1 UCO di Ginecologia e Ostetricia, Dipartimento di Scienze della Riproduzione e dello Sviluppo, Università di Trieste, Istituto per l'Infanzia `Burlo Garofolo', I.R.C.C.S., Trieste and 2 Laboratorio Analisi, Istituto per l'Infanzia `Burlo Garofolo', I.R.C.C.S., Trieste, Italy
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Abstract |
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Key words: highly purified urinary FSH/lipoprotein(a)/ovarian stimulation/progesterone/recombinant FSH
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Introduction |
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The administration of oral oestrogens in postmenopausal women has been shown to reduce Lp(a) concentrations (Farish et al., 1996; Haines et al., 1996
; Kim et al., 1996
; Hänggi et al., 1997
; Espeland et al., 1998
; Spencer et al., 1999
). No significant changes have been reported with the use of transdermal oestradiol, suggesting that the effects of orally administered oestrogens may stem from their capacity to influence hepatic metabolic processes (Hänggi et al., 1997
; Spencer et al., 1999
). Few studies are available on Lp(a) changes in women undergoing ovarian stimulation (Seed et al., 1990
, 1991
; Haines et al., 1997
); these studies evaluated the effects of urinary human menopausal gonadotrophin (HMG) and conflicting results were reported. No data concerning the effects of more recent gonadotrophin preparations on Lp(a) serum concentrations have been published.
The aim of this study was to evaluate the effects of highly purified urinary FSH (u-hFSH HP) and recombinant human FSH (r-hFSH) treatment on Lp(a) concentrations in a prospective randomized study.
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Materials and methods |
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Exclusion criteria included: chronic diseases, body mass index <18 or >27 kg/m2; past or current abuse of alcohol; >5 cigarettes per day; regular intake of drugs.
Thirty comparable volunteer Caucasian nulliparous women were concurrently recruited as controls. Inclusion criteria were: aged between 28 and 38 years; regular menstrual cycles lasting from 26 to 30 days; previous three cycles of regular length; no administration of sex steroids or drugs known to affect lipid metabolism within the previous 12 months. The exclusion criteria were the same as for infertile subjects.
Study design
This was an open, randomized, controlled study comparing the effect of u-hFSH and r-hFSH on Lp(a) serum concentrations. After confirming eligibility for the study, the infertile women were randomly allocated into two equally sized treatment groups (n = 25 per group) using a random number generator on a personal computer. Thirty non-randomized, comparable women were included in the untreated control group. Informed consent was obtained from each subject before the start of the study. The study was conducted in accordance with the guidelines proposed in The Declaration of Helsinki.
Study protocol
Starting on cycle day 2, infertile patients received u-hFSH (Metrodin HP; Serono, Rome, Italy) or r-hFSH (Gonal F; Serono, Rome, Italy) 150 IU/day. From cycle day 6, dose adjustment was performed, according to follicular development, as assessed by ultrasound scanning. Human chorionic gonadotrophin (HCG) 10 000 IU was administered to induce ovulation when at least one follicle 18 mm in diameter was present. The luteal phase was supported with 50 mg progesterone in oil (Prontogest, Amsa, Italy) daily i.m. beginning 3 days after HCG administration and continuing for at least 15 days. On the 18th day after HCG administration, a pregnancy test was performed. If positive, progesterone was continued for 14 days.
Blood samples for measurement of serum Lp(a), oestradiol and progesterone, were taken from all subjects on cycle day 2 before starting gonadotrophin administration, on cycle day 6, on the day of HCG administration, and 10 days after HCG administration. In patients who failed to achieve pregnancy, Lp(a) serum concentration measurements were repeated on day 2 of the following menstruation, providing one month of wash-out. In patients who achieved pregnancy measurements of Lp(a), oestradiol and progesterone serum concentrations were repeated after a comparable period at the 8th week. In the control group, blood was collected on cycle day 2. To standardize the different cycle lengths the timing of the successive blood samples was calculated personally. The presumed first day of the next menstruation, estimated on the basis of the length of the previous three cycles, was taken as day 0. The second, third and fourth blood samples were taken on days 21, 14, 7. The fifth sample was collected on cycle day 2 of the second successive menstrual cycle.
Each blood sample was collected between 0800 and 0900 h after a 12 h fast.
Laboratory analyses
Blood was taken from an antecubital vein with minimal stasis using standard venepunture techniques into serum tubes. Serum samples were separated by centrifugation at 3000 g for 10 min and stored at 80°C until analysis. Each subject's sample was analysed in the same assay to minimize interassay variation. All samples were tested for Lp(a), 17ß-oestradiol and progesterone concentrations. Lp(a) measurements were determined by means of a commercial enzyme-linked immunosorbent assay kit (Macra® Lp(a) manufactured by Strategic Diagnostics Inc. for Trinity Biotech USA, Jamestown, NY, USA); the test is a sandwich assay which utilizes both a monoclonal antibody and polyclonal antibodies which specifically bind to the apolipoprotein (a) moiety of Lp(a). All samples were run in duplicate and the results were expressed in mg/dl; the intra- and interassay coefficients of variation for this method were <5% and <10% respectively. Serum 17ß-oestradiol and progesterone were determined by means of a solid-phase, ligand-labelled, competitive chemiluminescent immunoassay with an Immulite Analyzer (Immulite® Estradiol and Immulite® Progesterone, Diagnostic Products Corporation, Los Angeles, CA, USA) and results were expressed in pg/ml and ng/ml respectively.
Statistical analyses
Given the skewed Lp(a) distribution, non-parametric statistics were used to protect against non-normal distribution of data. Statistical analyses of all baseline parameters for between-group differences were performed by means of Kruskal-Wallis analysis of variance (ANOVA) test. The 2-test was used to compare categorized measures when appropriate. Multiple comparisons of paired data during natural and stimulated cycles were performed with Friedman's repeated measures test followed by Dunn's multiple comparisons post-hoc test. Statistically significant differences between the stimulated and control groups were examined by the Mann-Whitney U-test. Spearman's rank correlation coefficient was used to assess correlations between parameters. Statistical significance was assigned when P < 0.05.
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Results |
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Discussion |
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In two small series, respectively 22 and 20 women undergoing ovarian stimulation, the effects of HMG administration (Seed et al., 1990, 1991
) were evaluated. An increase, albeit not statistically significant, probably because of the low number of subjects investigated, in Lp(a) median concentration from 3 to 9 mg/dl and from 6.4 to 7.9 mg/dl at the end of the HMG administration was observed. Unfortunately, luteal Lp(a) changes were not considered, thus the whole effect of HMG administration could not be evaluated.
In this study, we have shown that FSH administration does not directly influence serum Lp(a) concentrations. No increase in Lp(a) concentrations was observed during the follicular phase of r-hFSH or u-hFSH stimulated cycles. The different effects of HMG and uFSH on Lp(a) might be due to the LH content of HMG. In hypogonadotrophic women, HMG significantly increases follicular phase androgens when compared with u-hFSH HP (Couzinet et al., 1988). However, no conclusive data regarding androgen influence on Lp(a) concentrations are available. No significant correlations were found between Lp(a) and testosterone concentrations in myocardial infarction patients and healthy controls (Marques-Vidal et al., 1995
). In normal men, parenteral testosterone reduced Lp(a) concentrations (Zmuda et al., 1996
), whereas, in males suffering from prostatic carcinoma, parenteral testosterone administration lowered Lp(a) concentrations by 20%, while orchidectomy increased Lp(a) concentrations by 20% (Henriksson et al., 1992
; Berglund et al., 1996
). In patients with hypogonadism Lp(a) concentrations did not change significantly following parenteral testosterone or gonadotrophin treatment (Ozata et al., 1996
). No data have been reported on the relationship between Lp(a) and androgens in women. Alternatively, gonadotrophin-releasing hormone (GnRH) analogue administration before starting HMG treatment might influence Lp(a) concentrations. In young volunteer males, pituitary suppression by the GnRH antagonist Cetrorelix was associated with a pronounced increase in Lp(a) concentrations (Von Eckardstein et al., 1997
), although buserelin reduced concentrations of Lp(a) by 48% in elderly males suffering from cancer of the prostate (Arrer et al., 1996
). Unfortunately, in Seed's studies (Seed et al., 1990
, 1991
) Lp(a) serum concentrations prior to GnRH analogue administration were not evaluated.
Haines et al. (1997) reported an increased concentration of Lp(a) in the luteal phase of natural and HMG-stimulated cycles, suggesting that progesterone may cause an increase in Lp(a) serum concentrations. This conclusion, however, was speculative, as the design of this study did not allow for evaluation of the separate effects of increased progesterone and oestrogen concentrations on Lp(a) concentrations. Since only two blood samplings, in the late midfollicular and midluteal phases, were performed, and no base data were available, the results could not demonstrate whether the higher Lp(a) concentrations were the outcome of the raised progesterone or oestrogen luteal concentrations.
Our data on stimulated cycles demonstrated that Lp(a) increases only when progesterone is raised. There were no significant changes in Lp(a) concentrations at the end of the follicular phase, even when very high concentrations of oestrogens were present.
Furthermore, the luteal increase in Lp(a) concentrations in stimulated cycles was statistically correlated with luteal progesterone increase, but not with follicular or luteal oestradiol increase. We found that Lp(a) concentrations did not significantly change during the natural cycle. This finding is consistent with a previous study (Owens et al., 1993) but not with Haines' data (Haines et al., 1997
). Haines' study, however, has many limitations, such as a low number of blood samples during the menstrual cycle, or the lack of blood sample timing standardization. Therefore, we are led to conclude that progesterone only at supraphysiological concentrations significantly influences Lp(a) concentrations. However, we cannot rule out that some phenotypes have different responses to menstrual cycle progesterone changes. Alternatively, the luteal Lp(a) increase could be related to a pharmacological effect of the parenteral progesterone administration. Tonolo et al. (1995) in a small but well-designed study, considering only women with an ovulatory cycle, showed a significant luteal apo(a) increase in four cases, whereas no significant changes were detected in the remaining 11 cases. The four women with an increase of apo(a) had only S4 bands on sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Furthermore, these women had lower plasma mean concentrations (8 U/dl) compared to the 11 women who showed no significant apo(a) change (54 U/dl). Indeed, an inverse correlation between apparent molecular weight and plasma concentrations of apo(a) has previously been reported, i.e. small apo(a) phenotypes are associated with high concentrations of Lp(a), and large apo(a) phenotypes are associated with low concentrations of Lp(a) (Scanu and Fless, 1990
; Boerwinkle et al., 1992
; Lackner et al., 1993
; Rader et al., 1993
; Rader et al., 1994
; Querfeld et al., 1999
). Thus Tonolo's data (Tonolo et al., 1995
) suggested that in women with alleles coding high molecular weight apo(a), the synthesis of apo(a) could be stimulated by progesterone. In our study we found that women with low baseline Lp(a) (<5 mg/dl) had a greater increase in Lp(a) concentrations at midluteal phase than women with baseline Lp(a) >5 mg/dl, providing further evidence that there is a different sensitivity of the apo(a) phenotypes to progesterone changes.
We are unable to explain why progesterone should increase Lp(a) concentrations. Previous studies suggest that the effects of progestogens on Lp(a) concentrations are dependent on the dose and degree of androgenicity of the preparation employed. Consistent reductions in Lp(a) concentrations were observed in patients treated with norethisterone alone at doses of 10 mg/day (Farish et al., 1991), and, to a lesser extent, when administered at 1 mg/day in combination with oestradiol (Farish et al., 1996
; Spencer et al., 1999
). Tibolone, a synthetic steroid structurally related to norethynodrel and norethisterone, and effective in the relief of climacteric symptoms, has also been reported to lower Lp(a) concentrations (Hänggi et al., 1997
). Cyclical administration of dydrogesterone at different dosages has been reported not to modify significantly the favourable effects on Lp(a) induced by oestradiol (van der Mooren et al., 1993
; Mijatovic et al., 1997
). A large study regarding the effects of various progestogens combined with conjugated equine oestrogen (CEE) on Lp(a) concentrations has shown that medroxyprogesterone acetate (MAP) and norgestrel attenuated the Lp(a)-lowering effect of oestrogen (Kim et al., 1996
). On the contrary, in the PEPI trial, no significant differences were apparent between CEE only and each combination regimen with MAP or micronized progesterone (Espeland et al., 1998
).
The results of this study demonstrated that urinary and recombinant FSH administration had similar effects on Lp(a) concentrations. If no pregnancy occurred, we found that after 1 month Lp(a) concentrations fell to pre-treatment values, suggesting that the effect of ovarian stimulation with u-hFSH or r-hFSH was transitory and the 4-week wash-out period was probably sufficient to eliminate any residual drug influence. In women who have conceived, Lp(a) concentrations remained elevated. We cannot demonstrate whether an Lp(a) increase normally occurs during pregnancy or whether it was related to ovarian stimulation and/or parenteral progesterone administration. Few data are currently available on Lp(a) changes during spontaneous pregnancy and no study has evaluated Lp(a) concentrations before and after conceiving. Zechner et al. (1986) showed that Lp(a) concentrations rose steadily during the first trimester of pregnancy. However, this study did not evaluate Lp(a) concentrations before the eighth week; furthermore, Lp(a) was measured by the Laurell technique, a method with unacceptable analytical sensitivity. Recently, Sattar et al. (2000) reported a significant increase in Lp(a) values in normal pregnancy between 10 and 35 weeks. Other authors (Panteghini and Pagani, 1991) observed no significant differences between Lp(a) concentrations in non-pregnant controls and pregnant women before the eighth week of gestation. On the other hand, in stimulated cycles progesterone concentrations far exceed those in the natural cycle because of the presence of multiple corpora lutea and the luteal phase progesterone supplementation.
In conclusion, the administration of recombinant or urinary h-FSH does not directly influence Lp(a) concentrations. The total effects of ovarian stimulation with urinary and recombinant FSH on Lp(a) are comparable and are not related to gonadotrophin preparations, but appear to be related to the high luteal progesterone concentrations, physiologically or pharmacologically induced. The luteal Lp(a) increase in stimulated cycles is transitory. Therefore in women undergoing ovarian stimulation using the currently available FSH preparations, the cardiovascular risk as assessed by Lp(a) is not significantly affected.
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Acknowledgments |
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Notes |
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References |
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Submitted on September 4, 2000; accepted on December 7, 2000.