1 Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Saltshouse Road, Hull HU8 9HE, UK and 2 Clinical Development Department, NV Organon, Oss, The Netherlands
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Abstract |
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Key words: desogestrel/inhibition of ovulation/levonorgestrel/progestogen-only contraceptives
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Introduction |
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Previous studies (Skouby, 1976; Viinikka et al., 1976
; Rice et al., 1996
) have shown that when desogestrel is administered at a dose of 6075 µg/day, ovulation is inhibited completely. This suggests that it would be a more effective POP than levonorgestrel 30 µg/day, which prevents ovulation in only 40% of cycles and relies upon the other factors mentioned above for its contraceptive abilities. In this paper, the ability of desogestrel to inhibit ovulation in healthy female volunteers was compared with a currently available preparation of levonorgestrel.
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Materials and methods |
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Study design
A full medical history was taken and the volunteers then underwent a clinical examination including a pelvic examination. On day 10 of their menstrual cycle the women had a transvaginal ultrasound scan using an Ultra-mark 4-Plus (ATL) to measure follicular diameters. Both ovaries were assessed and every follicle above 5 mm, as a mean of two diameters (transverse and longitudinal), was recorded. The scans were performed on alternate days until the dominant follicle reached 15 mm in diameter. At this stage the scans were performed daily until follicular rupture (Queenan et al., 1980). Blood was taken at each visit and analysed for 17ß oestradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH) by Microparticle Enzyme Immunoassay (Imx assay; Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). At 4, 7 and 10 days post-ovulation, blood was taken for analysis of progesterone concentrations by solid phase fluorimmunoassay (Delfia assay; Wallac UK Ltd, Milton Keynes, UK) in addition to oestradiol concentrations. The women who had demonstrated ovulatory cycles were asked to commence medication on the first day of their next menstrual cycle. The tablets were taken daily with no break in between packets.
After three treatment periods, the women returned for a check to measure weight and blood pressure and to record any changes in physical well being, in addition to the compliance to the medication.
The women were evaluated throughout the 7th and 12th treatment period. During each of these 28 day treatment periods they attended twice a week and underwent an ultrasound examination to assess any follicular development. When a follicle greater than 15 mm was measured, the scans were performed daily until follicular rupture or until the measurements had been static for 3 consecutive days. The scans were then continued twice a week. A blood sample was taken for analysis of serum progesterone, oestradiol, FSH and LH concentrations at every visit.
Statistics
When testing at the usual 5% level, a sample size between 30 and 40 subjects per group would allow for an 80% chance of detecting a difference of 67 mm in mean maximum follicular diameter and a difference of 10% in the desogestrel group versus 4047% in the levonorgestrel group with respect to the incidence of progesterone concentrations 10 nmol/l.
The statistical analysis was carried out on the intent-to-treat groups. The treatment groups were compared for maximum progesterone values using the 2 test. Maximum FSH and LH values and maximum and mean oestradiol values were analysed using a Wilcoxon rank sum test.
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Results |
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Ultrasound observations from the two assessment periods were used to rank the degree of ovarian suppression achieved by each preparation at both 7 and 12 months. Decreasing rank order was taken to be from no follicular activity to a persistent follicle 30 mm (Queenan et al., 1980
) to follicular rupture. A persistent follicle was defined as a follicle between 15 and 30 mm in size which remained static in size for 3 successive days. Results are shown in Table III
. In treatment period 7, no follicular activity was seen in five subjects in both treatment groups, though in treatment period 12 this had increased to nine subjects in the desogestrel group and decreased to three in the levonorgestrel group. Follicular rupture was seen in 19 cycles in the levonorgestrel group compared to only three in the desogestrel group. The number of persistent follicles was greater in the desogestrel group.
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At screening, all the subjects showed follicular rupture on ultrasound and all but three subjects had progesterone levels >30 nmol/l, confirming ovulation. In both the 7th and 12th treatment period a comparison of ovarian suppression was also made using serum progesterone levels. Decreasing rank order was taken to be from progesterone values <10 nmol/l, to a value 1030 nmol/l to levels >30 nmol/l. The difference between the desogestrel and levonorgestrel groups for a maximum progesterone level >30 nmol/l is statistically significant (P < 0.001) for both assessment periods (see Table IV).
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Maximum LH and FSH concentrations
The maximum LH levels were significantly lower in the desogestrel group during treatment cycles 7 and 12, compared to the levonorgestrel group (P < 0.001 and P = 0.003 respectively). The difference in the FSH values between the two groups was not significant in either treatment cycle (P = 0.2 and P = 0.9). See Table VI.
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Discussion |
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Follicular rupture alone does not always signify fertility and similarly a raised serum progesterone level taken in isolation is not a definitive test, as it will include those cycles with LUF. Tayob et al. (1985) used ultrasound scanning alone to examine the effects of POP on follicular activity and the majority of earlier trials on progestogens, including desogestrel, have only studied endocrine parameters with regard to ovulation (Skouby, 1976; Viinikka et al., 1976
). Therefore in this study ovulation was defined as follicular rupture on scan followed by a rise in serum progesterone value. Using both criteria the desogestrel preparation demonstrated a significantly greater effect on the inhibition of ovulation. Only one subject ovulated in the desogestrel group during the 59 cycles studied. In the levonorgestrel group by comparison, 16 out of 57 cycles (28%) were shown to be ovulatory. These results strongly suggest that the desogestrel POP should be more reliable as a contraceptive agent.
The decrease observed for LH in both study periods was significantly greater in the desogestrel group indicating that with desogestrel the suppression of the hypothalamicpituitary axis is more pronounced. No difference was found for FSH. A similar number of women in both desogestrel and levonorgestrel groups formed persistent follicles.
However, the endocrine picture was very different between the two preparations. None of the women with persistent follicles or cysts in the desogestrel group showed any evidence of luteal activity compared to a 40% (12/30) incidence of LUF in the levonorgestrel group. None of the subjects required medical intervention for follicular cysts.
The maximum and mean oestradiol levels were significantly lower in the desogestrel group compared to the levonorgestrel group. Hypo-oestrogenism was not observed in this study population and all the oestradiol levels were above those which would lead to concern with regard to osteoporosis (Mehta, 1993).
Our findings on the levonorgestrel POP are in full agreement with earlier studies, i.e. that the primary mechanism of action of the levonorgestrel POP used in this study is not ovulation inhibition (McCann and Potter, 1994), but an abnormal luteal phase and inadequate cervical mucus contribute mainly to the effectiveness.
Desogestrel produced a significant inhibition of ovulation in comparison to levonorgestrel. This was illustrated by both the lack of follicular development and the suppression of endocrine values. Desogestrel, at a dose of 75 µg daily, is therefore expected to have a lower failure rate than the currently available POP.
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Acknowledgments |
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Notes |
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References |
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Submitted on June 1, 1998; accepted on November 30, 1998.