Reproductive endocrine effects of intranasal administration of norethisterone (NET) to women

Four consecutive menstrual cycles were studied in six healthy parous women. A solvent mixture comprising propylene glycol:ethanol:water (3:3:4) was sprayed intranasally daily using a glass atomizer between days 5 and 24 of the first (control) menstrual cycle. NET was dissolved in the solvent and similarly administered at a daily dose of 100 mcg during the second and third menstrual cycles. Nasal sprays were not administered during the fourth post-treatment cycle. Blood samples were taken during four consecutive cycles between days 8 and 15 and again between days 20 and 24 of the cycle to estimate levels of estradiol (E2), FSH, LH and progesterone (P). These studies revealed that nasal sprays of NET were well accepted and that no adverse clinical effects or menstrual disturbances occurred. NET inhibited ovulation in one cycle. The E2-induced mid-cycle rise in FSH and LH was either suppressed or inhibited in nine out of the 12 treated cycles. P levels in three treated cycles were indicative of luteal inadequacy. These endocrine effects of NET persisted into the post-treatment cycle in two cases.     

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.     

Pituitary, ovarian and endometrial effects of 300 micrograms norethisterone and 30 micrograms levonorgestrel administered on cycle days 7 to 10

The ovarian, endometrial and pituitary effects of 300 micrograms norethisterone (NET) and 30 micrograms levonorgestrel (L-NOG) administered orally on cycle days 7-10 were investigated in two groups of 10 women each, by daily analysis of plasma estradiol (E2), progesterone (PROG), immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a pretreatment control cycle and during NET or L-NOG administration. Endometrial biopsies were obtained for morphometric analysis on cycle day 11 in the control and treatment cycles. Treatment with 300 micrograms NET resulted in an increase in the area under the E2 peak (p less than 0.05), reduction in the number of subjects with normal progesterone profile (p less than 0.05) and a decrease in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 4 subjects and progesterone in 4 subjects. The follicular phase was prolonged in one subject. Norethisterone induced marked subnuclear vacuolation in the endometrium, while the glandular mitoses were decreased during NET treatment. Treatment with 30 micrograms L-NOG resulted in a decrease in subjects with normal progesterone profiles (p less than 0.05) and in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 3 subjects and progesterone in 4 women. The follicular phase was prolonged in one subject. L-NOG did not significantly increase the diameter of glands or induce subnuclear vacuolation in the endometrial glands.     

Effect of repeated hyperbaric exposures on the menstrual cycle: preliminary study

Two healthy female volunteers were subjected to hyperbaric air pressure of 5 ATA comparable to 130 feet of sea water (fsw) for 20 min 7 or 8 times during their menstrual cycles (experimental cycles). During the experimental cycles hormone assays for follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and testosterone were performed before and after each dive on alternate days between the 5th and 11th cycle days (follicular phase), daily during the time ovulation was expected to occur, and on alternate days during the luteal phase; these were compared with the same assays throughout control cycles, during which the subjects were not pressurized. Periodic pressurization produced no significant changes in hormone patterns; ovulation was not inhibited and menstrual periods were unchanged.     

Analysis of pre-ovulatory changes in cervical mucus hydration and sperm penetrability

Changes in cervical mucus occur during the proliferative phase of the menstrual cycle and are known to correlate with receptivity to sperm and to the endocrine milieu. Prior studies, however, have often lacked biological incisiveness and technical objectivity and precision. This study analyzed daily changes in mucus water content (hydration) prior to the LH surge (LH+0) in normal women, in relation to daily levels of serum LH, FSH, estradiol and progesterone, and to daily tests of sperm penetration of the mucus. Cervical mucus was studied for 12 cycles in 10 ovulating women. Three to ten mucus specimens were collected per cycle, over the days LH-8 to LH+0. Each specimen was subjected to measurement of both water content (hydration) and penetration by spermatozoa from fresh specimens of normal human semen. For the latter, a new microscale assay was developed and applied, which was amenable to very small volumes of mucus. The new technique determines objective measures of both the numbers of penetrating sperm (motile and non-motile) and the distance penetrated by the forwardmost vanguard sperm. In these experiments, variations in semen quality were controlled by performing a companion penetration assay in an artificial 1.5% polyacrylamide gel.The patterns of change in mucus hydration varied quantitatively among women, with preovulatory baseline levels ranging from 93.8-96.5%. All normal cycles (as defined by endocrine profiles) displayed a significant increase in hydration over a one-day period occurring 3-4 days before the LH peak. The magnitude of this shift varied among women between 2 and 3% (absolute hydration), a distinction well within the precision of the hydration assay. This quantum increase in hydration was more pronounced than the corresponding increase in serum estradiol on the same day. The change in mucus hydration, and the associated increase in sperm penetrability, were more consistent among cycles than the changes in reproductive hormones.There was a strong but non-linear correlation between mucus hydration and sperm penetrability. Once the value of hydration rose above approximately 97.5%, there was a substantial increase in penetrability. This 'cut-off point' in sperm penetrability was in the middle of the range of hydration values (across women) which preceded the quantum jump in hydration - which, itself, preceded the surge of L.H. Hydration began to increase approximately 2 days before measurable increases in sperm penetration of the mucus in vitro.These results demonstrate that mucus hydration may be a valuable marker of the approach to ovulation and delineation of the fertile period. They also provide new methods for assessing sperm penetration into both large periovulatory and very small samples of collected mucus.     

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).     

Pituitary, ovarian and endometrial effects of 300 μg norethisterone and 30 μg levonorgestrel administered on cycle days 7 to 10

The ovarian, endometrial and pituitary effects of 300 μg norethisterone (NET) and 30 fig levonorgestrel (L-NOG) administered orally on cycle days 7–10 were investigated in two groups of 10 women each, by daily analysis of plasma estradiol (E₂), progesterone (PROG), immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a pretreatment control cycle and during NET or L-NOG administration. Endometrial biopsies were obtained for morphometric analysis on cycle day 11 in the control and treatment cycles. Treatment with 300 μg NET resulted in an increase in the area under the E₂ peak (p<0.05), reduction in the number of subjects with normal progesterone profile (p<0.05) and a decrease in the area under the progesterone curve (p<0.05). The treatment suppressed the LH peak in 4 subjects and progesterone in 4 subjects. The follicular phase was prolonged in one subject, Norethisterone induced marked subnuclear vacuolation in the endometrium, while the glandular mitoses were decreased during NET treatment. Treatment with 30 μg L-NOG resulted in a decrease in subjects with normal progesterone profiles (p<0.05) and in the area under the progesterone curve (p<0.05). The treatment suppressed the LH peak in 3 subjects and progesterone in 4 women. The follicular phase was prolonged in one subject. L-NOG did not significantly increase the diameter of glands or induce subnuclear vacuolation in the endometrial glands.     

The endocrinological profile of normal menstrual cycles in a population of Chinese women

Endocrinological profiles of normal menstrual cycles were studied in 41 Chinese women. Daily serum concentration of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2) and progesterone (P) were determined by RIA. Thirty-four cycles were of normal length (26-35 days) and 6 cycles were prolonged up to 40 days with a follicular phase of 22-26 days. One cycle was anovulatory. Cyclical changes of LH, FSH, E2 and P were typical of ovulatory cycles in other populations as reported in the literature. In the normal cycle group the geometric mean of the LH midcycle peak level was 46 IU/1, the FSH peak was 10 IU/1, the preovulatory estradiol peak was 1229 pmol/1 and the progesterone luteal maximum was 50 nmol/1. The pattern of cyclical changes in the prolonged ovulatory cycles was similar to the normal length cycles, except that there were significantly higher levels of LH in both follicular and luteal phases, lower FSH in luteal phase, and lower progesterone in luteal phase. A majority of cycles had a midcycle elevation of prolactin and mean PRL levels in the late luteal phase were higher than those in the follicular phase.     

‘Escape’ ovulation in women due to the missing of low dose combination oral contraceptive pills

It is generally believed that in women taking anti-conceptional combined pills, the risk of pregnancy increases if a pill is missed. A study was undertaken in healthy, normally menstruating women who were given low dose combination contraceptive pills containing norethisterone acetate (NET Ac) 1 mg and ethinyl estradiol (EE₂) 30 g. In the control group, 10 women were asked to take the pills regularly daily for 21 days starting from the day 5 of the menstrual cycle. Whereas in the study group, consisting of similar women but who were sterilized, they were asked to ‘miss the pills’ on two consecutive days anywhere between day 5 to day 17 of the menstrual cycle. Thirty-five women were ‘made to miss’ the pills in the first treatment cycle and another 19 women were asked to ‘miss the pills’ in the fourth treatment cycle. Cervical mucus and lateral vaginal wall smears were studied thrice a week. Endometrial biopsy was done on day 23 ± 2. Two serum progesterone (R) levels were determined between day 22 to day 25 of the cycle.     

Postabortal contraception with norethisterone enanthate injections

Intramuscular injection of 200 mg norethisterone enanthate (NET-EN) was given to five women on the day of first trimester abortion. The injection was repeated twice at eight-week intervals, and thereafter at twelve-week intervals for one year. Plasma samples were collected for FSH, LH/hCG, estradiol, progesterone and norethisterone (NET) determinations. NET-EN did not affect the elimination of hCG, estradiol or progesterone. Plasma NET concentrations reached a peak (5.5–11 ng/ml) in about ten days after the injection and declined constantly thereafter, to levels of 0.18–0.64 ng/ml at 8 weeks after the injection. NET-EN postponed the increase in FSH secretion until 17–20 days after the injection, $\text{i.e.}$ until plasma NET concentrations fell below 3 ng/ml. In three out of five women some follicular activity was present 5 weeks after NET-EN injection as evidenced by increased plasma estradiol concentrations. No ovulation occurred within 8 weeks after NET-EN injection, as judged by low progesterone values. There was a definite accumulation of NET during the first six months, when NET-EN injections were given at eight-week intervals. Mean plasma NET concentrations increased from 0.34 ng/ml at eight weeks to 0.78 ng/ml at 24 weeks. When the injection interval was increased to twelve weeks, the plasma NET concentrations prior to the next injection started to decrease. This was accompanied by increased follicular activity, culminating with one ovulation observed. It is concluded that in this population of women, an injection interval of less than twelve weeks is needed for ovulation inhibition.     

Gonadal and pituitary responses to progesterone antagonist ZK 98.299 during the follicular phase of the menstrual cycle in bonnet monkeys

ZK 98.299 is a potent progesterone antagonist. Its effects on folliculogenesis, bioactive LH, ovulation and menstrual cycle (m.c.) length were studied in adult bonnet monkeys. ZK 98.299 (20 mg/day) was administered s.c., once daily on days 5 to 15 of m.c., to ten animals. The pretreatment m.c. was of 26.5 days (25 to 28 days, mean with 95% confidence limits) and on treatment it was significantly (p less than 0.001) prolonged to 46.9 days (39 to 54 days). The anticipated midcycle rise in estradiol and bioactive LH levels was completely blocked in six and attenuated in three animals during the treatment period. However, the levels did not drop below the early follicular phase levels. In one animal (#90), though the cycle length was prolonged by 5 days the midcycle rise in estradiol and bioactive LH levels was observed during the treatment period and this animal had normal luteal function. Seven animals had delayed ovulation whereas, two had anovulatory treatment cycles. The rise in estradiol and bioactive LH levels, prior to ovulation in the treatment cycles, was compatible with the midcycle rise observed in the pretreatment cycles. Serum progesterone levels during the luteal phase of the treatment cycles were normal in six animals whereas, in two they were indicative of luteal insufficiency. In two animals, the treatment cycles were anovulatory. ZK 98.299 had no effect on the duration of menses. The post-treatment cycles were of normal duration. This study suggests that the administration of ZK 98.299 during the follicular phase blocks estradiol and bioactive LH release and terminates the follicular phase in most of the animals. The follicular phase is reinitiated after the treatment is stopped.     

A randomized study of the effect of mifepristone alone or in conjunction with ethinyl estradiol on ovarian function in women using the etonogestrel-releasing subdermal implant,Implanon®

BackgroundMifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy.AimTo examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon.Study DesignWomen using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2–5. Measurements of serum estradiol (E₂), progesterone (P₄), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times.ResultsFollowing mifepristone intake, there was a dramatic increase in E₂ levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E₂ triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E₂ levels.DiscussionDespite a transient increase in E₂ levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E₂ levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation.ConclusionPregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.     

Effect of LH-RH peptide antagonist on serum LH, ovulation and menstrual cycle of crab-eating macaque.

The effects of the antagonistic LH-RH analogue, D-(PHE²)-D-(ALA⁶)-LH-RH (Wy-18,185), were studied in the female crab — eating macaque ($\text{Macaca fascicularis}$) with emphasis on length of menstrual cycle, length and intensity of menstrual bleeding, serum LH, quantity and properties of cervical mucus, growth of the follicle and ovulation during the treatment and subsequent control cycles. Prior to the expected ovulation, the compound was administered subcutaneously, 25 mg/kg body weight/day, for 3 or 6 days. Blood was collected daily before, during and after treatment. Cervical mucus characteristics were charted daily. Laparoscopy was performed 2–4 days after presumed ovulation.Neither the length of the menstrual cycle nor the quality of the cervical mucus were dramatically altered during treatment with Wy-18,185. Of the nine macaques that were treated with six doses of Wy-18,185, two had anovulatory cycles associated with premature LH surges and one was devoid of an LH surge. It is possible that the partial anti-ovulatory effectif Wy-18,185 in the monkey may be due to its mildly inherent gonadotropin releasing properties triggering an LH surge at a time when the follicles were incapable of a complete ovulatory response. However, the general lack of effect of the antagonist, coupled with reports on the comparative refractoriness to LH-RH and related agonists, on reproductive parameters in this primate species, in contrast to the rat, rabbit and hamster, indicate that the macaque may be an inappropriate model.     

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.     

Induction of menstruation by antiprogesterone ZK 98.299 in cycling bonnet monkeys

The antiprogestin ZK 98.299 (11 beta-(4-dimethylaminophenyl)-17 alpha-hydroxy-17 beta-(3-hydroxypropyl)-13 alpha-methyl-4,9-gonadien-3-one) was administered s.c. (30mg/day) to two groups of cycling bonnet monkeys. In Group I (n = 6), it was injected from day 16 to 18 and in Group II (n = 9) from day 21 to 23 of the cycle. Each animal served as its own control and in the pretreatment cycle the vehicle (benzyl benzoate: castor oil, 1:4) was administered. During the treatment cycle of these animals the peak in estradiol levels was observed between days 8 to 11 of the menstrual cycle. In Group I animals, administration of ZK 98.299 induced vaginal bleeding in three of the six animals within two days of its first injection. In the remaining three animals the menstrual cycle length was prolonged. However, in all the six animals a premature drop in serum progesterone levels was observed. On the other hand, in Group II in seven animals with ovulatory treatment cycles, administration of ZK 98.299 induced vaginal bleeding within four days of the first dose and significantly shortened the cycle length. A significant decline in progesterone levels was observed in these animals also. However, in two animals in each group, ZK 98.299 induced vaginal bleeding while the serum progesterone levels were still high. Post-treatment cycles were ovulatory but the cycle length was marginally increased in some animals. In two animals of Group II, in which the treatment cycle turned out to be anovulatory, ZK 98.299 did not induce bleeding and had no effect on serum progesterone levels. This study shows that when administered during the luteal phase ZK 98.299 induces vaginal bleeding and premature luteal regression in bonnet monkeys. However, induction of vaginal bleeding may not be associated with drop in progesterone levels. ZK 98.299, therefore, appears to have potential for fertility control which warrants clinical evaluation.     

检测围排卵期宫颈黏液中性激素的临床意义

目的：检测排卵前后人类宫颈黏液中雌孕激素及黄体生成激素（LH）分泌水平的变化。方法：宫颈黏液标本来自20名育龄女性,同时采集外周血,通过B型超声确认排卵。采用化学发光免疫分析法检测血液及宫颈黏液中雌二醇、孕激素及LH的浓度变化。结果：宫颈黏液中存在雌二醇和孕激素以及LH,其分泌模式与外周血相似,雌激素峰、LH峰发生在排卵前1 d,且孕激素分泌在排卵前1 d开始升高,但激素分泌浓度显著低于外周血。结论：检测围排卵期宫颈黏液中性激素水平对识别排卵有参考价值。     

Norethisterone enanthate as an injectable contraceptive in puerperal and non-puerperal women

Norethisterone enanthate (NET-EN) was intramuscularly administered to 5 puerperal women and 20 non-puerperal women for a total of 366 months. Contraceptive effectiveness and side effects of the drug were evaluated. Basal levels of LH, FSH, prolactin (PRL), estradiol 17 beta (E2) and progesterone (P) were measured in blood samples collected from 5 non-puerperal women, while LH, FSH, PRL and norethisterone (NET) plasma levels were evaluated in puerperal women. NET was also assayed in plasma from breast-fed newborns. No woman became pregnant. Side effects consisted of only menstrual abnormalities. Ovulation (P plasma levels higher than 2000 pg/ml) was achieved in 3 patients during the first month of NET-EN treatment but luteal function appeared to be insufficient. In puerperal women, NET plasma levels showed a course similar to the one observed outside puerperium. Lactation was not inhibited, and NET transfer to newborn through milk was negligible, since NET was undetectable in newborn plasma when maximal levels were measured in the mother. It was concluded that NET-EN is an effective contraceptive drug, deprived of major side effects, and particularly useful in women affected by metabolic diseases or during puerperium.     

A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol.

Two combined contraceptive vaginal rings (CVR) each releasing approximately 1 mg norethindrone acetate (NET-Ac) and either 20 micrograms or 15 micrograms ethinyl estradiol over 24 h were tested at three clinic sites in Los Angeles, San Francisco, and Sydney. A total of 61 women were enrolled to use the ring on a schedule of 3 weeks in/1 week out for four treatment cycles. Serum estradiol, progesterone, norethindrone (NET), and ethinyl estradiol (EE) levels were assayed twice weekly in all four treatment cycles. Both CVR performed well, with no pregnancies occurring and only one cycle of luteal activity suggestive of ovulation (serum progesterone > 32 nmol/L) occurring with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was significantly more luteal activity in women using the 1/15 CVR (5.9% compared with 1.2% of cycles), only three cycles with a marked degree of luteal activity (progesterone > 10 nmol/L) occurred among compliant women. Serum levels of NET and EE were consistently elevated during use of both rings. There was no significant difference between serum levels with the two rings because of wide interindividual variations, although both NET and EE levels tended to be higher with the 1/20 ring. However, there was a significant difference in EE levels between the women in Los Angeles and Sydney using the same dose rings. Total cholesterol, HDL, and LDL cholesterol values were not significantly changed during treatment. Triglycerides increased but remained within the normal range. Overall cycle control was good with both formulations, but there was slightly more cycle disturbance with the lower dose ring. There was no change in mean body weight during the study, and individual weight changes appeared to be idiosyncratic. Side effects were infrequent and similar to those reported with other steroidal contraceptive methods. Three women complained of vaginal discharge, one with accompanying itch and one with a vaginal Candida infection in cycle 1. Overall, both of these EE/NET-Ac rings performed well, with only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, and progesterone levels and lipids, and on vaginal bleeding patterns.     

A randomized study of the effect of mifepristone alone or in conjunction with ethinyl estradiol on ovarian function in women using the etonogestrel-releasing subdermal implant, Implanon®

BackgroundMifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy.AimTo examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon.Study DesignWomen using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2–5. Measurements of serum estradiol (E₂), progesterone (P₄), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times.ResultsFollowing mifepristone intake, there was a dramatic increase in E₂ levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E₂ triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E₂ levels.DiscussionDespite a transient increase in E₂ levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E₂ levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation.ConclusionPregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.     

Abnormal endocrine profile among women with confirmed or presumed ovulation during long-term Norplant use

FSH, LH, estradiol and progesterone were serially assayed during 8 cycles of six subjects using six subdermal implants releasing levonorgestrel (NORPLANT) for a period of 2 to 6 years. All 8 cycles studied had a very low LH peak and a low or nonexistent FSH peak as compared to 8 control cycles. The mean LH peak for NORPLANT users was 33.9 mIU/ml as compared to 142 mIU/ml in the control group; and FSH was 13.0 mIU/ml as compared to 31.3 mIU/ml in controls. A subsequent rise in progesterone was observed in the 8 cycles studied, but the mean mid-luteal levels were significantly lower than in controls (9.0 ng/ml vs. 15.6 ng/ml). No differences were observed in the estradiol curve. Two of the subjects using NORPLANT had a laparotomy performed on days 17 and 20 of the cycle, for surgical sterilization purposes. A distinctive corpus luteum with a stigma was observed. Our results indicate that women under prolonged use of NORPLANT do not have normal endocrine cycles, even though they may ovulate. It is doubtful however, that these ovulatory cycles can be fertile under the abnormal endocrine conditions found in our subjects. In addition to the possible effect of luteal insufficiency, the normal maturation of the oocyte may be impaired.