Vol. 58, No.6, December 1992
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright 10 1992 The American Fertility Society
Influence of ovarian cysts on the results of in vitro fertilization
Jean Parinaud, M.D., Ph.D.*t:j: Khalas Cohen, M.D.* Patricia Oustry, M.D.*
Marc Perineau, M.D.*§ Xavier Monrozies, M.D.* Jean-Michel Reme, M.D.*
Institut National de la Sante et de la Recherche Medicale, Contrat Jeune Formation (lNSERM CJF 89-08), and Centre de Fecondation In Vitro, Centre Hospitalier Universitaire (CHU) La Grave, Toulouse, France
Objective: To determine if ovarian cysts are associated with a particular basal endocrine profile and impair follicular growth. Design: Retrospective study. Setting: In Vitro Fertilization (IVF) Center. Patients: Nine hundred fourteen stimulation cycles stimulated with a combination of luteinizing hormone-releasing hormone analogues (LH-RH-a) and human menopausal gonadotropins (hMG) in a long protocol in an IVF program. Results: After 15 days of LH-RH-a therapy, ovarian cysts (2':20 mm) were observed in 8% of cases. These cysts were not related to a particular basal endocrine profile and did not impair follicular growth and IVF results. However, puncturing these cysts enhanced the quality of subsequent follicular growth. On the contrary, cysts appearing during hMG treatment (2':25 mm) were related with a lower LH:follicle-stimulating hormone ratio (0.79 ± 0.52 versus 0.92 ± 0.74 in absence of cyst) and to a lower ovarian response as assessed by the maximal estradiol level to the total number of hMG ampules ratio (51.6 ± 36.5 versus 65.9 ± 47.9 in absence of cyst). However, this difference had no influence on the pregnancy per stimulation rate (18% versus 16% in absence of cyst; not significant). Conclusions: Results show that the pathogens of ovarian cysts appearing during the blockage phase and during the stimulation phase are different. However, they do not impair the results of IVF, and thus it is not necessary to cancel the attempt in case of ovarian cyst. Fertil SterilI992;58:1174-7 Key Words: Luteinizing hormone-releasing hormone analogue, human menopausal gonadotropin, in vitro fertilization, ovarian stimulation, ovarian cysts
Ovarian cysts are commonly found during follicular growth stimulation. According to previous reports, ovarian cysts appear in 10% (1) to 56% (2) of stimulated cycles. However, many differences among the reports occurred in the definition of cyst (from 10 to 28 mm) (3,4) and the time of appearance (lu-
Received May 4, 1992; revised and accepted August 25, 1992.
* Centre de Fecondation In Vitro, CHU La Grave.
t INSERM CJF 89-08, CHU La Grave. :\: Reprint requests: Jean Parinaud, M.D., Ph.D., Centre de Fecondation In Vitro, CHR La Grave, 31052 Toulouse Cedex, France. § Present address: Clinique Sarrus-Teinturiers, Allees Charles de Fitte, 31000 Toulouse, France. 1174
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teinizing hormone-releasing hormone analogues [LH-RHa]) therapy (5-8), human menopausal gonadotropin (hMG) administration (3, 9), or postovulatory (2). Discrepancies also concerned the influence of these cysts on the fate of ovarian stimulations: no influence at all (7, 9) or a decrease of success rate (3, 10). Thus, there are no clear data to decide cancellation or continuation of gonadotropin therapy in the presence of a cyst. Moreover, no publication compared the basal endocrine profile of the patients who developed a cyst with those with normal ultrasonographic ovarian structure. In the present study, we examined 914 stimulated cycles in an in vitro fertilization (IVF) program. The follicular growth was stimulated by a combination Fertility and Sterility
of LH -RH -a and hMG . We studied the influence of cysts appearing during LH-RH-a and hMG treatment as well as the basal endocrine profile associated with these cysts. MATERIALS AND METHODS Patients
We studied 914 cycles from patients undergoing an IVF attempt in 1990 and 1991. The causes of infertility were as follows: tubal (544, 59.5%), endometriosis (50, 5.5%), unexplained (119,13%), male (110, 12%), immunological (23, 2.5%), polycystic ovarian disease (4, 0.5%), and failure of artificial insemination with donor sperm (64, 7%). Basal endocrine profile was determined on a pool of three blood specimens drawn over a 30-minute period in the early morning of cycle day 4. The mean age was 34 ± 4.1 years, and the mean duration of infertility was 6.2 ± 3.6 years. Ovarian Stimulation Procedures
First Step: Pituitary Blockage
Beginning on cycle day 1, patients received subcutaneously LH-RH-a: buserelin acetate, Suprefact ([D-Ser(But)6,Pro9-NEt]LH-RH; Hoechst, Puteaux, France) 0.3 mg two times a day; triptorelin, Decapeptyl ([D-Trp6]LH-RH; Ipsen, Paris, France) 0.1 mg once a day; or leuprorelin, Lucrino ([DLeu6,Pro9-NEt]LH-RH; Abott, Rungis, France) 0.2 mg once a day. On cycle day 15, plasmatic folliclestimulating hormone (FSH), LH, and estradiol (E 2) measurements and pelvic ultrasonography were performed to verify pituitary and ovarian blockage. When an ovarian cyst (defined as homogeneous anechoic structure with a diameter ~20 mm) was seen, an ultrasonic guided puncture was performed in most cases and in all cases the LH -RH -a therapy was continued until the E2 level was 15 mm and E2 > 300 pgjmL per growing follicle (> 15 mm) were obtained. During this step, cysts were defined as homogeneous anechoic structure with a diameter ~25 mm. Treatment by LH -RH -a was continued during the stimulation step and disrupted at ovulation induction. Cycles were canceled when E2 was >3,000 pgjmL or if less than three mature follicles (> 15 mm) were obtained. In Vitro Fertilization Procedures
In vitro fertilization procedures were identical for all patients. Briefly, follicular punctures were ultrasonically guided using an intravaginal probe. Culture medium was INRA Menezo B2 (Api System, Montalieu Vercieu, France) without any serum or substitute. Spermatozoa were prepared using the swimup method. Embryos were transferred 48 hours after follicular puncture (at the 2-cells or 4-cell stage), and four embryos were transferred when available. Progesterone (20 mg of Utrogestan; Besins-Iscovesco, Paris France) was given intravaginally for 10 days beginning on puncture day. Statistical Comparison
Data are given as means ± SD. Statistical comparisons were made using Student's tor X2 test as appropriate. RESULTS Ovarian Cysts During Pituitary Blockage
After 15 days of LH-RH-a therapy, the pelvic ultrasonography showed an ovarian cyst (~20 mm) in 74 patients (8%). These cysts were associated with higher plasmatic E2 (233 ± 257 pgjmL versus 58 ± 36 pgjmL in absence of cyst; P < 0.05) and LH levels (3.4 ± 1.4 versus 2.7 ± 1.5 mIUjmL; P < 0.05) and a lower FSH concentration (2.4 ± 1.6 versus 3.8 ± 1.9 mIUjmL; P < 0.05). These cysts were related neither to a difference in basal endocrine profile (FSH, LH, and LH:FSH ratio) nor to the use of one of the three LH -RH-a (buserelin acetate, triptorelin, or leuprorelin). No difference was found in the follicular growth parameters (Table 1) according to the presence or absence of cyst. Moreover, the clinical pregnancy per stimulation rate was identical (20% in presence of cyst versus 16% in absence of cyst; not significant [NS]). However, the presence of an ovarian cyst during piParinaud et al.
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Table 1
Follicular Growth Parameters According to the Presence or Absence of Ovarian Cyst During LH·RH·a Therapy* No cyst (n = 840)
1,689 ± 10.1 ± 14 ± 36.6 ± 63 ± 7.6 ± 52
Peak E2 No follicles> 10 mm Duration of stimulation (d) No. of ampules of hMG Edno. of ampules of hMG:j: No. of oocytes Fertilization rate (%) §
772 4.2 3.8 21.8 46 4
Cyst with puncture (n = 55)
Cyst without puncture (n = 19)
1,882 ± 1,029 10 ± 5 13.1 ± 3.5 33.7 ± 19.8 76 ± 55 7 ± 4.3 51
1,431 ± 693 10 ± 6 14.6 ± 3.6 42 ± 22.2t 46 ± 33t 4.7 ± 3.9 70
* Values are means ± SD. t p < 0.05 versus cyst with puncture. :j: E 2/number ofhMG ampules is calculated by dividing maximal plasmatic E2 by total number of injected hMG ampules.
§ Calculated by dividing the total number of embryos by the total number of occytes.
tuitary blockage was more frequently associated with cysts during hMG treatment than the absence (20/74, 27% versus 132/840, 16%; P < 0.05). Fifty-five (74%) punctures of cysts were performed and were associated with a better follicular growth than the 19 cases without puncture as assessed by the cancellation rate (16% versus 26%; NS), the E2 peak (1,882 ± 1,029 versus 1,431 ± 693 pg/mL; P < 0.05), the maximal E 2/total number of hMG ampules ratio (76 ± 55 versus 46 ± 33; P < 0.05). On the contrary, the percentage of ovarian cyst during hMG treatment was not reduced (27% versus 26%; NS), and the pregnancy per cycle rate was not increased (22% versus 16%; NS).
response as assessed by maximal E2 level, number of hMG ampules, duration of stimulation, and maximal E2 :total number of hMG ampules ratio. However, the cancellation rate was not increased (14% versus 13% in absence of cyst; NS), and the clinical pregnancy per stimulation rate not decreased (18% versus 16% in absence of cyst; NS). When considering the basal endocrine profile of the patients, the appearance of cysts during hMG therapy was related to a decrease of LH:FSH ratio (0.79 ± 0.52 versus 0.92 ± 0.74 in absence of cyst; P < 0.05), despite no difference in FSH (7 ± 5.7 mIU /mL versus 6.9 ± 2.6 mIU/mL; NS) and LH levels (5.2 ± 3 mIU/mL versus 5.6 ± 3.7 mIU/mL; NS). DISCUSSION
Ovarian Cysts During HMG Treatment
As shown in Table 2, 152 patients (17%) had an ovarian cyst during the follicular stimulation step. These cysts were associated with a lower ovarian
Table 2 Follicular Growth Parameters According to the Presence or Absence of Ovarian Cysts During hMG Therapy*
Peak E2 (pg/mL) No follicles> 10 mm Duration of stimulation (d) No. of ampules of hMG Edno. of ampules of hMG:j: No. of oocytes Fertilization rate (%) §
No cyst
Cyst
(n = 762)
(n = 152)
1,724 ± 10.2 ± 13.7 ± 35.6 ± 65.9 ± 7.8 ± 52
812 4.3 3.6 21.4 47.9 4.1
1,547 9.3 15.6 41.3 51.6 6.7
± 644t ± 4.1t ± 4.3t ± 22.9t ± 36.5t ± 3.8t 52
* Values are means ± SD. t p < 0.05 versus no cyst. :j: E 2/number of hMG ampules is calculated by dividing maximal plasmatic E2 by total number of injected hMG ampules. § Calculated by dividing the total number of embryos by the total number of oocytes.
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In the present study, we found that ovarian cysts appeared in 25% of stimulated cycles. These results are close to those reported by other authors (3-5, 9, 10). However, we differentiated these cysts according to the time of appearance: after LH-RH-a or hMG therapy. These cysts appeared very different in their frequency as well as in their influence on results and in the associated basal endocrine profile. The cysts appearing after 15 days of LH -RH-a therapy were associated with high levels of E2 (up to 1,380 pg/mL), indicating that they could be growing follicles more than cysts. Indeed, it has been reported that their hormonal content is close to normal follicles (6) and that embryos could be obtained from oocytes collected in these structures (11). The difference in gonadotropin levels observed in cycles with cyst in comparison with cycles without cyst after LH -RH -a treatment could be because of the feedback exerted by E2 on the pituitary (negative on FSH secretion and positive on LH secretion). The puncture of these LH -RH -a cysts did not avoid the occurrence of a cyst during hMG therapy Fertility and Sterility
but improved the follicular growth (4, 7). Because LH -RH -a cysts contain high concentrations of estrogens (6), these results could be explained by a quicker drop of E2 levels and thus could secondarily increase endogenous FSH levels by suppressing the negative feedback. The endogenous FSH could then enhance the effect of hMG on follicular growth. The origin of LH-RH-a cysts remains unclear. They could be because of either the rise of gonadotropins at the beginning of LH-RH-a (flare-up effect) or to a direct effect of LH-RH-a on the ovary as reported in animal (12) as well as in human (13, 14). In any hypothesis, the more surprising fact is the inconstancy of the phenomenon and the absence of any abnormality in the basal endocrine profile of the patients. The cysts that appeared during hMG therapy were associated with an impaired follicular growth as assessed by the peak of E2 and the maximal E 2:total number of hMG ampules ratio. They were also associated with a lower LH:FSH ratio that could suggest a slight degree of ovarian deficiency. The major question arising from these data is to know whether the presence of cysts induces or reflects an impairment of ovarian activity. Because in the presence of an hMG cyst the E2 peaks were lower than in the absence of a cyst, these ovarian structures seem nonfunctional and could be atretic follicles stimulated by the high hMG doses used during hyperstimulation for IVF. Indeed, when they were punctured no oocyte and no granulosa cells were harvested in their fluids. They could also be residue from a previous stimulation cycle as reported by other authors (2). Indeed, in our study, we found that hMG cysts are less frequent in the first stimulated cycle (13.6%) than in the subsequent cycles (18.3%, NS), despite at least two natural cycles between two stimulated cycles. In conclusion, these results suggest that even LHRH-a cysts are not detrimental; they must be punctured to improve subsequent hyperstimulation. Indeed, even though fertilizable oocytes have been found in these cysts (11), the oocyte quality and the endometrium maturation obtained under these conditions remain to be acertained. On the contrary, hMG cysts are associated with low ovarian response and probably reflect a slight ovarian deficiency. In all cases, the absence of any dramatic drop in pregnancy rate in the presence of ovarian cysts avoids canceling of attempt. However, the numbers are
Vol. 58, No.6, December 1992
quite low, and one cannot exclude the existence of small pregnancy rate difference. REFERENCES 1. Silvenberg KM, Olive DL, Schenken RS. Ovarian cyst as· piration prior to initiating ovarian hyperstimulation for in vitro fertilization. J In Vitro Fert Embryo Transf 1990;7: 153-6. 2. Tummon IS, Henig I, Radwanska E, Binor Z, Rawlins R, Dmowski WP. Persistent ovarian cysts following adminis· tration of human menopausal gonadotropins: an attenuated form of ovarian hyperstimulation syndrome. Fertil Steril 1988;49:244-8. 3. Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effect of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991;55: 319-23. 4. Aboulghar MA, Mansour RT, Serour GI, Sattar MA, Awad MM, Amin Y. Transvaginal ultrasonic needle guided aspiration of pelvic inflammatory cystic masses before ovulation induction for in vitro fertilization. Fertil Steril 1990;53: 311-4. 5. Feldberg D, Ashkenazi J, Dicker D, Yeshaya A, Goldman GA, Goldman JA. Ovarian cyst formation: a complication of gonadotropin· releasing hormone agonist therapy. Fertil Steril 1989;51:42-5. 6. Ben-Rafael Z, Bider D, Menashe Y, Maymon R, Zolti M, Mashiach S. Follicular and luteal cysts after treatment with gonadotropin-releasing hormone analog for in vitro fertilization. Fertil SterilI990;53:1091-4. 7. Rizk B, Tan SL, Kingsland C, Steer C, Mason BA, Campbell S. Ovarian cyst aspiration and the outcome of in vitro fertilization. Fertil Steril 1990;54:661-4. 8. Sampaio M, Serra V, Miro F, Calatayud C, Castellvi RM, Pellicer A. Development of ovarian cysts during gonadotrophin-releasing hormone agonists (GnRHa) administration. Hum Reprod 1991;6:194-7. 9. Hornstein MD, Barbieri RL, Ravnikar VA, McShane PM. The effects of baseline ovarian cysts on the clinical response to controlled ovarian hyperstimulation in an in vitro fertilization program. Fertil Steril 1989;52:437-40. 10. Thatcher SS, Jones E, DeCherney AH. Ovarian cysts decrease the success of controlled ovarian stimulation and in vitro fertilization. Fertil Steril 1989;52:812-6. 11. Parinaud J, Oustry P, Bussenot I, Tourre A, Perineau M, Monrozies X, et al. Paradoxical ovarian stimulation in course of treatment by LH -RH analogs. Eur J Obstet Gynecol Reprod BioI. In press. 12. Ranta T, Knecht M, Baukal AJ, Korhonen M, Catt KJ. GnRh agonist-induced inhibitory and stimulatory effects during follicular maturation. Mol Cell Endocrinol 1984;35:55-63. 13. Parinaud J, Beaur A, Bourreau E, Vieitez G, Pontonnier G. Effect of a luteinizing hormone-releasing hormone agonist (buserelin) on steroidogenesis of cultured human preovulatory granulosa cells. Fertil Steril 1988;50:597-602. 14. Latouche J, Crumeyrolle-Arias M, Jordan D, Kopp N, Augendre-Ferrante B, Cedard L, et al. GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study. Endocrinology 1989;125:1739-41.
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