Ovarian function in adolescents with turner syndrome

Adolesc Pediatr Gynecol (1994) 7:3-8

Adolescent and Pediatric Gynecology © 1994 Springer-Verlag New York Inc.

Mini Review Ovarian Function in Adolescents with Turner Syndrome H.J. Heinze, M.D. Department of Pediatrics, University of South Florida College of Medicine, Tampa, and All Children's Hospital, St. Petersburg, Florida

Abstract. This review will focus on endogenous ovarian function in adolescent girls with Turner syndrome (TS); newer treatment modalities including the latest hormone replacement therapy using continuous low-dose transdermal 1713-estradiol for puberty induction; complications and sequelae in TS girls; and outlook for future fertility including in vitro fertilization and embryo transfer as well as the newer modalities such as gamete and zygote intrafallopian tube transfer using donated ova.

The X Chromosome in Turner Syndrome Recent investigation has identified some of the genetic abnormalities associated with accelerated germ cell loss and development of streak gonads in females with TS. The maternal X chromosome is retained in nearly three-fourths of all 45,X conceptuses. I There is no difference in the maternal age of Turner children who retain the maternal X chromosome when compared with those who retain the paternal X chromosome; birth weight and length are similar. I "Critical region(s)" on both the long arm (Xq) and the short arm (Xp) of the X chromosome are essential for normal ovarian function.f Deletions in proximal Xq 13 and proximal Xq21 are associated with primary amenorrhea and complete ovarian failure, whereas individuals with deletions of Xq25~ 27 develop premature ovarian failure and secondary amenorrhea (Fig. 1). Complete deletion of Xp also results in dysgenetic gonads. Absence or deletion of a portion of Xp (Xpz l-e-Xpter) correlates with the presence of physical stigmata found in TS. 2,3 Complete deletion of Xq is likely to produce short stature, whereas distal Xq deletions may be less deleterious than proximal deletions with respect to final adult height (Fig. 2). A 90 kb segment located on the Y chromosome and homologous to region Xq13 [the so-called X inactivation center (vide infra)] expresses a riboAddress reprint requests to: Howard J. Heinze, M.D., Section of Pediatric Endocrinology, Children's Hospital Medical Center of Akron, One Perkins Square, Akron, OH 44308-1062 USA

somal protein, RPS4Y, implicated in the development of the Turner phenotype." Thus, there appear to be genes on both the long and short arms of the X chromosome that are essential for normal fetal ovarian development. These genes must be present on two intact and active X chromosomes for "maintenance" of the ovary, but not for its initial differentiation from the bipotential gonad. After ovarian differentiation, during the primordial germ cell stage, there is inactivation of one X chromosome under control of the X inactivation center in region Xq135 ; the second X chromosome is reactivated at the time of germ cell differentiation into oogonia." Absence of two complete sets of functional X chromosomal "gonadal maintenance genes" may explain the accelerated germ cell loss in TS. Fetal mortality studies demonstrate a fetoprotective effect of the X isochromosome and mosaic karyotypes, as 99% of 45,X fetuses do not survive pregnancy." These same karyotypes may also prevent rapid germ cell loss, thus explaining the higher incidence of spontaneous ovarian function at the time of puberty in such subjects. Those with 45,X karyotypes who undergo spontaneous puberty may be cryptic mosaics for a second X chromosome cell line in the ovary or other tissue critical for maintenance of ovarian function.V' The Hypothalamic-Pituitary Axis in Turner Syndrome In neonatal and infant girls with TS, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), concentrations are elevated, declining to prepubertal values by 2-4 years of age. 10 During the period of central suppression of gonadotropin secretion, a functioning hypothalamic gonadotropinreleasing hormone (GnRH) pulse generator can be demonstrated in TS girls as in normal girls; measurements of spontaneous gonadotropin secretion utilizing a sensitive, time-resolved fluoroimmunoas-

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say have demonstrated intact nocturnal pulsatile LH secretion. II Gonadotropin concentrations increase to castrate values between 10and 14years of age in the majority of girls with TS. In two adult women with 45,X gonadal dysgenesis and spontaneous puberty and regular menstrual periods, basal LH and FSH concentrations were normal for age, but the gonadotropin response to GnRH was depressed and similar to that seen in prepubertal girls and adult women with hypothalamic amenorrhea, both presumed to be an effect of reduced GnRH pulse frequency or amplitude. 12 This pattern of gonadotropin response to GnRH may reflect increased sensitivity to very low levels of circulating estrogens in spontaneously menstruating Turner women, or the effects of other ovarian or neurosecretory factors involved in GnRH modulation, including prolactin.Pi" A prolonged follicular phase was observed in one of the women, possibly representing inability to obtain a dominant follicle, resulting in an inadequate luteal phase, a situation analogous to the effects of accelerated follicle loss and menstrual dysfunction seen in the decade before menopause in normal women, 14 Spontaneous Ovarian Function in Turner Syndrome Though the majority of girls with TS develop ovarian failure early in infancy, 5-15% undergo sponta-

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Fig. I. Schematic illustration of the X chromosome demonstrating degree of impairment of ovarian function with associated X chromosome deletion. The bracket identifies the interstitial deletion of Krauss eM, et al: N Engl J Med 1987; 317:125. Reprinted with permission, [2].

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Fig. 2. Final adult heights and associated terminal deletions of the X chromosome in adult 45,X Turner syndrome women (> 15 years of age). Reprinted with permission, [2].

neous puberty (thelarche)." In one recent series, thelarche occurred in 17% of Turner girls, with a frequency of 6.4% in 45,X;25% in 45X/mosaics; and 33% in those with isolated Xp deletions. 15 Approximately 10% of nonmosaic (45,X) and 20% of mosaic adolescent Turner girls with thelarche experience spontaneous menarche. 3 Massa et al. 15 observed a spontaneous menarche rate of 59% following spontaneous onset of thelarche. In this series, average age of thelarche was 13.1 ± 1.1 (SD) years, whereas menarche occurred at 14.3 ± 0.6 years. Final height was not significantly different between those with spontaneous puberty (145.1 ± 6.2 em) and those with induced puberty (142.2 ± 5.5 cm).15

Activation of adrenal androgen secretion (adrenarche), as characterized by elevation of plasma dehydroepiandrosterone sulfate (DHEAS) concentrations, often begins at an appropriate age (;<;8 years) in TS and occurs independently of the hypothalamic-pituitary-gonadal axis. 16 , 17 Many females with gonadal dysgenesis have absent or sparse amounts of pubic (pubarche) and axillary hair de.spite adrenarchallevels of DHEAS, suggesting that some additional factor(s) may be necessary for pubic hair development. 17 Turner girls demonstrate enhanced pubic hair growth during initiation of sex hormone replacement therapy though estrogen itself does not enhance adrenal androgen production to account for this. IS

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Ovarian Function in Turner Syndrome

Among the few women with gonadal dysgenesis who have spontaneous thelarche and menarche, still smaller numbers of successful pregnancies have been reported (vide infrar.'" The typical course of these subjects is one of accelerated ovarian failure and premature menopause after a variable length of time. A review of the obstetric literature" identified 138 pregnancies in 62 patients with TS. The majority (85%) of pregnancies were conceived by Turner women with mosaic sex chromosome karyotypes (Table 1) whereas 45,X TS women delivered 15% of pregnancies in this series. Interestingly, 46% of 45,X TS women developed amenorrhea within 7 years after delivery. Overall, spontaneous abortions (26%) and stillbirths (6%) led to fetal wastage in one-third of these pregnancies. Of surviving term infants in this review (n = 80), 29% had congenital anomalies, with deleted X chromosome material (i.e., Turner syndrome) present in 35%. Seventeen percent of infants with congenital anomalies had Down syndrome. Additional clinical reports have confirmed the high incidence of both of these chromosomal anomalies in the offspring of TS mothers. 2o ,2 ] Hormonal Replacement Therapy Oral estrogen and progestin or intramuscular estrogen have been conventional replacement therapy for decades. Recently, Illig et al. 22 evaluated the effectiveness of continuous low-dose transdermal 17f3-estradiol for the induction of puberty in nine girls with TS. Sequential administration of transdermal patches delivering 5 fLg, 10 ug, and 25 ug/day stimulated breast development and uterine growth, increased growth velocity during the first 12-24 months of therapy, and did not compromise predicted final adult height. Adult breast size reflected genetic predisposition rather than estrogen dose.P Compliance was good, with minimal and transient dermatologic side effects. Cycled progestin therapy Table 1. Karyotype Distribution in 62 Fertile Turner Women° Karyotype (Patient No.) 45,X (13) 45,XJ46,XX (22) 45,XJ47,XXX (12) 45,XJ46,XXJ47,XXX (14) 45,X/46,XX/47,XXX/48,XXXX (1)

No. of Pregnancies 21 50

20 44 3

138 pregnancies Totals

45,X (15%) 45,X mosaics (85%)

"Modified from Kaneko N et al. 19

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was added after 18-24 months of therapy or after the first episode of uterine bleeding. Continuous transdermal estrogen replacement minimizes hepatic metabolism of 1713estradiol to estrone and appears adequate to suppress pituitary gonadotropin secretion thus preventing pituitary gonadotroph hyperplasia. Cycled replacement sex hormone therapy improves bone mineralization, a common problem in TS women (vide infra), and vaginal lubrication allowing normal sexual function. Use of low-dose estrogens to enhance linear growth in prepubertal girls with TS remains under investigation. 24 ,25

Complications/Sequelae in Turner Syndrome Radiographic osteopenia is a long recognized sequela of hypogonadisrrr" and recently has been associated with an increased fracture rate in TS girls. 27 Estrogen replacement enhances bone mineral density (BMD) in TS by decreasing bone turnover. 28 ,29 Duration of estrogen therapy is directly correlated with bone mineral content (BMC) in the spine and forearm and periosteal width, whereas BMD is significantly related to degree of physical fitness.P' Pathologic evidence of vascular connective tissue abnormalities (cystic medial necrosis) has been demonstrated in adult Turner women with aortic dissection and/or rupture while on estrogen replacement. 30 Additional risk factors included hypertension, coarctation of the aorta, and aortic valvular abnormalities. Lancman et al. 31 described a 43year-old Turner woman with fibromuscular dysplasia who suffered an ischemic stroke while on cyclic estrogen therapy. Standard dosages of estrogen replacement therapy (~50 ug/day ethinyl estradiol) are associated with few serious thromboembolic events (cerebrovascular accident, ischemic heart disease, venous thrombosis, pulmonary embolism) when compared with higher dosages.F Theoretically, high-dose estrogen replacement (;;:'50 ug/day EE 2) may pose a risk of serious cardiovascular events in TS women over 35 years of age, with a history of hypertension, tobacco use, and preexisting vascular connective tissue abnormalities.

Alternative Reproductive Modalities in Turner Syndrome With the advent of assisted reproductive techniques, women previously unable to conceive are achieving successful pregnancy. In vitro fertilization and embryo transfer (IVF-ET)33 and newer mo-

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Ovarian Function in Turner Syndrome

Table 2. Ovum Donation Pregnancies in Turner Syndrome/Gonadal Dysgenesis 1987-1990

Reference (33) (34) (35) (36) (37) (38)C (39) (40)

Totals

Method

TS

GO

Pregnancies"

ET ET/GIFT/ZIFT ET ET GIFT GIFT ET ET/ZIFT

5 16 7 4

8 2 4 4 2 9 5 I 35

8 4 0 2 I 5

4 3 39

NA 0 20

Miscarriages" Live Births" 4' 3d 0 I I

NAd NA 0 9

(%)

25 22 17 25 0 17 23 25 0--+ 25

TS = Turner syndrome (45,X and mosaic karyotypes); GO = gonadal dysgenesis (45,X or mosaics; 46XX; 46,XY; karyotype not specified); ZIFT = zygote intrafallopian transfer; GIFT = gamete intrafallopian transfer; ET = embryo transfer; NA = information not available. "Implantation in Turner syndrome + gonadal dysgenesis. bOveraIl miscarriage rate (46,XX normals + TS + GO).
dalities including gamete (GIFT) and zygote (ZIFT) intrafallopian tube transfer'? utilizing donated ova, show promise in women with primary ovarian failure (including Turner syndrome) and a variety of other disorders causing infertility. A review of eight clinical trials of ovum donation and embryo transfer (including ZIFT and GIFT) in women with primary ovarian failure demonstrated an overall pregnancy rate of between 20 and 75% per treatment cycle. 33-40 Tubal transfer appeared to afford the greatest opportunity for pregnancy; the likelihood of pregnancy improved with increasing numbers of embryos or zygotes transferred.t" In these trials, 20 pregnancies were reported in 74 women with TS or other form of gonadal dysgenesis (including 46,XX and 46,XY karyotypes) (Table 2). The miscarriage rate was 23-25% in two studies. 33 ,39 No fetal chromosomal abnormalities were reported and obstetric complications were few. These included cesarean section due to a small pelvic outlet.P pregnancy-induced hypertension, renal failure, and ectopic pregnancy." Live birth statistics were not available in all studies. Possible etiologies of poor outcome in ovum donation in TS recipients may be related to deficiencies in any of several circulating proteins including relaxin, a protein of corpus luteum origin thought to be important in uterine and cervical changes throughout pregnancy;" and/or placental protein 14 (PPI4), a glycoprotein synthesized by the secretory endometrium and decidua of early pregnancy. 42 One study that included TS women demonstrated a suboptimal endometrial response to standard hormone replacement'? similar to the often inadequate response of breast anlage to estrogen stimulation, also seen in TS. Together these variables may im-

pair implantation or the ability of the endometrium to maintain pregnancy. Development of methods for the cryopreservation of ova in those adolescent Turner women with spontaneous puberty and ovulation, or of ova donated by mothers or sisters of TS females for later fertilization, are additional considerations for future pregnancy after ovarian failure has developed.t" Numerous obstacles, including the presence of preexisting hypertension, cardiac or cerebrovascular anomalies, renal anomalies, or the development of carbohydrate intolerance and clinical diabetes mellitus, make the availability of these techniques as well as the actual pregnancy a theoretical risk to TS women. Likewise, the increased rate of fetal loss and sex/somatic chromosome disorders seen in fertile Turner women, along with the obvious ethical and religious considerations in those who seek ovum donation, indicate a need for genetic counseling and prenatal diagnostic evaluation for such individuals. As the majority of women with TS will most likely adopt their children, emphasis should be placed on their opportunity for normal personal relationships as well as satisfactory sexual relationships.

Acknowledgment. The author is grateful to Allen W. Root, M.D. for his review of this manuscript.

References 1. Mathur A, Stekol L, Schatz D, et al: The parental origin of the single X chromosome in Turner syn-

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Ovarian Function in Turner Syndrome

drome : lack of correlation with parental age or clinical phenotype. Am J Hum Genet 1991 ; 48:682 2. Simpson JL: Localizing ovarian determinants through phenotypic-karyotypic deductions . Progress and Pitfalls, Turner Syndrome. Edited by RG Rosenfeld and MM Grumbach. New York , Marcel Dekker, 1990, pp 65-78 3. Hall JG, Gilchrist DM: Turner syndrome and its variants. Pediatr Clin NA 1990; 37:1421 4. Fisher EMC , Beer-Romero P, Brown LG , et al: Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 1990; 63:1205 5. Brown CJ, Ballabio A, Rupert JL, et al: A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 1991; 349:38 6. Migeon BR, Jelalian K: Evidence for two active X chromosomes in germ cells of females before meiotic entry . Nature 1977; 269:242 7. Hook EB , Warburton D: The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet 1983 ; 64:24 8. Weiss L: Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J Med Genet 1971; 8:540 9. Lisker R, Jimenez R, Larrea F , et al: Cytogenetic and endocrine studies in a 45,X female subject with spontaneous sexual development . Am J Obstet Gynecol 1979; 133:149 10. Conte FA, Grumbach MM, Kaplan SL: A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 1975;40:670 11 . Hosoda A, Fujieda K, Matsuura N, et al: Age-related change of pulsatile gonadotropin secretion in Turner syndrome. Pediatr Res 1991 ; 29:196 12. Page LA, Beauregard LJ , Bode HH, et al: Hypothalamic-pituitary-ovarian function in menstruating women with Turner syndrome (45,X). Pediatr Res 1990; 28:514 13. Rudolf K, Kunkel S: Coincidence of gonadal dysgenesis and hyperprolactinemia. Exp Clin Endocrinol 1988; 92:363 14. Richardson SJ, Senikas V, Nelson JF: Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987; 65:1231 15. Massa G, Vanderscheueren-Lodeweyckx M, Malvaux P: Linear growth in patients with Turner syndrome: influence of spontaneous puberty and parental height. Eur J Pediatr 1990; 149:246 16. Teller WM, Homoki J, Wudy S, et al: Adrenarche is dissociated from gonadarche-studies in patients with Turner syndrome. Acta Endocrinol (suppl) 1986; 279:232

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17. Sklar CA, Kaplan SL , Grumbach MM: Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis , isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. J Clin Endocrinol Metab 1980; 51:548 18. Lucky AW, Marynick SP, Rebar RW, et al: Replacement oral ethinyloestradiol therapy for gonadal dysgenesis: growth and adrenal androgen studies. Acta Endocrinol 1979; 91:519 19. Kaneko N , Kawagoe S, Hiroi M: Turner's syndrome-review of the literature with reference to a successful pregnancy outcome. Gynecol Obstet Invest 1990; 29:81 20. Taysi K: Brief clinical report: del(X)(q26) in a phenotypically normal woman and her daughter who also has Trisomy 21. Am J Med Genet 1983; 14:367 21. Varela M, Shapira E, Hyman DB, et al: UllrichTurner syndrome in mother and daughter: prenatal diagnosis of a 46,X,del(X)(p21) offspring from a 45,X mother with a low-level mosaicism for the del(X)(p21). Am J Med Genet 1991; 39:411 22. Illig R, DeCampo C, Lang-Muritano MR, et al: A physiological mode of puberty induction in hypogonadal girls by low dose transdermal 17~-oestradiol. Eur J Pediatr 1990; 150:86 23. Lippe B: Turner syndrome. Endocrinol Metab Clin NA 1991; 20:121 24. Ross JL, Cassorla F, Carpenter G, et a1: The effect of short-term treatment with growth hormone and ethinyl estradiol on lower leg growth rate in girls with Turner's syndrome. J Clin Endocrinol Metab 1988; 67:515 25. Mauras N, Rogol AD, Veldhuis JD : Specific, timedependent actions of low-dose ethinyl estradiol administration on the episodic release of growth hormone, follicle-stimulating hormone and luteinizing hormone in prepubertal girls with Turner's syndrome. J Clin Endocrinol Metab 1989; 69:1053 26. Preger L, Steinbach HL, Moskowitz P, et al: Roentgenographic abnormalities in phenotypic females with gonadal dysgenesis . Am J Radiol 1968; 106:899 27. Ross JL, Long LM, Feuillan P, et al: Normal bone density of the wrist and spine and increased wrist fractures in girls with Turner's syndrome. J Clin Endocrinol Metab 1991; 73:355 28. Kirkland RT, Lin T-H, LeBlanc AD, et al: Effects of hormonal therapy on bone mineral density in Turner syndrome. Turner Syndrome. Edited by RG Rosenfeld and MM Grumbach. New York, Marcel Dekker, Inc, 1990, pp 319-325 29. Naeraa RW, Brixen K, Hansen RM, et al: Skeletal size and bone mineral content in Turner's syndrome: relation to karyotype, estrogen treatment, physical fitness, and bone turnover. Calcif Tissue Int 1991; 49:77 30. Lin AE, Lippe BM, Geffner ME, et a1: Aortic dilation, dissection, and rupture in patients with Turner syndrome. J Pediatr 1986; 109:820 31. Lancman M, Mesropian H, Serra P, et al: Turner's

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36. 37.

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38. Serhal PF, Craft IL: Oocyte donation in 61 patients. Lancet 1989; i: 1185 39. Devroey P, Camus M, Van Den Abbeel E, et al: Establishment of 22 pregnancies after oocyte embryo donation. Br J Obstet Gynecol 1989; 96:900 40. Abdalla HI, Baber RJ, Kirkland A, et al: Pregnancy in women with premature ovarian failure using tubal and intrauterine transfer of cryopreserved zygotes. Br J Obstet Gynecol 1989; 96:1071 41. Johnson MR, Abdalla H, Allman ACJ, et al: Relaxin levels in ovum donation pregnancies. Fertil Steril 1991; 56:59 42. Critchley HOD, Chard T, Lieberman BA, et al: Serum PP14 levels in a patient with Turner's syndrome pregnant after frozen embryo transfer. Hum Reprod 1990; 5:250 43. Li TC, Dockery P, Ramsewak SS, et al: The variation of endometrial response to a standard hormone replacement therapy in women with premature ovarian failure. An ultrasonographic and histological study. Br J Obstet Gynecol 1991; 98:656