Women with hypogonadotropic hypogonadism - Wiley Online Library

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cause of female infertility. While basal serum levels of follicle-stimulating hormone (FSH) and luteiniz- ing hormone (LH) ranging from 5 to 20 IU/l are considered ...
Acta Obstetricia et Gynecologica. 2006; 85: 1453 1457

ORIGINAL ARTICLE

Women with hypogonadotropic hypogonadism: cycle characteristics and results of assisted reproductive techniques Accepted as an oral presentation at the 1st Balkan Congress of Reproductive Medicine in Thessaloniki, Greece, September 2426, 2004

BANU KUMBAK & SEMRA KAHRAMAN Istanbul Memorial Hospital, ART and Genetics Center, Istanbul, Turkey

Abstract Objective. To present cycle characteristics and results of in vitro fertilization in 27 patients with hypogonadotropic hypogonadism. Further, to demonstrate the consequences of advanced age (]/35 years). Methods. Data from 27 hypogonadotropic hypogonadism patients treated with in vitro fertilization in the period from 2000 to 2004 were analyzed and compared with treatment results from 39 patients with unexplained infertility. Moreover, data from hypogonadotropic hypogonadism patients were analyzed according to the age factor. Mann Whitney U, Chi-square, and Student’s t -tests were used for statistical analysis. p B/0.05 was considered significant. Results. Higher gonadotropin consumption and a longer stimulation period were observed in the hypogonadotropic hypogonadism group. Peak E2 levels, and the total number of oocytes and metaphase II oocytes were higher in the unexplained infertility group. Although a higher number of grade I embryos were transferred in the unexplained infertility group, the implantation rate was found to be better in the hypogonadotropic hypogonadism group (36.5% versus 13%; p B/0.0001). Pregnancy rates were similar. When hypogonadotropic hypogonadism patients were evaluated according to the age factor, no significant difference was found with regard to cycle and outcome parameters, except higher gonadotropin consumption in aged patients. In aged hypogonadotropic hypogonadism patients, a pregnancy rate of 50% was achieved. Conclusion. Hypogonadotropic hypogonadism women undergoing in vitro fertilization were found to be good responders. In the presence of advanced age, management of these patients becomes challenging. However, even these patients still have a good chance of pregnancy.

Key words: Hypogonadotropic hypogonadism, in vitro fertilization, treatment outcome, advanced age

Hypogonadotropic hypogonadism (HH) is a rare cause of female infertility. While basal serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ranging from 5 to 20 IU/l are considered normal in reproductive-aged women, gonadotropin levels may be undetectable, low, or apparently normal in women with HH (1). Therefore clinical findings such as delayed puberty and amenorrhea rather than laboratory findings suggest the diagnosis. Treatment of HH is based on the substitution of the absent hormones when fertility is not an issue. In the case of infertility, treatment with gonadotropins is the widely used protocol. In these women both FSH and LH are required to achieve

full maturation of the follicles and obtain oocytes capable of fertilization (4,5). In case of infertility, additive factors may also be present together with the HH state. Therefore, if pregnancy is not achieved with gonadotropin therapy, patients should be re-evaluated and possible additional subfertility factors should be carefully assessed. In this study, we compared cycle characteristics and outcome in HH women who had undergone in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with women suffering from unexplained infertility. Further, we investigated the management of HH patients when additional

Correspondence: Banu Kumbak, Fahrettin Kerim Gokay cad. No: 282/10, 81080 Erenkoy, Istanbul, Turkey. E-mail: [email protected]

(Received 21 November 2005; accepted 24 May 2006) ISSN 0001-6349 print/ISSN 1600-0412 online # 2006 Taylor & Francis DOI: 10.1080/00016340600839619

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subfertility factors existed, advanced reproductive age (]/35 years) in particular. Materials and methods IVF cycle characteristics of 27 HH patients who had undergone infertility treatment during the years 2000 2004 at Istanbul Memorial Hospital, ART and Genetics Center were analyzed. All the HH patients had a history of primary/ secondary amenorrhea and no withdrawal bleeding after a progestogen challenge. All HH patients had normal serum thyroid-stimulating hormone (TSH), prolactin and testosterone concentrations. A possible pituitary lesion was excluded by sella X-ray or computed tomography. All HH patients had ultrasound scan showing atrophic endometrium (endometrial thickness B/5 mm) and bilateral inactive, small-sized ovaries. Before their referral to our center, repeated ovarian stimulations with human menopausal gonadotropin (HMG) either for intrauterine insemination (IUI) or IVF/ICSI had been carried out. A control group who underwent treatment with IVF/ICSI at the same center, comprising of 39 infertile couples with UEI, were included in the study. UEI was diagnosed in couples when the semen analysis was normal [concentration /20 million/ml, /50% total motility, /15% normal forms (WHO 1992)], uterine tubes were patent, no significant intrauterine or pelvic abnormalities were demonstrated on laparoscopy and hysteroscopy, and ovulation was revealed by ultrasound. The HH group was subanalyzed. Coexisting infertility factors were as follows: advanced age (]/35 years) in eight, tubal factor in one, endometrial factor in one, and recurrent implantation failure in two patients. No severe male factor existed. IVF cycles of HH patients were further analyzed according to the age factor. HH patients initiated the treatment by receiving daily injections of gonadotropins including both FSH and LH (HMG, Pergonal; Serono Laboratories; 300 600 IU/day) and follicular response was followed with ultrasound and serum E2 measurements. In patients with UEI, pretreatment with an oral contraceptive pill was performed during the cycle prior to the IVF/ICSI procedure. On the third day of menses after pill discontinuation, stimulation was carried out starting with a daily injection of 150 450 IU of recombinant FSH (Puregon; Organon) plus HMG (Pergonal; Serono Laboratories) in about equal doses. Starting doses of gonadotropins and adjustments thereafter were determined according to the patient’s profile and

ovarian response. When at least one leading follicle reached 14 mm in size, GnRH antagonist 0.25 mg daily injection was added to the gonadotropins and continued up to the HCG administration. An injection of 10,000 IU HCG was administered when the leading follicle reached 20 mm in diameter and transvaginal ultrasound-guided oocyte retrieval was performed 36 h later. IVF/ICSI procedures were performed as described previously (6). Oocytes and embryos were evaluated according to the established criteria (7,8). On days 35 after ovum pick-up, depending on the number of good quality embryos, 35 embryos were transferred into the uterine cavity. The luteal phase was supplemented with progesterone in oil 75 mg i.m. daily, starting on the day after oocyte retrieval, and was continued until a negative pregnancy test was obtained, or if pregnancy occurred, with vaginal progesterone (progestan, Kocak) 600 mg daily until week 12 of gestation. Pregnancy was confirmed by a positive blood test for b-HCG 12 days after the transfer procedure. Clinical abortion rate (pregnancy confirmed both by B-HCG measurement on day 12 after ET and by ultrasonic demonstration of an intrauterine gestational sac but subsequently lost before 12 weeks of gestation) and ongoing pregnancy rate (pregnancies /12 weeks of gestational age) were also evaluated. Data were analyzed using the SPSS version 12.0 for Windows (SPSS Inc., USA). Mann Whitney U, Chi-square, and Student’s t -tests were used for statistical analysis, where appropriate. p B/0.05 was considered significant. Results IVF cycle characteristics and outcome of 27 HH patients were compared with a control group of 39 patients with UEI. All underwent ovarian hyperstimulation for IVF/ICSI at the same center. Demographic characteristics of the patients were comparable (Table I). Significantly larger amounts of gonadotropins were used for the stimulation of HH patients; the mean was 60 ampoules (p /0.002). Mean duration of stimulation was 14 days in the HH group and 12 days in the UEI group, the difference being significant (p /0.001). Peak serum E2 concentration, and total and MII oocyte numbers were found to be higher in the UEI group (Table II). We evaluated the proportion of metaphase II (MII) oocytes to total oocytes retrieved in HH patients and found the rate to be 72%, which was similar to the UEI group. We performed ICSI or IVF/ICSI procedures and achieved an 89% fertilization rate in HH patients, which was significantly higher than

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Women with hypogonadotropic hypogonadism undergoing ART Table I. Demographic characteristics in women with hypogonadotropic hypogonadism and in women with unexplained infertility Hypogonadotropic hypogonadism group (n/27) Age (years) Infertility duration (years) BMI (kg/m2) FSH (IU/l)

Unexplained infertility group (n /39)

32.89/4.9 9.39/6.1 25.79/4.5 1.99/1.2

32.49/4.0 8.99/5.7 25.89/3.8 8.59/2.9

p NS NS NS B/0.0001

Values are means9/standard deviation (SD). Student’s t -test.

that of the UEI group (p/0.03). We also evaluated embryos; i.e. cleavage rate and the ratio of grade I embryos to all the embryos present on day 3. The results were similar in both groups. Although a higher number of grade I embryos were transferred in the UEI group, the implantation rate in the HH group was found to be better than that of the UEI group (36.5% in the HH group and 13% in group UEI; p B/0.0001). Pregnancy rates were similar in both groups (59% in the HH group and 46% in the UEI group; p /0.05). We achieved 16 clinical pregnancies in the HH group; 8 of them were delivered and the other 8 are ongoing. No abortions were observed in the HH group. In the UEI group we achieved 13 clinical pregnancies, 5 of which resulted in abortion. A significantly lower clinical abortion rate and a higher ongoing pregnancy rate were found in the HH group (p /0.006), even though the numbers were small.

Cycle characteristics and treatment results were further evaluated within the HH group according to the coexisting infertility factors, advanced age in particular. Out of 8 patients, who were ]/35 years, we had one cycle cancellation because of no follicular development and one ET cancellation because of fertilization failure. In the remaining 6 HH patients ]/35 years, 3 pregnancies were achieved. Two of them were delivered and the other one is ongoing. Two HH patients with recurrent implantation failure from previous IVF trials could again not achieve pregnancy. One HH patient with endometrial factor, whose endometrial thickness reached 7 mm at the HCG day, failed to achieve pregnancy. One HH patient with a coexisting tubal factor achieved pregnancy and delivered twins. IVF cycle characteristics and outcome were compared within the HH group as regards a coexisting age factor. No significant differences were observed,

Table II. ART cycle characteristics and outcome in women with hypogonadotropic hypogonadism and in women with unexplained infertility Hypogonadotropic hypogonadism group (n /27) Duration of stimulation (days) Total gonadotropins used (IU) Peak E2 level (pg/ml) Endometrial thickness on HCG day (mm) Total oocytes retrieved (n ) MII oocytes (n ) MII oocyte (%) Fertilization (%) Cleavage (%) No. embryos transferred (n ) ET day Grade I embryos transferred (n ) Grade I embryos/all embryos on day 3 (%) IR (%) PR/ET (%) Clinical abortion (%) Ongoing pregnancy (%)

14.09/3.0 4,5379/1,887 1,5419/840 11.59/2.1 10.39/5.9 7.29/4.5 72 89 96 3.59/0.8 3.69/1.0 2.49/1.2 70 36.5 59.3 0 100

Unexplained infertility group (n/39)

p

11.89/1.1 3,1789/1,076 2,4999/1,267 11.49/2.4 14.49/8.5 10.39/6.9 75 80 95 3.99/1.2 3.39/0.7 3.09/1.1 76 13 46.2 38.5 61.5

0.001 0.002 0.001 NS 0.02 0.03 NS 0.03 NS NS NS 0.04 NS B/0.0001 NS 0.006 0.006

Values are means9/standard deviation (SD) or percentages. E2, estradiol; HCG, human chorionic gonadotropin; MII, metaphase II; IR, implantation rate; PR, pregnancy rate; ET, embryo transfer; NS, not significant; p /0.05. Student’s t -test, Mann Whitney U -test, and Chi-square test.

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Table III. Patient and ART cycle characteristics in women with hypogonadotropic hypogonadism according to the existence of advanced reproductive age (]/35 years)

Age (years) Infertility duration (years) BMI (kg/m2) Duration of stimulation (days) Total gonadotropins used (IU) Peak E2 level (pg/ml) Endometrial thickness on HCG day (mm) Total oocytes retrieved (n ) MII oocyte (%) Fertilization (%) Cleavage (%) No. embryos transferred (n ) ET day Grade I embryos transferred (n ) IR (%) PR/ET (%)

Existent (n /8)

Deficient (n/19)

38.49/3.5 12.69/8.3 26.59/5.1 14.99/5.1 5,8139/2,283 1,1349/576 11.09/2.2 7.49/4.4 76 84 100 3.39/1.0 3.79/1.2 1.79/1.2 35 50

30.59/3.3 7.99/4.4 25.49/4.3 13.79/1.9 4,0009/1,445 1,6919/883 11.69/2.1 11.39/6.2 70 90 95 3.49/0.8 3.69/1.1 2.69/1.1 36.9 68.4

p B/0.0001 NS NS NS 0.02 NS NS NS NS NS NS NS NS NS NS NS

Values are means9/standard deviation (SD) or percentages. Student’s t -test, Mann Whitney U -test and Chi-square test.

except higher gonadotropin consumption in aged HH patients (Table III). Discussion With the present study we have shown that HH women undergoing IVF/ICSI are good responders. However, when advanced reproductive age exists, management of these patients becomes challenging. Until now, this study represents one of the largest series of infertile women with HH treated with IVF/ ICSI. It is difficult to recruit a large number of patients with a rare condition such as hypogonadotropic anovulation (1). Previous studies including HH patients have shown that both the treatment duration and gonadotropin consumption were higher compared with patients with other etiologies of infertility (9,10). This may be the result of silent ovaries, which need to be activated before follicular response is achieved. Consistently, we have demonstrated that the amount of gonadotropins required was higher and stimulation duration was longer in the HH group compared to the UEI group. Those high gonadotropin dosages used may be harmful on oocytes or embryos (11,12). We evaluated this point in our patient series. Although, MII oocyte ratio was similar in both groups, fertilization rate was found to be higher in HH patients (p/0.03). When the embryos were evaluated, no significant difference was found in both groups with regard to the ratio of grade I embryos to all the embryos present on day 3. Thus, these results suggest that the extreme dosages of gonadotropins used in the HH patients were not

detrimental to the oocytes and embryos. Moreover, the implantation rate was found to be higher in HH patients (p B/0.0001). In a study comparing HH patients with tubal factor infertility cases, similar fertilization and implantation rates were observed in both groups (10). Significantly higher fertilization and implantation rates found in our HH patients might be the result of our control group, in which ‘unexplained’ infertility existed. In total, we achieved 16 pregnancies in the HH group; 8 of them are delivered and the other 8 are ongoing beyond the 12th week of gestation. It is of interest that no abortion was observed among the pregnant HH patients. In the UEI group we had 5 clinical abortions out of 13 clinical pregnancies, which means a 38% clinical abortion rate, significantly different from that of the HH group (p/ 0.006). Even though the numbers were limited, this point should be investigated further with larger patient groups, as this may provide important clues regarding stimulation protocols and the implantation process. In most cases of HH, the diagnosis is made at an early age when pregnancy is desired, and with HMG treatment the patient has a good chance of success. Occasionally, HH patients present with fertility problems at an advanced age, which may complicate the situation. In our HH group we had 8 patients who were ]/35 years old. In this specific group we could reach embryo transfer stage in 6 patients and in those 6 patients we achieved 3 pregnancies; one of which is ongoing and the other two delivered. We cancelled one of the remaining 2 patients, who was 40 years

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Women with hypogonadotropic hypogonadism undergoing ART old, because she had no follicular response after 10 days with 8 ampoules of gonadotropin daily. We could not perform ET in the other patient, who was 45 years old and only had one oocyte, which was not fertilized. Although it is well documented that ovarian responsiveness deteriorates with increasing age, this study suggests that the age-dependent decline in ovarian response in patients with HH may not be established (9). The usual predictors of ovarian reserve are not useful in patients with HH. As such there is no way to predict the response to ovarian hyperstimulation. We can only measure response with close follow-up of a patient during IVF/ICSI treatment. In such challenging situations, the question is at which dose to start the stimulation and when to stop follow-up due to lack of response. There is very limited data regarding aged HH patients in the literature. Therefore, in such cases, using a high HMG dose for a longer time may be required, and for those patients who have low or no response, the criteria usually applied for other assisted reproductive technology (ART) patients should not be followed. In our aged HH patients a 50% pregnancy rate was achieved, which is exceptionally good for an aged IVF patient. Furthermore, no abortions were observed in such an at-risk group although the numbers were small. We support that if we can reach the embryo transfer stage in an aged HH patient, the pregnancy rate is excellent. In conclusion, HH patients undergoing IVF treatment were shown to be good responders. These patients were observed to be heterogeneous as regards patient and cycle characteristics. Although coexistence of age factor did not make a significant difference in IVF outcome, management of these patients is a challenge. Thus, aged patients with HH undergoing IVF should be treated with extreme dosages of gonadotropins for a long period before deciding to stop. Consequently, aged HH patients might have a good reproductive outcome with IVF.

References 1. Burgues S and the Spanish Collaborative Group on Female Hypogonadotropic Hypogonadism. The effectiveness and safety of rLH to support follicular development induced by rFSH in WHO group I anovulation: evidence from a multicentre study in Spain. Hum Reprod 2001; 16: 2525 32. 2. Campo S, Campo V, Lanzone A. Twin pregnancy using recombinant gonadotropins in a woman with hypogonadotropic hypogonadism. Gynecol Endocrinol. 2002;16:27 32. 3. Shoham Z, Mannaerts B, Insler V, Coelingh-Bennink H. Induction of follicular growth using recombinant human follicle stimulating hormone in two volunteer women with hypogonadotropic hypogonadism. Fertil Steril. 1993;59:738  42. 4. Balasch J, Miro F, Burzaco I, Casamitjana R, Civico S, Ballesca JL, et al. The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from IVF in a woman with long-standing hypogonadotrophic hypogonadism and using rFSH. Hum Reprod. 1995;10:1678 83. 5. Hayashi M, Tomobe K, Hoshimoto K, Ohkura T. Successful pregnancy following gonadotropin therapy in a patient with hypogonadotropic hypogonadism resulting from craniopharyngioma. Int J Clin Pract. 2002;56:149 51. 6. Kahraman S, Akarsu C, Cengiz G, Dirican K, Sozen E, Can B, et al. Fertility of ejaculated and testicular megalohead spermatozoa with intracytoplasmic sperm injection. Hum Reprod. 1999;14:726 30. 7. Veeck LL. Atlas of Human Gametes and Conceptuses. New York: The Parthenon Publishing Group; 1999. 8. Staessen C, Camus M, Bollen N. The relationship between embryo quality and the occurrence of multiple pregnancies. Fertil Steril. 1992;3:626 30. 9. Lewit N, Shahar K. The low responder hypogonadotropic hypogonadism female patient in IVF: do not give up! Fertil Steril. 2000;74:401 2. 10. Ulug U, Ben-Shlomo I, Tosun S, Erden HF, Akman MA, Bahceci M. The reproductive performance of women with hypogonadotropic hypogonadism in an in vitro fertilization and embryo transfer program. J Assist Reprod Genet. 2005; 22:167 71. 11. Edgar DH, Whalley KM, Mills JA. Effects of high-dose and multiple-dose gonadotropin stimulation on mouse oocyte quality as assessed by preimplantation development following in vitro fertilization. J In Vitro Fert Embryo Transf. 1987; 4(5):273 6. 12. Sato F, Marrs RP. The effect of pregnant mare serum gonadotropin on mouse embryos fertilized in vivo or in vitro. J In Vitro Fert Embryo Transf. 1986;3(6):353 7. /

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