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XY Female

Swyer syndrome, or XY gonadal dysgenesis, is a type of female hypogonadism in which no functional gonads are present to induce puberty in an otherwise normal girl whose karyotype is then found to be XY. Her gonads are found to be nonfunctional streaks. Estrogen and progesterone therapy is usually then commenced. The gonads are normally removed surgically because they do not function and may develop cancer. more...

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XY Female


The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation require the action of several genes, of which one of the earliest and most important is SRY, the "sex-determining region of the Y chromosome".

Mutations of SRY account for most cases of Swyer syndrome. When this gene is defective, testes fail to develop in an XY (genetically male) fetus. Without testes, no testosterone or antimullerian hormone are produced. Without testosterone the external genitalia fail to virilize, resulting in female genitalia. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Without AMH the mullerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).

A baby girl is born who is normal in all anatomic respects except that she has nonfunctional streak gonads instead of ovaries or testes. As girls' ovaries produce no important body changes before puberty, there is usually no suspicion of a defect of the reproductive system until puberty fails to occur.


Because of the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. Because the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these girls will develop pubic hair, though it often remains sparse.

Evaluation of delayed puberty usually reveals the presence of pubic hair, but elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome.


The consequences to the girl with Swyer syndrome of her streak gonads:

  1. Her gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.
  2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.
  3. Her gonads cannot produce eggs so she will not be able to conceive children the natural way. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).
  4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Rarely, this can begin as early as a few years of age, so the streak gonads are usually removed by surgery within a year or so after discovery of the diagnosis.


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Chromosomal studies in infertile men with oligozoospermia & non-obstructive azoospermia
From Indian Journal of Medical Research, 7/1/05 by Nagvenkar, Punam

Background & objectives: Chromosomal anomalies have been postulated to be as one of the principal genetic factors in male infertility. Cytogenetic evaluation of men with severely compromised semen parameters reveals an increased incidence of chromosomal aberrations when compared with the normal population. The objective of this study was to determine the chromosomal constitution and sperm characteristics among Indian males with severe male factor infertility.

Methods: In this prospective study we investigated 88 infertile men (42 men with azoospermia and 46 men with sperm count

Results: Constitutional chromosome abnormalities were identified in 14.3 per cent of azoospermic and 6.5 per cent of oligozoospermic men, with an overall rate of 10.2 per cent. Chromosomal abnormalities included gonosomal aberrations in 5 cases. Robertsonian translocation in one, trisomy 7 mosaicism in one case, deletion in chromosome 16 in one, and a marker chromosome in one case. Chromosome variants were observed in 33 (37.5%) subjects. Yqh- was the most frequent variant in sex chromosomes and increased length in heterochromatin and satellites were observed in autosomal chromosomes.

Interpretation & conclusion: The high rate of chromosomal anomalies among infertile men strongly suggests the need for routine cytogenetic analysis prior to employment of assisted reproduction techniques. In addition, meticulous follow-up of babies born after ICSI, especially male offsprings, is necessary.

Key words Chromosomal aberration - karyotyping - male infertility

Male factor infertility and recurrent miscarriages are distressing conditions that add to the psychological trauma of majority of the couples. Infertility affects about 15 per cent of all couples attempting pregnancy, with male-factor identified in approximately half the cases1.

Male factor infertility has been linked with numerous irregularities including sperm number, motility and morphology. It is a known fact that in a range of causes of male infertility, chromosomal aberrations occur in about 2-3 per cent of unselected patients with proven subfertility2. In patients with sperm counts below 10 x 10^sup 6^ spermatozoa/ml, the rate of chromosomal aberrations is estimated to be 5-7 per cent, with the percentage of cytogenetically abnormal cases increasing to 10-15 per cent in patients with azoospermia3.

The application of the advanced techniques of assisted reproduction, such as intracytoplasmic sperm injection (ICSI) is a boon to infertile couples for circumventing male factor infertility. With the use of this technique, even spermatozoa from men with extremely low sperm count, and with poor sperm motility and morphology can be successfully used to fertilize the oocyte allowing pregnancy rates close to those of natural conception4. The use of ICSI has raised concern regarding the potential risks associated with this technique5. Some of the genetic anomalies observed in children born after ICSI arise de novo without a predisposing parental chromosomal aberration6, others might be derived from a predisposing abnormality present in one of the parents7. It is worth mentioning that infertile men with azoospermia or severe oligozoospermia have a high occurrence of abnormal karyotypes compared to unselected male newborns3,8. Based on the increased incidence of chromosomal anomalies, cytogenetic analysis is widely recommended for male partners undergoing ICSI8.

We undertook this study to ascertain the occurrence of various chromosomal aberrations in the Indian males with abnormal semen parameters prior to ICSI treatment.

Material & Methods

Infertile men (n=88) were prospectively recruited for chromosomal analysis from April 2001 to October 2003 at Inkus IVF Centre, Mumbai. The patients were selected prior to ICSI treatment because of severe male-factor infertility and past history of infertility for more than two years. The mean age patients was 35.4 yr (range 26-50 yr). All of them underwent an andrological work-up, which included medical history, physical examination, hormonal estimation (excluding those with primary testicular failure), human immunodeficiency virus (HIV) testing and semen analysis according to World Health Organization recommendations and standards9. There were 42 men with non-obstructive azoospermia and 46 with oligozoospermia with a sperm count of 20x10^sup 6^/ml, progressive motility >50% and normal morphology >30%) and proven fertility were included as controls. None of them had any hisitory of childhood disease, environmental exposure, radiation exposure or prescription drug usage that could account for their infertility.

Informed consent was taken from the patients and donors prior to collection of heparinised blood samples. Chromosome investigations were performed on cultures of peripheral blood lymphocytes using standard techniques10. From each patient, 50 well-spread metaphases were analysed by G-banding. To characterize the polymorphisms, specific techniques such as C-banding and NOR staining were additionally applied. All chromosomal abnormalities have been reported in accordance with the current international standard nomenclature11. The Y/F index was calculated as Y/F= total length of the Y chromosome/average total length of the F group chromosomes (19 and 20). The Y chromosome belongs to the G group but its average total length is equivalent to the average total length of the F group chromosomes. Hence, the Y/F index was calculated to comparison to the F group. The average Y/F index for Y chromosome is defined as 0.95-1.09(12).

To screen for microdeletion in the AZF region of the Y chromosome by polymerase chain reaction (PCR), genomic DNA was prepared from the peripheral blood samples. Each man was analysed for the presence of sequence tagged sites (STS) in the AZFa, AZFb and AZFc regions. The STS probes used were sY84 and sY86 (AZFa), sY127 and sY134 (AZFb), sY254 and sY255 (AZFc), sY160 (heterochromatin) and SRY and ZFX/ZFY (controls). Female genomic DNA and DNA samples from fertile male were included as negative and positive controls respectively. In addition, a water sample that contains all reaction components but water instead of DNA was used for reagent contamination. The PCR products were separated on 2 per cent agarose gel stained with ethidium bromide and visualized using ultraviolet illumination. A PCR of the expected size was scored positive for the given STS, and scroed negative if no product was detectable after 3 successive PCR reactions.


Among the 88 infertile men studied, 9 showed some kind of constitutional chromosomal abnormality corresponding to a frequency of 10.2 per cent. The occurrence of chromosomal abnormality in the azoospermics and oligozoospermics was 14.3 per cent (6/42) and 6.5 per cent (3/46) respectively. Chromosomal variants were seen in 14 men with azoospermia and 19 with oligozoospermia, resulting in an occurrence of 37.5 per cent. A normal karyotype of 46,XY was observed in all the controls.

The type of chromosomal aberrations detected in the azoospermic and oligozoospermic men are given in Table I. Men with azoospermia underwent percutaneous epididymal sperm aspiration (PESA) or testicular sperm extraction (TESE). An absence or decreased sperm count (range 0- 4 million/ml) with reduced motility (range 6-12%) and morphology (normal form 2-10 %) was seen in these patients (Table I). The abnormalities observed in the two groups comprised of gonosomal aberrations (n=5) (Fig. 1, 3b, 3d), Robertsonian translocation (n=1) (Fig. 4a), trisomy 7 mosaicism (n=1), supernumerary marker chromosome (n=1) (Fig. 2) and deletion in chromosome 16 (n=1) (Fig. 4b).

Aberration in the heterochromatin region of the Y chromosome was the most frequently identified polymorphism in 27 (30.7%) infertile men. Among 3 (3.4%) men the Y/F index ratio was >1 (Fig. 3e) and in 24 (27.3%) males the Y chromosome was smaller than the G group chromosomes (Table II) (Fig.3c). The Y/F index ratio in the fertile controls was 0.9-1.09 (mean 0.96 ± 0.043). Besides, autosomal chromosome variants were observed in 6 (6.8%) infertile men (Tables I, II) (Figs 4c, 4d). Inversion of chromosome 9 is a polymorphism but was included in Table I for the sake of completeness. The heterochromatin area was increased in chromosomes 9 and 16. NOR staining of chromosome 22 showed it to be only satellite (22ps+). PCR analysis for the detection of AZF microdeletions showed deletion in the AZFc (sY254, sY255) region along with deletion of the heterochromatin (sY160) in only 1 male who presented with a karyotype of 46,X,delY(q11.2) on cytogenetic analysis. C banding in the same patient showed that the Y chromosome was not idic Yp. Y chromosome microdeletions were not observed in other men.

Among the 88 infertile men, the spouses of 64 undertooke the ICSI cycle. Fertilization rate and pregnancy rate were 57.8 and 15.6 per cent respectively.


Among numerous aetiologic factors, chromosomal abnormalities play a prime role in male infertility with abnormal semen parameters. Our results demonstrated an inverse correlation between chromosomal anomalies and sperm count. The exact mechanism by which chromosomal anomalies induce infertility is not clear. It is likely that the presence of abnormally distributed chromatin interferes with meiotic division and thus reduces sperm production. Spermatozoa bearing abnormal chromosomes may cause abnormal embryonic development, which can in turn, cause early pregnancy loss13.

The overall occurrence of 10.2 per cent constitutional abnormalities was observed in our study. The occurrence of karyotypic abnormalities among infertile men depends on a number of factors; the most important of these being the criterion for selection of patients based on the sperm counts. The frequency of chromosomal abnormalities ranged from 2.2 per cent in a non-selected group of males presenting with subfertility2 to 10.3 per cent in infertile males with a sperm count below 10 million/ml14. The presence of 14.2 per cent chromosomal anomalies in males with azoospermia and 6.5 per cent in men with oligozoospermia is within the range of 10-15 and 5-7 per cent respectively, as reported in literature3,15.

Sex chromosome abnormalities are the most frequent chromosome-related cause of infertility. In our study, we found one man with 47,XXY karyotype i.e., Klinefelter's syndrome. This abnormality is associated with severe spermatogenic failure causing a marked reduction in testicular size and azoospermia resulting in infertility13. A mosaic 46,XY/47,XYY/47,XXY karyotype was found in one azoospermic male. Infertile men with gonosomal mosaicism have a range of spermatogenic profile ranging from severe impairment to apparent normality16. Gonosomal mosaicism may be a probable cause for the failure of assisted reproduction17. A deletion in the long arm of the Y chromosome was seen in one patient. Studies have indicated that deletions on the long arm of the Y chromosome involving a particular and consistent segment might lead to azoospermia18 and sometimes to severe oligozoospermia19. There have been reports of vertical transmission of Yq deletions to the offspring via ICSI20. Two cases of inversion of Y chromosome were observed in our study. Pericentric inversion of Y chromosome is reported to be more prevalent among infertile men than in newborns21. A study on inversion of the Y chromosome in the Gujarati Muslim Indian population of South Africa failed to show any impairment in their reproductive fitness22.

A relationship between balanced autosomal translocation and infertility has been reported13. A single case of azoospermic male with Robertsonian translocation t(14;21) is reported in our study. An increased number of carriers of Robertsonian translocations has been reported among severely oligozoospermic and azoospermic men8. The testicular histology of such carriers shows a variable picture ranging from severe impairment to near normality2. Balanced translocations interfere with normal chromosome pairing and segregation at meiosis I, thus providing a potential for formation of unbalanced gametes and subsequent unbalanced abnormal offspring23. A unique finding observed in our study was the presence of deletion in chromosome 16q12.2 locus. Data published earlier point to the probable association of deletion in chromosome 16q with human neoplasias (including retinoblastoma, breast, ovarian, hepatic and prostatic cancers)24,25. However, we did not observe any of the above mentioned features in our case, indicative of a possible relation of such a deletion to subfertility. Further research in this direction is necessary.

Several reports on male infertility mention the presence of chromosomal variants or polymorphisms. The overall occurrence of chromosomal variants in the present study was 37.5 per cent. This was comparable with the one reported by Penna et al26 but was more than the occurrence cited in another study27.

Y chromosome polymorphisms have been preferentially seen in azoospermia and severe oligozoospermia8. 'Long Y chromosome' and 'short Y chromosome' are known to exist21. The variation in the length of Y chromosome is usually due to variation in the distal part of the long arm that is known to contain heterochromatin21. The occurrence of long Y (Yqh+) and short Y (Yqh-) was 3.4 and 27.3 per cent respectively, in our study. The presence of Yqh+ was quite similar to the frequency of 4.4 per cent reported in literature28. However, the occurrence of Yqh- was raised as compared to 1.6 per cent stated in a study3. Long Y chromosome has been seen to be associated with an increased risk of foetal loss29. However, another study21 did not show any relationship between the size of the Y chromosome and the risk of abortion. Genest and Genest30 reported that short Y chromosome does not seem to represent an increased risk of pregnancy loss. The contribution of Y chromosomal variants to alter the carrier's fertility is still a controversial topic and further studies are required to understand this.

In our study, autosomal polymorphisms were observed as increase in the centomeric heterochromatin in chromosomes 9 and 16 and as presence of satellites in acrocentric chromosome 22. Pericentric inversion of chromosome 9 was seen in one azoospermic patient. Although inversion 9 is included in the group of 'variant chromosomes', contradictory information is reported about its effect on reproductive fitness in males31.

We found one phenotypically normal male having a trisomy 7 with a frequency of aneuploid mitoses of 6 per cent in the lymphocytes. Few cases of trisomy 7 mosaicism with skin pigmentary variation and dysmorphism have been described32. Marker chromosome was observed in one male. It has been postulated that presence of an extra structurally abnormal chromosome might lead to reduced fertility in males due to meiotic arrest and instability that results in maturation arrest at spermatocyte stage23,33.

In conclusion, the occurrence (10.2%) of chromosomal anomalies among infertile men strongly suggests genetic testing and counselling prior to the ICSI treatment. Moreover, prenatal diagnosis in the case of abnormalities is of utmost importance. Such investigation is a pre-requisite to minimize the risk of propagation of chromosomal abnormalities into the next generation. Additionally, a thorough follow-up of babies conceived through ICSI, in particular the male progeny, is essential.


1. Bhasin S, de Kretser DM, Baker HW. Clinical review 64: Pathophysiology and natural history of male infertility. J Clin Endocrinol Metab 1994; 79 : 1525-9.

2. Chandley AC, Edmond P, Christie S, Gowans 1, Fletcher J, Frackiewicz A, et al. Cytogenetics and infertility in man. I. Karyotype and seminal analysis: results of a five-year survey of men attending a subfertility clinic. Ann Hum Genet 1975; 39 : 231-54.

3. Relief AE, Van Zyl JA, Menkveld R, Fox MR, Kotze GM, Brusnicky J. Chromosome studies in 496 infertile males with a sperm count below 10 million/ml. Hum Genet 1984; 66 : 162-4.

4. Van Steirteghem AC, Liu J, Joris H, Nagy Z, Janssenswillen C, Tournaye H, et al. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Hum Reprod 1993; 8 : 1055-60.

5. Engel W, Murphy D, Schmid M. Are there genetic risks associated with microassisted reproduction? Hum Reprod 1996; 11 : 2359-70.

6. van Opstal D, Los FJ, Ramlakhan S, van Hemel JO, van den Ouweland AM, Brandenburg H, et al. Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection. Hum Reprod 1997; 12 : 682-6.

7. Kremer JA, Tuerlings JH, Meuleman EJ, Schoute F, Mariman E, Smeets DF, et at. Microdeletions of the Y chromosome and intracytoplasmic sperm injection: from gene to clinic. Hum Reprod 1997; 12 : 687-91.

8. De Braekeleer M, Dao TN. Cytogenetic studies in male infertility; a review. Hum Reprod 1991; 6 : 245-50.

9. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge; Cambridge University Press; 1999.

10. Barch MJ, Knutsen T, Spurbeck JL, editors. The AGT cvtogenettcs laboratory manual. 3rd ed. Philadelphia: Lippincott-Raven; 1997.

11. Mitelman F, editor. ISCN 1995 - An international system for human cytogenetic nomenclature. Basel: S. Karger; 1995.

12. Verma RS, Dosik H, Scharf T, Lubs HA. Length heteromorphisms of fluorescent (f) and non-fluorescent (nf) segments of human Y chromosome; classification, frequencies, and incidence in normal Caucasians. J Med Genet 1978; 15 : 277-81.

13. Pandiyan N, Jequier AM. Mitotic chromosomal anomalies among 1210 infertile men. Hum Reprod 1996; 11 : 2604-8.

14. Bourrouillou G, Dastugue N, Colombies P. Chromosome studies in 952 infertile males with a sperm count below 10 million/ml. Hum Genet 1985; 71 : 366-7.

15. Peschka B, Leygraaf J, Van der Ven K, Montag M, Schartmann B, Schubert R, et al. Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection. Hum Reprod 1999; 14 : 2257-63.

16. Egozcue S, Blanco J, Vendrell JM, Garcia F, Veiga A, Aran B, et al. Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion. Hum Reprod Update 2000; 6 : 93-105.

17. Toncheva D, Ilieva P, Mavrudieva M. Detection of low-level sex-chromosomal mosaicism. Genet Couns 1994; 5 : 363-7.

18. Reijo R, Lee TY, Salo P, Alagappan R. Brown LG, Rosenberg M, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995; 10 : 383-93.

19. Reijo R, Alagappan RK, Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 1996; 347 : 1290-93.

20. Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu B, et al. Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions. Fenil Steril 2000; 74 : 909-15.

21. De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5 : 519-28.

22. Bernstein R, Wadee A, Rosendorff J, Wessels A, Jenkins T. Inverted Y chromosome polymorphism in the Gujarati Muslim Indian population of South Africa. Hum Genet 1986; 74 : 223-9.

23. Johnson MD. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility; recommendations for genetic counseling and screening. Fertil Steril 1998; 70 : 397-411.

24. Sheu JC, Lin YW, Chou HC, Huang GT, Lee HS. Lin YH, et al. Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan. Br J Cancer 1999; 80 : 468-76.

25. Yeung RS. Bell DW, Testa JR, Mayol X, Baldi A, Grana X, et al. The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19. Oncogene 1993; 8 : 3465-8.

26. Penna Videau S, Araujo H, Ballesta F, Ballesca JL, Vanrell JA. Chromosomal abnormalities and polymorphisms in infertile men. Arch Androl 2001; 46 : 205-10.

27. Micic M, Micic S, Diklic V. Chromosomal constitution of infertile men. Clin Genet 1984; 25 : 33-6.

28. Abramsson L, Beckman G, Duchek M, Nordenson I. Chromosomal aberrations and male infertility. J Urol 1982; 728 : 52-3.

29. Verp MS, Rzeszotarski MS, Martin AO, Simpson JL. Relationship between Y-chromosome length and first-trimester spontaneous abortions. Am J Obstet Gynecol 1983; 145 : 433-8.

30. Genest P, Genest FB. The influence of the length of the human Y chromosome on spontaneous abortions. A prospective study in family lines with inherited polymorphic Y chromosomes. Ann Genet 1985; 28 : 143-8.

31. Yamada K. Population studies of INV (9) chromosomes in 4,300 Japanese: incidence, sex difference and clinical significance. Jpn J Hum Genet 1992; 37 : 293-301.

32. Kayser M, Henderson LB, Kreutzman J, Schreck R, Graham JM Jr. Blaschkolinear skin pigmentary variation due to trisomy 7 mosaicism. Am J Med Genet 2000; 95 : 281-4.

33. Steinbach P, Djalali M, Hansmann I, Kattner E, Meisel-Stosiek M, Probeck HD, et al. The genetic significance of accessory bisatellited marker chromosomes. Hum Genet 1983; 65 : 155-64.

Punam Nagvenkar+*, Kundan Desai*, Indira Hinduja+* & Kusum Zaveri*

+ Research Department, Jaslok Hospital & Research Centre & * Inkus IVF Centre, Mumbai, India

Received March 23, 2004

Reprint requests: Dr Indira Hinduja, Inkus IVF Centre, Mehta Bhavan 311, Charni Road, Mumbai 400004, India


Copyright Indian Council of Medical Research Jul 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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