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Key Words: Turner syndrome, fetal ovary, follicle, oocyte

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FERTILITY AND STERILITY�VOL. 81, NO. 4, APRIL 2004

Copyright ©2004 American Society for Reproductive MedicinePublished by Elsevier Inc.

Printed on acid-free paper in U.S.A.

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eceived May 8, 2003;evised and acceptedecember 1, 2003.upported by grant no..0166.98 from the Belgianociety for Pediatricndocrinology, the Fondsoor Wetenschappelijknderzoek Vlaanderen

FWO), and Ares Serononternational (GF9405).eprint requests: Johanmitz, M.D., Ph.D., Follicleiology Laboratory, AZ-UB, Laarbeeklaan 101,-1090 Brussels, Belgium

FAX: 32-2-477-50-60;-mail: [email protected]).Follicle Biologyaboratory.Department of Pediatrics.Department of Anatomy-

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athology.

015-0282/04/$30.00oi:10.1016/j.fertnstert.2003.2.011

112

umber of ovarian follicles in humanetuses with the 45,X karyotype

arine Reynaud, Ph.D.,a Rita Cortvrindt, M.Sc.,a Franciska Verlinde, M.D.,b

ean De Schepper, M.D., Ph.D.,b Claire Bourgain, M.D., Ph.D.,c andohan Smitz, M.D., Ph.D.a

cademisch Ziekenhuis van de Vrije Universiteit Brussel, Brussels, Belgium

bjective: To evaluate the numbers of ovarian follicles during fetal life in the gonads of human femaleith the 45,X karyotype (Turner syndrome, TS) and to compare them with those from age-matched

etuses.

esign: Retrospective study.

etting: An academic hospital.

atient(s): Ovarian samples from TS fetuses (aged 17–37 weeks), mainly obtained after induced aborvaries from eight control fetuses (matching gestational ages).

ntervention(s): Embedded blocks of ovaries were collected from anatomy-pathology departments oniversity hospitals and were sectioned and stained with hematoxylin-eosin.

ain Outcome Measure(s): Observation of primordial and growing follicles.

esult(s): In the fetal ovaries of controls, numerous oogonia were observed at 18 weeks. Primordialere present in all ovaries from 20 weeks’ gestation onward, whereas preantral and antral folliclbserved from 26 weeks onwards. In ovaries from 45,X TS fetuses, oogonia were observed in someut no primordial, preantral, or antral follicles were found, even in ovaries from the third trimester of ge

onclusion(s): Follicle formation and growth are severely reduced in ovaries from aborted 45,X TS feFertil Steril� 2004;81:1112–9. ©2004 by American Society for Reproductive Medicine.)

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In a normal human fetus, gonadal develent starts during the 4th week of gestaith the migration of primordial germ cel

hrough the hindgut to the differentiating getal ridges. The primordial germinal cells priferate (mitosis) and enter meiosis asynchously (10–14 weeks). The first oocytes iniplotene stage are found several weeks a

nitiation of meiosis, at approximately we6. From the 12th to 20th week of gestatiogonia and oocytes are present at the higumbers (several millions) in the ovary, a

he first primordial follicles are formed at aroximately 20 weeks’ gestation. Oocytes h

ost their intercellular connections by this stand are surrounded by a single layer of fl

ened cells. At 23–26 weeks, primordial, pary, and preantral follicles are present,fter 35 weeks all follicle stages (from primoial up to antral) can be observed in the fe
vary (1). 1
t

Turner’s syndrome (TS) was first describy Henry Turner in 1938(2) and is characte

zed by an abnormality of the chromosomaryotype involving the X chromosomainly a 45,X karyotype. Individuals with th

yndrome are phenotypically femaleresent several physical abnormalities, suchort stature. In the TS population, a few spaneous pregnancies (�20) have been reporteut more than 80% of TS women suffer frovarian failure or incomplete sexual develent during childhood(3). It has been sugested that sterility in TS girls is due toassive germ-cell loss during fetal life(4).owever, little is known about the germ-cnd follicle content of TS ovaries at the diffent stages of fetal development. Very few fe5,X ovaries have been histologically exa

ned(5, 6). When they have been studied, there found to be histologically normal befo
8 weeks’ gestation. Some authors suggested

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hat the majority of oocyte degeneration occurs in the firstew months or years of postnatal life (7), but a few folliclesan still be found in some ovaries of adolescent TS girls (8).

In the present study, we attempted to evaluate the numberf follicles and their growth in control and TS ovaries frometuses at different stages of gestation to determine whetherormal folliculogenesis (constitution of the pool of primor-ial follicles and follicular growth) occurs in TS fetuses.

MATERIALS AND METHODS

The study was planned under the auspices of the Belgianociety for Pediatric Endocrinology and after approval of theAZ-VUB) institutional review board.

6,XX and 45,X Fetal Human OvariesEmbedded parts of fixed ovaries or slides were obtained

rom 17 TS fetal ovaries, diagnosed by an amniotic 45,Xaryotype. This material was collected from anatomy-pa-hology departments from academic institutions (three Bel-ian and one French). Fourteen control fetal ovaries (46,XXaryotype) were obtained from the Department of Pathologyt the University Hospital of the Free University of Brussels,elgium.

In the TS group, fetal terms ranged from 14 to 37 weeks.ll TS ovaries were obtained at autopsy after spontaneous or

nduced abortions after detection of 45,X karyotype at am-iocentesis. The abortion procedure and progression greatlynfluenced the histologic quality of the ovaries: only 10varies were finally found suitable for histologic examina-ion. These ovaries were from fetuses with gestational ages

T A B L E 1

haracteristics of the control fetuses studied.

etuso.

Stage ofgestation

(wk) Type of delivery Associated mal

18 Induced abortion None22 Spontaneous abortion None25 Induced abortion Spina bifida � hy

26 Premature birth Cardiac � pulmomalformation

28 Premature birth Spina bifida � hy

30 Induced abortion Spina bifida � hy

34 Premature birth Hydrops � cardia

35 Premature birth Cardiomyopathy

eynaud. 45,X and 46,XX human fetal ovaries. Fertil Steril 2004.

f 17, 18, 20, 23, 25, 27, 31, 33, and 37 weeks. (

ERTILITY & STERILITY�

To compare the developmental changes in ovarian fol-iculogenesis, eight normal fetuses (control group) were se-ected. They had gestational ages that overlapped those ofhe TS ovaries studied. In this control group, the gestationalges of fetuses ranged from 18 to 35 weeks (18, 22, 25, 26,8, 30, 34, and 35 weeks). These ovaries were obtained fromutopsied fetuses after induced abortion for prenatally de-ected malformations or from neonates that died in the firsteek after a premature delivery. None of these fetuses had

bnormal karyotyping, such as trisomy 13, 18, or 21, whichre known to induce germ-cell defects (9). Details concern-ng the origin of control ovaries are summarized in Table 1.

istologyAll ovaries were cut in 5-�m sections and stained with

ematoxylin and eosin. From each TS ovary a variableimited number of slides was available from this archivedaterial.

In Table 2, we have specified how many ovarian sectionsrom TS ovaries were observed. Because entire ovaries wereot available from these TS fetuses, it was impossible toalculate total numbers of follicles (follicle distribution isighly heterogenous within a human ovary). For the controlvaries, at least 50 sections were prepared and observed.

Germ cells were identified by their large size (at leastwice as large as somatic cells) and their faintly stainedytoplasm. Oocytes surrounded by flattened granulosa cellsere counted as primordial follicles. The follicle stages were

lassified according to the criteria from Gougeon and Chainy

tion Ovarian content Figure no.

Numerous oogonia 1 ANumerous oogonia and primordial follicles 1 B, B�

phaly Numerous primordial follicles 1 C, C�Some primary folliclesNumerous primordial follicles 1 D, D�Growing follicles (preantral to antral)

phaly Numerous primordial follicles 1 E, E�Growing follicles (preantral to antral)

phaly Numerous primordial follicles 1 F, F�Growing follicles (preantral to antral)

blems Numerous primordial follicles 1 G, G�Growing follicles (preantral to antral)Numerous primordial follicles 1 H, H�Some primary/secondary follicles

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RESULTSOf the 17 embedded ovarian materials from 45,X fetuses,

had to be discarded because pronounced autolysis of theissue made analysis unreliable. Images from representativereas from all TS ovaries and from gestational age-matchedontrols were archived for analysis and illustrative purposes.

olliculogenesis in Normal Fetal OvariesFolliculogenesis in normal fetal ovaries is illustrated in

igure 1. In the 18-week fetal ovary (Fig. 1A), there were norimordial follicles observed; only large pale germ cellsere abundantly present. These cells were clearly organized

n cordlike structures. In the ovaries from 22 weeks’ gesta-ion onward, histologic sections illustrated the involvementf somatic cells in forming individualized follicular struc-ures around the oocyte. These primordial follicles wereistributed within an interstitium densely populated bymaller cells containing a dense nucleus.

Primordial follicles were observed in the ovaries of con-rol fetuses from 22 weeks to the end of gestation (Fig. 1B,�, C, and D). Primary follicles were characterized by an

ncreased oocyte diameter surrounded by cuboidal granulosaells (Fig. 1C�). Preantral and antral follicles were observedn ovaries of control fetuses (Fig. 1D�, E�, F, F�, G, and G�).ormation and organization of the theca cells around theasal membrane was also observed in some ovaries (Fig.D�, E�, F�, G�, and H�).

olliculogenesis in Turner Fetal OvariesThe evolution in the ovarian structures of TS ovaries is

T A B L E 2

haracteristics of the Turner fetuses studied.

etus no.

No. ofsectionsstudied

Stage ofgestation (wk)

1 18 17 S2 10 18 In3 28 20 In

4 32 23 In

5 10 25 In

6 20 25 In

7 13 27 N

8 24 31 In

9 30 33 In

10 22 37 In


llustrated in Figure 2. Germ cells, characterized by their r

114 Reynaud et al. 45,X and 46,XX human fetal ovaries

arge size and their pale cytoplasm, were identified in 8 ofhe 10 45,X ovaries. As can be seen from the individualanels in Figure 2, only very low numbers of germ cells wereresent, except perhaps for the earliest gestational ages (upo 20 weeks). Whatever the fetal age studied, no clearlyelineated follicle structures could be found. In the TSvaries, neither preantral nor antral follicles were found.onnective tissue was found to be very abundant in the

troma of all ovaries. The somatic cells in these fetal ovariesere never organized around germ cells. Table 2 lists theistologic findings in the TS ovaries studied.

DISCUSSIONArchived material from aborted fetuses enabled this de-

criptive study of the numbers of follicles in ovaries from 10S ovaries and 8 gestational age-matched controls. We fo-used our descriptive analysis on the earliest stages of fol-iculogenesis to study whether primordial follicles could bebserved in TS ovaries. This is the largest histologic study inS describing the follicle status in fetal ovaries throughout

he second half of gestation. A tabulated review of publishedistologic data on fetal and newborn 45,X ovaries is pre-ented in Table 3. We studied the ovaries during late fetaltages and could evaluate whether some germ cells were ableo survive. The majority of ovaries that were of a sufficientuality for histologic analysis were obtained after inducedbortion, which guaranteed a better structural integrity thann the case of prolonged spontaneous abortion. Furthermore,he fetuses produced by induced abortion are probably more

of delivery Ovarian content Figure no.

neous abortion Numerous oogonia 2 A, A�abortion Few germ cells 2 Babortion Numerous germ cells 2 C

No primordial folliclesabortion Few germ cells 2 D, D�

No primordial folliclesabortion No germ cells 2 E

No primordial folliclesabortion Few germ cells 2 F, F�

No primordial folliclesa available Few germ cells 2 G, G�

No primordial folliclesabortion Numerous germ cells 2 H, H�

No primordial folliclesabortion Numerous germ cells 2 I

No primordial folliclesabortion Few germ cells 2 J, J�

No primordial follicles

Type

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epresentative of liveborn TS neonates than spontaneously

Vol. 81, No. 4, April 2004

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F I G U R E 1

A) Ovarian section of a control ovary at 18 weeks’ gestation. Numerous oogonia are visible, organized in cordlike structuresithin mesenchymal cells. (B, B�) Sections through a control fetal ovary at 22 weeks. Primordial follicles are present,urrounded by flattened pregranulosa cells. (C, C�) Fetal ovary at 25 weeks’ gestation, showing growing follicles with cuboidalranulosa cells. (D, D�) Fetal ovary at 26.5 weeks’ gestation. Numerous primordial follicles can be observed (D), and largerowing preantral and antral (D�) follicles are present. (E, E�) Fetal ovary (28 weeks’ gestation) showing primordial follicles (E)nd growing follicles. Theca cells are well organized around the basal membrane (E�). Presence of primordial and growingollicles was also observed on sections at later gestational stages: 30 weeks’ (F, F�), 34 weeks’ (G, G�), and 35 weeks’ (H, H�)estation. Scale bars � 20 �m (H, H�), 50 �m (H, H�), 100 �m (B, C, D, E, E�, F, G�), or 200 �m (D�, F�, G, H).


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F I G U R E 2

varian section of Turner ovaries at different gestational stages. (A, A�) Fetal Turner ovary at 17 weeks’ gestation, withumerous small oogonia, histologically preserved. Large oogonia (white arrow) are degenerated, with a contracted nucleus andthin layer of cytoplasm bordering the inner side of the cell. Parenchymal cells (ovoid nucleus) are present. (B) Fetal ovary at

8 weeks’ gestation. Germ cells are rarely observed. (C) Fetal ovary (20 weeks’ gestation) with numerous germ cells but norimordial follicles. (D, D�) Fetal ovary at 23 weeks’ gestation. Some oogonia with histologically preserved nucleus are visible.o primordial follicles can be detected. (E) Fetal ovary at 25 weeks’ gestation revealing a complete absence of germ cells orrimordial follicles.


116 Reynaud et al. 45,X and 46,XX human fetal ovaries Vol. 81, No. 4, April 2004

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F I G U R E 2 Continued.

F, F�) Fetal ovary at 25 weeks’ gestation containing few germ cells (white arrows) but no primordial follicles. (G, G�) Fetal ovaryt 27 weeks’ gestation containing a lot of stroma and few small oogonia (white arrow) but no primordial follicles. (H, H�) Fetalvary at 31 weeks’ gestation. Numerous oogonia are present, but primordial follicles are totally absent. Fibroblasts andregranulosa cells (with numerous mitosis) were clearly visible. (I) Fetal ovary at 33 weeks’ gestation showing numerousogonia (not histologically preserved). (J, J�) Fetal ovary at 37 weeks’ gestation showing few oogonia (white arrow) andregranulosa cells (proliferating). Scale bars � 45 �m (A�, B, D, D�, F, F�, G�, H�, J, J�) or 90 �m (A, C, E, G, H, I).


ERTILITY & STERILITY� 1117

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borted fetuses. We also evaluated ovaries of a control groupf gestational age-matched fetuses obtained under similaronditions. Although our control fetuses were not healthynd had severe internal and external abnormalities, theseongenital malformations are not known to affect ovarianunction, and histologic examination revealed normal oogen-sis and folliculogenesis in accordance with literature data.umerous oogonia were present in the ovary at 18 weeks’estation, and primordial follicle formation took place atpproximately 20 weeks’ gestation in controls. In ovariesrom fetuses 27 weeks old or more, all follicle stages fromrimordial to antral were present in the ovary.

In the 45,X TS fetuses, germ cells were found in ovaries25 weeks of age, which confirmed that primordial germi-

al cells’ migration to the genital ridges had indeed occurredn TS fetuses (5). When oogonia were detected in the slidesf TS ovaries, their number seemed to be severely reduced inost cases. Organization of somatic cells around the oocyte

o form primordial follicles and transformation of pregranu-osa cells to granulosa cells were not observed. Even if a fewollicles might have been present in another part of thevaries (because ovarian tissue and follicle density is highlyeterogeneous in humans), the vast majority of primordialollicles was not formed. This indicates that folliculogenesiss severely impaired in ovaries of 45,X fetuses, and thisefect is probably due to the absence of germ cells. Gener-lly, the ovaries from TS fetuses were mainly made up ofbundant connective tissue. It is still unclear whether the

T A B L E 3

eview of data previously published on ovarian structures

uthors (reference) Age fetus/newborn

ingh and Carr (5) 8 XO fetuses: from 11 to 23 wk (11,12, 13, 14, 14, 17, 21, 23 wk)

Spontaneous abortions

peed (4) XO fetuses: 15, 17, and 24 wkInduced abortions

unniff et al. (9) 4 XO or XO/XX fetuses: 22, 37, 38,and 40 wk

onen and Glass (11) 2 newborns

roland et al. (12) 1 newborn: 25 days oldrown and Smith (13) 2 newborns: age unknownodel and Egli (14) 1 newborn: age unknownarr et al. (6) 1 newborn: 8 days oldove (15) 1 newborn: 19 days old


educed amount of germ cells in 45,X fetuses is due to fewer s

118 Reynaud et al. 45,X and 46,XX human fetal ovaries

ogonial mitoses or to an increased frequency of meioticairing errors (16).

Our results are in agreement with the results of studiesonducted by Speed (4), Singh and Carr (5), and Cunniff etl. (9) (Table 3). In 1986, Speed (4) analyzed Turner fetalvaries during meiosis (15, 17, and 24 weeks) and reportedhat germ-cell loss took place in the early stage of meioticrophase, which explained the low number of germ cells. Inhe work of Singh and Carr (5), eight ovaries, but at earliertages (from 11 to 23 weeks) than in the present experiment,ere examined. In the cases of the later gestational ages (17,1, and 23 weeks), they reported that the connective tissueepta between the sex cords was abnormally thick and that—ith the exception of one unique fetus of 17 weeks—norimordial follicles were observed. Cunniff et al. (9) studiedour TS fetuses at a later gestational age and described theresence of cords of granulosa cells but no oocytes in thevaries. Instead of normal formation of primordial follicles,hey reported an increase in the connective tissue of theonad.

Few TS cases have been studied during the neonataleriod. Bove (15) proposed, on the basis of findings inewborns, that in the 45,X ovary oogonia and pregranulosaells might persist after 40 weeks’ gestation but that theirltimate regression resulted in a contracted fibrous “streak”onad. In 1978, Rivelis et al. (17) studied ovaries of 17 TSomen (from 5 to 30 years old). They reported bilateral

fetal or neonatal Turner ovaries.

Ovarian phenotype

al appearance of XO ovaries before 14 weeksweeks, connective tissue septa abnormally thick, but primordial folliclespregranulosa cells presentweeks, no primordial follicles in XO, but pregranulosa cells and

senchymal cells presentweeks, a single primordial follicle detected � pregranulosa cells �ordial germinal cells

cell meiosis is largely blocked at the preleptotene stageroportion of oocytes reaching the pachytene stage is extremely small andproportion of degenerative pachytene germ cells (Z cells) is increased

tes at the dictyotene stage are apparently undetectableords of granulosa cells and no oocytes

ries very thin and small, with stroma and without ovanormal ovary and one thin with few ova

rimordial folliclesrm cellsrm cells, but islands of cells resembling primordial follicleser of oogonia greatly reduced and only 1.4% of follicles are normalcontains excess stroma, immature germ cells (pachytene stage), and noordial follicles

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ontents microscopically, no follicles in the 4 ovaries ofpure” TS women (45,X) were found, whereas a singleollicle was found in 3 of 13 ovaries from women with aosaicism (45,X/46,XX). These data suggest that folliclesight survive in TS patients with a mosaic karyotype, and it

s known that Turner’s syndrome patients with mosaicisman maintain ovarian function up to an early adult age andan have more spontaneous pregnancies than women withure TS (18). However, these women often experience pre-ature menopause.

Finally, these histologic data, generated from 45,X TSvarian tissue abortion material, which focused on the sec-nd part of gestation, emphasized the absence of significantollicle formation. Our findings of a low number of oogoniand the occasional presence of single primordial follicles in5,X fetuses, points to defects during initiation of meiosisnd to the inability to obtain normal follicle assembly andolliculogenesis.

Recently, new techniques have been developed that allowryopreservation of ovarian tissue (19, 20). This tissue,hich would be ideally removed at an early age in TSatients, could eventually be grafted back into patients whoxpress the wish to become pregnant with their own biolog-cal material (21). Although this idea might be attractive,ome caution is warranted, because even if 70% to 80% ofhe already reduced pool of follicles in TS ovaries mighturvive to cryopreservation, there is still a substantial lossuring the transplantation procedure due to revascularizationroblems. Moreover, TS germ cells might be less develop-entally competent and might bear a higher risk for chromo-

omal aberrations causing physical or genetic abnormalitiese.g., cleft palate, Down’s syndrome) (22). Consequently,varian cryopreservation for young TS girls should be dis-ussed within a multidisciplinary team before this option isffered for gamete preservation.

cknowledgments: The authors thank Katy Billooye for her technical help
ith histology work; and P. Moerman, M.D., (Histopathology Department
ERTILITY & STERILITY�

f the University Hospital, Leuven, Belgium) and J. Martinovic, M.D.,Unite de foetopathologie, Hopital Necker-Enfants Malades, Paris, France)or their help in providing material from Turner fetuses.

eferences1. Baker TG. A quantitative and cytological study of germ cells in human

ovaries. Proc R Soc Lond B Biol Sci 1963;158:417–33.2. Turner HH. A syndrome of infantilism, congenital webbed neck, and

cubitus valgus. Endocrinology 1938;23:566.3. Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontane-

ous pubertal development in Turner’s syndrome. J Clin EndocrinolMetab 1997;82:1810–3.

4. Speed RM. Oocyte development in XO foetuses of man and mouse: thepossible role of heterologous X-chromosome pairing in germ cellsurvival. Chromosoma 1986;94:115–24.

5. Singh RP, Carr DH. The anatomy and histology of XO human embryosand fetuses. Anat Rec 1966;155:369–83.

6. Carr DH, Haggar RA, Hart AG. Germ cells in the ovaries of XO femaleinfants. Am J Clin Pathol 1968;49:521–6.

7. Weiss L. Additional evidence of gradual loss of germ cells in thepathogenesis of streak ovaries in Turner’s syndrome. J Med Genet1971;8:540–4.

8. Hreinsson JG, Otala M, Fridstrom M, Borgstrom B, Rasmussen C,Lundqvist M, et al. Follicles are found in the ovaries of adolescent girlswith Turner’s syndrome. J Clin Endocrinol Metab 2002;87:3618–23.

9. Cunniff C, Jones KL, Benirschke K. Ovarian dysgenesis in individualswith chromosomal abnormalities. Hum Genet 1991;86:552–6.

0. Gougeon A, Chainy GBN. Morphometric studies of small follicles inovaries of women at different ages. J Reprod Fertil 1987;81:433–42.

1. Conen PE, Glass IH. 45/XO Turner’s syndrome in the newborn: reportof two cases. J Clin Endocrinol 1963;23:1–10.

2. Froland A, Lykke A, Zachau-Christiansen B. Ovarian dysgenesis(Turner’s syndrome) in the newborn. Acta Pathol Microbiol Scand1963;57:21–30.

3. Brown RK, Smith WL. Chromosomal studies in ovarian dysgenesis.Trans N Engl Obstet Gynecol Soc 1964;18:47–54.

4. Hodel C, Egli F. Ullrichturner syndrome in the newborn associated withcoarctation of the aorta and left-sided superior vena cava. Ann Paediatr1965;204:387–96.

5. Bove KE. Gonadal dysgenesis in a newborn with XO karyotype. Am JDis Child 1970;120:363–6.

6. Gosden RG. Ovulation 1: oocyte development throughout life. In:Grudzinskas JG, Yovich JL, eds. Gametes—the oocyte. Cambridge,United Kingdom: Cambridge University Press, 1995:119–49.

7. Rivelis CF, Coco R, Bergada C. Ovarian differentiation in Turner’ssyndrome. J Genet Hum 1978;26:69–83.

8. Birkebaek NH, Cruger D, Hansen J, Nielsen J, Bruun-Petersen G.Fertility and pregnancy outcome in Danish women with Turner syn-drome. Clin Genet 2002;61:35–9.

9. Newton H, Aubard Y, Rutherford A, Sharma V, Gosden R. Lowtemperature storage and grafting of human ovarian tissue. Hum Reprod1996;11:1487–91.

0. Hovatta O, Silye R, Krausz T, Abir R, Margara R, Trew G, et al.Cryopreservation of human ovarian tissue using dimethylsulphoxideand propanediol-sucrose as cryoprotectants. Hum Reprod 1996;11:1268–72.

1. Oktay K, Karlikaya G. Ovarian function after transplantation of frozenbanked autologous ovarian tissue. N Engl J Med 2000;342:1919.

2. Kaneko N, Kawagoe S, Hiroi M. Turner’s syndrome—review of theliterature with reference to a successful pregnancy outcome. Gynecol
Obstet Invest 1990;29:81–7.
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