Absorption of oral progesterone is influenced by vehicle and particle size

The oral route of progesterone administration has long been considered impractical because of poor absorption and short biologic half-life. Recent reports suggest that micronization of progesterone enhances absorption and increases serum and tissue levels of progesterone. This study checks serum progesterone levels before and 0.5, 1, 2, 3, 4, and 6 hours after oral administration of 200 mg of progesterone in seven subjects. Progesterone was plain milled, micronized, plain milled in oil, micronized in oil, or micronized in enteric-coated capsules. All patients exhibited a significant increase in serum progesterone levels after oral progesterone administration. Mean peak progesterone levels (30.3 +/- 7.0 ng/ml) (p less than 0.005) were achieved with micronized progesterone in oil at 2.0 +/- 0.3 (p less than 0.05) hours after administration. Four types of oral progesterone had equivalent mean peak elevations and mean times to peak: plain milled, 9.6 +/- 2.5 ng/ml at 4.0 +/- 0.5 hours; micronized 13.2 +/- 2.4 ng/ml at 3.2 +/- 0.4 hours; plain milled in oil, 11.3 +/- 3.0 ng/ml at 4.0 +/- 0.5 hours; and micronized in enteric-coated capsules, 11.2 +/- 3.0 ng/ml at 4.1 +/- 0.7 hours. Contrary to traditional teaching, these data show that significant serum progesterone levels can be achieved by oral administration. Absorption can be significantly improved by the physical characteristics of the progesterone and the vehicle used with oral administration.     

Mode of action of DL-norgestrel and ethinylestradiol combination in postcoital contraception.

Possible mechanisms of action of a combination of ethinylestradiol (EE) and dl-norgestrel as a postcoital contraceptive agent were studied in 12 healthy female volunteers. An oral dose of 0.1 mg of EE and 1.0 mg of dl-norgestrel was given at the predicted time of ovulation and again 12 hours later. Serum luteinizing hormone, prolactin, progesterone, 17 alpha-hydroxyprogesterone, and estradiol were measured by specific radioimmunoassays in blood samples obtained daily from the 8th day of the menstrual cycle to the 1st day of menses. Hormone profiles suggested that the medication elicited a range of individual variations in pituitary and/or ovarian responses. Histologic examination of the endometrium consistently showed significant alteration in endometrial development with a dissociation in maturation of glandular and stomal components. This postcoital contraceptive acts either by (1) suppressing ovulation or (2) disrupting luteal function by acting directly on the corpus luteum or by interfering with appropriate endometrial responses to ovarian steroids.     

A clinical study on the contraceptive effect of vaginal application of levonorgestrel]

50 healthy women aged 27-39 were screened and participated in an clinical study on the vaginal application of levonorgestrel (LNG) as a contraceptive. Among the 50 women, 27 had live births and 23 had abortions as the result of their last pregnancy within 5 years. They had regular menstruation for the past 3 months, and no disease of the liver, heart, or urinary system. 0.75 mg LNG tablets produced by Beijing Pharmaceutical Manufacturers were chosen for the study. All the participants were instructed to put one tablet into the upper end of vagina every other day from the seventh day of the menstrual cycle with 8 tablets per cycle. 258 cycles of pills were used by the 50 participants. 953 acts of sexual intercourse were recorded during the study with 3.69 per cycle on average. Even though pills were missed in 28 cycles, there was only 1 case of pregnancy. The pill use affected the duration of the menstrual cycle, with mean duration of 27.8 days + or - 4.1 days. Vaginal bleeding occurred in 13 cycles (4.06). Side effects including sickness, backache, breast pain, and increased vaginal secretion occurred only in 3.89% of the cycles, which was much lower than in oral administration. No vaginal infection occurred in any of the cases. 10 participants dropped out before the end of study, including 1 who became pregnant. 44 participants, including 4 drop-outs, wanted to continue with the method. Vaginal application of progesterone is a promising means of contraception. But, as the study has a small sample size and short duration, is further research to prove the advantage of vaginal application over oral administration in terms of effectiveness, side effects, longterm safety, an acceptability.     

左旋18-甲基炔诺酮经阴道给药的药代动力学和药效学研究

本文比较了左旋18-甲基炔诺酮(LNG)制剂Postinor单剂量(0.75mg)口服和阴道给药的药代动力学,并研究了这种制剂经阴道多次给药的药代动力学及对卵巢功能的影响。征集6例月经规则的健康育龄妇女。第一周期,每例对象每次于阴道深处放置一片Postinor,共8次,每2次间隔为48小时;第二周期,每例对象口服一片相同的LNG制剂,放免测定血清LNG、雌二醇和孕酮水平。结果表明在第一周期,除1例对象在中期有一较高的雌二醇峰以外,其余雌、孕激素水平均呈明显低平状态;口服和阴道放置相同的单剂量LNG以后血清LNG浓度时间曲线分别符合二室与一室开放模型。由此提示与口服相比,Postinor经阴道给药后吸收缓慢,且血清LNG峰值低,而消除过程则两种给药途径较为相似;Postinor经阴道给药可明显抑制排卵。     

Prediction of ovulation with the use of oral and vaginal electrical measurements during treatment with clomiphene citrate

This study was undertaken to evaluate the usefulness of measuring salivary and vaginal electrical resistance in monitoring ovulation induced by clomiphene citrate (CC). Data from 28 cycles of 12 women treated with CC were compared with those of 18 cycles of 13 women who were ovulating spontaneously. Patterns of salivary readings in CC and spontaneous cycles were similar and showed a preovulatory peak 6.2 (mean) days before the luteinizing hormone peak. The trend in vaginal readings for CC cycles differed from that of spontaneous ovulations in that the values were depressed during and shortly after CC therapy. Occurrence of the periovulatory nadir and subsequent rise was common to both groups. The rise in vaginal readings CC cycles occurred within 24 hours of the luteinizing hormone peak in 88% of cases. Retrospective analysis showed that, based on this method, artificial insemination would have been timed appropriately in 25 of 27 cycles or in every cycle, depending on the protocol used. The results indicate that the method is equally useful for predicting and confirming ovulation in cycles in which CC was used to induce ovulation as it is in spontaneous cycles.     

Inadequate luteal phase usually indicates ovulatory dysfunction: observations from serial hormone and ultrasound monitoring of 115 cycles

We have studied 100 women with regular menstrual cycles and infertility and tried to assess how frequently an 'inadequate' luteal phase (defined by low-peak progesterone levels) follows 'normal' ovulation. Normal follicular growth on serial ultrasound scan and follicular disappearance or collapse within 48 hours of the recorded LH peak were taken together as convincing evidence of ovulation. Eighty-three of 115 cycles were judged to be ovulatory and 32 to be anovulatory. A peak mid-luteal phase maximum serum progesterone (Po) level of 32 nmol/L (10 ng/ml) was taken arbitrarily as the cut-off level of discrimination between 'adequate' and 'inadequate' corpus luteum function. Serum progesterone was undetectable (less than 2.5 nmol/L) throughout in 2 cycles while the maximum was above 32 nmol/L in 102 and detectable but less than 32 nmol/L in 11. Of the latter only 1 was ovulatory. We conclude that cycles with low luteal phase Po levels represent luteinization without ovulation.     

Plasma concentrations of endogenous hormones during one regular treatment cycle with a low-dose oral contraceptive and during two cycles with deliberate omission of two tablets.

In this open, prospective, phase-I study we closely monitored levels of endogenous progesterone, 17beta-estradiol, luteinizing hormone (LH) and follicle stimulating hormone in six healthy women. We determined plasma concentrations every 1-3 days during one untreated baseline cycle and during the first treatment cycle with regular pill intake of an oral contraceptive containing 30 microg ethinylestradiol plus 75 microg gestodene. During the following two treatment cycles, two tablets were deliberately omitted (in cycle 2 on days 6/7 and in cycle 3 on days 11/12). All but possibly one volunteer ovulated in the untreated pre-cycle, as concluded from LH peaks followed by marked increases of progesterone. During the regular first treatment cycle and even after deliberate omission of two tables in treatment cycles 2 and 3, the progesterone and estradiol levels remained low, so that we concluded that no ovulation took place. However, two volunteers showed some sort of LH peak in the first regular treatment cycle and all women showed LH increases of > 40 microg/ml in at least one omission cycle. In ten out of 12 cycles, omissions of pill intake were followed by an episode of intermenstrual bleeding. In conclusion, we have shown that, after omission of two consecutive oral contraceptive tables, the endogenous hormone parameters did not provide evidence for ovulation. Although this provides confirmation of the robustness of this oral contraceptive towards non-compliance, the widely published practical recommendations should be followed.     

Cervicovaginal peroxidases: sex hormone control and potential clinical uses

Thirty-one normal women were studied daily in 41 cycles. Venous blood samples were taken for measurements of luteinizing hormone (LH), estradiol (E2), and progesterone (P), and vaginal examinations were done to obtain cervical mucus and vaginal fluid. The specific activity of guaiacol peroxidase (GP), extracted from cervicovaginal secretions with 0.5 M CaCl2, was determined in the vaginal samples. In the follicular phase, from day -7 to day 0 (the LH +1 day, when ovulation presumably occurred), there was a strong negative correlation between GP and the rising E2 (r = -0.94). On days 1 to 10 after ovulation, there was a strong positive correlation between GP and P (r = 0.84). In nine ovulatory cycles in which P levels did not exceed 8 ng/ml on any day, indicating possible luteal phase inadequacy, there were significantly lower GP levels than in another 32 ovulatory cycles with higher P (P = 0.04). These results suggest that (1) at midcycle, E2 seems to "down-regulate" the GP specific activity; and (2) in the luteal phase, serum P levels parallel those of GP activity, even in the presence of high luteal E2. GP activity profiles during the menstrual cycle can be used to define the fertile period, may prove useful in diagnosing pregnancy, and may be a simple, convenient test for an inadequate corpus luteum.     

The correlation between LH determination in the urine (Hi-Gonavis) and serum LH, FSH, oestradiol, progesterone, prolactin levels, and vaginal cytology at midcycle

Radioimmunoassays (RIA) of serum gonadotrophins, prolactin, oestradiol, and progesterone were carried out from day 10 to 20 in 25 normal women for two cycles. In addition, we measured LH in urine twice daily using semiquantitative Hi-Gonavis kits. Finally, vaginal cytology was assessed daily in order to find out the optimum time for conception. LH in serum, as well as in urine, increased significantly at midcycle and so did FSH, prolactin, oestradiol, and the cornification index. Hi-Gonavis showed a significant increase 12 hours prior to the day of ovulation (day 0). The levels reached the peak on the day of ovulation and remained high 12 hours after the peak level on day 0. For the evaluation of the optimum time for conception in normal women who receive artificial insemination, or to improve fertility in those who have irregular ovulatory cycles, determination of the urinary LH by means of Hi-Gonavis appears to be useful, reliable, and economic, both in time and expense.     

Diagnosis of fertility with a personal hormonal evaluation test

BACKGROUND: To evaluate the efficacy of the urinary test "Persona" in the recognition of the fertile period comparing hormonal assay and monitoring the follicular growth by ultrasonography. METHODS: Twenty women have used "Persona" for 13 cycles (200 cycles). This device evaluates changes in E-3-G and LH concentrations and estimates the fertile days which are displayed by a red light. Inclusion criteria were: age 22-45, regular menstrual cycles (23-35 days), absence of the polycystic ovary syndrome. The participants underwent vaginal ultrasonography in several days (one of the first 7 "green days", the first "red day", the ovulation day "O", and the first "green day" after ovulation) and determination of blood concentration of LH, in the ovulation day, and progesterone, in the 21st day of cycle. RESULTS: Vaginal ultrasonography was in agreement with predictions of "Persona" in 96% in the first "green days", in 94% in the first "red day", in 95,8% in the ovulation day and in 97,5% in the first "green day" after ovulation. All participants with ultrasonographic evidence of ovulation had a concentration of LH included in 13-71 mUI/ml range and of progesterone included in 12-50 ng/ml range. CONCLUSIONS: These results suggest that the "Persona" test is effective in the recognition of the fertile period, but a correct maintenance of the microcomputer is important for the best reliability of method. The method seems to be a wellcome alternative for couples who want to use natural family planning.     

Temporal relationships of estrogen, progesterone, and luteinizing hormone levels to ovulation in women and infrahuman primates.

These studies were undertaken to ascertain the interval between the estrogen and LH peaks and ovulation in women, rhesus monkeys, and baboons. Estrogen, progesterone, and LH were measured by RIA. Ovulation was documented by visual examination of the ovaries, histology of the corpora lutea, and recovery of ova. The data for human subjects was based on a group of 23 normal women scheduled for surgical sterilization. Blood was drawn daily between 8:30 and 10:30 P.M. beginning on day 10 of the cycle. Surgery was performed 1 to 5 days after the LH peak. The hormonal findings were correlated with the histology of the corpus luteum. The mean interval from the estrogen peak to ovulation was 34 hours, the interval from the estrogen peak to the LH peak was 24 hours, and that from the LH peak to ovulation was 9 hours. In 46 rhesus monkey cycles and in 53 baboon cycles diagnostic serial laparoscopic examinations were initiated following the estrogen peak and repeated every 24 hours until ovulation was confirmed. The mean interval between the estrogen peak and ovulation was 34 hours in the monkey and 41 hours in the baboon. The intervals from the estrogen peaks to the LH peaks were 12 hours in the monkey and 23 hours in the baboon. The intervals from LH peak to ovulation were 22 hours in the monkey and 18 hours in the baboon. Plasma progesterone levels were significantly increased prior to the LH peak in all three species.     

Plasma concentrations of endogenous hormones during one regular treatment cycle with a low-dose oral contraceptive and during two cycles with deliberate omission of two tablets

In this open, prospective, phase-I study we closely monitored levels of endogenous progesterone, 17β-estradiol, luteinizing hormone (LH) and follicle stimulating hormone in six healthy women. We determined plasma concentrations every 1–3 days during one untreated baseline cycle and during the first treatment cycle with regular pill intake of an oral contraceptive containing 30?μg ethinylestradiol plus 75?μg gestodene. During the following two treatment cycles, two tablets were deliberately omitted (in cycle 2 on days 6/7 and in cycle 3 on days 11/12). All but possibly one volunteer ovulated in the untreated pre-cycle, as concluded from LH peaks followed by marked increases of progesterone. During the regular first treatment cycle and even after deliberate omission of two tables in treatment cycles 2 and 3, the progesterone and estradiol levels remained low, so that we concluded that no ovulation took place. However, two volunteers showed some sort of LH peak in the first regular treatment cycle and all women showed LH increases of >?40?μg/ml in at least one omission cycle. In ten out of 12 cycles, omissions of pill intake were followed by an episode of intermenstrual bleeding. In conclusion, we have shown that, after omission of two consecutive oral contraceptive tables, the endogenous hormone parameters did not provide evidence for ovulation. Although this provides confirmation of the robustness of this oral contraceptive towards non-compliance, the widely published practical recommendations should be followed.     

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.     

Single luteal phase serum progesterone assay as an indicator of ovulation

A study was undertaken to determine whether solitary progesterone as says performed on serum samples obtained in the midluteal phase would provide the clinician with a convenient indicator that ovulation had occurred in that cycle. After a normal luteal-phase range was establish ed, single luteal-phase serum progesterone sampling was performed in 51 infertile women with regular menses and 35 oligomenorrheic women undergoing clomiphene citrate therapy. In the follicular phase of the cycle, progesterone levels were consistently less than 2 ng/ml. Between 11 and 4 days prior to the onset of menses in presumptively ovulatory cycles, serum progesterone levels were always 3 ng/ml or greater. Progesterone values in this range were always accompanied by a secretory endometrium and can be considered presumptive evidence of ovulation. This rapid, easily performed technique enables 1 technician to assay 30 or more samples for progesterone in a single working day and the results are available within 24 hours. This assay technique is easier to perform and more reproducible than a urinary pregnanediol assay, and it is expected that clinical laboratories will soon perform serum progesterone assays as a routine procedure.     

Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones

Mucosal immunity in the female reproductive tract is influenced by immunoglobulins (Igs), cytokines, and reproductive hormones. Previous studies of reproductive-aged women demonstrated that IgA and IgG increases in cervical mucus corresponded to elevated levels of IL-1beta which occurred 1 day before the peak of endogenous estradiol production prior to ovulation. We sought to determine the effect of exogenous hormones on reproductive tract immunity in women on oral contraceptive pills (OCPs) and to compare the results with respect to naturally cycling women. Twelve women of reproductive age who had negative cervical cultures, a normal pap smear, and agreed to abstain from sexual intercourse during the study initiated OCPs. Cervical mucus and vaginal washes were collected at six intervals (2-3 days apart) throughout the treatment cycle. Fifteen naturally cycling women had similar samples collected prior to, during, and subsequent to ovulation. Cervical mucus samples were assayed for IgA, IgG, IL-1beta, IL-6, and IL-10 by enzyme-linked immunosorbent assay (ELISA). IgA, IgG and IL-1beta levels in women on OCPs paralleled increasing levels of norethindrone. Mean values of IgA increased from a low of 14.4+/-3.1 to 41.1+/-9.4 mg/dl and decreased significantly after the cessation of the pills (P < 0.001). In naturally cycling women, the largest quantities of Igs were detected prior to ovulation. By comparison, mean values of IgA in the cervical mucus of women on OCPs (24.4 mg/dl) exceeded peak levels of IgA in the cervical mucus of naturally cycling women (14.6 mg/dl). IgA was the predominant Ig detected in cervical mucus of women on OCPs. Both immunoglobulins in each group exhibited changes relative to their hormonal status. The increased levels of IgA in the cervical mucus of women on OCPs may explain the clinical observation of a lower incidence of sexually transmitted diseases.     

Vaginal absorption of two estriol preparations. A comparative study in postmenopausal women

In a comparative randomized cross-over study the absorption of a single dose of 0.5 mg estriol from a vaginal cream or a vaginal suppository (OvestinR, Organon, The Netherlands) was studied. Eight healthy postmenopausal women participated and the preparations were given with an interval of 14 days. Blood sampling was performed twice before application and then after 1/4, 1/2, 1, 2, 4, 6, 8, 24 and 48 hours. Serum was analysed for unconjugated and conjugated estriol (E3), FSH and LH by radio-immunoassay. Considerable interindividual variations in serum levels of unconjugated E3 were found but mean values were about equal throughout the study for the two preparations. Peak levels of 0.5-0.6 nmol/l were achieved 1-2 hours after application of the preparations and after 24 hours no unconjugated E3 was measurable. Conjugated E3 rose rapidly but within 48 hours serum concentrations reached baseline levels. A maximum decrease in serum LH levels of about 40% was obtained with both preparations after 6 hours and the return to baseline within 24 hours indicates a relationship to unconjugated E3. FSH in serum was maximally suppressed 6-12%. Estriol is thus readily absorbed by the vaginal route and peak levels of unconjugated E3 after insertion of 0.5 mg estriol seem to be comparable to those obtained after 8-12 mg estriol given orally.     

Clinical performance and endocrine profiles with contraceptive vaginal rings containing a combination of estradiol and d-norgestrel

Contraceptive vaginal rings, impregnated with d-norgestrel (77 mg) and estradiol (29-66 mg) were studied in 10 subjects aged 24-28. 5 subjects were studied for 3 cycles and 5 for 6 cycles. The rings were inserted (on Day 5) for 3 weeks and removed for 1 week to allow withdrawal bleeding. Serum samples were obtained at least 3 times/week; estradiol and d-norgestrel were assayed in each sample, and progesterone weekly. Clinical acceptance was good. Ovulation was inhibited in all treatment cycles and resumed within 1 month following completion of the trial. There was regular withdrawal bleeding, no episodes of failure of withdrawal bleeding, and only 3 days of breakthrough spotting. Serum d-norgestrel levels were relatively constant in each subject except for the 1st half of the 1st treatment cycle which had slightly higher levels. Serum estradiol levels rose rapidly following insertion of the ring to levels between 100-300 pg/ml, but then declined over the next few days to levels generally less than 50 pg/ml. After treatment, mean levels of the binding capacity of corticosteroid-binding-globulin did not become significantly elevated and serum triglycerides declined. This method has the advantage of inhibition of ovulation and good control of bleeding without the disadvantage of producing some adverse metabolic effects.     

Stimulation of luteinizing hormone (LH) and follicle-stimulating hormone by (D-Leu6, des-Gly10-NH2)-LH-releasing hormone ethylamide after subcutaneous, intravaginal, and intrarectal administration to women.

Women, most of whom had regular menstrual cycles, were administered D-Leu6,des-Gly10-NH2)-luteinizing hormone-releasing hormone (LH-RH) ethylamide (D-Leu6-LH-RH-EA)via different routes during the early or midfollicular phase of the cycle. Plasma LH, follicle-stimulating hormone (FSH), and estrogen levels were determined by radioimmunoassay before and after administration of D-Leu6-LH-RH-EA. plasma LH and FSH increased and reached peak levels 3 to 4 hours and 3 to 6 hours, respectively, after subcutaneous injection of 25 mug of the analog of LH-RH. Intravaginal or intrarectal application of 2 mg of D-Leu6-LH-RH-EA also increased plasma LH and FSH levels in most of the women, but the magnitude of the rise, the time of initiation of response, and the peak level varied among the women. The plasma estrogen level also rose after administration via either route.     

LH surge induction by GnRH agonist at the time of ovulation

Eight women were treated for 1 cycle at the time of ovulation with GnRH agonist (3 injections of 0.2 mg buserelin s.c. at 12-hour intervals) to obtain follicular rupture. Clomiphene citrate was administered to 1 patient and pure FSH to 2 patients, whilst in the case of a woman with hypothalamic amenorrhea a pulsatile GnRH regimen was used. Four patients had an untreated follicular phase. When the maximal follicular diameter was 20-22 mm all treatments were withheld and GnRH-A was administered. Plasma LH, FSH, progesterone and estradiol were determined 24 hours before, at the time of and 12, 24 and 48 hours after the 1st injection of buserelin. Ovulation was detected in all cycles. LH levels increased dramatically from baseline levels of 14.4 +/- 4.1 to 155 +/- 48 IU/l 12 hours after the beginning of treatment, then returned to preovulatory values 48 hours later (13.0 +/- 3.9 IU/l). The duration of the luteal phase was 13.2 days and normal mid-luteal progesterone plasma levels were detected (39.8 +/- 9.3 nmol/l). These data suggest that the GnRH agonist can be successfully used at the time of ovulation to induce an endogenous ovulatory LH peak and that it can be used in conjunction with different medical treatments to induce follicular maturation.     

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.