Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency

doi:10.1016/j.ejogrb.2014.09.033

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 182, November 2014, Pages 211-215

https://doi.org/10.1016/j.ejogrb.2014.09.033 Get rights and content

Abstract

Our objective was to identify the distribution of cytogenetic abnormalities of 175 Turkish women with primary amenorrhea (PA) or premature ovarian insufficiency (POI). A retrospective study was performed using medical records of 94 patients with PA and 81 patients with POI at the Genetics Department, Zeynep Kamil Women's and Children's Research and Training Hospital, Istanbul, Turkey. G-banded metaphase karyotype analysis were prepared and analyzed. Chromosomal abnormalities were present in 44 of 175 cases (25%). 15 were full blown or mosaic numerical X chromosome abnormalities (8.5%), 10 were full blown or mosaic X-chromosome structural anomalies (5.7%), one was X-autosome translocation (0.5%), 3 were autosomal anomalies (1.7%), 12 were XY karyotype (6.8%), one was 45,X/46,XY mosaic and 2 were full blown or mosaic structural anomalies of Y chromosome (1.7%). The prevalence of chromosomal abnormalities was 25% in this large series of Turkish women with primary amenorrhea or premature ovarian insufficiency, most cases involving X-aneuploidy or X-structural abnormalities or 46,XY karyotype. High prevalence of chromosomal abnormalities is associated with POI starting at an early age (average age: 26 years).

Introduction

Amenorrhea affects 1–3% of women of the reproductive age. Primary amenorrhea (PA) is defined as the absence of menarche in 14-year-old girls without the development of secondary sexual characteristics, or the absence of menses in 16-year-old girls with normal developement of secondary sexual characteristics [1]. Primary amenorrhea is a symptom of many potential causes, including developmental anomaly of the genital organs, failure of the ovaries to receive or maintain oocytes, and delayed pubertal development [2]. Previous reports showed that the most common etiologies were gonadal dysgenesis, hypothalamic/pituitary hypogonadism and mullerian agenesis [3], [4]. Chromosome abnormalities are very common in gonadal dysgenesis [3], [5].

Premature ovarian insufficiency (POI) is defined as primary ovarian defect characterized by secondary amenorrhea for at least 4–6 months duration before the age of 40 years [6]. Gonadotropins are elevated (FSH > 40 mIU/ml) and estrogen (E2) is in the menopausal range [1]. A wide spectrum of known causes of POI are genetic disorders; which can involve the X chromosome (monosomy, trisomy, mosaicism, deletions or FMR1premutations) or autosomes; FSHR (follicle-stimulating hormone receptor), GDF9 (growth differentiation factor-9) and BMP15 (Bone Morphogenic Protein 15) gene mutaions; autoimmune ovarian damage; metabolic conditions such as deficiency of 17-hydroxylase and galactose-1-phosphate uridyltransferase (GALT); environmental factors, such as infections and toxins; and iatrogenic ovarian damage following surgery, radiotherapy, or chemotherapy [7], [8], [9], [10], [11].

Among genetic causes of amenorrhea, chromosome abnormalities are the most common, with widely varying percentages in reported series (8.8–32%) (3, 12–17). X chromosome monosomy is the most common chromosomal abnormality characterized by Turner syndrome, but numerous different X chromosomal abnormalities have been found, and autosomal rearrangements have been reported. The purpose of this study was to analyze the phenotypes and determine the prevalence and type of cytogenetic anomalies in a large series of 181 Turkish women affected by PA or POI.

Section snippets

Materials and methods

A retrospective study was conducted in the Genetics Department, Zeynep Kamil Women's and Children's Research and Training Hospital, Istanbul, Turkey. Medical examination and cytogenetic records of 175 female patients, distributed as 94 PA and 81 POI patients from the year 1997 to 2011 were reviewed. PA patients had absence of menses until 14 years of age without the development of secondary sexual characteristics, or absence of menses until 16-years of age with normal development of secondary

Results

In the 175 cases, 94 (53.7%) presented with primary amenorrhea (PA) and 81 (46.2%) with premature ovarian insufficiency (POI). Characteristics of 175 Turkish women with PA and POI are given in Table 1.

Chromosomal abnormalities were detected in 44 of 175 cases (25%). These abnormalities were distributed as 35 of 94 (37%) PA patients, and 9 of 81 (11.1%) POI patients. There were 15 patients with full blown or mosaic numerical X chromosome abnormality (15/175, 8.5%), 10 patients with full blown or

Comment

This study is the largest series of cytogenetic studies performed on 175 Turkish women with PA or POI, revealing the prevalence of chromosomal abnormalities to be 25%. Chromosomal abnormalities have been estimated to occur in 8.8% to 32% women with amenorrhea [3], [13], [14], [15], [16], [17], [18] (Table 5). Ceylaner et al. [14], in a series of 75 Turkish POI patients reported it to be 22.7% (13). This is higher than our results (11.1%) which probably reflects selection bias. High prevalence

Condensation

Prevalence of chromosomal abnormalities was 25% in this series of Turkish women with primary amenorrhea or premature ovarian insufficiency.

References (31)

M. Schachter et al.
Amenorrhea during the reproductive years—is it safe?
Fertil Steril
(1994)
S.S. Desai et al.
Association of allelic combinations of FSHR gene polymorphisms with ovarian response
Reprod Biomed Online
(2013)
G. Ceylaner et al.
Genetic abnormalities in Turkish women with premature ovarian failure
Int J Gynaecol Obstet
(2010)
A.S. Devi et al.
45,XX/46,XX mosaicism in patients with idiopathic premature ovarian failure
Fertil Steril
(1998)
S. Prakash et al.
Single nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome
Genet Med
(2014)
H. Elghezal et al.
Chromosome abnormalities in one thousand infertile males with nonobstructive sperm disorders
Fertil Steril
(2006)
L. Speroff et al.
Amenorrhea
R.H. Reindollar et al.
Delayed puberty: an update of 326 patients
Trans Am Gynecol Obstet Soc
(1989)
J.O. Schorge et al.
Amenorrhea
P. Tanmahasamut et al.
Clinical findings of 295 patients with primary amenorrhea
Obstet Gynaecol Res
(2012)

C.B. Coulam et al.

Incidence of premature ovarian failure

Obstet Gynecol

(1986)

D. Goswami et al.

Premature ovarian failure

Hum Reprod Update

(2005)

S. Vujovic

Aetiologyof premature ovarian failure

Menopause Int

(2009)

D. Tiotiu et al.

Variants of the BMP15 gene in a cohort of patients with premature ovarian failure

Hum Reprod

(2010)

P. Laissue et al.

Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure

Eur J Endocrinol

(2006)

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The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old.
Data regarding females aged <21 years diagnosed with POI during the years 2000–2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded.
For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009–2016, compared with 2000–2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15–21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years.
In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.
Primary ovarian insufficiency and human papilloma virus vaccines: a review of the current evidence
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Citation Excerpt :
POI has diverse etiologies, including chemotherapy and radiation treatment for cancer, abnormalities involving the X chromosome (eg, Turner syndrome), an FMR1 gene premutation, autoimmune disorders, and other rare conditions.27 A higher prevalence of chromosomal abnormalities, up to 50%, is associated with POI in younger, adolescent women, especially those who present with primary amenorrhea.35–38 However, in up to 90% of POI patients with a normal 46, XX karyotype, excluding those with prior gonadotoxic cancer treatment, the underlying cause is not known after a comprehensive evaluation.26
Human papilloma virus is the primary causative agent for cervical cancer, and vaccination is the primary means of preventing anogenital cancers caused by human papilloma virus infection. Despite the availability of human papilloma virus vaccines for more than a decade, coverage rates lag behind those for other vaccines. Public concerns regarding safety of human papilloma virus vaccines have been identified as an important barrier to vaccination, including concerns that the human papilloma virus vaccine may cause primary ovarian insufficiency, driven in part by isolated reports of ovarian failure following the human papilloma virus vaccine. We summarize published peer-reviewed literature on human papilloma virus vaccines and primary ovarian insufficiency, reviewing information contained in the case reports and series. Healthcare providers should address any patient concerns about primary ovarian insufficiency and the human papilloma virus vaccine by acknowledging the case reports but noting the lack of association found in a recently published epidemiologic study of approximately 60,000 female individuals. Current evidence is insufficient to suggest or to support a causal relationship between human papilloma virus vaccination and primary ovarian insufficiency.
Clinical and Genetic Investigation of Premature Ovarian Insufficiency Cases from Turkey
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Another study aiming to determine the frequency of fragile X associated POI among Turkish fragile X premutation carriers found that POI could be manifested in up to 34.2% of these women [25]. Geckinli et al. [26] emphasized the importance of routinely assessing chromosomal studies in patients with primary amenorrhea and POI because of the high prevalence of chromosomal abnormalities. In our study population, we investigated whether there is an association between nonsyndromic POI and chromosome aberrations, -CGG- repeat size expansions of the FMR1 gene, and variants of eight genes encoding proteins that are important in differentiation and development of gonadal cells (BMP15, FIGLA, FSHR, GDF9, INHA, NOBOX, NR5A1, POF1B), also further with a human homologous gene of Pdpk1 (PDPK1) previously demonstrated to cause premature ovarian failure in mice with encoding phosphoinositide 3-kinase enzyme deficient oocytes [27].
Premature ovarian insufficiency is a lack of ovarian functions in patients younger than 40 years old. Genetic causes leading to accelerated follicle depletion may result in premature ovarian insufficiency. We aimed to determine genetic etiology of nonsyndromic premature ovarian insufficiency cases from Turkey.
We analyzed 86 nonsyndromic premature ovarian insufficiency cases and 26 matched control female participants. Participants have been investigated in cytogenetic analysis followed by FMR1 repeat size expansions and search of variants for nine premature ovarian insufficiency-associated genes.
Four cases had a structural cytogenetic abnormality. Two cases revealed with premutation size FMR1 triplet repeat expansion. Four cases carried variants in which two were very rare in FSHR and PDPK1, and three were novel in NR5A1, PDPK1, and POF1B genes. Six novel variants have been identified in NOBOX, NR5A1, POF1B, and PDPK1 in control population assigned to be benign alterations.
Mosaicism of sex chromosomes was responsible in 4.6% and FMR1 premutation in 2.4% of premature ovarian insufficiency cases, while the association of premature ovarian insufficiency-related genes was found very subtle. Novel variants in NR5A1, PDPK1, and POF1B may necessitate further evaluation for their association with premature ovarian insufficiency via functional studies.
Etiology and management of primary amenorrhoea: A study of 102 cases at tertiary centre
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People have also studied the patterns of chromosomal abnormalities in cases of primary amenorrhoea and gonadal failure. A previous study from Turkey had shown high incidence of chromosomal abnormalities in one-fourth cases (25%) of primary amenorrhoea or premature ovarian failure [14]. We have reported this study to highlight etiology and management of primary amenorrhoea at a tertiary centre in the north India.
To determine the prevalence of etiologic causes of primary amenorrhea in Indian population.
A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo-sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype.
The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis.
The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea.
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ReviewPrevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency

Abstract

Introduction

Section snippets

Materials and methods

Results

Comment

Condensation

Fertil Steril

Reprod Biomed Online

Int J Gynaecol Obstet

Fertil Steril

Genet Med

Fertil Steril

Amenorrhea

Delayed puberty: an update of 326 patients

Trans Am Gynecol Obstet Soc

Amenorrhea

Clinical findings of 295 patients with primary amenorrhea

Obstet Gynaecol Res

Incidence of premature ovarian failure

Obstet Gynecol

Premature ovarian failure

Hum Reprod Update

Aetiologyof premature ovarian failure

Menopause Int

Variants of the BMP15 gene in a cohort of patients with premature ovarian failure

Hum Reprod

Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure

Eur J Endocrinol

Review
Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency