Single luteal phase serum progesterone assay as an indicator of ovulation. 1972.
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Biomarkers↗
Biomedical subjects
D R Mishell
Publications and source records attributed to D R Mishell.
Levonorgestrel concentrations during use of levonorgestrel rod (LNG ROD) implants.
In a three-year randomized trial that included 398 women, blood samples were collected for the purpose of assaying levonorgestrel concentrations in women using a new two-rod contraceptive implant system or an earlier implant formulation, Norplant-2 implants. Sample collection was at 1, 3, 6, 9, and 12 months after placement and semiannually thereafter through three years. Resulting assays and analyses showed that levonorgestrel concentrations of each implant formulation decreased significantly with time after placement, with increasing body weight, and with ponderal index. In the third year, several measures indicated that concentrations of the contraceptive drug were higher in women using the LNG ROD implants than in users of the original formulation. No pregnancies occurred among women in either group in the three years. This study provides evidence that the minimum levonorgestrel concentration needed to protect against pregnancy is below 200 pg/ml, and possibly is below 175 pg/ml.
Adolescent↗
Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.
From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.
Administration, Intravaginal↗
Effect of different insertion regimens on side effects with a combination contraceptive vaginal ring.
The study population included 159 women aged 18 to 37 years requiring contraception (60 in Sydney, 99 in Los Angeles). The design consisted of a 6 month study of a contraceptive vaginal ring (CVR) releasing 20 micrograms ethinyl estradiol and 1 mg of norethindrone acetate daily over two successive cycles with a new ring on each of three different insertion regimens. A total of 831 woman-months of exposure were recorded, and 129 women completed the study. The overall incidence of side effects was similar in the two centers and differences between the insertion regimens were not observed. Transient nausea following insertion of a new ring (mainly lasting 0.5 to 48 h) was the most prominent side effect, with no significant difference between the insertion regimens (although the incidence tended to be highest with bedtime insertion [34%] and lowest with early evening insertion and temporary removal during the first night [27%]). Transient vomiting occurred in about 10% of women in the first 24 h after first insertion of a new ring. The incidence and severity of nausea was greatly reduced in cycle 2 with each regimen (6% to 9% of women). Nausea could be prevented by overnight soaking of the ring in water before use. Other side effects such as headache, dizziness, uterine cramps, breakthrough bleeding, weight gain, and ring expulsion occurred with similarly low frequency in all three insertion groups. One pregnancy occurred with probable ovulation between cycles 5 and 6, the only pregnancy recorded to date in studies with this ring. The study demonstrated that this effective and generally well tolerated CVR causes a relatively high incidence of transient nausea after insertion of a new ring, which is probably due to accumulation of ethinyl estradiol on the ring surface during storage. Acceptability is still high, and this particular CVR merits further development.
Adult↗
First week drug concentrations in women with levonorgestrel rod or Norplant capsule implants.
Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p < 0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p < 0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.
Adolescent↗
Colposcopic evaluation of a vaginal gel formulation of iota-carrageenan.
There is an urgent need to develop safe, effective, and acceptable vaginal products for the prevention of sexually transmitted infections. Preliminary in vitro results suggest that vaginal formulations of sulfated polysaccharides, including iota-carrageenan, have the potential to block mucosal transmission of human immunodeficiency virus (HIV). Twenty-five women in five sites participated in Phase I trials to evaluate the safety of a formulation containing iota-carrageenan (PC 213). The results of this study indicate that a 5 mL 2% gel formulation of iota-carrageenan is not associated with significant irritation of the female reproductive tract when administered once daily in the absence of sexual intercourse. Given the small number of participants in this initial study, careful observation for potential irritation must also be included in larger studies of this and other vaginal formulations.
Administration, Intravaginal↗
Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy.
OBJECTIVE: To investigate whether the incidence of persistent ectopic pregnancy after linear salpingostomy can be reduced by prophylactic administration of a single dose of methotrexate postoperatively. METHODS: Women who underwent linear salpingostomy for treatment of unruptured ectopic pregnancy and who agreed to participate in the study (n = 129) were randomly assigned to the prophylaxis or control group. Women with anemia, renal insufficiency, or liver disease were excluded. In the prophylaxis group, patients received a single dose of methotrexate, 1 mg/kg intramuscularly, within 24 hours postoperatively. No treatment was used in the control group. Both groups were followed with serial serum beta-hCG titers; titers were measured on the seventh postoperative day, then every 72 hours until levels were lower than 15 mIU/mL. A blood count and chemistry panel were also obtained on postoperative day 7, and any side effects related to methotrexate were noted. Persistent ectopic pregnancy was defined as a rise in the serum beta-hCG level or a decline of less than 20% between two consecutive measurements taken 3 days apart. RESULTS: A total of 116 women completed the postoperative follow-up: 54 in the prophylaxis group and 62 in the control group. Ten women had persistent ectopic pregnancy, one in the prophylaxis group (1.9%) and nine among the controls (14.5%); this difference was statistically significant (P < .05). The relative risk of developing persistent ectopic pregnancy after prophylactic methotrexate was 0.13 (95% confidence interval 0.02, 0.97). Three women (5.5%) reported mild side effects after methotrexate, but these resolved spontaneously. CONCLUSION: The incidence of persistent ectopic pregnancy was significantly reduced after a single prophylactic dose of systemic methotrexate administered postoperatively. This regimen is safe and can be used to decrease the extent of postoperative monitoring after conservative treatment of unruptured ectopic pregnancy.
Adult↗
Pregnancy and the timing of intercourse.
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Female↗
Performance of the TCu380A and Cu-Fix IUDs in an international randomized trail.
To compare the clinical performance of the TCu380A, the most widely used copper IUD in the world today, and a new frameless device, the Cu-Fix, we report results from a randomized international two-year clinical trial involving 874 parous women followed for an average of fourteen months. Event rates at the end of two years (per 100 women) for pregnancy were 0.0 for the TCu380A and 1.5 for the Cu-Fix. Termination due to expulsion was significantly less for TCu380A as compared with Cu-Fix users (2.0 and 11.4 per hundred women, respectively); other medical reasons for termination (bleeding/pain, pelvic inflammatory disease (PID), and other) did not differ significantly. PID incidence rates at two years were 1.0 per hundred women for the TCu380A and 1.6 for the Cu-Fix (equivalent to 6.0 and 8.3 per 1,000 woman-years, respectively). The net cumulative continuation rates at two years per hundred women were 78.8 for TCu380A, and 71.9 for the Cu-Fix. Both IUDs provide highly effective protection against pregnancy, but the TCu380A has a lower expulsion rate. The low rate of PID indicates that it is an in-frequent occurrence in appropriately selected candidates.
Adolescent↗
The use of misoprostol for termination of early pregnancy.
Misoprostol is a prostaglandin analogue which has uterotonic properties. Administered vaginally, it is an effective agent for induction of second trimester abortions. This study was undertaken to determine if the vaginal administration of misoprostol is effective for inducing first trimester abortions. Fifty-eight women with pregnancies less than 10 weeks gestation who desired pregnancy termination received varying dosages of vaginal misoprostol, either alone or in combination with laminaria or tamoxifen. The overall success rate for a complete abortion was 61%. The use of laminaria or tamoxifen did not affect success rates. Abortions occurred within 24 hours of administration of misoprostol. Side effects were minimal. There were no significant differences in any of the following between those who had a successful abortion and those who did not: gravidity, parity, prior elective abortion, age, gestational age of the pregnancy, and level of human chorionic gonadotropin. Although not as successful as other combination regimens, misoprostol alone is readily available, easy to administer, and without major side effects. The use of this agent could eliminate the need for about two-thirds of surgical abortions in the first 10 weeks of gestation.
Abortifacient Agents, Nonsteroidal↗
A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
OBJECTIVE: Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester. STUDY DESIGN: Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 micrograms of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostol. RESULTS: The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, 15.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead. CONCLUSIONS: Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy.
Abortifacient Agents, Nonsteroidal↗
Pharmacokinetics of depot medroxyprogesterone acetate contraception.
Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension of 17-acetoxy 6-methyl progestin administered by intramuscular injection for long-term contraception. This highly effective injectable formulation of medroxyprogesterone acetate (MPA) has a prolonged duration of action since the progestin is released slowly from the muscle. MPA is detected in the serum within 30 minutes after an injection of 150 mg. Serum concentrations vary between individual women but generally plateau at about 1.0 ng/mL for about three months, after which there is a gradual decline. In some women, MPA can be detected in the serum for as long as nine months after a single injection of 150 mg. The circulating MPA initially inhibits the midcycle leutinizing hormone (LH) peak, but LH and follicle stimulating hormone (FSH) levels remain in the range of those for the luteal phase of a pretreatment control cycle. Since ovulation is inhibited, serum progesterone levels remain low (< 0.4 ng/mL) for several months following an injection of DMPA. When MPA levels fall below 0.1 ng/mL, ovulation resumes. Thus, return to fertility is delayed for several months if a woman wishes to conceive after receiving one or more injections of DMPA. Following an injection of DMPA, serum estradiol levels initially are in the early to midfollicular phase range (mean approximately 50 pg/nL). Serum estradiol levels begin to rise about four months after a single injection when MPA levels fall below 0.5 ng/mL. For women who have used DMPA for several years, serum estradiol levels range between 10 and 92 pg/mL, with mean levels of about 40 pg/mL. Despite these low levels of estradiol, hot flushes are a rare event, and the vaginal epithelium remains moist and well rugated. Women using DMPA for several years do not observe a change in breast size. DMPA causes the endometrium to become atrophic, with small, straight endometrial glands and decidualized stroma. The cervical mucus remains thick and viscid. DMPA is a very effective form of contraception because of its multiple mechanisms of action and slow release into the circulation.
Contraceptive Agents, Female↗
The acceptability of a combined oestrogen/progestogen contraceptive vaginal ring.
The acceptability of a vaginal ring releasing ethinyl oestradiol 20 mcg per day and norethindrone acetate 1 mg per day was assessed during a six-month phase II trial comparing three different regimens, which was carried out simultaneously in Los Angeles and Sydney. Sixty women were enrolled in Sydney and 90 in Los Angeles. On admission into the study, the women were asked to complete a questionnaire which gave details of age, last contraceptive method used, contraceptive methods used in the past and their reason for liking or disliking previous contraceptive methods, as well as their reason for stopping the last method. On completion of the study or leaving the study for any reason, each woman was asked to complete an acceptability questionnaire which included her experiences with the ring and the rating of the method. The responses to these two questionnaires form the basis of this report. The overall rating of the ring was similar in both the Sydney and Los Angeles groups. Sixty-nine percent of women rated the method as very good. Seventy-two percent of women in Los Angeles and 62% of women in Sydney liked the ring much more than their most liked previous method. In both groups the method they liked best apart from the ring was the pill (62% in Sydney and 53% in Los Angeles). The major reasons for liking the ring were convenience of use, effectiveness and no requirements for taking medication daily. Most women in both studies would recommend the ring to others (92% in Sydney and 89% in Los Angeles).
Adolescent↗
A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy.
BACKGROUND: The most widely used medical method of terminating second-trimester pregnancy is the intravaginal administration of prostaglandin E2 (dinoprostone [PGE2]). This treatment is highly effective but is associated with severe gastrointestinal side effects and hyperpyrexia. METHODS: We conducted a prospective, randomized trial comparing the efficacy and safety of misoprostol, a prostaglandin E1 analogue (200 micrograms intravaginally every 12 hours), with the efficacy and safety of PGE2 (20 mg intravaginally every 3 hours). The study population included 55 pregnant women between 12 and 22 weeks' gestation who were undergoing termination of pregnancy for either intrauterine fetal death (37 women) or medical or genetic reasons (18 women). RESULTS: The rate of successful abortions within 24 hours was 81 percent (22 of 27 women) with PGE2 and 89 percent (25 of 28 women) with misoprostol (P = 0.47). All the women who received misoprostol had successful abortions within 38 hours. Among those who had an abortion within 24 hours, the mean interval from treatment to abortion was similar in both groups (10.6 hours with PGE2 and 12.0 hours with misoprostol, P = 0.33). The rate of complete abortion, defined as the passage of the fetus and the placenta simultaneously, was 32 percent for PGE2 and 43 percent for misoprostol (P = 0.56). Certain side effects were more frequent in the women receiving PGE2 than in those receiving misoprostol: pyrexia (63 percent vs. 11 percent; P < 0.001), uterine pain (67 percent vs. 57 percent, P = 0.58), vomiting (33 percent vs. 4 percent, P = 0.005), and diarrhea (30 percent vs. 4 percent, P = 0.012). The average cost per treatment was $315.30 for PGE2, as compared with $0.97 for misoprostol. CONCLUSIONS: Misoprostol is at least as effective as PGE2 for the termination of second-trimester pregnancy involving either a dead or a living fetus, but it is less costly, is easier to administer, and is associated with fewer adverse effects.
Abortion, Induced↗
A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol.
A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.
Administration, Intravaginal↗
Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol.
A core design contraceptive vaginal ring (CVR) with average daily release of 650 mcg of norethindrone acetate (NA) and 30 mcg of ethinyl estradiol (EE) inhibited ovulation and controlled vaginal bleeding well, but caused some nausea. This study was designed to minimally alter the dose of steroid to see if nausea could be reduced without loss of contraceptive efficacy. This 30/650 CVR was compared to a CVR releasing 20 mcg of EE and 1000 mcg of NA (20/1000) and another releasing 25 mcg of EE and 650 mcg of NA (25/650) in 69 subjects. Twenty-three subjects using an oral contraceptive containing NA/EE served as controls. Ovulation inhibition was excellent and comparable to the OC for all formulations. The CVR provided better control of vaginal bleeding than did the OC. Side effects were equivalent to the OC with the exception of a slight increase in nausea in CVR users. Lipid changes and globulin increases were comparable to oral contraceptive users. The 20/1000 CVR increased sex hormone binding globulin-binding capacity less than the other two CVRs. The performance of the three CVRs was not significantly different, but the 25/650 showed a trend of reduced performance relative to the other two formulations.
Administration, Intravaginal↗
Breast cancer risk with oral contraceptives and oestrogen replacement therapy.
A detailed review of the international epidemiological literature is very reassuring in confirming that exogenous oestrogen in oral contraceptives and postmenopausal hormone replacement therapy does not induce breast cancer in women. However, there may sometimes be a promotional effect which accelerates the time of breast cancer diagnosis in certain subgroups of women. This promotional effect may occur in young oral contraceptive users, and in long term users of high dose oestradiol postmenopausal replacement formulations. Use of oral contraceptives while young may protect against the development of breast cancer after age 45. Physiological doses of conjugated equine oestrogens do not appear to increase breast cancer risk even with long-term postmenopausal use. Current data do not support an effect of progestogens in increasing or decreasing risk of breast cancer.
Adult↗