Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer

The objective of this study was to compare the implantation rate, pregnancy rate and endometrial thickness of frozen-thawed embryo transfers using endometrial preparation with either an artificial cycle or stimulated cycle. This was a prospective randomized trial at a single academic IVF centre. Seventy-seven patients undergoing artificial cycles received oral oestradiol; patients with endometrium < 7 mm on day 9-10 were switched to vaginal oestradiol. Eighty-six patients undergoing stimulated cycles received recombinant FSH followed by human gonadotrophin hormone injection. Vaginal progesterone was begun 2 or 3 days prior to embryo transfer. There was no difference in implantation rate (8.5% versus 7.3%), pregnancy rate (16% versus 13%), cancellation rate (both 23%) or endometrium thickness (8.7 +/- 1.1 mm versus 8.7 +/- 1.0 mm) between artificial and stimulated cycles. Stimulated cycles had a higher incidence of thin endometrium (27% versus 5%, P < 0.01). In artificial cycles, patients switched to vaginal oestradiol had improved pregnancy rate (31%) versus patients who received oral oestradiol alone (13%) (P = 0.05). It is concluded that artificial and stimulated cycles produce comparable pregnancy rates, implantation rates, cancellation rates and endometrial thickness, although stimulated cycles have a higher incidence of thin endometrium. Vaginal oestradiol supplementation improved implantation rates.     

The emergency contraceptive drug, levonorgestrel: a review of post-coital oral and peri-coital vaginal administration for prevention of pregnancy

The objective of our study was the evaluation and elucidation of levonorgestrel (LNG) as emergency contraception (EC) administered through oral and vaginal routes. Data regarding post-coital oral and peri-coital vaginal application of LNG were extracted from the literature through MEDLINE database service for years 2001-2010. It was found that a single dose of 1.5 mg LNG or two doses of 0.75 mg LNG 12 h apart were used for EC. Currently, LNG is also on trial for vaginal application as EC in Carraguard gel for 'dual protection'. The oral or vaginal dose of 1.5 mg LNG resulted in peak plasma concentration, C(max) 19.2 or 3.21 ng/ml, with shorter time, T(max) 1.4 or 6.6 h, and greater AUC, 152.7 or 52.5 ng.h/ml, with shorter half-life, 25 or 32 h, respectively. LNG EC inhibited mid-cycle LH surge and delayed or prevented ovulation when administered before ovulation. Mechanism of action of LNG EC appeared to inhibit or delay ovulation. The risk of pregnancy was 4.12%. A single dose of 1.5 mg LNG could reduce the pregnancy rate to 0.7%. Occurrence of ectopic pregnancy following failure of LNG EC was reported. This EC caused no serious adverse effects but was associated with menstrual disturbance. Although widely acceptable, the cost and short-supply to rural areas pose a barrier to access EC for the poor and rural-dwellers, respectively. It was concluded that unlike post-coital oral administration, peri-coital vaginal application of 1.5 mg LNG needs further study to be an alternative option for women to use it for prevention of pregnancy.     

复方左旋18-甲基炔诺酮避孕片阴道持续和间断用药的临床比较

500例育龄妇女、志愿受试者，随机分为二组。阴道应用含左旋18－甲基炔诺酮0.25mg、炔雌醇0．05mg的避孕片。比较持续用药和间断用药的避孕效果、可接受性和副作用。间断用药组（249例）于每个月经周期的第5～25天，每天阴道塞药一片；连续用药组（251例）每天阴道塞药一片，二组的观察期都为一年。结果：两种给药法无一例因药物而失败。用药前后的血压、体重、血红蛋白含量、红细胞压积和红细胞数均无明显差异。月经周期在间断用药组与用药前比较无明显差异；但在连续用药组，多数对象在用药期间持续闭经，仅少数对象在头二个月中有月经。各种副作用的总发生率连续用药组高于间断用药组，主要副作用为恶心、乳房胀痛和腹痛等。用药后患宫颈炎的病例较用药前增加，但两组间无明显差别。两组相比，间断用药组的月经周期规则，点滴出血率低。因药物之故的停药率，两组间无明显区别。     

Progesterone supplementation during cryopreserved embryo transfer cycles: efficacy and convenience of two vaginal formulations

Sequential exogenous oestradiol and progesterone are often used to prepare the endometrium in frozen embryo transfer (FET) cycles. This open-label, randomized study compared the efficacy and acceptability of self-administered once daily vaginal progesterone gel and vaginal micronized progesterone tablets (three times daily) for luteal support in FET cycles. An Asian population of women (aged < or = 45 years) were assigned randomly to receive progesterone gel (90 mg, once daily, n= 100) or vaginal micronized progesterone tablets (200 mg, three times daily, n= 100). All received oestradiol from day 2 of the menstrual cycle, for at least 10 days (or until endometrial thickness was > or =8 mm), before self-administering progesterone for 2 days before FET and up to 14 weeks afterwards if pregnancy occurred. Clinical pregnancy rates (31% for gel and 28% for tablets) and implantation rates (9.8% and 8.8%, respectively) were not significantly different between the treatment groups. Asian women using once daily progesterone gel found the gel easy to use and comfortable, and preferred it to their previous experience of vaginally administered tablets. In summary, once-daily vaginal progesterone gel has similar efficacy to vaginal tablets and is associated with high patient satisfaction.     

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

OBJECTIVE: To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. DESIGN: This was an open-label study. PATIENTS: Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. MAIN OUTCOME MEASURES: Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. RESULTS: Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. CONCLUSIONS: The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.     

Experience with ethynodiol diacetate and mestranol as an oral contraceptive

A study was made in Bombay, India of oral contraception using 2 combinations of ethynodiol diacetate and mestranol in 521 women over a period of 3 years with a total of 5196 menstrual cycles. The women were divided into 2 groups: 1 using 1 mg of ethynodiol diacetate plus .1 mg of mestranol and the other using .5 mg of ethynodiol diacetate and .1 mg of mestranol. 70% of the women studied were aged 21-30 years. Women over 35 and those with more than 3 children were urged to undergo operative procedures. Most had used no contraceptive method previously, 56.6% desired planned families, and 43.4% wanted no more children. There was a monthly interview when a new supply of tablets was distributed. No pregnancies followed in either group when tablets were taken regularly, but 2 did occur otherwise. Side effects were most severe during the first cycle. 55 women (10.5%) discontinued medication at the end of 3 years because of side effects. 267 discontinued the program because pills were not available near their homes. Of these, 71 became pregnant over the 3-year period, only 10 of whom desired pregnancy. None showed evidence of thromboembolic phenomena. Liver function tests showed no change. The cycle length of most women taking the preparations became more regular at 27-28 days. There was little difference in side effects of the 2 preparations.     

A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 micrograms/20 micrograms versus triphasic norethindrone/ethinylestradiol 500-750-1000 micrograms/35 micrograms: a multicenter, randomized, open-label study.

OBJECTIVES: This multicenter, randomized, open-label study was undertaken to compare the effects on menstrual cycle control of two oral contraceptive regimens: monophasic levonorgestrel (LNG) 100 micrograms/ethinylestradiol (EE) 20 micrograms (Alesse or Loette) and triphasic norethindrone (NET) 500-750-1000 micrograms/EE 35 micrograms (OrthoNovum 7/7/7). METHODS: Healthy women with normal menstrual cycles were enrolled and completed up to four cycles of study medication. A total of 384 cycles in the LNG/EE group and 400 cycles in the NET/EE group were evaluable for analysis of cycle control. RESULTS: For all treatment cycles, the percentage of cycles classified as normal was consistently higher in the LNG/EE group than in the NET/EE group. By cycle 4, 69.9% of cycles with LNG/EE and 54.4% with NET/EE (p < 0.05) were normal. In individual cycles, consistently lower occurrences of intermenstrual bleeding (total bleeding and/or spotting) were seen for the LNG/EE group, although these differences were not statistically significant. Withdrawal bleeding characteristics were comparable between the two groups, except for the length of the latent period, which was significantly longer in the LNG/EE group. The incidence of treatment-emergent adverse events was similar in the two groups. CONCLUSION: This study indicates that the monophasic LNG/EE 100 micrograms/20 micrograms provides better cycle control than the multiphasic NET/EE product, despite its lower EE dose.     

Noncomparative contraceptive efficacy of cellulose sulfate gel

OBJECTIVE: To estimate the 6-month cumulative probability of pregnancy, short-term adverse effects, and acceptability of cellulose sulfate vaginal contraceptive gel. METHODS: Two hundred fertile heterosexual couples were enrolled in this single-center, phase II, 6-month noncomparative study conducted at the California Family Health Council in Los Angeles, California. Couples did not desire pregnancy, were at low risk for sexually transmitted diseases, and agreed to use 3.5 mL of cellulose sulfate gel intravaginally before each coital act as their primary means of contraception. Scheduled follow-up visits took place after one menstrual cycle and at study completion, which occurred after 6 months and six menstrual cycles had elapsed. In addition, participants were instructed to call the site at the onset of each menses to review their diary cards. RESULTS: The cumulative probabilities of pregnancy during 6 months and six cycles of typical use were 13.4% (95% confidence interval [CI] 7.5-19.4%) and 13.9% (95% CI 7.7-20.2%), respectively, and during 6 cycles of correct and consistent ("perfect") use: 3.9% (95% CI 0.0-9.2%). Slightly over one fourth of the women and one man reported experiencing gel-related adverse events, two thirds of which were mild and only possibly related to the gel. Three quarters of women and men reported that they would buy cellulose sulfate gel for contraception. CONCLUSION: Cellulose sulfate vaginal gel yields pregnancy rates comparable to nonoxynol-9 and few adverse events among couples at low risk for sexually transmitted diseases.     

Norgestrel and ethynyl estradiol: a new low-dosage oral agent for fertility control

To study the safety and efficacy of a norgestrel-ethinyl estradol oral contraceptive compound, 300 Mexican women, 16-42 years of age were orally administered .5 mg norgestrel and .05 mg ethinyl estradiol (Ovral) daily over a total of 3175 study cycles. Most of the women were poor., uneducated and of high parity. None of the patients in the study became pregnant, even in the cycles where 1 or more doses were omitted. The menstrual cycle remained basically unaltered with breakthrough bleeding or spotting sometimes reported, usually when doses were missed. Unexplained amenorrhea occurred in 1.2% of the cycles. Though 5% of the women were ovulatory at one time of another as determined by pregnandiol levels, no pregnancy resulted, which is probably explained by changes in the cervical mucus caused by the pills making an inhospitable environment for sperm migration. Psychosomatic-related side-effects included nausea, headache and decreased libido in less than 1% of the cycles. Chloasma aggravated by poor dietary intake occurred in .5% of the cycles. No malignant, peripheral vascular or other serious disease occurred during the treatment and no significant endometrial alterations were seen.     

Human vaginal leukocytes and the effects of vaginal fluid on lymphocyte and macrophage defense functions.

OBJECTIVES: The purpose of this study was to quantify, characterize, and further define the role of vaginal white blood cells in defense mechanisms and human immunodeficiency virus infection. STUDY DESIGN: Vaginal lavages were obtained from five healthy women throughout three menstrual cycles. Lymphocyte subpopulations, macrophages, and granulocytes were characterized and quantified by an immunohistologic technique. Vaginal lavage fluid was added to peripheral blood mononuclear cells, and effects on cell viability, lymphocyte proliferation, macrophage phagocytosis, and expression of various cell surface molecules critical to immunologic functions were assessed. Data were analyzed by Student's t test. RESULTS: Few lymphocytes were found at any stage of the menstrual cycle; however, granulocytes and macrophages were abundant at menstruation and present at low levels through the proliferative phase. Vaginal lavage fluid collected during menses, at midcycle, and after coitus suppressed mitogen-induced lymphocyte proliferation but had no effect on surface expression of human leukocyte antigen or CD4 antigens, or on macrophage function. Likewise, low pH (less than 5.0) medium significantly inhibited lymphocyte proliferation but had no effect on macrophage phagocytosis. The spermicide nonoxynol 9 was toxic to both lymphocytes and macrophages. CONCLUSION: White blood cells, including lymphocytes and macrophages, are infrequently present in cervicovaginal secretions of healthy women except during menses; the vaginal environment may effect their function.     

Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts

OBJECTIVE: To compare the efficacy and tolerability of the levonorgestrel intrauterine system (LNG IUS) with mefenamic acid in the management of objective idiopathic menorrhagia. DESIGN: Phase III, Single centre, open, randomised, comparative, parallel group study. SETTING: District General Hospital in the United Kingdom. POPULATION: Fifty-one women with objective menorrhagia. METHODS: Twenty-five women randomised to receive the LNG IUS and 26 to oral mefenamic acid for six cycles. MAIN OUTCOME MEASURES: Change from baseline in menstrual blood loss (MBL), total menstrual fluid loss (TMFL) and pictorial blood loss assessment chart (PBAC) score at the third and sixth cycle of treatment. RESULTS: After six cycles the median menstrual blood loss was 5 mL in the LNG IUS group and 100 mL in the mefenamic acid group (P < 0.001). Median TMFL was 27 mL in the LNG IUS group and 157 mL in the mefenamic acid group (P < 0.001). Median PBAC score was 25 in the LNG IUS group and 159 in the mefenamic acid group. Changes in menstrual blood loss correlated strongly to changes in TMFL (r= 0.88) but PBAC correlated less well to blood loss and total fluid loss (r= 0.53 and r= 0.58). CONCLUSIONS: Both the LNG IUS and mefenamic acid significantly decreased menstrual blood loss, TMFL and PBAC scores. The LNG IUS produced greater reductions in all parameters than mefenamic acid. Comparison of the different measurements suggests that TMFL assessment may be an easier and a more relevant measure of symptom severity than menstrual blood loss.     

Reference period analysis of vaginal bleeding with triphasic oral contraceptive agents containing norethindrone or levonorgestrel: a comparison study.

The World Health Organization recommends the use of fixed reference periods for quantification of the incidence and severity of vaginal bleeding when patients use various forms of contraception. Ninety- and 110-day reference periods were used in the analysis of data from daily menstrual diaries kept by 72 healthy women in a one-year study of oral contraceptive agents containing ethinyl estradiol and either norethindrone or levonorgestrel. Analysis of bleeding patterns reported during both 90-day and 110-day periods revealed fewer days of bleeding and/or spotting overall with norethindrone than with levonorgestrel (e.g., a mean of 16.06 vs. 19.55 days, respectively, over the first 90-day period; P = .013) and significantly shorter bleeding and/or spotting episodes with the norethindrone preparation. This trend persisted when data were adjusted for a day-1 pill start. Using either method of analysis, duration of bleeding episodes was shorter among subjects taking norethindrone than levonorgestrel. Pills were missed in both study groups, but more women in the LNG/EE group missed from 1 to 3 pills in at least one cycle (31 vs. 21 in the NET/EE group). The between-group difference in bleeding events may be due to intrinsic hormonal differences in regimens or to the greater number of pills missed among levonorgestrel users.     

Clinical and laboratory evaluation of prolonged administration of microdoses of d-Norgestrel

Experience with a small dose of d-Norgestrel as an oral contraceptive in 60 patients is reported. 336 cycles were observed. 2 pregnancies occurred, after 1 month and 9 months treatment; in both cases the patients had not taken the medication regularly. Side effects included spotting (50%), menstrual cycle irregularity (40%), headache, increased appetite, venous congestion, and raised blood pressure (1 patient each). 33 patients left the study. Serum FSH and LH levels were studied in 3 patients, vaginal smears in 38 patients, cervical mucus in 10 patients, and endometrial biopsy in 9 patients. Hepatic function was not affected in the 10 patients studied.     

Multicenter trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrel

A clinical trial was conducted at 47 centers in 11 countries to assess the efficacy and acceptability of a monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms desogestrel. 1,613 women took part for a total of 23,258 cycles. One pregnancy occurred in a cycle where two consecutive tablets had been forgotten. Cycle control was excellent, with reported decreases in the duration and amount of withdrawal bleeding during consecutive treatment cycles and a low incidence of irregular bleeding. Blood pressure was not affected during 2 years of use. The incidence of minor side effects was already low in the first treatment cycle and decreased further in the subsequent cycles. The combination (Marvelon) was shown to be a very reliable and acceptable oral contraceptive.     

Blood levels of levonorgestrel in women following vaginal placement of contraceptive pills

6 healthy women aged 25-38 years, attending a family planning clinic in the Dominican Republic, participated in an experiment to determine blood levels of levonorgestrel (1Ng) resulting from daily vaginal placement of contraceptive pills containing .5 mg dl-norgestrel and .05 mg ethinyl estradiol and to evaluate the effect on ovulation. Subjects were observed for 3 cycles. Blood samples were taken on days 14, 18, 23 and 27 following the 1st day of menses on a pretreatment cycle. In 1 cycle the pill was taken daily for 21 days by the oral route, and in another it was placed in the vagina on the same schedule. Blood samples were taken frequently during the 1st 24 hours and subsequently on days 5, 8, 12, 15, 18, and 21 of experimental cycles. Plasma levels of 1Ng reached a peak of 3-4 ng/ml 1-4 hours after oral administation of dl-norgestrel and fell slowly thereafter to a level slightly over 1 ng at 24 hours after ingestion. Plasma concentrations of 1Ng rose at a slower rate and reached a lower peak value after vaginal placement. After 4 hours the 2 curves were approximately parallel. The mean 1Ng plasma concentration 24 hours after vaginal insertion was less than 1/2 the value after oral administration. The differences in plasma levels were statistically significant for each of the times studied. Differences were most pronounced in the 1st 2 weeks. In each pretreatment cycle, progesterone levels reached a peak above 4 ng/ml, indicating ovulation. All but 1 treatment cycle by either route had progesterone values suggesting anovulation; the exception was a vaginal administration cycle. 4 of the 6 women maintained low estradiol levels, mostly between 20-40 pg/ml, during treatment cycles by either route. The lower plasma levels of 1Ng after vaginal insertion of pills may reflect inefficient absorption of steroids within the vagina, or a difference in metabolic degradation when the drug is administered parenterally via the vaginal blood supply. It was still possible to suppress ovulation in 5 of the 6 vaginal cycles without attempting to adjust the dose.     

Incidence of abnormalities following the use of hormonal contraceptives

In order to get evidence about the incidence of malformations as because of intrauterine exposition of steroids as after cessation of hormonal contraception in dependence on the time interval between the last intake of hormonale contraceptives (h.c.) and on different pills 5,866 pregnant women have been entered into a case-control-study. 2,834 pregnant women had taken h.c. during pregnancy or got pregnant within 6 menstrual cycles after discontinuation of pills (= cases). For control the data of 3,032 pregnant women were examined. These one had never taken pills or their pregnancy occurred after 7 menstrual cycles after cessation of pill ingestion. Perinatal mortality, Apgar-score (5 min) and incidence of twins were not different in cases and controls. The incidence of malformations was significant (p less than or equal to 0.01) higher in controls than in cases. It depended on age in form of an increase with rising age. The incidence of malformations in both groups increased significantly (p less than or equal to 0.01) with a rising cigarette consumption during pregnancy. The results of this study suggest that smoking regarding malformations represents a higher risk than the intake of h.c.     

Genital tract and plasma human immunodeficiency virus viral load throughout the menstrual cycle in women who are infected with ovulatory human immunodeficiency virus

OBJECTIVE: The purpose of this study was to determine the vaginal, cervical, and plasma viral load through the menstrual cycle in women who are positive for human immunodeficiency virus. STUDY DESIGN: A prospective cohort study was performed on 14 women with ovulatory menstrual cycles who have human immunodeficiency virus. Duplicate cervical and vaginal viral load samples (n = 301) were taken at four stages (menstrual, follicular, periovulatory, and luteal) of two consecutive cycles. RESULTS: Participant characteristics were mean age of 32.7 years, median human immunodeficiency virus helper cell count value of 355, and median plasma viral load of 24,000 copies/mL. Through the menstrual cycle, there was no statistically significant difference in plasma viral load, but there was a significant decrease in genital tract viral load at the periovulatory phase (vagina, P =.018; cervix, P =.007). Vaginal and cervical viral load were correlated (r = 0.582, P <.001). CONCLUSION: Although the plasma viral load remained constant throughout the menstrual cycle, the genital viral load decreased at the periovulatory phase. These results suggest that local factors may affect the genital viral load compartment independent of plasma viral load.     

A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for acne treatment

OBJECTIVE: To evaluate the efficacy of a low-dose oral contraceptive (OC) containing 100 microg of levonorgestrel (LNG) and 20 microg of ethinyl estradiol (EE) compared with placebo for the treatment of moderate acne. DESIGN: Multicenter, randomized, double-blind, placebo-controlled clinical trial. SETTING: Outpatient dermatology clinics. PATIENT(S): Women (> or =14 years old; n = 350) with normal menstrual cycles and moderate acne were randomized to receive LNG/EE or placebo for six cycles.Intervention(s): Twenty microg of EE and 100 microg of LNG. MAIN OUTCOME MEASURE(S): Acne lesion counts and clinician global assessment were performed at baseline and at each cycle. Patient self-assessment was carried out at baseline and at cycles 4 and 6; blood pressure and weight were measured at baseline and at cycles 1, 3, and 6. RESULT(S): Inflammatory, noninflammatory, and total lesion counts at cycle 6 with LNG/EE were significantly lower compared to placebo. Patients in the LNG/EE group also had significantly better clinician global and patient self-assessment scores than those in the placebo group at cycle. Changes in weight from baseline were similar between patients in the LNG/EE and placebo groups at all measured time points. CONCLUSION(S): This double-blind, placebo-controlled study demonstrates that a low-dose OC containing 20 microg of EE and 100 microg of LNG is an effective and safe treatment for moderate acne.     

Final Canadian Report of a Clinical Trial Evaluating the Safety and Efficacy of a New,Low-Dose Oral Contraceptive,Alesse™

The efficacy and safety of a new, low-dose, 21-day combination oral contraceptive containing 100 μg of levonorgestrel and 20 μg of ethinyl estradiol were evaluated in an open-label, multicentre trial. A total of 254 Canadian subjects were enrolled and received 4,564 cycles of exposure over the three-year course of the study. Of these, 137 completed 18 cycles of treatment. During the total 4,482 evaluable cycles of treatment, one pregnancy occurred, for a Pearl Index of 0.29 (82 cycles were excluded from this calculation due to protocol violations, including use of a second form of contraception or missing three or more consecutive pills in a cycle). Over the course of the study, 129 subjects withdrew for any reason, including 43 (17%) due to adverse events. The cumulative failure rate by life table analysis was 0.0048 per woman entering the 14th cycle. Breakthrough bleeding alone occurred in 3.9 percent of the cycles and breakthrough bleeding and spotting occurred together in 9.6 percent of the cycles. Of evaluable cycles, 1.3 percent were amenorrhoeic. The most commonly reported adverse events in this trial considered to be at least possibly due to the test drug were headache (36%) and metrorrhagia (36%). This formulation provides contraceptive efficacy similar to higher-dose oral contraceptives, while maintaining a safety and common OC side-effect profile that is consistent with prior years of reported use with kvonmgestrel-containing products.