of Sims-Huhner test. However, neither the cycle stage nor the postcoital test had an absolute prognostic value over sperm migration.

Serum prolactin profiles of normal human conceptual cycles.

Commencing on day 10 of the menstrual cycle through onset of subsequent menses, or confirmation of pregnancy, daily sera collected from 15 women planning pregnancy were analyzed by radioimmunoassays (RIA) for prolactin (hPRL), estradiol-17 beta and luteinizing hormone (hLH). Two of the observed subjects became pregnant in the single cycles studied. The profiles of these hormones during the early gestation following spontaneous ovulation were established. No distinct midcycle peaks of hPRL were observed in either subject. Enormous spikes were observed in daily prolactin values, with wide variations between subjects.

PIP: Commencing on day 10 of the menstrual cycle through onset of subsequent menses, or confirmation of pregnancy, daily sera collected from 15 women planning pregnancy were analyzed by radioimmunoassays for prolactin (hPRL), estradiol-17beta, and luteinizing hormone (hLH). Two of the subjects became pregnant in the single cycles studied. The profiles of these hormones during the early gestation following spontaneous ovulation were established. No distinct midcycle peaks of hPRL were observed in either subject. Enormous spikes were observed in daily hPRL values, with wide variations between subjects.