Long-term contraception by steroid-releasing implants. II. A preliminary report on long-term contraception by a single silastic implant containing norethindrone acetate (ENTA) in women.

A preliminary report on the long-term contraceptive effectiveness and acceptability of a single subdermal silastic implant containing norethindrone acetate (ENTA) is presented. The 4 types of implants used varied in length, wall thickness, and amount of ENTA; implant A contained 20-25 mg ENTA, implant B contained 30-35 mg ENTA, implant C contained 45-50 mg ENTA as was longer than all the other implants, and implant D contained 40 mg ENTA and had a greater wall thickness than all the other implants. 213 women volunteers received a single implant and were followed for a total of 909 cycles. 2 of 13 women receiving implant A, 2 of 39 women receiving implant B, 3 of 76 women receiving implant C, and none of the 85 women receiving implant D became pregnant. Implant D had the longest expected life-span (10 months). Menstrual irregularities were fewest with implants A (23%) and D (20%), and greatest with implant C (42%). there were no complaints of nausea, insomnia, tender breasts, or loss of libido. 4 patients with implant B and 6 patients with implant C had the capsules removed for medical reasons. More detailed studies of implant D are in progress.     

Release of norethisterone from a bioabsorbable implant in female bonnet monkeys (Macaca radiata)

Bioabsorbable implants prepared by fusion of 85% norethisterone (NET) and 15% cholesterol were inserted subdermally in four cycling bonnet monkeys (Macaca radiata). No skin reaction or inflammation was observed at the site of implantation. Plasma concentration of norethisterone (NET) measured by radioimmunoassay were monitored for 14 to 16 months at monthly intervals. In the first month weekly samples were analysed. NET was released into circulation within 24 hours after insertion of the implant. In all the monkeys, except one, a sharp rise in NET (1.9 to 20 ng/ml) occurred immediately after insertion. Levels then remained between 1.7 and 0.6 ng/ml for about 4 months. Thereafter they remained steady up to about 9 months in two monkeys and gradually declined to about 0.4 ng/ml in the remaining two. In all except one, there was a sudden burst of NET release between the 10th and 11th month. The hormone almost cleared out of circulation by the 14th to 16th month. Initial menstrual cycles after pellet insertion were disturbed, leading to spotting and irregular bleeding. Regular cycles appeared from 5 to 8 months after the insertion of the implant. These cycles were ovulatory, as determined by the progesterone levels.     

Pharmacokinetic and pharmacodynamic studies of levonorgestrel-releasing intrauterine device

Intrauterine devices releasing 20 micrograms/day levonorgestrel were inserted in 10 women (ages 25-34). Bleeding and spotting patterns were recorded on a menstrual card during one year of follow-up. Blood samples were collected for radioimmunoassays of LH, estradiol (E2), progesterone (P) and levonorgestrel (LNG) and for sex hormone binding globulin (SHBG) 3 times a week during the 1st month of use, and twice a week during the 6th and 12th treatment months. Among the 10 women, two experienced irregular cycles with prolonged intermenstrual spotting, four had amenorrhea in the latter part of treatment months, while the other four had regular cycles. According to the serum levels of E2 and P, the hormone profiles were divided into four types of reaction: A) anovulatory, B) anovulatory but with high follicular activity, C) ovulatory but with luteal insufficiency, and D) ovulatory. Among the 29 treatment cycles, there were 10 D-type, 3 C-type, 13 B-type and 3 A-type of ovarian reactions: 44.8% of the cycles were ovulatory (C + D) and 55.2% were anovulatory (A + B). In general, serum levels of levonorgestrel were low in ovulatory cycles and were high in anovulatory cycles. The difference was statistically significant. There were marked individual differences. The decline of serum LNG from the 1st (492 pmol/l) to the 6th (320 pmol/l) treatment months was 34.9% on average. The amenorrheic cycles coincided mostly with the hormonal profile of ovulatory types, which indicated that the cause of amenorrhea is due to the local effect of levonorgestrel on the endometrium. The levonorgestrel levels were significantly correlated with serum SHBG, r = 0.8856, p less than 0.001, and with E2, r = 0.4661, p less than 0.05.     

Effect of long-term centchroman treatment on plasma steroid and peptide hormones in female rhesus monkeys (Macaca mulatta)

Effect of weekly oral administration of Centchroman (3,4-trans-2, 2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)-phenyl)-7-met hoxychroman) at 1 and 2.5 mg/kg for 12 months on plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone of female rhesus monkeys was studied. Centchroman administration at both doses did not disturb the menstrual pattern of rhesus monkeys except for a prolongation of the first treatment cycle. The subsequent cycles were of normal duration. The general pattern of plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone was not affected by Centchroman treatment. The basal and peak levels were similar in pretreatment, control and treatment cycles. The results clearly indicate that Centchroman treatment up to 1 year does not affect the hypothalamo-pituitary-ovarian axis in female rhesus monkeys.     

Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle

This study examined serum glycodelin concentrations and endometrial expression during the luteal phase following oral administration of levonorgestrel (LNG) at different stages of the ovarian cycle. Thirty women were recruited and allocated into three groups. All groups were studied during two consecutive cycles, a control cycle and the treatment cycle. In the treatment cycle, each woman received two doses of 0.75 mg LNG taken 12 h apart on days 3–4 before the luteinizing hormone (LH) surge (Group 1), at the time of LH rise (Group 2) and 48 h after the rise in LH was detected (Group 3). Serum progesterone (P) and glycodelin were measured daily during the luteal phase, and an endometrial biopsy was taken at day LH +9 for immunohistochemical glycodelin-A staining. In Group 1, serum P levels were significantly lower, serum glycodelin levels rose earlier and endometrial glycodelin-A expression was weaker than in Groups 2 and 3, in which no differences were found between control and treatment cycles. Levonorgestrel taken for emergency contraception (EC) prior to the LH surge alters the luteal phase secretory pattern of glycodelin in serum and endometrium. Based on the potent gamete adhesion inhibitory activity of glycodelin-A, the results may account for the action of LNG in EC in those women who take LNG before the LH surge.     

Ultrasonic measurement of ovarian follicles during chronic LRH agonist treatment for contraception

Ultrasonic examinations of ovarian follicles were performed in seven healthy women on continuous luteinizing hormone-releasing hormone (LRH) agonist treatment for contraception. Four of the women had 1-4 uterine bleedings during the four-month study period and the remaining three women developed amenorrhea. The follicle diameter varied during LRH agonist treatment up to or above the preovulatory size of the normal menstrual cycle in the menstruating group of women. No ovulation occurred as judged by the low progesterone levels in serum. Slightly raised progesterone concentrations (mean 7.6 nmol/l) were observed during four treatment cycles with persistent follicles indicating luteinization of unruptured follicles. No or only small ovarian follicles (8-10 mm) were visualized by ultrasound in the amenorrheic group of women. This study further establish previous reports that chronic LRH agonist treatment effectively inhibits normal ovulation in regularly menstruating women.     

A luteolytic effect of a prostaglandin F2α analogue in non-pregnant wohen?

Four healthy non-pregnant volunteers with regular cycles were exposed to vaginal suppositories containing a PGF_2α analogue (ICI 81.008, 500–600 μg) twice at 24-hour intervals in the early or mid-luteal phase. In comparison to serum progesterone levels of ovulatory control cycles, this treatment caused a significant decrease of serum progesterone combined with a shortening of the length of the luteal phase by 1.4 days. No gastrointestinal or other adverse effects were noticed during this treatment. Administration of ICI 81.008 in the follicular phase interfered neither with ovulation nor with the length or shape of the following luteal phase. Although limited, these data suggest a luteolytic effect of ICI 81.008 in women.     

Long-term contraception by steroid-releasing implants. IV. Biological effectiveness of norethindrone acetate (ENTA) implants in rats and rabbits.

In this study, results are presented on the long-term contraceptive effectiveness in the rats and rabbits of silastic implants containing either norethindrone acetate (ENTA) or norgestrel. A comparison of the relative biological potencies of ENTA administered by silastic capsule and by gavage, using inhibition of compensatory ovarian hypertrophy (COH) as the end point, showed that 25 times less norethindrone acetate was needed when administered by subcutaneous silastic implants than when administered orally. A single implant of ENTA releasing approximately 125 μg of ENTA/24 hr was found to be highly effective in preventing pregnancy in the rats and rabbits up to 4 months. Ovulation, in both species, was not suppressed.The major mode of action of ENTA so administered appeared to be mediated via the inhibition of implantation in the two species. Following removal of implant at the end of the treatment period, the fertility was restored within $\text{1}\text{to}\text{1}\text{1}\text{2}\text{months}$ in rats. The antifertility effects and the mode of action of norethindrone acetate released from subdermal silastic implants are discussed.     

Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women

The effects of nomegestrol acetate on circulating hormone levels, metabolic and hemostatic parameters and blood pressure were studied in 36 premenopausal women. The progestogen was administered from day 7 to 25 of the cycle during six cycles at a dosage (5 mg/d) known to inhibit ovulation. Analysis were performed before and in the third and sixth cycles. Estradiol and progesterone levels decreased significantly (p < 0.001) during treatment. Body weight, fasting blood glucose and insulin, total HOL and LDL cholesterol, apolipoprotein B. fibrinogen and plasminogen did not change significantly. Triglycerides in the third cycle (p < 0.05) and apolipoprotein Al levels (p < 0.01) in both periods of sampling decreased significantly. There was a significant increase in antithrombin III (p < 0.01). p ]These results indicate that nomegestrol acetate has no deleterious effect on blood glucose and lipids. The decrease in apolipoprotein Al and increase in antithrombin III may be related either to the decrease in estradiol levels induced by the treatment or to the effect of the progestogen itself.     

Serum profile of gonadotropins and ovarian steroids in women during six months of treatment with ORG 485-50

The effect of Org 485-50¹ on endocrine parameters of the pituitary and ovarian function has been studied in seven healthy women. Daily serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol-17β and progesterone were measured by specific radioimmunoassay throughout the control and seventeen treatment cycles during a drug trial period of six months. The results show that Org 485-50 at this dose caused anovulation in seven medication cycles. All other treatment cycles had a significant, though variable, suppression of progesterone secretion. The biphasic pattern of estradiol secretion was similar in control and medication cycles, but the overall output of estradiol decreased during prolonged treatment. Midcycle LH surge was abolished in seven and impaired in ten of the treatment cycles. It is noteworthy that the alteration of the hormone profiles caused by Org 485-50 was markedly different between the individuals. The changes of the endocrine parameters indicative of anovulation or inadequate corpus luteum function were, in different individuals, constant or variable during treatment with Org 485-50.     

Hormonal assessment of women submitted to tubal ligation

Sixteen fertile women aged 30-35 years with regular menstruations were studied before and 6 months after tubal ligation (TL). The diagnosis of ovulation was based on clinical ultrasonographic and hormonal parameters [follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2 and P4]. The menstrual pattern did not vary before and after surgery. Follicular or luteal phase FSH and E2 levels did not differ between the pre- and post-TL period. Luteinizing hormone levels on days -2 and 0 of the follicular phase were significantly higher during the post-TL period, while no difference was observed for the luteal phase. P4 levels during the follicular phase did not differ between the two periods, except for day -4, while they were lower during the post-TL luteal phase. The results of the study suggest that in the present patient group, no modifications in the menstrual pattern could be observed 6 months after TL, and TL appears not to interfere with ovulation. Luteinizing hormone levels showed an increase during the ovulatory period after TL, and progesterone secretion decreased during the post-TL luteal phase.     

Effects of a new oral progestagen on pituitary-ovarian function

A new progestagen, Org 3236 (13-ethyl-11-methylene-18, 19-dinor-17α--pregn-4-en-20-yn-3-one), which is a 3-keto derivative of another new progestagen, Org 2969 (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4--en-20-yn) was administered to seven healthy female volunteers in doses 0.025 mg/day (3 volunteers) and 0.050 mg/day (4 volunteers) to evaluate its biological properties. The function of the hypophyseal-ovarian axis was tested by measuring serum follicle stimulating hormone, luteinizing hormone, estradiol and progesterone daily on days 7–23 of two consecutive cycles, of which the first served as a control. Org 3236 was given on days 1–21 during the second menstrual cycle. The results revealed that ovulation was inhibited in 3 out of 4 volunteers with the 0.050 mg daily dose. Also in the fourth volunteer the occurrence of ovulation is questionable. In the group with a daily dose of 0.025 mg two of the three volunteers had anovulatory treatment cycles. The ovulation inhibiting activity of Org 3236 is comparable to that reported for Org 2969.     

Postovulatory contraception in women with large doses of norethindrone

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

Endometrial histology and progesterone levels in women using norethindrone acetate implants for contraception

The effect of a single implant-D containing 40 mg of norethindrone acetate on the endometrium and serum progesterone, and its mode of contraceptive action was investigated. 20 women aged 20-40 (parity 1-5) had used implant-D for periods of 7-27 months. Endometrial biopsies and peripheral venous bloods were collected between the 16th-28th days of the menstrual cycle. Endometrial dating was done according to the criteria of Noyes et al. 19 of the 20 biopsies taken showed the endometrium in the secretory phase, and serum progesterone levels above 3 ng/ml confirming that ovulation had occurred. The biopsy of the remaining woman showed proliferative endometrium and serum progesterone of 2.15 ng/ml. The dating of the endometrium revealed disparity between stromal, glandular, and vascular components of the specimens; thus, only approximate dates could be assigned to a particular specimen. In the dating of the endometrium, 5 women showed retardation by more than 3 days and 4 women showed enhancement of 3 or more days. The results show that the norethindrone-acetate-containing silastic implant-D does not inhibit ovulation and 1 mode of its interaction in fertility control is by bringing about an imbalance in endometrial maturation during the luteal phase.     

补肾益气胶囊治疗卵巢早衰临床效果观察

目的:观察补肾益气胶囊治疗卵巢早衰的临床疗效及安全性。方法:将41例卵巢早衰患者随机分治疗组21例采用补肾益气胶囊治疗,对照组20例采用口服倍美力治疗。两组均连续治疗3个疗程(3个月为1疗程),分别观察两组的临床疗效及治疗前后患者血清E2、FSH、LH、P、PRL水平及外周T淋巴细胞亚群的变化。结果:治疗组临床治愈8例,显效7例,有效4例,无效2例,有效率90.48%;对照组临床治愈4例,显效7例,有效3例,无效6例,总有效率70.00%,两组差异有统计学意义(P<0.05)。两组患者治疗前血清FSH、E2、LH、P、PRL含量比较差异无统计学意义(P>0.05);两组患者治疗后血清E2、P含量水平升高,而FSH、LH、PRL含量水平下降,与治疗前比较差异有统计学意义(P<0.01)。两组患者治疗前外周血T淋巴细胞亚群CD3+、CD4+、CD8+、CD4+/CD8+比值比较差异无统计学意义(P>0.05);治疗组治疗后CD3+、CD4+、CD4+/CD8+比值上升,CD8+含量下降,与对照组比较差异有统计学意义(P<0.01)。结论:补肾益气胶囊能明显改善卵巢早衰患者的临床症状,具有良好的治疗作用。     

Two oral contraceptives, efficacy, serum proteins, and lipid metabolism. A comparative multicentre study on a triphasic and a fixed dose combination

A triphasic, combined oral contraceptive containing 30 - 40 - 30 micrograms ethinyloestradiol (EE), and 50 - 75 - 125 micrograms levonorgestrel was compared with a fixed dose combination containing 30 micrograms EE and 150 micrograms desogestrel in a randomized multicentre trial in 193/199 women and 1 063/1 073 cycles, respectively. The duration of the trial was six months. Eleven centres in Denmark, Sweden, and Norway participated. Contraceptive reliability, bleeding control and side effects were evaluated. Influence on serum sex hormone binding globulin (SHBG) and transcortin was assayed as well as lipid metabolism. Three pregnancies occurred in the group using the triphasic regimen but none in the fixed dose regimen. Two of the three pregnancies were considered drug failures and the third a possible interaction. Possible reasons for the triphasic contraceptive failure are discussed with special reference to a British report on eight pregnancies. Bleeding control appeared to be equally good for the two preparations. However, the number of cycles with spotting, breakthrough bleeding and missed withdrawal bleeding were above the levels reported earlier on the triphasic regimen. About 80 per cent of the women completed the planned six months on either combination. Side effects were generally mild and in accordance with earlier reports on low dose oral contraceptives. Metabolically the triphasic levonorgestrel combination increased SHBG 100 per cent versus 200 per cent for the fixed desogestrel combination. Transcortin rose about 98 and 110 per cent, respectively. Both preparations induced similar changes in the levels of lipids and lipoproteins with the exception of a significant increase in the arachidonic content of cholesterol during treatment with the desogestrel-containing preparation.     

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

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

坤泰胶囊联合黄体酮对围绝经期功能失调性子宫出血患者性激素水平的影响

目的 探讨坤泰胶囊联合黄体酮对围绝经期功能失调性子宫出血患者性激素水平的影响。方法 126例围绝经期功能失调性子宫出血患者随机分为两组各63例,对照组采用黄体酮治疗,观察组采用坤泰胶囊联合黄体酮治疗,比较两组治疗前后的肾阴虚证症状评分及性激素水平。结果 治疗3个月后,观察组的盗汗、失眠、腰膝酸软、耳鸣、五心烦热评分均显著低于对照组（P <0.05）。治疗3个月后,观察组的血清FSH、 LH水平均显著低于对照组,E2水平显著高于对照组（P <0.05）。结论 坤泰胶囊联合黄体酮可有效改善围绝经期功能失调性子宫出血患者的肾阴虚证症状,调节患者的性激素水平。     

A pilot study on the assessment of a progesterone/estradiol sustained release as once-a-month-injectable contraceptive

A pilot study to assess the use of natural hormones in macrocrystalline sustained release system was undertaken in normal menstruating women. Progesterone at a dose of 100 mg in combination with 5 mg estradiol-17 beta aqueous macrocrystalline suspension (3ml) of defined particle size range (100-250 microns) were administered to five female volunteers of reproductive age, on day 5 of their normal menstrual cycles and then every 28 days consecutively for the next two months. Peripheral venous blood samples were obtained from the women three times a week for 60 days after the third injection for the measurement of serum progesterone, estradiol-17 beta, LH and FSH. The menstrual bleeding patterns were closely monitored during the study period. The results obtained indicate that the exogenous hormone administration produces blood levels similar to those observed during the luteal phase of the menstrual cycle. Follicular maturation as assessed by endogenous estradiol rise, above 150 pg/ml, occurred 29.7 days s.d. 6.4 after the injection. Ovulation as measured by progesterone levels above 5 ng/ml was documented 34.4 days s.d. 4.3 after the third injection. The bleeding patterns were regular though initially shorter but these increased progressively towards normal pattern during course of the study. The data suggest that progesterone/estradiol-17 beta combination administered as an aqueous macrocrystalline suspension is capable of producing sustained ovulation inhibition and could be applied in the design of new once-a-month injectable contraceptives.     

The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy

In a group of 5 women on long-term anticonvulsant and oral contraceptive therapy, the plasma ethynylestradiol (EE) concentration on 50 μg EE daily was 11.1 ± 4.5 pg/ml. These values were at the lower end of the range found in normal women in this laboratory taking 30 μg EE daily (6–190 pg/ml). Four women have been studied prospectively for 3 months, over 1 cycle before and 2 cycles during phenobarbital 30 mg b.i.d. therapy. Significant falls in the plasma EE concentration were seen in two women (from 104.8 ± 13.4 to 37.7 ± 2.0 pg/ml and from 125.6 ± 23.8 to 34.8 ± 6.7 pg/ml p < 0.01) and breakthrough bleeding was seen in both women. No changes in plasma concentrations of follicle stimulating hormone, progesterone, norethindrone or norgestrel were seen. There was a significant increase in the sex hormone binding globulin capacity from 100.7 ± 5.8 to 133.3 ± 1.2 nmoles/1 (p < 0.05). These changes are consistent with the known microsomal enzyme inducing effect of phenobarbital.