Human Reproduction, Vol. 14, No. 6, 1440-1444,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Effect of prednisolone on serum and follicular fluid androgen concentrations in women with polycystic ovary syndrome undergoing in-vitro fertilization
1 Department of Clinical Science, Division of Obstetrics and Gynecology, Huddinge University Hospital, Stockholm, and 2 Fertility Center Scandinavia, Carlanderska Hospital, Göteborg
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Abstract |
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Increased androgen concentrations are thought to be detrimental to oocyte quality and reproductive potential. Adjuvant treatment with glucocorticoids has been tried to suppress androgens in women undergoing infertility treatment. In the present study 20 infertile women with polycystic ovary syndrome were prospectively randomized in a placebo-controlled study to receive either placebo or prednisolone 10 mg at night, during standard in-vitro fertilization (IVF) treatment. Serum samples for assays of gonadotrophins, steroids and sex hormone-binding globulin (SHBG) were collected before treatment, at down-regulation, and at oocyte retrieval. Up to five follicles in each ovary were analysed separately regarding follicular fluid and oocytes, the rest according to the clinic's routines. In the placebo group, serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA-S) did not change between down-regulation and oocyte retrieval, whereas adjuvant prednisolone resulted in a significant decrease. In follicular fluid, adjuvant prednisolone resulted in significantly lower concentrations of DHEA-S as compared to placebo, no other significant differences were found. No significant differences were found in embryo characteristics or pregnancy rates between the groups.
Key words: : androgens/follicular fluid/glucocorticoids/in-vitro fertilization/PCOS
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Introduction |
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Women with polycystic ovaries (PCO) and oligo/amenorrhoea, comprising the polycystic ovarian syndrome (PCOS), present a challenge in clinical in-vitro fertilization (IVF). They are often high-responders to ovarian stimulation, leading to increased risk of the ovarian hyperstimulation syndrome (OHSS). Despite the vigorous response to stimulation, follicle quality may be compromised, leading to poor embryo quality, low implantation rates, and early miscarriage (Howles et al., 1986
; Dor et al., 1990; Homburg et al., 1993a,b). Impairment of oocyte quality could be due to high endogenous follicular phase luteinizing hormone (LH) concentrations or to hyperandrogenism, commonly seen in women with PCOS (Regan, 1991; Shoham et al., 1993; Franks, 1995). Hyperandrogenism, regardless of origin, is detrimental to female fertility and elevated androgen concentrations will down-regulate the action of follicle-stimulating hormone (FSH) on the granulosa cells and thus impair follicular development (Hillier and Tetsuka, 1997).
Down-regulation with gonadotrophin-releasing hormone (GnRH) analogues depresses LH concentrations as well as ovarian androgen production, but does not affect adrenal androgen secretion (Chang et al., 1983; Dale et al., 1992). The adrenal cortex is an important androgen source in women and peripheral conversion of the weak adrenal androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S) and 4-androstene-3,17-dione is responsible for about 60% of circulating testosterone in healthy women (Crilly et al., 1981). Circulating adrenal androgens are also reported to be converted into testosterone in the ovarian follicles. Using infusion of [3H]DHEA-S, Longcope and co-workers reported circulating DHEA-S as a precursor for as much as 48% of the testosterone found in follicular fluid (Haning et al., 1993).
Successful use of corticosteroids in treatment of anovulatory infertility has been reported (Jones et al., 1953; Greenblatt et al., 1956). Later corticosteroids were used as adjuvant therapy together with clomiphene citrate or gonadotrophins in ovulation induction. The theoretical basis for this application has not been fully elucidated, but it has been postulated that corticosteroid treatment could improve ovulation through reduced influence of the adrenal androgens on follicular development (Lobo et al., 1982; Isaacs et al., 1997). There have been reports on improved ovulation and pregnancy rates with adjuvant corticosteroid treatment in anovulatory women with elevated androgens or androgens within the higher range (Diamant and Evron, 1981; Lobo et al., 1982; Evron et al., 1983; Daly et al., 1984), as well as in normoandrogenic women (Singh et al., 1992). Adding dexamethasone to gonadotrophins in ovulation induction in women with normal serum concentrations of gonadotrophins, androgens, and prolactin did not give an improved outcome in other studies (Bider et al., 1996).
Corticosteroids have also been used as adjuvant therapy in IVF treatment. In 1986, Kemeter and Feichtinger reported a significantly better pregnancy rate in a group of women with various infertility causes, except cycle abnormalities, undergoing IVF with adjuvant prednisolone treatment, as compared to a group of women without adjuvant prednisolone. They stated that prednisolone would improve follicle maturation and thereby improve the pregnancy rate. In contrast, others (Rein et al., 1996) did not see any beneficial effects of adjuvant dexamethasone in a group of women with serum DHEA-S >2.5 µg/ml (6510 nmol/l) undergoing IVF treatment, neither did Bider et al. (1996), in a group of women with tubal factor infertility after addition of dexamethasone.
In the above-mentioned study by Lobo (Lobo et al., 1982), decreased serum concentrations of testosterone, unbound testosterone, and DHEA-S were noted after dexamethasone and clomiphene administration. In women who ovulated, testosterone and unbound testosterone increased again when clomiphene was added despite the continuation of dexamethasone. Decreased serum concentrations of DHEA-S and testosterone after ovarian stimulation with clomiphene citrate and human menopausal gonadotrophin (HMG) and adjuvant prednisolone have been reported (Kemeter and Feichtinger 1986). The other studies did not report data on androgen concentrations after glucocorticoid treatment. The present prospective, randomized, placebo-controlled study was performed to find out if adrenal suppression with prednisolone during ovarian stimulation before IVF in a group of women with PCOS resulted in any changes in serum and follicular-fluid androgens. Clinical outcome variables, such as embryo quality, implantation rate, and clinical pregnancy rate were also noted.
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Materials and methods |
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Subfertile patients referred to the IVF-unit of Huddinge University Hospital were recruited during the period May 1996 to December 1997. All 20 women who fulfilled the criteria of oligomenorrhoea, polycystic ovaries as seen by vaginal ultrasound, hyperandrogenism and/or elevated LH/FSH ratio, consented to participate in the study. They were all normoprolactinaemic. Their partners had normal spermiograms, including morphology according to strict criteria (Krüger et al., 1987
). Two of the recruited women had episodic problems with allergic asthma and medicated with glucocorticoid inhalations during the spring season. Neither of these two patients medicated during the study period. The other women were healthy. One woman in the control group was excluded from the study. Because of monofollicular growth, oocyte retrieval was never performed. Instead, the patient underwent ovulation induction.
Randomization
Patients were randomized at down-regulation in a double-blind fashion to receive either placebo or prednisolone tablets from jars coded at the hospital pharmacy. The codes were revealed after treatment of the last patient.
The women gave written consent to participate in the study which was approved by the Local Ethics Committee of Huddinge University Hospital.
Treatment
The women received standard IVF treatment with a long protocol down-regulation using buserelin, 1.0–1.2 mg/day; (Suprecur®/Suprefact®, Hoechst, Frankfurt, Germany). When down-regulation was achieved (serum oestradiol 
100 pmol/l, and endometrial thickness 4 mm), follicle stimulation was performed with purified FSH (Fertinorm HP®; Ares-Serono, Geneva, Switzerland), until the leading follicle exceeded 17 mm in diameter. Ovulation was induced with 10 000 IU human chorionic gonadotrophin HCG (Profasi®, Ares-Serono). Adjuvant treatment with one tablet containing either 10 mg prednisolone or placebo was given at night every day of FSH injections, continuing until HCG administration.
Transvaginal ultrasound-guided oocyte recovery was performed under local anaesthesia combined with light sedation 37 h after HCG injection. The diameters of up to five follicles in each ovary were measured before aspiration and the oocyte and follicular fluid from each of these follicles were kept separate. Only the first clear portion of aspirated fluid was collected and centrifuged for 10 min at 240 g. The supernatant was stored at –20°C until analysis. The remaining follicles were aspirated according to routines. After fertilization using 20 000 spermatozoa in a 50 µl medium drop under oil, the oocytes were cultivated in IVF-50 and S2 media for day 3 culture (Scandinavian IVF Sciences AB, Göteborg, Sweden). Blood samples were drawn at 8.00–9.30 a.m. after a night's fasting, firstly on cycle day 3–5 after spontaneous or gestagen-induced bleeding, secondly at down-regulation, and thirdly at oocyte retrieval. The serum was stored at –20°C until analysis.
The morphology of the embryos was evaluated from a previously published system (Mohr and Trounson 1985). Thus, for defects in each of the following respects 0.5 points were subtracted from a starting score of 3.5 (indicating a perfect embryo): at least four or eight blastomeres at 44 h and 68 h post-insemination respectively; no fragmentation; clear and translucent cytoplasm, and only one normal-sized nucleus; blastomeres filling the space under the zona; equal-sized blastomeres; spherical blastomeres; membranes smooth and glossy and blastomere borders clearly distinguishable. For embryo freezing a score of at least 2.5 was required.
Two embryos were replaced 2 or 3 days after oocyte retrieval. As luteal support daily i.m. injections of 50 mg progesterone (Progesteron®, Apoteksbolaget, Umeå, Sweden) was administered until pregnancy test 2 weeks after embryo transfer. If serum HCG was >40 IU/l, indicating pregnancy, the luteal support was continued until an ultrasound scan revealed fetal heart beats a few weeks later.
Analytical methods
Serum concentrations of oestradiol-17ß during stimulation and at oocyte retrieval and of LH, FSH, and progesterone were analysed by chemiluminescence immunoassay using commercial kits (Immulite®) obtained from Diagnostic Products Corp., Los Angeles, CA, USA (DPC). LH and FSH concentrations are expressed as IU/l of the World Health Organization (WHO) first international reference preparation (IRP) 68/40 and the WHO second FSH IRP 78/549, respectively. Serum oestradiol before and after down-regulation and serum testosterone were determined by radioimmunoassay using commercial kits obtained from DPC (`Estradiol Double Antibody' and `Coat-a-Count Testosterone'), and serum sex hormone-binding globulin (SHBG) by time resolved fluorescence immunoassay, using a commercial kit (Autodelfia®) obtained from Wallac OY, Turku, Finland. Serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S), and 4-androstene-3,17-dione were analysed after extraction with diethyl ether by radioimmunological methods developed at our department (Brody et al., 1983; Stege et al., 1987; Carlström et al., 1988). In the assay of DHEA-S the sulphoconjugate was cleaved by thermal hydrolysis, followed by extraction of the liberated DHEA. The assay for androstenedione used an anti-androstenedione-19-(O-carboxymethyl) ether-bovine serum albumin antibody (BioClin, Cardiff, UK). The cross-reactivity with progesterone for this antibody at different progesterone concentrations was found to vary from 0.76% at a progesterone concentration of 3.2 µmol/l to 0.17% at a progesterone concentration of 63.7 µmol/l. The cross-reaction with progesterone can be neglected in the serum androstenedione assay but not when androstenedione is measured in follicular fluid. The contribution of progesterone to the androstenedione values measured in follicular fluid followed the equation: androstenedione (nmol/l) = 16.3 + 3.213xP – 0.027xP2, where P is progesterone concentration expressed in µmol/l. Final follicular fluid androstenedione values were obtained by subtraction of the contribution from cross-reacting progesterone from the measured androstenedione values.
Unconjugated and conjugated steroids in follicular fluid were separated by extraction with diethyl ether and follicular fluid concentrations of oestradiol, progesterone, testosterone, androstenedione, DHEA and DHEA-S were analysed by radioimmunoassay as described previously (Bergh et al., 1996). Commercial kits obtained from DPC (`Coat-a-Count') were used for the analysis of oestradiol, testosterone, and progesterone in follicular fluid extracts and the methods described above for serum were also used for the analysis of follicular fluid concentrations of androstenedione, DHEA, and DHEA-S. Detection limits and within and between assay coefficients of variation were for oestradiol double antibody 9 pmol/l, 5% and 5%; for oestradiol Immulite 200 pmol/l, 9% and 8%; for oestradiol Coat-a-Count 35 pmol/l, 5% and 9%; for progesterone Immulite 0.1 pmol/l, 9% and 10%; for progesterone Coat-a-Count 0.3 nmol/l, 4% and 5%; for LH 0.7 IU/l, 6% and 10%; for FSH 0.1 IU/l, 6% and 8%; for testosterone 0.1 nmol/l, 6% and 10%; for DHEA 1.6 nmol/l, 5% and 7%; for DHEA-S 200 nmol/l, 8% and 12%; for androstenedione 0.6 nmol/l, 6% and 10%, and for SHBG 0.5 nmol/l, 5% and 6% respectively.
Statistical methods
Statistical analysis was carried out by t-test for unpaired observations or Mann–Whitney U-test, according to distribution; by Wilcoxon's signed-rank test and by Spearman's rank correlation test. A P level of 0.05 was considered significant. Within each individual patient, follicular fluid concentrations of steroids were normally distributed except for DHEA. Statistical analysis of follicular fluid data as well as the values presented in Table IV are based upon mean (median for DHEA) values from each patient.
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Results |
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There were no significant differences between the placebo group and prednisolone group with regard to age (34.5 years versus 33 years), infertility duration (5.5 years versus 6 years), number of primigravidae (seven in both groups), body mass index (BMI) (26 kg/m2 versus 23.3 kg/m2) or number of smokers (three versus two). Serum concentrations of steroids, SHBG and gonadotrophins at baseline (before start), after pituitary suppression with buserelin and at oocyte retrieval are given in Table I
. In the combined clinical material (data not shown), down-regulation resulted in a significant decline in serum concentrations of oestradiol (P < 0.001), androstenedione (P < 0.01), testosterone (P < 0.001), FSH (P < 0.01), and LH (P < 0.001), but not in adrenal steroids or in SHBG. The concentrations of oestradiol, androstenedione, testosterone, SHBG, and progesterone increased significantly in both groups as a result of ovarian stimulation. In the placebo group, DHEA-S and DHEA did not change significantly between down-regulation and oocyte retrieval, whereas adjuvant prednisolone treatment resulted in a significant decrease. This indicates that the glucocorticoid was effectively suppressing adrenal function.
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Follicular fluid concentrations of steroids from follicles
17 mm at oocyte retrieval are given in Table II. Compared to placebo, adjuvant treatment with prednisolone resulted in significantly (P < 0.05) lower concentrations of DHEA-S in follicular fluid. No other significant difference was seen between the groups. When mean (median for DHEA), follicular fluid concentrations in the patients (all follicles included) and serum concentrations at oocyte retrieval were correlated, a highly significant positive correlation was found for DHEA-S (rs = 0.88, P < 0.001). No significant correlations were found for any of the other steroids. Ovarian stimulation characteristics in patients with adjuvant prednisolone treatment as compared to placebo are given in Table III. No significant differences were noted between the groups regarding dose of FSH required, duration of stimulation, number of medium-sized or large follicles, or endometrium thickness. Table IV
shows oocyte and embryo characteristics, which seemed very similar in both groups. There was a tendency to more oocytes being retrieved in the prednisolone group but this did not reach statistical significance.
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Discussion |
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To our knowledge this is the first study in which both serum concentrations and follicular fluid concentrations of steroids have been measured after ovarian stimulation in combination with adjuvant corticosteroid treatment. The results do not support the view that prednisolone treatment leads to a significant reduction of biologically active androgens in serum or follicular fluid. In contrast, a tendency towards a higher testosterone concentration in follicular fluid was observed. Furthermore, in the small sample of this study an effect by the adjuvant corticosteroid treatment on the clinical outcome was not apparent. Thus, the rationale for corticosteroid treatment as an adjuvant to ovarian stimulation with gonadotrophins in women with hyperandrogenism and/or PCOS may be questioned.
Nevertheless, under some conditions a positive effect of adjuvant corticosteroid treatment cannot be excluded. Theoretically corticosteroids could affect hypothalamic and/or pituitary functions directly or indirectly by suppressing endogenous adrenal steroids thereby influencing secretion of gonadotrophins (Daly et al., 1984; Isaacs et al., 1997). However, the direct action of exogenous gonadotrophins on the ovaries might mask these effects. Further studies in this field could lead to improved and simplified stimulation protocols for patients with PCOS, in accordance with previous discussions (Olivennes and Frydman, 1998).
Despite the fact that DHEA-S concentrations both in follicular fluid and in serum at oocyte retrieval were about one-third lower in the prednisolone group than in the placebo group, neither follicular fluid nor serum concentrations of the other androgens presented lower values in the former group. No correlation was found between the follicular fluid concentration of DHEA-S on the one hand, and follicular fluid testosterone and androstenedione on the other. At first this seems not to support the view of Longcope and co-workers (Haning et al., 1993; Longcope, 1996) of peripheral DHEA-S as a precursor for 48% of the intrafollicular testosterone formed during ovarian stimulation. However, in contrast to the normal subjects studied by Longcope and co-workers, our study population consisted of women diagnosed with PCOS, who may differ in follicular steroidogenesis and who may have an increased de-novo ovarian androgen synthesis (Barnes and Rosenfield, 1989; Gilling-Smith et al., 1994; Ehrmann et al., 1995). Finally, the stimulation regimen used by Longcope and co-workers was HMG, whereas highly purified FSH was used in the present study. Differences in study subjects and stimulation regimen, as well as the rather modest decrease in DHEA-S may thus explain the absence of effect on intrafollicular and serum androgens in the present study.
A significant correlation between follicular fluid and serum steroid values was only found for DHEA-S. DHEA-S is of exclusive adrenal origin in women (Crilly et al., 1981). Circulating DHEA-S is strongly bound to albumin and constitutes a stable pool with the very slow metabolic clearance rate of only 7 l/24 h (Tulchinsky and Little, 1994). The very close correlation between follicular fluid and serum DHEA-S found in the present and in previous studies (Haning et al., 1985, 1993) indicates that intrafollicular DHEA-S arises exclusively by transport into the follicles from the peripheral circulation. The unconjugated steroids measured in the present study have much higher metabolic clearance rates, varying from 600 to 2000 l/24 h (Mahoudeau et al., 1972; Tulchinsky and Little, 1994), thus making their serum concentrations much more variable. This can explain the lack of correlation between follicular fluid and serum values for these steroids.
Besides suppression of androgens it has been suggested that the immunosuppressive effect of corticosteroids may be beneficial in assisted reproduction. Thus, use of corticosteroids after oocyte retrieval has been described (Cohen et al., 1990). They reported an improved implantation rate of embryos subjected to partial zona dissection. Similarly, an improved implantation rate in patients with tubal factor infertility receiving corticosteroids has been found (Polak de Fried et al., 1993). The mechanisms are not clear, but e.g., diminished presence of uterine lymphocytes, release of immunosuppressive factors from the human endometrium as well as enhanced fibronectin biosynthesis serving as a trophoblast `glue' have been proposed, thereby supporting implantation or preventing early embryonic loss. None of these effects were, however, actually shown in the above studies. In these studies, the corticosteroids were administered on the day of oocyte retrieval and following days, whereas in the present study, the drug was administered daily during the ovarian stimulation in order to influence follicular development. Thus the studies are not comparable. Another possible site of corticosteroid action is the endometrium and the influence on receptivity (Arcuri et al., 1996). Little is yet known about this, and further studies are needed to elucidate this area.
To conclude, the results of the present study show that adjuvant glucocorticoids in ovarian stimulation before IVF do decrease the concentrations of adrenal androgens in serum and follicular fluid in polycystic ovary syndrome. Whether there are beneficial effects on ovum quality or implantation rate could not conclusively be determined in the present study with this small number of patients.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council (Grant no. 12644), Svenska Hoechst AB and Serono Nordic AB.
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Notes |
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3 To whom correspondence should be addressed at: IVF unit, K 57, Department of Clinical Science, Division of Obstetrics and Gynecology, Huddinge University Hospital, S-141 86 Huddinge, Sweden
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Submitted on August 24, 1998; accepted on January 22, 1999.
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S.D. Keay, E.A. Lenton, I.D. Cooke, M.G.R. Hull, and J.M. Jenkins Low-dose dexamethasone augments the ovarian response to exogenous gonadotrophins leading to a reduction in cycle cancellation rate in a standard IVF programme Hum. Reprod., September 1, 2001; 16(9): 1861 - 1865. [Abstract] [Full Text] [PDF]
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