Spontaneous pregnancy and birth of a normal female from a woman with Turner syndrome and elevated gonadotropins Sarantis Livadas, M.D., Paraskevi Xekouki, M.D., Georgia Kafiri, M.D., Antonis Voutetakis, M.D., Maria Maniati-Christidi, M.D., and Catherine Dacou-Voutetakis, Ph.D. Endocrine Unit, First Pediatric Department, Athens University School of Medicine, and Agia Sophia Children’s Hospital, Thivon & Livadias, Athens, Greece
Objective: To provide data for pregnancies in girls with Turner syndrome. Only 5%–10% of TS girls undergo spontaneous puberty and have menses. Spontaneous pregnancy occurs in 2%–7% of TS girls and is associated with a high rate of miscarriages, stillbirths, malformations, and chromosomal aberrations. Besides fetal problems, pregnancy in TS girls is of high risk for the mothers as well. Design: Case report. Setting: Academic unit. Patient(s): One patient, now aged 28 years, was referred for short stature at age 13 years after an operation for coarctation of the aorta. The karyotype was 88% 45X, 5% 46XX, 5% 47XXX, 2% XO⫹Fr. The gonadotropin values at presentation and on follow-up ranged from high normal to high levels. Pubertal development and menses occurred spontaneously. At the age of 20 and 21 years, dominant follicles of 14 and 17 mm, respectively, were found on sonography. She conceived spontaneously at the age of 26 years and had an uneventful pregnancy, giving birth to a normal girl with normal chromosome constitution and birth weight of 2,800 g. Intervention(s): None. Main Outcome Measure(s): Pregnancy outcome. Result(s): Successful spontaneous pregnancy. Conclusion(s): Bearing in mind the serious problems of fertility and pregnancy outcome encountered in TS girls, we considered such a rare escape from the expected course of biological events to be worth reporting. (Fertil Steril威 2005;83:769 –72. ©2005 by American Society for Reproductive Medicine.) Key Words: Turner syndrome, pregnancy, karyotype, gonadotropins, ovulation, dominant follicle
Turner syndrome (TS) occurs in 1 in 2,500 female newborns. In about 50% of the cases, complete loss of one X chromosome is disclosed, whereas the rest of the TS patients display mosaicism or structural abnormalities of the X chromosome (1). The phenotypic spectrum of TS is variable and includes any one of the following abnormalities in different combinations: cardiac defects (primarily coarctation of the aorta), kidney abnormalities, frequent ear infections, and anatomic stigmata like short or webbed neck. Short stature constitutes the most frequent finding, and it may be associated with minor anatomic stigmata (2). Increased incidence of thyroid disorders and especially Hashimoto’s thyroiditis also has been reported in girls with TS (3).
of secondary sexual characteristics. Consequently, infertility is one of the major problems that these women face at reproductive age (5). Nevertheless, spontaneous pregnancy occurs in 2% to 7% of girls with TS, but it is associated with a high rate of miscarriages, stillbirths, malformations, and chromosomal aberrations (6). We report a woman with TS who conceived spontaneously and gave birth to a normal girl, along with a review of pertinent literature data and perspectives.
With regard to ovarian dysfunction, TS is one of the principal causes of primary amenorrhea, caused by an accelerated loss of oocytes after the 18th gestational week or over the first postnatal months or years (4). The majority of TS patients have streak ovaries and partial or complete absence
CASE REPORT The patient, now aged 28 years, was initially referred to our hospital at age 13 years for short stature after an operation for coarctation of the aorta. At the initial examination, the height was 126 cm (SDS: ⫺3.6), and she weighed 28 kg. She did not have the typical features of Turner’s syndrome except for mild neck webbing. The breast development was stage III, according to Tanner criteria, and the pubic hair was stage I.
Received May 2, 2004; revised and accepted September 27, 2004. Reprint requests: Catherine Dacou-Voutetakis, Ph.D., Endocrine Unit, First Department of Pediatrics, Agia Sofia Hospital, Thivon & Livadias, Athens, Greece (FAX: 210-7796312; E-mail:
[email protected]).
A GnRH test was performed, and basal FSH and LH values were 12 and 3.8 mIU/mL, respectively; no rise of either FSH (peak, 11.8 mIU/mL) or LH (peak, 4 mIU/mL) was observed. The external genitalia were normal. Ultra-
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Fertility and Sterility姞 Vol. 83, No. 3, March 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
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sonography revealed a horseshoe kidney. Karyotype analysis showed 88% 45X, 5% 46XX, 5% 47XXX, and 2% XO⫹Fr. She received treatment with growth hormone for 2 years. Her final height is 152 cm (standard deviation score (SDS): ⫺1.85). At the age of 14 years, hypothyroidism caused by Hashimoto’s thyroiditis was documented, and thyroxine substitution therapy was initiated. Her puberty progressed normally without estrogen therapy and menarche occurred at the age of 14 years. After the age of 16 years, her cycles were regular (menstrual cycle every 28 days; duration of menses, 4 –5 days). LH and FSH values determined at different times ranged from high normal to very high levels (Fig. 1). At the ages of 20 and 21 years, dominant follicles with a diameter of 14 and 17 mm, respectively, were observed sonographically (Fig. 2). At the age of 26 years, hypertension was detected, and the patient was started on antihypertensive medication. She married at age 26 years. She became pregnant spontaneously at 28 years, and treatment with antihypertensive agents was stopped. The pregnancy progressed uneventfully. Amniocentesis was carried out for karyotyping and showed a normal karyotype (46,XX). She delivered vaginally a normal female infant, weighing 2,800 g. Institutional review board approval was not obtained for this study because all studies carried out and medications used were related to the patient’s management requirements. 770
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DISCUSSION Ovarian function in patients with TS is variable; only 5%– 15% of the girls have follicles at the time of puberty, undergo spontaneous pubertal development, and have menses. From one large series of patients with TS, it was shown that spontaneous puberty was positively correlated with the type of karyotype abnormality; spontaneous puberty was observed in 14% of 45,X0 patients and in 32% of patients carrying cell lines with more than one X (7). It seems that the presence of the second X has a significant influence on the occurrence of spontaneous puberty. It is assumed that these patients possess the so-called critical region Xq13-q26, which contains genes that allow adequate ovarian development and function (8). A small percentage of patients with TS (2–7%) have spontaneous pregnancies (9). Karyotype structure is not decisive for spontaneous pregnancy, because pregnancies have been reported in patients with mosaics (as in our case) (10), with structural abnormalities (ring chromosome) (11), with 45,X (12, 13) and with 45,X /47,XXX mosaicism (14). The possible favorable effect of the presence of a small percentage of 46,XX and 47,XXX in our patient cannot be substantiated. With regard to gonadotropin levels, it has been found that in TS girls with spontaneous puberty, gonadotropin levels are higher than those observed in normal girls who ovulate regularly but are lower than those observed in girls with streak ovaries (7). In our patient with spontaneous puberty and normal Vol. 83, No. 3, March 2005
FIGURE 2 Ultrasound of the patient showing a dominant follicle. The patient uterus was of normal morphology and size. The left ovary volume was 1.3 cm3. A 14-mm follicle is observed in the right ovary.
Livadas. Turner and pregnancy. Fertil Steril 2005.
menstruation, a very interesting finding was the response to GnRH test. It was performed at puberty stage III, and no rise after GnRH of either the FSH (peak, 11.8 mIU/mL) or LH (peak, 4mIU/mL) was detected. We have no good explanation for this response because a normal prepubertal girl presents a two- to fourfold rise of FSH, a pubertal girl a greater response of LH, and a girl with primary hypogonadism generally presents a 5- to 10-fold rise of both gonadotropins. We may hypothesize that the gonadotrophs were already at their maximal response to the endogenous GnRH at this particular developmental stage. During the observation period, in which normal menses were present, high or normal FSH and LH values were noted (Fig. 1). This variation in FSH levels may, in effect, reflect a waxing and waning in ovarian function at different periods, a phenomenon that is not unusual in a hypofunctioning organ. Whatever the interpretation, these findings confirm the view that gonadotropins should not be used as predictors of fertility in TS girls. In fact, some clinicians suggest estrogen– progestin replacement therapy in patients with spontaneous menses, if gonadotropin levels are elevated, to avoid the risk of endometrial hyperplasia, ovarian torsion, and the appearFertility and Sterility姞
ance of ovarian cysts (15). However, this suggested approach should be applied with caution, considering the effects of contraceptive pills in girls who already are at high risk for cardiovascular disorders and liver function abnormalities (16). In our patient, we also documented by ultrasound the presence of normal dominating follicles (14 and 17 mm) at the age of 20 and 21 years, respectively. Ovarian volume (1.3 cm3) was smaller than expected in the normal population but was consistent with that of other TS patients with spontaneous ovulation (7, 17). However, the size of the uterus was that of a normal girl. This is considered a very critical factor for the outcome of pregnancies in girls with TS. As a matter of fact, the high incidence of miscarriages, stillbirths, and fetal malformation has been attributed not only to genetic factors but also to low blood flow and/or a hypoplastic uterus (18). Hypoplastic uterus also has been considered as a main factor of a high rate of miscarriage in patients with TS who are enrolled in oocyte donation programs (19). In recent years, however, the early detection of girls with TS and the use of adequate hormone replacement 771
therapy have improved the uterine size in TS girls, contributing to higher rates of fertility in assisted reproduction programs (20). Besides risks incurred to the fetus, pregnancy, whether spontaneous or assisted, is not without risk for the mothers because many of these girls have hypertension or cardiovascular anomalies (21). There are reports of fatal dissection of the aorta during pregnancy in women with TS. Overall, the mortality rate in pregnancies achieved with oocyte donation is ⱖ2%. Specialists who treat patients with TS need to be aware of their cardiac risk and of the potential burden to the cardiovascular system from the increased cardiac demands of pregnancy. Echocardiography or magnetic resonance imaging techniques should be carried out before the enrollment of a TS patient in an assisted fertility program, or in the rare case of normal menstruation, before the planning of pregnancy (22). Another point of concern is the increased risk of trisomy 21 or TS in the offspring (23). However, reliable antenatal diagnostic means are available for prompt recognition of these events (24, 25). From a recent study by Hreinsson et al. (4), it was found that anovulatory adolescent girls with TS had follicles and that the number of these was inversely correlated to FSH levels and age. The best approach to ensure future fertility of TS patients probably should be the removal and cryopreservation of ovarian tissue early in life and fertilization of patients’ own follicles at the appropriate later time, along with preimplantation genetic evaluation. We considered it worth reporting the course of the present case, which is a rare escape from the expected and anticipated course of biological events. REFERENCES 1. Gravholt CH. Medical problems of adult Turner’s syndrome. Horm Res 2001;56(Suppl 1):44 –50. 2. Dacou-Voutetakis C, Karavanaki-Karanassiou K, Petrou V, Georgopoulos N, Maniati-Christidi M, Mavrou A. The growth pattern and final height of girls with Turner syndrome with and without human growth hormone treatment. Pediatrics 1998;101:663–8. 3. Chiovato L, Larizza D, Bendinelli G, Tonacchera M, Marino M, Mammoli C, et al. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner’s syndrome. Eur J Endocrinol 1996;134:568 –75. 4. Hreinsson JG, Otala M, Fridstrom M, Borgstrom B, Rasmussen C, Lundqvist M, et al. Follicles are found in the ovaries of adolescent girls with Turner’s syndrome. J Clin Endocrinol Metab 2002;87:3618 –23.
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