Sex hormone binding globulin: the carrier protein for d-norgestrel.

The binding of different synthetic steroids, used in hormonal contraception, to Sex Hormone Binding Globulin (SHBG) was studied by measuring their ability to displace tritiated testosterone from SHBG in a competitive protein binding system. Only 19-nortestosterone derivates had any significant ability to displace testosterone from SHBG, d-norgestrel (d-Ng) being the strongest displacer. Increasing the SHBG levels in women with previous constant plasma d-Ng levels increased these levels two- to sixfold. It is concluded that SHBG is the main carrier protein for d-Ng. The strong testosterone displacing activity of d-Ng might also explain androgenic side effects observed with d-Ng containig oral contraceptives.

Vaginal progesterone for contraception.

Silastic vaginal rings impregnated with progesterone (P) or progesterone and estradiol (E) were used in nine women for thirty 21-day cycles to study the effect on ovarian function. The average daily rates of release of P and E from the rings were 2.2 mg/day and 220 microgram/day, respectively. In anovulatory treatment cycles the mean plasma level of P was 0.9 ng/ml. E levels fluctuated in the range seen in normally cycling women due to endogenous E production. In a menopausal woman the E levels increased to 50 to 100 pg/ml during treatment and FSH levels declined. Ovulation occurred in 18 (60%) of the treated cycles, and resulted in one pregnancy. Although the results rule out the use of these rings for contraceptive purposes, they indicate that at higher dosages the Silastic vaginal ring offers a mode of administration of natural steroids to be used in hormonal contraception.

PIP: This study was conducted to determine whether a relatively low dose of P (progesterone) alone or in combination with estradiol (E) administered from silastic vaginal rings would suppress ovulation, thus providing a safe contraceptive form women. 9 healthy fertile women with regular menstrual cycles were studied for a total of 30 21-day cycles. 4 women used a ring with a P dose while the other 4 used the combination ring. 1 65 year old menopausal woman used both types of ring for 2 weeks. Venous blood samples were collected 2-3 times a week from the subjects and were analyzed for E, P, and FSH levels using radioimmunoassay and radioimmunosorbent technique. The average daily rate of release for P from the rings was 2.2 mg/day and 220 ug/day for E. Mean plasma level of P in anovulatory treatment cycle was 0.9 ng/ml. E levels fluctuated in the range seen in normal women because of endogenous E production. The E levels for the menopausal woman increased from 50 to 100 pg/ml during treatment. Ovulation was observed in 18 (60%) of the treated cycles, resulting in 1 pregnancy. The pregnancy which occurred in this series suggests that P does not provide the 'local' protective effect of synthetic gestagens used in low dose gestagen contraceptive pills. However, the pregnancy may also be attributed to the passage of spermatozoa 7 days after the ring was removed. Further studies should be done on P-releasing contraceptive rings.

Observations on the antigenicity and clinical effects of a candidate antipregnancy vaccine: beta-subunit of human chorionic gonadotropin linked to tetanus toxoid.

Observations on the antibody response and clinical effects of injection of purified beta-subunit of human chorionic gonadotropin covalently linked to tetanous toxoid were made in 15 healthy young women who had previously undergone tubal ligation. Antibodies detectable by radioimmunoassay were found in 14 of the women. Clinical surveillance and immunologic, hematologic, and biochemical tests indicated excellent local and systemic tolerance to the antigen. No significant adverse effects on menstrual function, endocrine status, or health were found.

PIP: A vaccine for pregnancy prevention made of purified beta-subunit of human chorionic gonadotropin (hCG) covalently linked to tetanous toxoid was tested in 15 healthy women who had previously undergone tubal ligation. The objectives of the trial described were to 1) evaluate the magnitude, constancy, and duration of the antibody response; 2) to determine whether immunization gave any evidence of toxicity or unwanted side reactions; 3) to determine whether the antibodies neutralized the biologic activity of hCG in vitro and in vivo test systems; and 4) to examine the cross-reactions between the antibodies and other glycoprotein hormones. This was a multicentered clinical trial with 1 clinic each in Sweden, Finland, Chile, and Brazil participating. 14 of 15 women had antibodies detectable by radioimmunoassay, the longest response lasting 400 days after injection. Duration of response to hCG antibody varied among participants. Clinical and immunological, hematological, and biochemical surveillance of the study participants lasted over 2 years, and during that time no significant signs of local or systemic intolerance to the vaccine were noted. Menstrual and endocrine changes were evaluated, and, aside from 1 case of 120-day amenorrhea postinjection, menstrual and endocrine changes were judged insignificant or unrelated to the vaccine. Body weight increase was the single greatest complaint among the women involved, followed by breast and andexal tenderness, and in a few cases colostrum development. In vitro, antisera were capable of neutralizing the activity of hCG in stimulating testosterone production in Leydig cell cultures.

The return of the pharmaceutical industry to the market of contraception.

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.

Pharmacokinetics and pharmacodynamic effects of vaginal oestradiol administration from silastic rings in post-menopausal women.

Silastic rings releasing approximately 200 microgram of 17beta-oestradiol per day were inserted into the vaginas of 4 post-menopausal women for one to three 21-day periods. Plasma concentrations of oestrone and oestradiol were analysed by radioimmunoassay. The effect of circulating oestrogens on FSH, LH and sex-hormone binding globulin (SHBG) levels as the well as on the endometrium was studied. During the first 24 h of treatment the plasma oestradiol levels were higher than the oestrone levels. But during the following days of the 21-day periods, the levels of the two oestrogens were almost equal, varying between about 100 and 200 pg/ml plasma, a pattern similar to that seen in fertile women. the release of oestradiol from the ring gave stable plasma oestrogen levels. The FSH and LH levels were clearly depressed while the SHBG levels did not change. Characteristics of oestrogen influence were found in endometrial biopsies. The rings were well accepted and could be inserted and removed easily by the women. Absorption of oestradiol from the vagina is good and more complete than after oral administration allowing lower doses to be used for treatment.

Plasma levels of medroxyprogesterone acetate (MPA), estradiol and progesterone in the rhesus monkey after intramuscular adminstration of Depo-Provera.

PIP: Plasma levels of medroxyprogesterone acetate (MPA), estradiol, and p rogesterone in the rhesus monkey after im administration of Depo-Provera were studied. An injection of 150 mg MPA resulted in initially high blood levels of MPA until 3 weeks postinjection in 4 mature cycling monkeys. MPA levels were below .5 ng/ml 70, 83, 90, and 150 days postinjection. Ovulatory rises of progesterone were detected 101, 113, 123, and 233 days postinjection. A parallel study revealed that the same dose of MPA as used in humans (150 mg) resulted in similar peripheral concentrations and durations in the monkeys as in women. A significant (p less than .001) rise in estrogen levels was found at the end of the experiment. It is concluded that the patterns of plasma MPA, estradiol, and progesterone concentrations in the rhesus monkey appear to be related to each other in a similar manner as in women, however, MPA metabolism in the monkey appears to be faster than in women.^ieng

Megestrol acetate concentrations in plasma and milk during administration of an oral contraceptive containing 4 mg megestrol acetate to nursing women.

PIP: An oral contraceptive containing 4 mg megestrol acetate + 50 mcg ethinyl estradiol was given to 5 fully lactating and nursing women, starting 2 months postpartum. Milk and blood samples were collected simultaneously to allow a comparison between plasma and milk levels of megestrol acetate. Megestrol acetate was estimated by radioimmunoassay. The plasma:milk ratio of megestrol acetate was found to be 100:80. About 2 mcg of megestrol acetate was calculated by be transferred with 600 ml of milk/day corresponding to about .1% of the given dose to the mother.^ieng

Plasma levels of norethindrone and effect upon ovarian function during treatment with silastic implants containing norethindrone.

The study was made to evaluate the effect upon the ovarian steroid pattern during treatment with subcutaneously implanted silastic rods containing norethindrone. Four rods, each containing 37 mg norethindrone (NET), were implanted subcutaneously in five women and left in place for 135--200 days. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. After an initial peak found in all subjects, the plasma level of NET declined. Great day-to-day variations of NET were found. Ovulations were suppressed during treatment in three subjects. One subject had regular ovulations throughout treatment and in one subject a single ovulation was recorded. Peaks of estradiol without subsequent ovulation were found in two subjects. The bleeding pattern was irregular; three subjects had varying degrees of spotting and bleeding, two subjects were amenorrheic. The average daily release rate was 300/micrograms, calculated from the amount of steroids lost from the removed rods. This study indicates that the release of steroid from four NET rods is high enough only initially to completely inhibit ovulation.

Effects of Epostane on progesterone synthesis in early human pregnancy.

Healthy women requiring abortion in early normal pregnancy were recruited to study the abortifacient effects of different doses of Epostane, an inhibitor of 3 beta-hydroxy steroid dehydrogenase, that previously has been shown to interfere with progesterone production in the luteal phase of humans and to have abortifacient effects in animals. A single dose of 100 mg resulted in decreasing progesterone and estradiol, which rapidly recovered, and none of the women started to bleed. Repeated doses of 50 or 100 mg during one day resulted in a more pronounced decrease in both progesterone and estradiol, but no bleeding. When treatment was prolonged over several days with 100 mg X 4 for five days and 400 mg X 2 for four days, respectively, a suppression of progesterone and estradiol was found and two out of four and eight out of ten women started to bleed and subsequently aborted. The treatment was well tolerated by most of the women. Routine laboratory parameters remained unaltered throughout treatment. Cortisol levels remained within the normal range.

Inhibition of the positive feedback of oestradiol during treatment with subcutaneous implants of d-norgestrel.

PIP: The effects of d-norgestrel (40 mg), contained in a single dimethylp olysiloxane rod implanted subcutaneously in the gluteal region, were studied in 4 women. The rods were left in place for 93-128 days. Based on the pattern of plasma progesterone levels; all of the subjects appeared to ovulate. However, the inhibition of the positive feedback effects of natural estrogens indicated that ovulation was suppressed. There was no increase in plasma progesterone concentrations over the 3-4 month treatment period. Plasma estradiol concentrations fluctuated irregularly and showed surges characteristic of the midcycle peak. Plasma gonadotropin levels fluctuated periodically, though midcycle peaks of luteinizing hormone (LH) and follicle stimulating hormone (FSH) did not occur. FSH and LH concentrations were low when estradiol concentrations were high, and vice versa. Plasma concentrations of the hormone were similar to those found during the 1st 6-8 hours after ingestion of low-dose d-norgestrel. All the subjects had unpredictable bleeding patterns during treatment.^ieng

The contraceptive efficacy of 10mg or 25mg of norethindrone given orally on day 15-22 of the human menstrual cycle.

PIP: 25 mg or 10 mg norethindrone (NET) were administered on Day 15-22 of the menstrual cycle. 71 women participated during 319 cycles in the 25 mg group and 59 participated during 381 cycles in the 10 mg group. About 75% of the women had been pregnant before. Before each cycle treatment, plasma progesterone (P) and estradiol (E) were determined. 5 ng/ml or more of 5 NG/ML OR MORE OF P was regarded as postovulatory. 1.2-4.9 ng/ml P with a concommittant E level of 100 pg/ml were regarded as periovulatory. In the 25 mg group, of 87 blood samples from Day 15, 10.3% had postovulatory P levels, while 23% had periovulatory levels of P and E. Corresponding frequencies for 81 samples in the 10 mg group were 11.1% and 18.5% respectively. 17 pregnancies occurred (Pearls index of 29), 7 in the 25 mg group and 10 in the 10 mg group. 2 of the 10 in the mg group were tubal pregnancies. The early development of the remaining 15 pregnancies was normal, as judged by the absence of vaginal bleeding, normal P levels and normal histology of the fetal tissue after curettage. The NET contraceptive efficacy of this dose schedule is too low to merit clinical use.^ieng

Plasma levels of estrogens during long-term treatment with depo-medroxyprogesterone acetate as a contraceptive agent.

PIP: To determine the levels of endogenous immunoreactive estrogens in women taking medroxyprogesterone as a contraceptive agent, 20 healthy parous women who had received intramuscular injections of 150 mg of medroxyprogesterone acetate every 12th week for 18 months, were studied by radioimmunoassay of blood samples taken between contraceptive injections. Plasma estrogen was found to rise significantly at the end of each 12-week injection period (p less than .01), indicating continuation of cyclic ovarian activity despite the medroxyprogesterone, which apparently does not accumulate in the body. The ratio of estradiol to estrone content in 10 samples studied was about 2:1, which is normal. All of the estrogen determinations made within the 12-week period were within the normal range of levels expected to be found in normal women in the early follicular phase of their menstrual cycle. No sign of an estrogen lack was found in any of the patients.^ieng

Postovulatory contraception in women with large doses of norethindrone.

PIP: To test the contraceptive efficacy of norethindrone (NET), the effect of NET on peripheral plasma levels of progesterone and estradiol after ovulation was investigated, since low levels of ovarian steroids might affect the postovulatory endometrium and thereby impair normal blastocyst implantation. Two studies were conducted: 1) to test NET effect on progesterone and estradiol levels, and 2) to test NET contraceptive efficacy and side effects. Daily blood samples of the 10 volunteers under treatment with various doses (5-100 mg) of NET revealed that plasma levels of the 2 steroids were drastically reduced. In the second study, 80 volunteers were followed through 301 menstrual cycles. A total oral dose of 200 mg of NET was used in 2 different postovulatory schedules. 70% of the cycles were ovulatory; control of vaginal bleeding was good; side effects were minor. 22 pregnancies resulted, which is lower than the average number of expected pregnancies from unprotected coitus for that group of women. Despite this mild contraceptive effect, the efficacy of NET is hardly sufficient using this experimental model. The NET treatment does appear contraceptively effective if administered before implantation, and further research with a different experimental design is indicated.^ieng

Plasma protein binding of norethisterone.

Norethisterone (NET) is transported in the blood stream bound to plasma proteins. It is generally believed that only the part of the hormone that is not bound to plasma proteins can exert biological activity. NET binds to albumin and, like other 19-nortestosterone derived progestins, it also binds to sex hormone binding globulin (SHBG). The binding of NET to SHBG was studied in five women during a 21-day treatment cycle with an oral contraceptive containing 3 mg NET-acetate and 50 microgram ethinylestradiol. The total and SHBG-bound concentrations of NET increased in parallel with SHBG during treatment. The fraction not bound to SHBG and the free fraction of NET increased proportionately less, indicating that the total concentrations of NET measured by radioimmunoassay only in part reflect the biologically active fraction of the steroid.

17 beta-estradiol levels in blood and cerebrospinal fluid after ocular and nasal administration in women and female rhesus monkeys (Macaca mulatta).

17 beta-estradiol was applied ocularly to menstruating and postmenopausal women. The absorption by blood was measured. A rapid increase of both estradiol and estrone was seen with higher plasma levels in the menstruating group, possibly due to a better conjunctival circulation. Twenty-one rhesus monkeys were given estradiol suspension or solution ocularly or nasally. The absorption by blood and cerebrospinal fluid was measured and compared to intravenous injection of 0.5 mg estradiol. Estradiol increased in plasma after 1'. Maxima were reached at 15'. Estradiol solution gave higher plasma levels than estradiol suspension. At 5' they amounted to the levels found after i.v. injection. The estradiol levels in cerebrospinal fluid never exceeded the corresponding plasma levels and were generally low. The increase in cerebrospinal fluid was thought to be secondary to the raised plasma levels.

PIP: The present investigations studied the uptake of 17 beta-estradiol by blood and cerebrospinal fluid (CSF) after ocular and nasal application. For ocular administration, female human volunteers received 50 mcl of a .5% suspension in the lower conjunctival sac of each eye and monkeys were dosed with the same procedure. For nasal application, 100 mcl of a .5% suspension (n=10) or 50 mcl of a 5% suspension (n=5) was placed in the nasal cavity via polyethylene tubes, or .5-mg estradiol of a .5% solution was sprayed in 1 nostril (n=3). .5 mg intravenous administration was also employed. The female volunteers were either menstruating or post menopausal. In the menstruating group, a rapid increase of both estradiol and estrone was seen and higher plasma levels were found, possibly due to better conjunctival circulation. 21 rhesus monkeys were dosed either ocularly or nasally and the absorption by blood and CSF was measured and compared with the intravenous injection. Estradiol increased in plasma after 1 minute. Maximum values were reached in 15 minutes. The estradiol solution gave higher plasma levels than the suspension. At 5 minutes, these levels amounted to the levels found after intravenous injection. Estradiol levels in the CSF never exceeded the corresponding plasma levels and were generally low. Any increase in CSF was assumed to be secondary to the raised plasma levels.

Contraception with NORPLANT implants and NORPLANT-2 implants (two covered rods). Results from a comparative clinical study in Sweden.

Two-hundred-and-forty healthy women, ages 18 to 40 years, were randomized in a ratio of 2:5 to use NORPLANT implants or NORPLANT-2 implants. Through three years of use, no pregnancies were recorded among women using NORPLANT implants and two pregnancies were noted among women using NORPLANT-2 implants resulting in a cumulative net pregnancy rate of 1.3 +/- 0.9 per 100 acceptors (mean +/- SE) by the end of year three. This difference was not statistically significant. During the fourth year, no pregnancies were observed in the NORPLANT group, but 4 pregnancies occurred in the NORPLANT-2 group. The most common reason for terminating the study was bleeding disturbances. During the first year there were significantly more terminations due to bleeding problems in the NORPLANT group than in the NORPLANT-2 group. However, during the second year of use the proportion of women discontinuing for bleeding problems dropped considerably among NORPLANT users and during the third year very few women in either group discontinued because of bleeding problems. The continuation rates after one year were for NORPLANT users 59.4% and for NORPLANT-2 users 77.2%. Corresponding figures after three years of use were 46.1% and 51.7%, respectively. The second most common reason for discontinuation was depression and other mood changes. In both groups we noted a slight increase in weight during the study and a slight decrease in blood pressure and hemoglobin levels with time. In conclusion, both NORPLANT and NORPLANT-2 implants are very effective methods for contraception. The efficacy of NORPLANT-2 implants, however, was not acceptable during the fourth year of use in this study. The latter system could, however, become a suitable three-year contraceptive method, possibly with less bleeding disturbances than NORPLANT in the first year.

Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT-2).

Plasma levels of levonorgestrel, sex hormone binding globulin (SHBG) and estradiol were studied during four years in 283 healthy women using either NORPLANT implants or two covered rods (NORPLANT-2). The women were randomized to use either type of implant. Both implant systems have previously been shown to have similar release rates of levonorgestrel. In both groups plasma levels of levonorgestrel decreased throughout the study, and there were no statistically significant differences between the two groups in mean plasma levels of levonorgestrel. During the study 8 women became pregnant. All pregnancies but one occurred after 35 months of implant use and only in women using the covered rods. No significant differences were seen between the women who became pregnant and the rest of the group using two covered rods with respect to plasma levels of levonorgestrel. SHBG capacity tended to be somewhat higher in women using the two covered rods. As levonorgestrel is to a great extent bound to SHBG, and in that form not biologically active, a "free levonorgestrel index" was calculated as a ratio between levonorgestrel and SHBG. This index was significantly lower in users of two covered rods than in users of NORPLANT implants at 1, 12 and 48 months of use. Women who became pregnant had significantly lower "free levonorgestrel index" than had the rest of the group. It is postulated that the difference in "free levonorgestrel index" between users of the two implant systems reflect differences in release rate, the covered rods having a lower release rate of levonorgestrel than NORPLANT throughout the observation period. It is concluded that "free levonorgestrel index" is a better parameter than levonorgestrel plasma levels to describe implant function, and to discriminate women who are at risk of pregnancy.

PIP: The plasma levels of levonorgestrel, sex hormone binding globulin (SHBG), and estradiol were compared over a 4-year period in 283 users of 2 types of Norplant systems--implants and covered rods. Plasma levels of norgestrel decreased throughout the study period in both groups, and there were no significant differences in mean plasma levels of levonorgestrel. 7 of the 8 pregnancies recorded during the study occurred after 35 months of implant use, and all involved women in the covered rods group. No significant differences were found between the women who became pregnant and the rest of the study subjects in terms of plasma levels of levonorgestrel. SHBG capacity was slightly higher in women using the 2 covered rods. The free levonorgestrel index, calculated as a ratio between levonorgestrel and SHBG, was significantly lower in users of 2 covered rods than in users of implant capsules at 1, 12, and 48 months of use. In addition, women who became pregnant had a significantly lower free levonorgestrel index. These findings suggest that the 2 covered rods had a lower release rate of levonorgestrel than Norplant implants, despite almost identical plasma levels. Thus, the free levonorgestrel index is considered a better parameter than levonorgestrel plasma concentrations to describe implant function and to predict the risk of pregnancy.

A detailed analysis of menstrual blood loss in women using Norplant and Nestorone progestogen-only contraceptive implants or vaginal rings.

Changes to the pattern of menstrual bleeding are almost universal in women using progestogen-only methods of contraception, and are an important cause of discontinuation of these methods. The present study was designed to explore the changes in menstrual bleeding patterns and objectively measure menstrual blood loss (MBL) in 110 women before and during one year of use of 4 different progestogen-only contraceptives: Norplant subdermal levonorgestrel implants; Nestorone progestogen 4-cm or 6-cm implants nominally delivering 100 microg or 150 microg daily; or a vaginal ring (CVR) delivering 100 microg of Nestorone (NES) daily (CVR users were limited to only 6 months of use). Groups could not be directly compared because of the differences in numbers of subjects and durations of treatment. The total MBL during each of the three 8-week collection periods during treatment decreased significantly in each group compared to the total blood loss in the two control cycles (greater than 50% decrease in all groups during the first 6 months), although the differences between individual women at the extremes remained considerable. The highest blood loss measured on any single day during the treatment collection periods was significantly reduced (p <0.001) in users of all four devices in all three collection periods compared to the control period (CVR users did not have a 3rd collection period). The Nestorone-releasing CVR was associated with an 88% reduction in mean MBL and a high incidence of amenorrhea at 6 months. There was considerable variation in percentage reduction in total blood loss at 6 and 12 months between individual women ranging from 100% (women with amenorrhea) to a small minority experiencing an increase compared with control cycles. The increases in measured blood loss during treatment were almost entirely in women with light bleeding in the control period and were related to prolonged episodes of light bleeding rather than heavy bleeding. Women contemplating use of a progestogen-only contraceptive method need to be counseled about alterations to the menstrual cycle but can be reassured that total blood loss will usually be much less than with normal cycles.

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

PIP: 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.^ieng

Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin, ST-1435.

Three women received one subcutaneous SilasticR capsule containing 40 mg of ST-1435 for contraception. Plasma levels of ST-1435, a 19-norprogesterone derivative, were measured during the treatment period of 13-15 months. The effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. The mean concentrations of ST-1435 during the treatment varied from 52 to 220 pg/ml in different subjects. These low concentrations of progestin were sufficient to suppress ovulation and make the implant effective for more than one year. No mid-cycle gonadotropin peaks were observed during the treatment. The subjects showed constantly low estradiol levels, thus also indicating a suppression of follicle development. Regular cyclic activity of the pituitary and ovaries, without the occurrence of ovulation, was observed in one subject. Increasing levels of estradiol parallelled a decrease of FSH and LH. It therefore seems that the negative feedback action of estradiol on gonadotropin release is unaffected but the positive feedback action of estradiol on LH appears to be blocked by the progestin ST-1435.