Ales Rarus

The first post in this series can be found here.

Last time I looked at a couple literature reviews about the methods of action of Plan B emergency contraception (levonorgestrel, LNG). This time I'm presenting On the the mechanisms of action of short-term levonorgestrel administration in emergency contraception (Durand, et al., 2001)

Experimental Design

Forty-five healthy, surgically sterilized women, aged 29 years to 35 years old (mean age 31 years), with regular menstrual cycles (cycle lengths between 25 days and 32 days) were recruited for this study. None had used hormonal contraception or any other medication within 6 months prior to the study. Participants were in good health as determined by medical history, physical examination, and routine screening laboratory tests, including Papanicolaou smear. Body weight, height, and blood pressure of each participant were registered by one investigator. Participants were issued a menstrual calendar on which they recorded details of all bleeding episodes throughout the study.

This bit tells us that were these women not surgically sterilized, we would have no reason to not expect that they were capable of both ovulation and, under the right circumstances, pregnancy.

The study was conducted in two consecutive cycles. Cycle was defined as the time elapsed from the first day of a spontaneous menstrual bleeding until the day preceding the next menses.

That is, cycles were defined symptomatically, not based on the mythical average 28-day cycle. Two cycles were tracked for each participant, control cycle in which no drug was administered and a treated cycle in which LNG was administered.

All participants were admitted during the first 10 days of their menstrual cycle. Before the control cycle, women were randomly allocated into three different groups as follows: Group A women received two doses of 0.75 mg LNG (Postinor, Gedeon Richter, Budapest, Hungary) taken 12 h apart, with the first dose given on the morning of day 10 of the menstrual cycle; Group B women received the same dose of LNG immediately after positive LH [luteinizing hormone] detection in urine; and Group C women received the same dose of LNG 48 h after positive detection of urinary LH.

• Group A received the drug on cycle day 10, regardless of when they ovulated.
• Group B received the drug after the LH surge, which shortly precedes ovulation.
• Group C received the drug 48 hours after the LH surge, i.e., presumably after ovulation has occurred.

During both cycles (control and treated), all women were asked to monitor urinary LH every morning, starting on the 11th day of the menstrual cycle until the presence of LH was detected. At this time, transvaginal ultrasound was performed daily until follicle rupture (FR) was observed. This was established by the presence of at least three of the following findings: acute decrease in mean diameter or disappearance of the follicle, presence of thickened irregular borders, increased echogenecity within the follicle, and presence of free intraperitoneal fluid [16]…

The LH surge was used as an indicator of imminent ovulation. Ovulation was observed and timed via ultrasound. The determination that ovulation had occurred was made by observing the follicle (which had contained the ovum) get smaller, disappear, thicken, or show up more brightly in the image, or the presence of fluid in the abdominal cavity.

Daily blood samples were obtained from the day of positive LH detection in urine until the day menses began…The main purpose for measuring serum LH was to precisely determine, rather than based only on urinary LH detection, the actual time at which LNG was administered during the menstrual cycle. Follicular phase was considered from the first day of bleeding until the day of maximum serum LH concentrations and the luteal phase from the next day of serum LH surge until the day before menses began.

LH levels in urine served only as a rough indicator of the onset of ovulation. Blood tests were used to get a more precise indicator of cycle day. The first phase of the cycle, the follicular phase, was considered to be from the first day of menstrual bleeding until the day of the highest level of LH was measured in a blood sample.

In addition, endometrial biopsies were taken from all participants during both control and treated cycles on day LH + 9. This day lies within the implantation window, the time during which the endometrium has optimal receptivity to implantation…

[…]

Endometrial morphology was assessed by correlating the chronological date (day after LH surge) with the morphological endometrial characteristics of specimens as an indicator of hormone action. The dating of the endometrium was related to the serum LH surge, FR, and luteal concentrations of E₂ [estrogen] and P₄ [progesterone], rather than to the “ideal” 28-day cycle, as previously described [22]. The parameters examined were number of glands, stromal edema, and predecidual changes as evaluated by the presence of prominent spiral arteries…

On the ninth day of the luteal phase, a sample of the uterine lining was taken in order to access its receptivity to implantation (had there been an embryo implant).

Timing comparisons between serum with urinary LH demonstrated inconsistencies in 12 out of 90 studied cycles (13.3%). In four control cycles (8.8%) and eight treated cycles (17.7%), urinary LH did not correlate with the day of maximum concentrations of serum LH. In these cases, serum LH, along with E₂ and P₄ concentrations, were used rather than urinary LH for cycle dating. Thus, eight participants during the treated cycle were identified as not corresponding to the originally assigned groups. Therefore, in four participants originally included in Group B and four in group C, the administration of LNG took place 3 ± 1 day prior to serum LH surge and were reassigned into a new group (group D). This new group received LNG during the late follicular phase, a few days prior to the occurance of LH surge. Thus, the groups studied consisted finally of 15 participants in Group A, 11 in groups B and C, and 8 in Group D.

Like I said, urine LH level is just a rough indicator. As such, it led to premature administration of LNG in 8 cases. Rather than waste data, a fourth study group was formed.