1 Departments of Obstetrics and Gynecology, and 2 Biochemistry Laboratory, Rabin Medical Center, Golda Campus, Petah Tikva and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Abstract |
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Key words: assisted reproductive technology/pharmacokinetics/progesterone/vaginal tablets
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Introduction |
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Natural progesterone is devoid of any androgenic activity that might compromise lipoprotein metabolism or induce teratogenicity. Moreover, it probably has a direct beneficial effect on blood vessels (Jiang et al., 1992). The major problem with natural progesterone is its route of administration. Oral intake is hampered by rapid and extensive intestinal and liver metabolism leading to poorly sustained serum concentrations and low bioavailability (Nillus and Johanson, 1971
; Adlercreutz and Martin, 1980
; Whitehead et al., 1980
; Ottosson et al., 1984; Padwick et al., 1986
; Chakmakjian and Zachariah, 1987
; Arafat et al., 1988
; Nahoul et al., 1993
). Injection i.m assures reliable absorption, but is related to low compliance. It is painful, can cause local irritation and cold abscesses (Devroey et al., 1989
), and must be administered by trained medical personnel. Thus the vaginal route has become the most established way in which to deliver natural progesterone. The progesterone is easily administered and avoids liver first-pass metabolism, and the vagina has a large potential for absorption. Many vaginal formulations have been assayed, mostly as suppositories (Price et al., 1983
; Norman et al., 1991
; Archer et al., 1995
; Pasquale et al., 1997
), gelatin capsules (Devroey et al., 1989
; Smitz et al., 1992
; Miles et al., 1994
), and recently as bio-adhesive gels (Fanchin et al., 1997
; Ross et al., 1997
). Although the suppositories are easily inserted, they melt at body temperature and lead to disturbing vaginal discharge. Oral gelatin capsules containing micronized progesterone have also been used vaginally (Devroey et al., 1989
; Smitz et al., 1992
; Miles et al., 1994
), but insertion of a small capsule high into the vagina is difficult and large doses of 600800 mg are needed to achieve adequate plasma concentration (Bourgain et al., 1990
; Smitz et al., 1992
; Miles et al., 1994
).
The use of a vaginal tablet containing progesterone has been reported in dogs (Fulper et al., 1987), but has not been pharmacologically evaluated in humans. In the present study we examined the pharmacokinetics of natural progesterone administered in the form of vaginal tablets to non-oestrogen-primed post-menopausal women. Dosages of 50 and 100 mg were used to determine single-dose pharmacokinetics. The effect of continuous use on hormonal, chemical, and lipid profiles were evaluated.
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Materials and methods |
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Study design
The study was divided into two parts: The first was designed to evaluate the pharmacokinetics of natural progesterone administered by a single vaginal tablet. Micronized progesterone (Upjohn Company, Kalamazoo, MI, USA) was condensed into a 1.2 g effervescent tablet formulation using a direct compaction method (Floris Company Ltd., Gush Segev, Israel). The tablets contained either 50 or 100 mg of micronized progesterone. At 8 a.m. (day 0) in a fasting state an intravenous indwelling catheter was introduced into the cubital vein. Blood was drawn for baseline hormonal [progesterone, oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulphate (DHEAS), cortisol and aldosterone], liver [bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT)] and lipid [cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low density lipoprotein (VLDL)] profiles. The women were then instructed to self-administer the progesterone vaginal tablet using a plastic applicator and lie down for 20 min. Repeat blood samples for progesterone concentration were withdrawn , 1, 2, 4, 6, 8, 10, 12 and 24 h after the vaginal insertion. Blood was allowed to clot at room temperature for 1 h, after which the serum was separated by centrifugation and stored at 20°C until analysis.
The second part of the study was designed to evaluate clinical use of the drug. The women were instructed to insert progesterone vaginal tablets containing the same dose as that on day 0, twice daily starting on day 1, and to recline for 20 min after each insertion. Blood for the same assays as in the baseline tests was drawn on days 14 and 30, in the morning before progesterone administration and in a fasting state. The women were instructed to observe and record every unusual feeling or side-effect.
Hormonal assays
Immulite enzyme immunoassay (Diagnostic Products Corporation, Los Angeles, CA) was used to measure plasma progesterone (SI conversion factor 3.18; sensitivity 0.2 ng/ml (0.6 nmol/l, inter- and intra-assay coefficients of variation precision <10%), oestradiol (SI conversion factor 3.67; sensitivity 12 pg/ml (44 pmol/l, inter- and intra-assay coefficients of variation precision <10%), DHEAS (SI conversion factor 0.02714; sensitivity 2 µg/ml (0.054 µmol/l, inter- and intra-assay coefficients of variation precision <10%). Cortisol was measured using the Access immunoassay (Sanofi Diagnostics Pasteur, Paris, France). This assay has a sensitivity of 0.4 mg/dl with inter- and intra-assay coefficients of variation precision <10%. Aldosterone was measured by a radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles, CA, USA). This assay has a sensitivity of 16 pg/ml with inter- and intra-assay coefficients of variation precision <10%. Luteinizing hormone and FSH were measured by enzyme-linked immunosorbent assay (ELISA) Enzyme-Test kit (Boehringer Mannheim Immunodiagnostics, Sussex, UK) which has a sensitivity of 0.5 mIU/ml for LH and FSH with inter- and intra-assay coefficients of variation precision <10%.
Statistical analysis
The area under the curve (AUC) was calculated by the trapezoidal rule. Concentrations up to 24 h were considered. The pharmacokinetic parameters calculated from the concentration curve were compared between the two study groups by the Wilcoxon test and by analysis of variance (ANOVA) models. The significance of changes of the other laboratory measurements from baseline values was determined by the paired t-test.
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Results |
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Single dose pharmacokinetics
A single vaginal application of a 50 mg progesterone tablet resulted in the rapid increase of plasma progesterone concentration (Figure 1). Mean peak plasma progesterone concentrations (Tmax) occurred after 6.1 ± 2.63 h, with a mean elimination half-life (T1/2) of 13.18 ± 1.3 h (Table II
). The 100 mg dose exhibited similar kinetics (Figure 1
), with a Tmax of 6.4 ± 3.35 h and T1/2 of 13.7 ± 1.05 h (Table II
). A significantly higher mean maximal serum concentration (Cmax) of 31.61 ± 12.62 nmol/l was achieved by the 100 mg dose, compared to 20.43 ± 8.01 nmol/l achieved by the 50 mg progesterone vaginal tablet (P = 0.0004). The 100 mg dose also resulted in a significantly higher mean AUC of 247.61 ± 123.04 nmol/h/l, compared to 154.15 ± 60.31 nmol/h/l in the 50 mg dose (P = 0.001).
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Discussion |
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The present study defines the pharmacokinetics of micronized natural progesterone administered by the novel formulation of a vaginal tablet. Non-oestrogen-primed post-menopausal women were chosen in order to avoid confusion with endogenous progesterone secretion and oestrogen influence on vaginal mucosa absorption (Villanueva et al., 1981). Both the 50 mg and 100 mg vaginal tablets demonstrated similar pharmacokinetic patterns (Figure 1
) of rapid absorption, reaching a Tmax within 6 h, with a T1/2 of about 13 h. These results indicate that the progesterone vaginal tablet should be administered twice daily. Indeed, plasma progesterone concentration after 14 and 30 days of treatment revealed sustained concentrations with this twice-daily regimen (Table IV
).
A wide variation exists in progesterone serum concentrations during the menstrual cycle. It is accepted that concentrations above 3.3 ng/ml (10.5 nmol/l, SI conversion factor 3.18) indicate that ovulation has occurred (Israel et al., 1972), while mid-luteal phase values of 10 ng/ml (31.8 nmol/l) and above demonstrate adequate corpus luteum function (Rosenfeld et al., 1980
). The current data show that similar concentrations were achieved with the 100 mg progesterone vaginal tablet, with a Cmax of 31.61 ± 12.62 nmol/l (9.94 ± 3.96 ng/ml) and progesterone concentrations of 26.08 ± 13.96 nmol/l (8.4 ± 4.4 ng/ml) after receiving 100 mg b.d. for 14 days. The wide standard deviation probably reflects different times of progesterone insertion the evening prior to the clinic visit. These serum progesterone values were obtained without vaginal priming by oestrogen. It was previously reported that oestrogen therapy markedly increases vaginal progesterone absorption (Villanueva et al., 1981
). Shushan et al. (1994) have shown that a combined vaginal tablet containing 6 mg of oestradiol and 50 mg of progesterone produced by the same manufacturer as the tablets in the present study achieved midluteal progesterone concentrations of 21.6 ± 2.5 ng/ml (68.6 ± 7.95 nmol/l) with a twice-daily treatment regimen. Endometrial biopsies showed in-phase endometrial histology in eight of nine women (Shushan et al., 1994
). No endometrial biopsies were obtained in our study, since only progesterone was evaluated and transvaginal sonography at the completion of the 30 days of treatment revealed only a thin (23 mm) endometrium in all women.
Furthermore, Miles et al. (1994) described a uterine `first pass' effect induced by vaginal progesterone administration. The authors reported a higher concentration of progesterone in the endometrium (11.5 ± 2.6 ng/ml) after continual administration vaginally for 6 days, compared to i.m. treatment (1.4 ± 0.4 ng/ml), in normal ovulatory women. Interestingly, after the vaginal progesterone application, the endometrial and plasma progesterone concentrations were similar (11.5 ± 2.6 ng/ml, and 11.9 ± 1.2 ng/ml respectively). These results may suggest that adequate endometrial concentrations can be achieved even with low doses of progesterone.
To date, vaginal tablets were used to deliver antimycotic or antibacterial drugs. To the best of our knowledge, this is the first report of pharmacokinetic evaluation of a progesterone-containing vaginal tablet in humans. The advantage of the vaginal tablet is that it absorbs the vaginal secretions and disintegrates into an adhesive powder that adheres to the vaginal epithelium, thus facilitating sustained release. This effect is also evident from the results obtained in women from different age groups. It appears that women >40 years demonstrated enhanced absorption of vaginal progesterone (5.47 ± 2.33 h for the 50 mg and 5.89 ± 3.25 h for the 100 mg), compared to women 40 years (8.0 ± 2.83 h and 7.27 ± 3.5 h for the 50 and 100 mg tablets respectively) (Table III
). These data are probably explained by thinner and more atrophic vaginal mucosa in older women. However, no significant difference was observed in the Cmax or AUC between the age groups (Table III
), indicating that the tablet was fully absorbed.
Other advantages are related mostly to patient compliance. Vaginal tablets are easily administered by the woman herself. There is no messy discharge as is sometimes seen with vaginal suppositories or creams. Only three women (6%) experienced minimal vaginitis during the treatment, and none withdrew from the study due to local vulvovaginal irritation. The vaginal tablet should be inserted only twice daily. This is a convenient schedule also for working women who can insert the tablet in the morning before going to work and in the evening when they return, compared to the vaginally used oral progesterone gelatin capsule that needs to be inserted 3 or 4 times per day (Devroey et al., 1989; Smitz et al., 1992
; Miles et al., 1994
).
The continuous use of the vaginal tablet was well tolerated with no influence on liver enzymes or lipid profiles. This is probably a result of direct absorption of progesterone from the vaginal mucosa into the blood stream, bypassing the liver. Also, the hormonal concentrations of LH, FSH, cortisol, and aldosterone were not affected by the progesterone treatment, since no significant difference from baseline concentrations was observed.
In conclusion, natural micronized progesterone given as an effervescent vaginal tablet, is a well-tolerated and safe product. Reliable release and absorption were obtained with both 50 mg and 100 mg vaginal tablets. Adequate luteal plasma concentrations were achieved with the 100-mg dose even in non-oestrogen primed women. The easy administration and lack of side effects assure good patient compliance. Further pharmacokinetic studies are currently being conducted to evaluate oestradiol and progesterone concentrations after the combination of oestradiol and vaginal tablets, as well as their effect on endometrial histology.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 8, 1998; accepted on November 23, 1998.