1 Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong and 2 Department of Pharmacology, The University of Hong Kong, China
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, China. e-mail: cwcchan{at}graduate.hku.hk
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Abstract |
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Key words: hCG/intramuscular/obese/subcutaneous
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Introduction |
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The pharmacokinetic behaviour of hCG may also be affected by obesity. In general, a larger distribution volume results in a lower serum concentration (Dobbs et al., 1994). In a standard IVF programme, serum hCG levels at 12 h after injection were found to be significantly lower in obese women, regardless of the route of administration (Elkind-Hirsch et al., 2001
). However, a direct comparison of the bioavailability of hCG in obese and non-obese women has not been reported. The aim of the present study was to make such as comparison after i.m. or s.c. injection of hCG.
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Materials and methods |
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Study design
The study was performed in the early follicular phase up to day 7 of the start of a spontaneous or progestogen-induced menstruation. A blood sample was taken 5 min before hCG administration to ensure that there was no endogenous hCG present. An i.m. injection of 10 000 IU hCG (Pregnyl®; N.V. Organon, The Netherlands) was given under ultrasound guidance to ensure that the needle was correctly placed in the muscle layer of the deltoid muscle. Blood was taken at intervals (12, 24, 36, 48, 72, 96 and 120 h) for determination of hCG concentration by immunoassay using direct chemilluminometric technology (Bayer, New York, USA). These sampling intervals were based on a study conducted on the pharmacokinetics of hCG in normal patients (Mannaerts et al., 1998). The mean (± SD) time to reach maximum serum concentration (tmax) after i.m. injection of 10 000 IU hCG was reported as 20.78 ± 9.68 h, and the half-life (t
) was 33.55 ± 4.14 h. The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) from zero to infinity after i.m. administration were determined.
At 4 weeks after the initial (i.m.) administration of hCG, the same patients each received a s.c. injection of 10 000 IU hCG. The 4-week interval was utilized to allow clearance of hCG after i.m. dosing, and also to allow drug administration during the early follicular phase of the cycle. The injections were given using an injection pen and insulin needle to ensure that the drug was deposited in the subcutaneous layer of the periumbilical region. Blood was taken at the same intervals as after i.m. injection. The Cmax and AUC of hCG after s.c. administration were determined. All hCG used in the present study was from the same batch in order to avoid batch-to-batch variability of the drug.
Statistical analysis
Based on the results of a previous study (Mannaerts et al., 1998), the mean AUC after i.m. hCG administration (10 000 IU) was 28130 ± 5870 IU·h/l. In order to detect a 20% reduction in AUC after s.c. injection, nine patients were required in each group to provide a power of 80% and P-value of 0.05. In order to allow a drop-out rate of 20%, 12 patients were recruited for each group; such a sample size also allowed detection of a 27% difference in the AUC of hCG between the obese and non-obese groups, with the same power.
Distributions of the variables were given as median and inter-quartile range. The Cmax and AUC of hCG between the two different routes of administration in each group were compared by the Wilcoxon Signed Rank test. Similar comparisons between the obese and non-obese groups were made with the MannWhitney U-test. A P-value < 0.05 was considered statistically significant.
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Results |
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Discussion |
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Several studies have compared the pharmacokinetics of hCG after i.m. and s.c. administration, but the results obtained have been controversial. In a preliminary study performed in male subjects (Saal et al., 1991), the bioavailability of hCG was significantly higher after i.m. than s.c. injection. However, when the study was repeated in female subjects of normal body weight, no difference was observed (Mannaerts et al., 1998
). Another group (Wikland et al., 1995
) studied hCG levels at 12 and 36 h after hCG injection to induce oocyte maturation during IVF cycles, and found serum levels of hCG to be significantly higher in women receiving i.m. compared with s.c. injections. By contrast, and using the same model, no difference in the serum concentration of hCG could be found at either 12 h (Elkind-Hirsch et al., 2001
) or 24 h (Sills et al., 2001
) after injection when the study was repeated. A recent study reported an even higher serum hCG level at 36 h after a single i.m. injection than after a s.c. injection in an IVF programme (Stelling et al., 2003
), though the comparison of a single serum concentration does not reflect the true bioavailability of the drug. The absorption of hCG after s.c. injection appeared to be delayed (Saal et al., 1991
), and this cast doubt on the validity of comparing serum levels at a particular time point. It was also noticed that the difference in serum hCG levels between the i.m. and s.c. administration was smaller at 36 h, despite the serum level still being higher after i.m. injection.
Furthermore, all of these studies failed to confirm the site of drug deposition, which might explain the discrepancy in observation. For example, when studying the pharmacokinetics of hMG, one group (Dobbs et al., 1994) confirmed correct placement of the needleand thus the site of drug depositionby using electromyography. These authors noticed that it was often necessary to insert the needle considerably further than 4 cm (1.5 in) to reach the muscle layer. Undoubtedly, the relative obesity of their subjects contributed to the depth of needle placement required to reach this depth. Nevertheless, it was possible that some of these intended i.m. injections were given subcutaneously, even in women of normal body stature, thereby diluting any possible difference between the two routes of administration. During injection in the present study, the needle was confirmedusing ultrasound guidanceto be correctly placed in the muscle layer. Moreover, the women were used as their own control, so that any difference in drug bioavailability was attributable to absorption from the injection site rather than to inter-individual variation. The deltoid muscle was chosen as the site for i.m. injection because the subcutaneous fat layer there appeared to be thinner than that overlying the gluteus muscle. Unfortunately, the depth of the subcutaneous layer was not measured as this was not an intended observation to be made when the study was designed. In retrospect however, this information may have been helpful.
Obese women have a larger volume of distribution than non-obese women, and this may lead to a lower serum concentration after drug administration (Dobbs et al., 1994). A negative correlation between the BMI and serum hCG levels at 12 h after injection was observed in patients treated by IVF (Elkind-Hirsch et al., 2001
). In the present study, it was confirmed that after single injection, obese women had a lower bioavailability of hCG compared with non-obese women, irrespective of the route of administration. If this information can be extrapolated to infer the pharmacokinetics of other gonadotrophins (namely hMG), it may help to explain the observation that obese patients show less favourable responses to ovarian stimulation. For example, patients with polycystic ovary syndrome (PCOS) who were overweight required more ampoules of hMG in order to achieve ovulation (Chong et al., 1986
; Hamilton-Fairley et al., 1992
; McClure et al., 1992
). Even in women without PCOS who were undergoing IVF treatment, the odds ratio of a negative response both on day 7 and at the end of treatment increased with BMI (Crosignani et al., 1994
). Furthermore, in a more recent study a negative association between BMI and the number of oocytes retrieved in IVF cycles was found (Ng et al., 2000
). Only one investigationa case-controlled retrospective study involving women with a BMI
28 kg/m2reported a comparable ovarian response, though the peak estradiol level was still significantly lower in the heavier women (Lashen et al., 1999
). Direct pharmacokinetic data on hMG is difficult to obtain because of the presence of endogenous gonadotrophins. Even with the use of combined oral contraceptives or GnRH analogues, the suppression of endogenous FSH and LH secretion is often not complete (Dobbs et al., 1994
; Duijkers et al., 1995
). hCG is absent in non-pregnant women, and therefore serves as the ideal surrogate marker to study the pharmacokinetics of gonadotrophins. The low bioavailability of hCG (and perhaps also of other gonadotrophins) in obese women bears an important clinical implication that these women should either be given a higher dose or, more effectively, be advised to reduce their body weight before embarking on such treatment. The latter factor is especially important when the cost of treatment must be considered.
Different doses of hCG have been used in various IVF treatment protocols to induce final maturation. There is as yet no agreement on the minimum dose required, but evidence has suggested that different patients have different thresholds for their response to hCG. In one study, single i.m. administration of either 5000 or 10 000 IU hCG was enough to stimulate final oocyte maturation in the majority of patients (Abdalla et al., 1987), though unfortunately the body weights of the patients were not reported. Later studies showed comparable clinical outcomes in non-obese patients after 10 000 IU hCG given by either the i.m. or s.c. route in IVF programmes (Wikland et al., 1995
; Stelling et al., 2003
). These observations indicate that i.m. administration of 10 000 IU hCG probably exceeds the minimum threshold for non-obese patients. A lower bioavailability of hCG after s.c. administration still gives an adequate serum level in non-obese women. In the present study, the AUC of hCG after i.m. injection in obese patients was slightly lower than that after s.c. injection in non-obese patients. Such an approach may still reach the minimum hCG threshold for final oocyte maturation in most obese patients, although the dosage may need to be individualized in extremely obese women. Given its poor bioavailability, the s.c. administration of hCG in obese women is not advisable.
In conclusion, the higher bioavailability of hCG after i.m. injection than after s.c. injection was demonstrated, and a significantly lower bioavailability of hCG was observed in obese women, irrespective of the route of hCG administration. These findings support the advice that obese women should reduce their body weight before embarking on subfertility treatment, as the poor bioavailability of gonadotrophins is one of the many problems that these women might encounter.
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References |
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Submitted on June 2, 2003; accepted on July 22, 2003.