1 Centre for Reproductive Medicine, St Bartholomews Hospital and the London Hospitals Trust, London EC1A 7BE and 2 Department of Obstetrics and Gynaecology, St Bartholomews and Royal London Hospitals School of Medicine and Dentistry, Queen Mary and Westfield College, St Bartholomews Hospital, London EC1A 7BE, UK
3 To whom correspondence should be addressed. e-mail: ggrudzinskas{at}thebridgecentre.co.uk
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Abstract |
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Key words: antibodies/corticotherapy/FSH/infertility
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Introduction |
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This case describes a young woman with markedly elevated basal FSH levels, regular menses, ovarian antibodies and infertility who responded excessively to controlled ovarian stimulation (COS) and required coasting for the prevention of ovarian hyperstimulation syndrome (OHSS) and subsequently had a live birth.
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Case report |
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In view of her regular cycle, it was decided to proceed with a trial of COS for IVF using a long GnRH analogue protocol and a maximum 450 IU of a recombinant FSH per day. Prednisolone (10 mg BD) was commenced at the same time as the GnRH analogue. A repeat autoimmune screen was performed 3 weeks after commencing the GnRH analogue, just prior to starting ovarian stimulation, no antiovarian antibodies being found. An ultrasound was performed on the 8th day of stimulation when 20 follicles between 10 and 17 mm in diameter were identified. The serum oestradiol and FSH levels were 10 461 pmol/l and 137.9 IU/l respectively. Gonadotrophin administration was withheld for a total of 9 days until the oestradiol level returned to 6938 pmol/l, in accordance with the Centres protocol for avoidance of severe OHSS. The level of serum FSH was 10.4 IU/l. HCG (10 000 IU s.c.) was given and oocyte retrieval was performed 36 h later. Ten oocytes were retrieved, of which six fertilized and developed to the two-pronuclear (2PN) stage. Two grade I 4-cell embryos were transferred 48 h later with progesterone (Cyclogest pessaries: 200 mg BD) as luteal support. A pregnancy did not follow and the prednisolone was gradually reduced and stopped. Mild, early onset, OHSS developed (Navot et al., 1992).
Seven months later, a second cycle of COS for IVF was undertaken using a similar protocol of long down-regulation, prednisolone and 300 IU of a recombinant FSH daily. The serum FSH level taken 3 months prior to treatment was 38.8 IU/l, antiovarian antibodies not being detected. Gonado trophins were withheld for 4 days due to an excessive ovarian response by day 11 with 25 follicles between 10 and 20 mm in diameter and an E2 level >13 200 pmol/l. Nineteen oocytes were retrieved, of which nine fertilized and developed to the 2PN stage. Two grade I 4-cell embryos were transferred 48 h later, giving rise to a singleton pregnancy. OHSS did not develop. The pregnancy continued uneventfully and a healthy male was delivered vaginally at term.
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Discussion |
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Increasing levels of early follicular phase serum FSH is a characteristic of reproductive ageing and is in common usage for the determination of diminished ovarian reserve (Cahill et al., 1994; Sharif et al., 1998
). It has been suggested that young women with otherwise unexplained infertility, who have increased basal FSH levels, have poor outcomes compared with those with a normal FSH and unexplained infertility (Flood et al., 1989
) and an impaired response to COH has been observed (Cameron et al., 1988
; Scott et al., 1989
). Ahmed Ebbiary et al. (1994
) showed these women to have endocrine and follicular growth patterns characteristic of the menopause and concluded that a gradual rise in plasma FSH indicates a reduced reproductive potential regardless of chronological age and may represent a stage of menopausal transition consequent on POF. However, in this particular case, an excessive follicular response was observed following 8 days of stimulation, albeit that an initial high dose of gonadotrophin was used. Of note in this case was the presence of antiovarian antibodies. Autoimmune abnormalities are believed to play a role in reproductive failure and antiovarian antibodies have been found to be an independent marker associated with unexplained infertility (Luborsky et al., 2000
). Serological evidence of ovarian autoimmune disease may be a marker for those patients who are good candidates for COS using glucocorticoids as immunosuppressive agents in an ovarian stimulation regime (El-Roiey et al., 1987
; Barbarino-Monnier et al., 1995
) and in this particular case prednisolone was given at the commencement of GnRH analogues. This immunosuppression may explain the observed unexpected response to COS seen by day 8 in the first cycle and again by day 11 of the second cycle and it would have been interesting to observe the response to COS without the use of prednisolone. In a case report by Barbarino-Monnier et al. (1995
), when prednisolone was given during a third IVF cycle where ovarian autoimmunity was present, a greater number of oocytes was retrieved with fewer units of gonadotrophin. This patient, however, differed in that the FSH level was normal.
There are several documented causes of elevated levels of FSH other than a diminished ovarian reserve resulting in a peri-menopausal state. Technical laboratory errors should be considered, including the presence of heterophilic antibodies that can interfere with the FSH immunoassay giving falsely elevated levels of FSH (Cahill et al., 1992; De Konig et al., 2000
). Perez Mayorga et al. (2000
) have shown that the ovarian response to FSH stimulation is dependent upon the FSH receptor genotype with a less active FSH receptor requiring higher levels of FSH for normal function. Different isoforms of FSH have been described with differing receptor binding/immunoactivity (Zambrano et al., 1999
). FSH binding inhibitors or FSH antibodies may also affect the ovarian response to FSH (Meyer et al., 1990
). In a recent paper, Lambalk (2003
) discussed the differential diagnosis of elevated basal levels of FSH and suggests the need to differentiate between the various causes during the diagnostic fertility work-up. Inhibin levels, which are believed to decrease secondary to follicular exhaustion, lead to a monotropic FSH rise and could have provided further information regarding the ovarian reserve of this patient. However, they are not currently routinely available at our hospital and were consequently not performed.
Certainly this case reflects the need for further investigations into any young patient with a regular menstrual cycle and elevated FSH levels with respect to the detection of ovarian autoantibodies and the need to differentiate among the possible causes of an elevated FSH. If antibodies are detected, the use of prednisolone may be considered in an attempt to improve the ovarian response to COS and the choice of a trial of COS should be offered before discussing ovum donation. This patient will require follow-up for POF.
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References |
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Barbarino-MonnierP, Gober B, Guillet-May F, Bene MC, Barbarino A, Foliuet B and Faure GC (1995) Ovarian autoimmunity and corticotherapy in an in-vitro fertilization attempt. Hum Reprod 10,20062007.[Abstract]
Cahill DJ, Fox R and Thomas PH (1992) Spurious elevation of follicle-stimulating hormone. Acta Obstet Gynecol Scand 71,388389.[ISI][Medline]
Cahill DJ, Prosser CJ, Wardle PG, Ford WC and Hull MG (1994) Relative influence of follicle stimulating hormone, age and other factors on ovarian response to gonadotrophin stimulation. Br J Obstet Gynecol 101,9991002.[ISI][Medline]
Cameron IT, OShea FC, Rolland JM, Hughes EG, deKrester DM and Healy DL (1988) Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations. J Clin Endocrinol 67,11901194.[Abstract]
De Koning CH, Popp-Snijders C, Martens F and Lambalk CB (2000) Falsely elevated follicle-stimulating hormone levels in women with regular menstrual cycles due to interference in immunoradiometric assay. J Assist Reprod Genet 17,457459.[CrossRef][ISI][Medline]
El-RoieyA, Gleicher N, Friberg J, Confino E and Dudkiewicz A (1987) Correlation between peripheral blood and follicular fluid: autoantibodies and impact on in-vitro fertilization. Obstet Gynecol 70,163170.[Abstract]
Flood JT, Csott RT and Brzyski RG (1989) The occult ovarian factor in unexplained infertility. Abstract of the American College of Obstetricians and Gynecologists annual Meeting, Reno, NV, p. 22.
Kligman I and Rosenwaks Z (2001) Differentiating clinical profiles: predicting good responders, poor responders, and hyperresponders. Fertil Steril 76,11851190.[CrossRef][ISI][Medline]
Lambalk CB (2003) Value of elevated basal follicle-stimulating hormone levels and the differential diagnosis during the diagnostic subfertility work-up. Fertil Steril 79,489490.[CrossRef][ISI][Medline]
Luborsky J, Llanes B, Roussev R and Coulam C (2000) Ovarian antibodies, FSH and inhibin B: independent markers associated with unexplained infertility. Hum Reprod 15,10461051.
Meyer WR, Lavy G, DeCherney AH, Visintin I, Economy K and Luborsky JL (1990) Evidence of gonadal and gonadotrophin antibodies in women with a suboptimal ovarian response to exogenous gonadotrophin. Obstet Gynecol 75,795799.[Abstract]
Navot D, Bergh PA and Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58,249261.[ISI][Medline]
Perez MayorgaM, Gromoll J, Behre HM, Gassner C, Nieschlag E and Simoni M (2000) Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab 85,33653369.
Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S and Rosenwaks Z (1989) Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 51,651654.[ISI][Medline]
Sharif K, Elgendy M, Lashen H and Afnan M (1998) Age and basal follicle stimulating hormone as predictors of in vitro fertilisation outcome. Br J Obstet Gynecol 105,107112.[ISI][Medline]
Tinkanen H, Blauer M, Laippala P, Tuohimaa P and Kujansuu E (1999) Prognostic factors in controlled ovarian hyperstimulation. Fertil Steril 72,932936.[CrossRef][ISI][Medline]
Zambrano E, Zarinan T, Olivares A, Barrios-de-Tomasi J and Ulloa-Aguirre A (1999) Receptor binding activity and in vitro biological activity of the human FSH charge isoforms as disclosed by heterologous and homologous assay systems: implications for the structurefunction relationship of the FSH variants. Endocrine 10,113121.[CrossRef][ISI][Medline]
Submitted on April 4, 2003; resubmitted on June 25, 2003; accepted on September 17, 2003.