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.     

Immediate postabortal contraception with a microdose combined preparation: Suppression of pituitary and ovarian function and elimination of HCG

The effect of an oral contraceptive on the pituitary and ovarian function as well as on the elimination of HCG was studied in women volunteers who had had a first-trimester abortion. The contraceptive regimen was a combined preparation containing 30 micrograms of ethinylestradiol and 150 micrograms of d-norgestrel. The treatment was started on the day of abortion. Plasma concentrations of LH, FSH, HCG, estradiol and progesterone were measured by radioimmunoassay.The contraception was well tolerated and no objective side-effects were found. There were no ovulations during the 32-day observation period following the abortion, as indicated by the suppression of LH and FSH, and low plasma levels of progesterone. Plasma FSH concentrations were the best indicators of pituitary suppression during the treatment. However, individual variations in the degree of suppression were found. In each case, the FSH concentrations rose to follicular phase levels during the treatment-free week, indicating the recovery of pituitary function. Plasma estradiol concentrations remained at the low, prefollicular level throughout the observation period, except in one subject during the treatment-free week. Plasma progesterone concentrations were low except for a transient elevation between days 7 to 12 after the abortion when there were high levels of HCG. The treatment did not affect the elimination of HCG; an estimate of 36.7 days for the complete elimination was calculated from the results obtained with the specific RIA for the beta subunit of HCG.     

Immediate postabortal contraception with Norplant: levonorgestrel, gonadotropin, estradiol, and progesterone levels over two postabortal months and return of fertility after removal of Norplant capsules

Six Silastic levonorgestrel-releasing capsules, Norplant, were introduced subcutaneously into the ventral aspect of the left forearm or upper arm of thirteen patients immediately after first trimester pregnancy termination. Blood samples were taken twice a week over two months after abortion and from one subject over one month after removal of Norplant capsules. Plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. If removal of Norplant capsules took place because of planning pregnancy, the subjects were asked to inform us if they had become pregnant. During the first month after abortion the mean levonorgestrel concentration (489 pg/ml) was statistically significantly higher than during the second month (237 pg/ml). The mean estradiol values fell to prefollicular levels within four days, remaining a little suppressed. The mean progesterone concentrations were below 2 ng/ml three days after abortion. Three subjects had a transient increase in plasma progesterone concentrations nine days after abortion. Thereafter no ovulatory progesterone concentrations were seen. The LH concentrations ranged within normal values of the follicular phase and FSH values were just beneath the lower limit of follicular phase FSH values, apart from a few peaks, indicating mild suppression. After removal of Norplant capsules, progesterone concentrations increased to ovulatory levels fifteen days after removal. The Norplant capsules were removed from two subjects because of planning pregnancy and they delivered healthy babies 9.5 and 12.5 months after removal.     

Pituitary and ovarian function and clinical performance during the use of a levonorgestrel-releasing intracervical contraceptive device

A levonorgestrel-releasing intracervical device (ICD) was inserted postmenstrually to twenty-one voluntary women. Eight subjects gave blood samples twice a week during the initial three months of use of the ICD and during the seventh and twelfth months of use. Clinical performance was studied; plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of the treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. The results of the first year are presented. Dysmenorrhea, menstrual flow and the number of days of bleeding decreased during the first treatment year. Three spontaneous expulsions occurred; two at the very beginning of the treatment and one after six months of use. Side-effects were few. The plasma level of levonorgestrel remained fairly constant during the observation time of 12 months. Thirty-one of the 36 cycles were ovulatory as judged by plasma progesterone elevations. No pregnancies occurred during the study period of one year.     

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

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.     

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.     

Levonorgestrel plasma concentrations and hormone profiles after insertion and after one year of treatment with a levonorgestrel-IUD

Plasma concentrations of levonorgestrel, progesterone, estradiol, FSH and LH were measured in seven volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. Blood samples were collected twice weekly during a mean of 93 days immediately postmenstrually and during a mean of 41 days over the twelfth to fifteenth month of treatment. Patterns of bleeding were studied during the first year of treatment. The IUDs used were designed to release 25 micrograms/day of levonorgestrel. The mean +/- SD plasma concentration of levonorgestrel for all subjects during the first three months was 260 +/- 68 pg/ml, and 129 +/- 28 pg/ml after one year of treatment. During the initial period of blood sampling only two of the subjects ovulated, while only two did not ovulate after one year of treatment. Intermenstrual spotting occurred during the first sixty days of treatment. Three subjects developed amenorrhea at the end of the first year. All the subjects continued the use of the IUD and no pregnancies occurred.     

Contraception with subdermal ST-1435 capsules: side-effects, endocrine profiles and liver function related to different lengths of capsules

One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered. Blood samples were taken from selected subjects twice a week during the 1st, 2nd, 3rd, 6th, 7th and 12th month of use. Plasma concentrations of ST-1435 were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. There were no differences in hormonal side-effects between subjects who had a 30 mm capsule or subjects who had 20 mm or 15 mm capsules, but subjects who had 20 or 15 mm capsules had significantly longer bleeding or spotting periods in comparison with subjects who had a 30 mm capsule. There were no changes in blood pressure, body weight or liver function test results in comparison with pre-insertion values. The plasma level of ST-1435 was not significantly higher during the use of 30 mm capsules than during the use of 20 or 15 mm capsules. During the use of the shorter ST-1435 capsules, plasma estradiol elevation and slightly suppressed FSH were seen, while the use of longer capsules resulted in a slight suppression of LH. Progesterone concentrations during monitored cycles indicated anovulation. No pregnancies occurred during the study period of one year. The continuation rate at one year was 71% in the 30 mm capsule group and 57% in the 20 and 15 mm capsule groups taken together.     

Inhibitory effects of treatment with an LHRH antagonist on the ovulatory cycle are reduced when administered during the late follicular phase

To compare the effects of transitory suppression of pituitary gonadotropin secretion by an LHRH antagonist at the mid or late follicular phase of the menstrual cycle, adult macaques with normal menstrual cycles were treated with an LHRH antagonist (N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LHRH (detirelix) administered subcutaneously at a dose of 300 micrograms/kg, daily for 3 days beginning either during the mid or late follicular phase. In all eight animals treated during the mid follicular phase, serum concentrations of LH and FSH declined and remained suppressed for 4 days. This caused a fall in serum concentrations of estradiol and the expected ovulation failed to occur. During the recovery period a marked rise in serum FSH occurred followed by normal follicular development and ovulation 14.8 +/- 0.6 days after the last injection of antagonist. Of the 9 macaques given the same treatment during the late follicular phase, only in two was the expected rise in serum progesterone prevented. In 4 of the animals a transitory suppression in LH and estradiol was observed but this was followed by a recovery and occurrence of an LH surge and rise in serum progesterone indicating ovulation during the course of treatment. In the remaining 3 macaques treatment commenced on the day of the initiation of the LH surge and was associated with a progesterone rise of normal duration but lower than normal magnitude during the early luteal phase. These results show that LHRH antagonist treatment causes rapid inhibition of pituitary-ovarian function when administered up to the mid follicular phase of the cycle and is effective in blocking ovulation. The suppressive effects of the antagonist are reduced when administered during the late follicular phase. This may be due to decreased dependence of the pituitary gonadotrope on LHRH at this time and on decreased dependence of the dominant follicle on the gonadotropins.     

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.     

Effects of low dose oral contraceptives containing norethindrone and ethinyl estradiol on serum levels of progesterone and pituitary gonadotropins

Serum gonadotropin and progesterone levels were studied in longterm (>18 months) patients receiving oral contraceptives containing either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg of ethinyl estradiol. In ten patients treated with 1.0 mg norethindrone and 35 μg ethinyl estradiol, no mid-cycle surges of LH were noted and LH levels never exceeded 225 ng/ml. FSH levels were generally elevated during the first half of the cycle. Serum progesterone concentrations in these patients and in fourteen additional women whose blood was sampled intermittently were generally less than 1 ng/ml, and no characteristic luteal phase elevation of this hormone was detected. Of six patients treated with 0.5 mg norethindrone and 35 μg ethinyl estradiol, five clearly had no mid-cycle surge of LH, and levels of this hormone never exceeded 250 ng/ml. The concentrations of FSH and progesterone in these patients and serum progesterone levels in two additional women whose blood was sampled intermittently were similar to those found in patients treated with 1 mg norethindrone and 35 μ ethinyl estradiol. In the sixth patient, hormonal levels did not follow the same pattern, but they were not characteristic of ovulation. It is concluded that there is no evidence of cyclic fluctuations in FSH, LH and progesterone characteristic of ovulation in patients treated longer than eighteen months with either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg ethinyl estradiol.     

Immediate postabortal insertion of a levonorgestrel-releasing IUD

Experimental IUDs releasing only 10 μg levonorgestrel per day and established copper-releasing IUDs (Nova-T) were inserted in 60 women in connection with legal first-trimester abortion. Bleeding and spotting and other events were recorded during the first year. Restoration of the menstrual cycle was studied. Blood samples were collected twice a week over a three-month period from five women receiving a levonorgestrel-releasing IUD to determine plasma levels of estradiol, progesterone, levonorgestrel, LH and FSH. FSH showed an increase approximately ten days (range 4–19) after abortion. LH/hCG concentrations reached a plateau approximately 24 days (range 9–42) after abortion. Initially, levonorgestrel concentrations were two-fold compared with concentrations of 90 pg/ml after four weeks. After four weeks the plasma levonorgestrel concentrations were stable. All five women had an ovulatory menstrual cycle. The first periods occurred 35 days after operation in the levonorgestrel-IUD group and 30 days after operation in the Nova-T group. The median duration of bleeding and spotting after the insertion was 12 days (range 3–26) in the Nova-T group and 12.5 days (range 3–93) in the levonorgestrel-IUD group. The difference was not statistically significant. From the second month on, menses-like bleeding was more common in the copper-releasing IUD group than in the levonorgestrel-IUD group. The difference was statistically significant (p < 0.001). After one year 75 percent of the patients continued with their IUDs in both groups. One pregnancy occurred in the experimental levonorgestrel-IUD group. One total expulsion was noticed in both groups, and one partial expulsion in the levonorgestrel-IUD group. Two levonorgestrel-IUDs and four Nova-Ts were removed because of bleeding and/or pain. One infection was noticed in the whole group six days after the operation. In the levonorgestrel-IUD group 74 percent of the women had a regular cycle after one year, while all Nova-T patients had a regular cycle. Twelve percent (7 women) were lost to follow-up at one year. The results of this study suggest that a levonorgestrel-releasing IUD can be inserted after legal first-trimester abortion and the results are comparable with those of previous studies that have been made using copper-releasing IUDs.     

Contraception with subcutaneous capsules containing ST-1435. Pituitary and ovarian function and plasma levels of ST-1435

An RIA for a new progestin, ST-1435, was developed. Plasma concentrations of this steroid were measured in three women having three subcutaneous capsules, each containing 40 mg of ST-1435. Pituitary and ovarian functions were assessed by measuring plasma levels of LH, FSH, estradiol and progesterone.Plasma profiles of ST-1435 were characterized by high and irregular peaks all the way through the study period of 7–9 months. Concentrations below 100 pg/ml were not observed, whereas the highest peaks reached concentrations of 10.1 ng/ml. Plasma estradiol concentrations remained uniformly suppressed below 100 pg/ml, thus indicating a suppression in follicle development. As judged by constantly suppressed progesterone concentrations, no ovulations occurred during the treatment. Plasma FSH concentrations remained at the upper limit of the follicular phase, and those of LH at the lower limit of the luteal phase of the normal menstrual cycle. No midcycle gonadotropin peaks were observed.     

Hormonal effects of the 300 μg norethisterone (NET) minipill: 2. Daily gonadotrophin levels in 43 subjects during a pretreatment cycle and during the second month of NET administration

The peripheral plasma levels of immunoreactive follicle-stimulating hormone (hFSH) and luteinizing hormone (hLH) were measured daily in 43 normally menstruating women during a pretreatment (control) cycle and during the second month of daily administration of the 300 μg norethisterone (NET) minipill. In addition, the levels of biologically active LH were also determined in 29 of the 43 subjects.

As described in detail in the first paper of these series (1), the 43 women studied exhibited four distinctly different types of ovarian reaction to NET, as indicated by the daily estradiol and progesterone levels. Seven women (16 %) showed neither follicular, nor luteal activity (group A), 10 women (23 %) exhibited a cyclic follicular activity, but no luteal function (group B), 9 women (21 %) had normal follicular function, but insufficient luteal activity (group C), and 17 women (40 %) had estradiol and progesterone levels undistinguishable from those seen in a normal ovulatory cycle (group D).

Administration of the NET minipill did not influence the mean FSH lvel of cycle days 1–6, or those of 3 to 7 days before the LH peak; it slightly decreased the mean luteal phase FSH level in group C, but no in group D, and markedly suppressed the FSH peak value in all groups. There was no difference in this respect between women exhibiting different types of ovarian reaction. Similar to its effect on FSH, the administration of NET did not diminish the mean LH levels of days 1–6, those of 3 to 7 days before the LH peak, or of the luteal phase, but greatly suppressed the LH peak. Again, there was no difference in LH levels during NET administration among women showing different types of ovarian response to the drug. On the other hand, significant differences were found in the LH levels of the pretreatment (control) cycles of the various groups. The mean levels of LH both during days 1–6 and during the luteal phase of the pretreatment cycles were significantly lower in women in whom the minipill subsequently abolished all lutaeal activity (groups A+B) than in women exhibiting different degrees of luteal function (groups C+D). Hence the NET minipill will preferentially inhibit ovulation in women exhibiting relatively low tonic LH-levels in untreated cycles.

The results of the daily LH bioassays were in good agreement with those of the radioimmunoassays.

In the majority of women who exhibited normal (“ovulatory”) estradiol and progesterone profiles during NET administration, the preovulatory FSH, and especially LH peaks were below the lower limit of normal values, and in several instances, normal estradiol and progesterone profiles were found in the virtual absence of any FSH and LH surge.

It is concluded that ovarian suppression by the NET minipill is unrelated to the degree of inhibition of FSH and LH secretion as far as this is reflected by their peripheral levels measured daily.     

Further studies on pituitary and ovarian function in women receiving hormonal contraception

Pituitary and ovarian function was evaluated in women receiving 3 combined oral contraceptive preparations. Basal levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and gonadotropic responses to gonadotropic releasing hormone (GnRH) were studied in 36 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment, control). These same women were then divided into 3 groups with 12 volunteers in each. Each group received an oral contraceptive preparation cyclically for 3 months. The preparations were: Nordette (30μg ethinyl estradiol and 150 μg d-norgestrel), Nordiol (50μg ethinyl estradiol and 250μg d-norgestrel) and Biphasil (50μg ethinyl estradiol and 50μg d-norgestrel × 11 days and 125μg d-norgestrel × 10 days). In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active therapy, basal FSH and LH were similarly suppressed in the 3 groups. LH had varied responses to a bolus of GnRH, whilst the FSH responses were similar in the 3 groups. After 7 days of inactive tablets, basal FSH and LH had returned to pre-treatment, early follicular phase levels. However, the LH responses to a bolus of GnRH varied in the 3 groups, but again, no differences were noted in the FSH responses. Basal FSH, LH and E2 recovered earlier in the Nordette group during the 7 days of inactive tablets.     

The effect of deliberate omission of Trinordiol or Microgynon on the hypothalamo-pituitary-ovarian axis

The effect of deliberate omission of a phased formulation pill, Trinordiol (ethinyl estradiol 30 micrograms + levonorgestrel 50 micrograms: 6 tablets; ethinyl estradiol 40 micrograms + levonorgestrel 75 micrograms: 5 tablets; ethinyl estradiol 30 micrograms + levonorgestrel 125 micrograms: 10 tablets) or a low-dose, combined, oral contraceptive pill, Microgynon (ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms: 21 tablets) on the hypothalamo-pituitary-ovarian axis were studied. Thirty-six women were recruited to the study and divided equally between the two types of pill. Medication was begun on the 8th pill-free day of the cycle and continued for 7 days (Group 1), 14 days (Group 2) or 21 days (Group 3). Levels of FSH, LH, estradiol (E2) and progesterone (P) were measured in plasma on alternate days during the final week of pill therapy, and daily for the 7 days after stopping the pill. For the first 2 weeks of pill therapy, follicular activity, as judged by plasma levels of E2, was greater in women taking Trinordiol than in those taking Microgynon, but was similar in both groups by the third week of pill treatment. Five women taking Trinordiol (2 in Group 1 and 3 in Group 2) had plasma levels of E2 in excess of 500 pmol/l whilst taking the pills, and only 1 patient achieved this degree of follicular activity after stopping the tablets. One woman who had taken 7 days of Trinordiol (Group 1) showed a rise of plasma levels of P to 6.8 nmol/l, but luteinization did not occur in any of the remaining 35 women who took Trinordiol or Microgynon. These findings suggest that follicular activity is less completely suppressed by Trinordiol than Microgynon, at least in the first 2 weeks of pill therapy, but that normal ovulation is still a rare event in the week after cessation of either of these pills, even if only 7 days of medication have been taken.     

Hormonal changes during the first year of use of subdermal levonoregestrel implants, Norplant

Sixty-three women had NORPLANT implants inserted during the first eight days of the menstrual cycle. Blood specimens were withdrawn at the time of insertion and every three days during one of the following months of observation; the first, third, sixth, ninth and twelfth month after insertion. Ten subjects were sampled at multiple times during implant use. A total of 83 months of observation was available. The serum concentrations of levonorgestrel (LNG), FSH, LH, prolactin (PRL), estradiol (E2) and progesterone (prog) were measured in each specimen. LNG concentration rapidly declined during the first 15 days of use, the decline became more gradual during the subsequent two weeks, and an almost steady level was reached during the remainder of the year. There were no significant trends of change in the levels of FSH, LH, E2 and prog during the year. Frequent peaks in E2 concentration were observed and were generally associated with or followed by LH surges. PRL concentration showed a slight but significant rise during the second half of the year. Rises in prog concentration suggestive of ovulation occurred in 36 percent of the months of observation. However, in all these instances, there were evidences suggestive of deficient luteal phase. The bleeding episodes were usually, but not always, related to decline in E2 and prog concentrations.     

Ovulation inhibition with nafarelin acetate nasal administration for six months

A group of 24 women with normal menstrual cycles were treated with nafarelin acetate administered in doses of either 125 ug or 250 ug daily intranasally for 6 months. Each subject was studied for one ovulatory control cycle, six treatment cycles, and post-treatment until the return of ovulation was documented. Once a week progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone were measured in the serum. Acute hormone responses to nafarelin acetate were determined on-day 1, day 98 and day 186 of treatment.

Two subjects failed to complete the treatment phase. One subject using the 250 ug daily dose of nafarelin acetate discontinued treatment on the sixth day because of heavy uterine bleeding. One subject using the 125 ug daily dose of the study drug terminated treatment on day 126 because of a 21-pound weight gain.

There were significantly less presumed ovulatory cycles at the higher dose (2 out of 60 cycles) than at the lower dose (10 out of 54 cycles) (p<0.01). On the average menstrual cycles were reestablished 28.5 ± 8.3 (S.D.) days after discontinuing the 125 ug daily dose and 33.7 ± 17.9 (S.D.) days after terminating the 250 ug daily dose. With the higher dose of nafarelin acetate there were significantly fewer bleeding episodes, less number of days of bleeding, and longer cycles. During the treatment phase the area under the LH curve was significantly less and the acute response of LH in the last week of treatment was significantly less with the higher dose of drug. With both doses of nafarelin acotate the acute responses of LH, FSH and estradiol were significantly greater on day 1 than on either day 98 or day 186. Side effects observed during this study included galactorrhea (2 subjects) and vasomotor symptoms (7 subjects).     

Effects of intranasal administration of norethisterone on folliculogenesis, cervical mucus, vaginal cytology, endometrial morphology and reproductive-endocrine profile in women.

The effects of intranasal administration of norethisterone (NET) on menstrual cycle length, folliculogenesis, serum levels of estradiol, FSH, LH and progesterone, vaginal cytology, cervical mucus and endometrial morphology were studied in 8 volunteers (age 28 to 39 years, weighing between 46 and 54 kg). The study period comprised 4 consecutive menstrual cycles. In the first cycle (pretreatment cycle), only the vehicle (alcohol, propylene glycol, water; 3:3:4) was sprayed intranasally (100 microliters in each nostril), using a metered nebulizer, once daily from day 3 to the last day of menstrual cycle. In the next two cycles (treatment cycles), NET (300 micrograms/day) was administered once daily, starting from day one of menstrual cycle, between 9 and 10 a.m. The fourth cycle was a post-treatment cycle in which the volunteers were monitored for recovery. Blood samples (about 5 ml each) were collected once daily from day 8 to 24 and thereafter on alternate days until the last day of cycle during all the 4 cycles. Levels of estradiol, FSH, LH and progesterone were measured in the serum samples by radioimmunoassay methods. Cervical mucus samples and vaginal smears were collected once daily starting from day 7 or 8 of each cycle until the mucus was very scanty. Serial pelvic ultrasonography was performed starting from day 7 or 8 until the growing follicle disappeared or throughout the cycle in case a growing follicular cyst was observed. Endometrial aspirates were collected once around day 22 in each cycle and processed for routine histological examination.     

Recovery of ovarian function after the use of a d-norgestrel-releasing IUD.

The recovery of ovarian function after discontinuation of the use of three different d-norgestrel-releasing IUDs was studied by determination of plasma concentrations of progesterone and estradiol, and by urinary determination of LH concentrations. Urinary LH levels were determined during and after treatment with the d-norgestrel-releasing IUD to study the effect on baseline LH values. Two subjects had an LRH-stimulation test performed during the use of the d-norgestrel-releasing IUD. Ovulatory function was restored immediately after removal of the IUD. Baseline LH levels in urine were unaffected by the use of the d-norgestrel-releasing IUD, and a normal response to stimulation by LRH was found during treatment. Two planned pregnancies occurred after discontinuation of the use of the d-norgestrel-releasing IUD.