Effects of d-norgestrel induced decreases in sex hormone binding globulin capacity on the d-norgestrel levels in plasma

The effect on the plasma sex hormone binding globulin capacity (SHBGc) and the relation between the plasma SHBGc and the plasma concentration of the synthetic (d-Ng) steroid has been studied in women treated with ovulation inhibiting doses of d-norgestrel and medroxyprogesterone acetate (MPA). The steroids were administered by means of steroid impregnated Silastic intravaginal rings (IVRs). In the women using d-Ng impregnated IVRs the SHBGc was depressed to subnormal levels. After treatment the SHBGc returned to normal within three weeks. A close correlation between the SHBGc and the d-Ng concentration was found when the dose of d-Ng delivered from the IVR was about 200 μg per day or more. Oral administration of 250, 500 and 1000 μg of d-Ng resulted in doubling of the plasma concentration d-Ng on doubling of the d-Ng dose. These results suggest that at a certain SHBG level, the plasma concentraition of d-Ng is dose dependent and that at a certain d-Ng dose level, the plasma concentration of d-Ng is SHBG dependent. No effect on the SHBGc and no correlation between the SHBGc and the MPA concentration was found in the women using IVRs impregnated with MPA. The results show that the decrease in SHBGc found in women on d-Ng is not due to anovulation or decreased estradiol levels in plasma.     

Contraceptive rings; self-administered treatment governed by bleeding

In an attempt to overcome bleeding problems and reduce the risk of ovulation during treatment, a new treatment schedule for contraceptive Silastic intravaginal rings (IVR) was studied in 16 women. The IVRs released about 300 μg of d-norgestrel (d-Ng) per day. They were used continuously and removed for five days only when bleeding occurred or after several days of spotting. A total treatment period of 2279 days was studied corresponding to 81 28-day cycles. After an initial peak, the height of which was correlated with the plasma sex hormone binding globulin capacity (SHBGc), the d-Ng concentrations in plasma decreased and stabilized at mean concentrations between 0.8 and 2.2 ng/ml. The mean d-Ng concentration correlated well with the body weight of the women. Follicular activity was depressed during treatment as judged by plasma estradiol concentrations and no ovulations occurred. Four women were amenorrheic for treatment periods between 101 and 197 days. In most of the other women the incidence of bleeding and spotting was less than would have been expected during a comparable period without treatment. Systemic side effects in the form of aggressiveness, weight gain, acne and headache were noted by some of the subjects. No local side effects were obsered and no pregnancy occurred.     

The effect of progestin R 2323 released from vaginal rings on ovarian function.

The effect of progestin R 2323 released from intravaginal rings (IVR) on ovarian function was studied in 20 young healthy volunteers. The silastic IVRs containing 10, 20, 50, or 200 mg of progestin R 2323 were inserted on the 1st day after menstrual bleeding and removed 21 days after insertion. The IVRs were tolerated well without irritation or alteration of the vaginal mucosa. Control plasma estradiol and progesterone levels revealed 18 of 20 cycles were ovulatory. No ovulation was observed during treatment, as revealed by consistently suppressed progesterone levels. Normal ovulation resumed after removal of the rings. 3 women experienced withdrawal bleeding; 9 had breakthrough bleeding and 13 had a normal postovulatory bleeding 15-33 days after ring removal. It was concluded that the bleeding control was unsatisfactory with every dosage of R 2323 used in this study.     

Plasma levels of d-norgestrel and ovarian function in women using intravaginal rings impregnated with dl-norgestrel for several cycles

Silicone polymer intravaginal rings (IVR) of a new “shell” design were used in the present study. The steroid containing part of the rings was impregnated with different amounts of dl-norgestrel. The rings were designed to give two different release rates. Forty-one treatment cycles were studied. The mean plasma level of d-norgestrel, as measured by radioimmunoassay, varied between 2.6 and 0.3 ng/ml. The highest levels were found during the first treatment cycle and declined thereafter. No correlation could be found between the plasma levels of d-norgestrel and the release of d-norgestrel from the rings.Signs of ovulation occurred in 6 (15 %) and breakthrough bleeding or spotting was encountered in 26 (63 %) of the cycles. Breakthrough bleeding and spotting was a constant finding in cycles with a mean plasma level of d-norgestrel below 1.1 ng/ml but never appeared in cycles with a mean level above 1.7 ng/ml. No effects on vaginal flora or the vaginal smear were found.Although the high frequency of bleeding irregularities casts doubt on the acceptability of the IVRs used in this study as a contraceptive method, the study has shown that it is possible to design IVRs capable of releasing dl-norgestrel for several consecutive cycles at fairly constant rates and in amounts sufficient to inhibit ovulation.     

Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women

The release of contraceptive steroids through different drug delivery systems into serum and breast milk was investigated in a group of lactating women. Four women in each group were taking either a low dosage progestogen compound like norethisterone (NET) 350 μg or d-norgestrel (d-Ng) 50 μg alone or low dosage combination pills containing NET 1 mg or d-Ng 150 μg with 30 μg ethinyl estradiol (EE₂) or a biodegradable implant containing 25 mg NET or d-Ng. Peak levels in plasma and milk were seen in oral contraceptive users around 2 hours. Of the two low dosage progestogen compounds, d-Ng was below the detection limit in milk within 4 hours whereas NET was still detectable at the 24-hour interval. In contrast to this, because of the larger quantity of steroids in the combination pills, the NET/d-Ng levels in serum as well as in milk were high throughout the 24-hour period. With the subdermal route because of the sustained low release of the drug from the biodegradable implants, the levels in milk were below the detection limit within a day with d-Ng and within a week with NET.     

Plasma levels of d-norgestrel and sex hormone binding globulin during oral d-norgestrel medication immediately after delivery and legal abortion

To investigate the concentration of d-Norgestrel (d-Ng) in plasma when d-Ng is administered to women with physiologically high concentration of Sex Hormone Binding Globulin (SHBG), 30 μg d-Ng tablets were given daily starting 0–1 day after delivery or abortion. During the first 3–4 days of treatment d-Ng increased to levels 6–8 times higher than found during the same medication to women not recently pregnant. Thereafter, the d-Ng concentration in plasma decreased despite continuous medication in parallel with decreasing levels of SHBG until SHBG reached its normal level after 2–4 weeks. The decrease rate for SHBG after delivery or abortion corresponded to a half life of about nine days.The results indicate an $\text{in vivo}$ binding of d-Ng to SHBG and a SHBG influence on the metabolic clearance rate of d-Ng. The $\text{in vivo}$ binding of d-Ng to SHBG may have importance in hormonal contraception during lactation.     

Levels of contraceptive steroids in breast milk and plasma of lactating women

Hormonal contraceptives have been used in breast feeding women by many clinicians. However, secretion of these drugs in the breast milk has not been adequately investigated. In the present study, radioimmunoassay methods were used for estimating the contraceptive drug levels in breast milk and plasma samples. In 7 lactating women, after the injection of 150 mg medroxyprogesterone acetate = MPA (Depo-Provera), MPA levels in breast milk were similar to plasma; the ratio being almost 1: 1 throughout the study period (up to 87 days). In a group of women using oral pills (2 women took a combination pill containing 150 μg d-norgestrel (d-Ng) and 30 μg ethinylestradiol, another 5 women took progestogen-only pills containi 350 μg norethisterone (NET)), the levels of d-Ng and NET in breast milk were about 1/10th or less than those found in plasma.     

Initial clinical studies of intravaginal rings containing norethindrone and norgestrel.

29 volunteer subjects aged 21-40 with regular menstrual cycles were given intravaginal rings (IVRs) made of polysiloxane containing various doses of norethindrone and norgestrel. All pretreatment cycles and posttreatment recovery cycles were ovulatory, except 1. Out of a total of 193 treatment cycles patient acceptance was good with normal vaginal mucosa. When IVRs with 100 and 200 mg norethindrone were in place there was a high incidence of bleeding, an offensive odor, and ovulation occurred in 1/4 of treatment cycles. 50 and 100 mg norgestrel IVRs caused a lower incidence of bleeding and ovulation, but a previous study with similar rings containing medroxyprogesterone acetate (MPA) produced more favorable results. Further clinical trials with MPA are under way, and it is planned to make polysiloxane devices of different design with norgestrel as well as other C-19-nor-testosterone gestagens.     

Clinical assessment of subdermal implants of megestrol acetate, d-norgestrel, and norethindrone as a longterm contraceptive in women

Megestrol acetate (MA), d-norgestrel (d-Ng), and norethindrone (NET) contained in Silastic capsules were implanted under the skin for clinical evaluation as a longterm contraceptive in women. 1509 woman-months of exposure and 4 pregnancies were recorded within the first twelve months of use in 135 women who received 6 MA implants. 1049 woman-months and 19 pregnancies were recorded within the first twelve months of use in 131 women who received 4 d-Ng implants. After twelve months use, the implants were replaced with a new set of capsules. The contraceptive effectiveness of the second and subsequent set of implants was similar to that of the first. Five NET implants failed completely to prevent pregnancy and 4 MA implants combined with 2 d-Ng implants were as effective as 6 MA implants. Other doses tested were: 5 MA, 3 d-Ng, and 4 MA plus 1 d-Ng. They were significantly less effective than the higher doses. No adverse effect upon the outcome of unplanned pregnancies was noted and prompt recovery of fertility was observed after termination of treatment. Ovulation took place in most cycles of women treated with 5 or 6 MA implants, as judged from the occurrence of LH peak in urine, pregnanediol excretion, changes of cervical mucus, BBT, and endometrial biopsy. Intermenstrual bleeding was by far the most common side effect recorded. Initially, it occurred in about 30 % of the cycles, but the incidence decreased gradually and by the end of the second year, it was below 10 %. Adnexal complications were observed in some of the treatment groups.     

Intracervical release of levonorgestrel for contraception

Twenty-one women used a levonorgestrel-releasing intracervical contraceptive device, which was designed to release 20 μ/day. The devices were inserted after cessation of menstrual bleeding. Patterns of bleeding and clinical performance were evaluated and plasma concentrations of levonorgestrel, estradiol and progesterone in selected subjects were measured by radioimmunoassay. The results of the initial 90-day treatment are presented. Levonorgestrel was detected in peripheral plasma by 30 minutes after insertion of the device. Considerable variation of plasma levonorgestrel concentrations was observed between subjects, but within each subject, the plasma level of levonorgestrel was very stable with time. Of 24 cycles monitored by blood sampling, 19 were ovulatory. One subject did not ovulate at all. During the first 30-day period of treatment, frequent intermenstrual bleeding or spotting periods occurred. Two spontaneous expulsions occurred 9 and 22 days after insertion. Both of these subjects were nulligravidas. Side-effects were few and no pregnancies occurred during the study period.     

Plasma concentrations of ethinylestradiol and d-norgestrel during two immediate postabortal oral contraceptive cycles

Three voluntary women started a microdose, combined oral contraception (30 μg of EE₂ and 150 μg of d-Ng) within ten hours after an induced abortion on week 8–10 of gestation. Plasma samples were taken during the next two cycles. Samples were taken more frequently during the first 12 hours after intake of the first pill of the two cycles. Plasma concentrations of EE₂ and d-Ng were determined by RIA.Peak concentrations of EE₂ were achieved in plasma 75–120 min after ingestion of the pill. Considerable individual variation in peak concentrations was seen (60–160 pg/ml). Plasma concentrations 12 hours after pill intake remained relatively constant throughout each cycle (range 60–120 pg/ml). Profiles during the first and second treatment cycle were essentially identical.Peak concentrations of plasma d-Ng were achieved within 3–4 hours after the first pill intake. These were about two times higher during the first cycles (2.7–4.2 ng/ml) than during the second cycle (1.25–2.5 ng/ml). Plasma concentrations of d-Ng 12 hours after pill intake were higher during the first cycle. In two subjects d-Ng concentrations increased towards the end of the cycle. In these same two subjects plasma concentrations were equally high at the end of the cycle.Judging by plasma concentrations of EE₂, it appears that the preceding pregnancy has little if any effect on the metabolism of EE₂ when contraception is begun immediately after abortion.The preceding pregnancy initially causes higher plasma d-Ng concentrations than those seen during cycles not preceded by pregnancy. This is due to the increased binding capacity of sex hormone binding globulin to bind d-Ng. This is, however, transient and disappears before the next cyc1e.     

The effect of weekly administration of an oral progestogen -R 2323- on the ovarian function.

An oral progestogen - R 2323 - was given in the dose of 10 mg as a weekly contraceptive pill. The effect on the ovarian function was followed by measuring the plasma levels of progesterone and estradiol. Seventeen cycles were studied and, in three of these, ovulation occurred. In all other cycles, progesterone and estradiol were depressed to early follicular phase levels. Intermenstrual bleeding or spotting was noticed in all cycles except the ovulatory ones. It is concluded that R 2323 in this dosage probably gives a better contraceptive effect than lower dosages. The occurrence of intermenstrual bleeding and spotting seems to be related to the timing of drug intake.     

Postovulatory contraception in women with large doses of norethindrone

The postovulatory administration of large doses of norethindrone to women has previously been shown to drastically reduce the peripheral plasma levels of progesterone. In 10 treatment cycles, compared to 10 control cycles from the same women, this effect was confirmed and a similar effect upon the peripheral plasma levels of estradiol was found. The contraceptive efficacy of this treatment was tested. Eighty volunteers were treated during 301 cycles. Eighty per cent of the women had been pregnant before. The plasma levels of progesterone and estradiol were determined before and after treatment in each cycle. A very sensitive test for the detection in serum of human chorionic gonadotrophin (HCG) was included. A total dose of 200 mg of norethindrone was used in two different schedules (100 mg daily on day 21–22 and 50 mg daily on day 19–22). Twenty-two pregnancies occurred, but in 4 of these women, the only indication of pregnancy was the detection of HCG. Two women did not take the tablets according to schedule, leaving 16 patients who had to be aborted therapeutically. At least 70 per cent of the cycles were found to be ovulatory. Control of vaginal bleeding was good and only minor side effects occurred. The treatment possibly reduced fertility in this group of women but the contraceptive efficacy was obviously too low to merit further use of the present dose and schedules.     

Contraception with a norethisterone-releasing IUD. Plasma levels of norethisterone and its influence on the ovarian function

Five healthy women had a norethindrone (NET)-releasing intrauterine device inserted postmenstrually. During a treatment time ranging between 80 and 114 days, plasma concentrations of NET, estradiol, and progesterone were determined by radioimmunoassay. Initial high plasma concentrations of NET were followed by fairly constant levels between 200 pg/ml and 400 pg/ml. Ovulation occurred regularly during nine out of sixteen studied treatment cycles, four cycles were anovulatory and three cycles showed a suppressed luteal phase. High estradiol peaks in plasma were seen at the time of disturbed ovulation. The bleeding pattern was regular and the menstrual bleeding was reduced in amount.     

Contraception with megestrol acetate implants. Megestrol acetate levels in plasma and the influence on the ovarian function

The ovarian steroid pattern and the levels of megestrol acetate in plasma were assessed in 4 women after the insertion of six silastic capsules filled with approximately 35 mg megestrol acetate. The implants were inserted subcutaneously in the ventral part of the left forearm and left in place for 121–226 days.

Judged by the plasma progesterone pattern, no ovulation occurred during treatment, but ovulatory patterns of estradiol and progesterone were restored within 30 days after removal of the capsules.

The estradiol levels in plasma varied. Development of follicles as judged from surges of estradiol was evident in two of the subjects throughout the study.

Frequent and prolonged episodes of spotting and bleeding were found in all subjects during treatment, especially when low plasma levels of estradiol were observed.

A release of approximately 300 μg MA gives a plasma level of around 0.6 ng MA/ml and is sufficient to inhibit ovulation, probably by inhibition of the positive feedback of estradiol on the release of LH.     

Patterns of ovulation and bleeding with a low levonorgestrel-releasing intrauterine device

Patterns of bleeding and plasma concentrations of levonorgestrel, progesterone, estradiol, LH and FSH were studied in ten volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. The IUD was designed to release 12 microgram/day. All but two of the volunteers ovulated during treatment. The ovulatory cycles differed from the control cycles by being longer and by having depressed plasma progesterone levels during the luteal phases. Intermenstrual spottings occurred frequently during the first sixty days of treatment. No pregnancies occurred during the course of the study.     

Bleeding and ovulation control with use of a small contraceptive vaginal ring releasing levonorgestrel and estradiol.

Levonorgestrel and estradiol releasing contraceptive vaginal rings (CVR) with an outer diameter of 50 mm were used by twenty women. The treatment was given in three-week cycles followed by one treatment-free week. The treatment was planned to cover six cycles. All subjects kept records of bleeding and were controlled clinically in the course of treatment. Three subjects were followed by blood sampling. Plasma levonorgestrel, estradiol, progesterone and gonadotropins were determined. The subjects experienced no difficulties in using the CVR and 90 per cent continued the treatment through the whole experimental period of six months. One subject discontinued after three cycles because of irregular bleedings and one subject after five cycles because of urinary discomfort. Regular bleedings were observed only in three subjects and in nine cases the bleeding started with the CVR in situ during the last days of the three-week treatment period. Breakthrough bleeding occurred in the remaining eight subjects. The subjective side-effects were as follows: weight gain in four subjects, oedema in one subject and urinary discomfort in one subject. Pituitary function was not generally suppressed as judged by plasma gonadotropins. Out of the three subjects studied, two experienced ovulatory plasma progesterone concentrations.     

Pituitary and gonadal function during the use of norgestrel-estradiol vaginal rings

Four women used polysiloxane contraceptive rings (CVR) impregnated with d-Norgestrel and estradiol for contraceptive purposes. The treatment was given in three-week cycles, leaving one treatment-free week between the cycles. Subjects were followed by blood sampling twice a week for three or four treatment cycles. Plasma concentrations of d-Norgestrel, estradiol, progesterone, and gonadotropins were determined by radioimmunoassay.The bleeding patterns were very acceptable. One subject experienced acne and weight gain, but no other side-effects were observed. Furthermore, no local irritation was found during the follow-up period of six or seven months.The individual variation in the mean plasma concentrations of d-norgestrel was between 3.2 and 1.1 ng/ml. Apart from one case, the highest individual levels were observed at the beginning of the first treatment cycle. Plasma estradiol was low during the treatment, but in some cases low post-insertion peaks were observed. No ovulatory progesterone values were found.Plasma LH was generally suppressed, but FSH was not. During the treatment-free week increasing concentrations of both LH and FSH were found, indicating an activation of pituitary function.     

Intracervical release of ST-1435 for contraception

Seven women used an ST-1435-releasing intracervical contraceptive device (ST-ICD), inserted immediately after the cessation of menstrual bleeding. Patterns of bleeding and clinical performance were evaluated and plasma concentrations of ST-1435, estradiol, progesterone and gonadotropins were measured by radioimmunoassays. The results of ten months of treatment are presented. There were no uniform patterns of bleeding. No hormonal side-effects were registered. The plasma concentration of ST-1435 reached 100 pg/ml within two hours after insertion of an ST-ICD. No ovulations occurred during the initial three months of treatment. A rapid decline in the plasma concentrations of ST-1435 was observed; during the tenth month the concentration of ST-1435 was under the sensitivity of the radioimmunoassay of ST-1435. Hence, the release of ST-1435 from Silastic was too rapid for long-acting contraceptive purposes.