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Biomedical Research

Vanishing Testis Syndrome in a 46 XY Male

Author(s): J.E. Waghmare, P.D. Kamble, S.K. Kale, A.K. Pal

Vol. 22, No. 2 (2011-04 - 2011-06)

J.E. Waghmare1, P.D. Kamble2, S.K. Kale3, A.K. Pal 4

(1) Department of Anatomy, MGIMS, Sevagram, India
(2) Department of Biochemistry, MGIMS, Sevagram, India
(3) Department of Radiology, MGIMS, Sevagram, India
(4) Department of Anatomy, MGIMS, Sevagram. India

Abstract

A 30 years old male patient with bilateral anorchia, feminine hair pattern on the body and longer lower body segment than the upper body segment reported Surgery OPD with a com-plaint of gynecomastia. Suspecting a patient of Klinefelter’s syndrome he was referred for karyotyping. His Follicle stimulating hormone (FSH) and Leutinizing hormone (LH) levels were eleveted while testosterone level was below normal. Chromosomal analysis confirmed he is having normal male karyotype, i.e. 46, XY. Absence of testis in 46 XY male with normal penis indicates that testis were functioning in the early weeks of embryogenesis and had van-ished afterwards. Relevance of bilateral anorchia with normal penis and gynecomastia has been discussed in relation to embryogenesis.

Key words: Gonad, Anorchia, Vanishing testis, Chromosome
Accepted December 27 2011

Introduction

Sex determination and differentiation are sequential proc-esses that involve successive establishment of genetic sex at the moment of conception, determination of gonadal sex by the genetic sex and regulation by the gonadal sex of the differentiation of the genital apparatus and hence the phenotypic sex. Sex determination is concerned with control of the development of the primary or gonadal sex and sex differentiation encompasses the events subse-quent to gonadal organogenesis.

Development of the male gonads is a very interesting and balanced play of the genetic, endocrinal and vascular sys-tems. The successful and complete development of go-nads depends on the appropriate functioning of the above mentioned systems. The undifferentiated genital ridge of the embryo in the presence of ‘SRY’ gene on the ‘Y’ chromosome develops as the testis [1]. Initially the testis are abdominal organs later they descents in the bottom of scrotum at the end of 9th month of intrauterine life by tra-versing the inguinal canal [2]. During the descent if there is any torsion of testis, it may cause vascular insult and consequently the testis atrophies and disappear leading to a condition called as ‘vanishing testis syndrome’ [3].

Clinical Report

A 30 yrs old male patient reported surgical OPD with a complaint of gynecomastia. On physical examination it was found that he had (i) Both the scrotal sacs were emp-ty (Fig.1A), (ii) Gynecomastia (Fig.1B), (iii) The penis was normal(Fig.1B), (iv) Body hair pattern was femi-nine(Fig.1B), (v) Length of the lower body segment was distinctly longer than upper segment (Fig.1B).

Suspecting a patient of Klinefelter’s syndrome he was referred to our cytogenetic lab for karyotyping.

Investigations

  1. Radiological: On sonography it was found that the pa-tient had bilateral anorchia and not cryptorchidism. His Prostate and seminal vesicle were normal, vas deference was also atrophied. Rests of the abdominal and pelvic organs were normal.
  2. Hormonal: Hormonal evaluation was done by the ra-dioimmunoassay method. (Table: 1)
  3. Semen analysis: Semen analysis was done following the WHO laboratory manual for the examination of human semen [4]. It was found that the subject had asper-mia.
  4. Chromosomal analysis: By in vitro lymphocyte culture method the chromosomal analysis was done [5]. 50 G-banded metaphases were analysed. The patient had nor-mal male karyotype i.e. 46, XY. (Fig. 2)

Table 1: Different hormonal levels of the subject with testicular vanishing syndrome.

Sr. No. Hormone Result Normal values
in adult male
1 Anti mullerian hormone Undetectable 3.0-5.4 ng/ml
2 Testosterone 7.76 ng/dl 241-827 ng/dl
3 Estrogen (E 2) 5 pg/ml 7.63-42.6pg/ml
4 Follicle stimulating hormone 85.54 mIU/ml 1.4-18.1mIU/ml
5 Leutinizing hormone 41.15 mIU/ml 3.1-34.6 mIU/ml

Fig's 1A & 1B

Figure 1A: Photograph showing empty scrotum (Bilateral anorchia). Figure 1B: A male with gynecomastia, normal penis and feminine body hair pattern.

Fig 2

Figure 2: Karyotype: 46, XY.

Discussion

Vanishing testis syndrome is a very uncommon type of testicular abnormality.Various terms (XY gonadal dys-genesis, rudimentary testis syndrome, congenital anor-chia, and vanishing testis syndrome) have been used to describe the spectrum of genital anomalies resulting from cessation of testicular function during the middle phase of male sex differentiation i.e. between 8 to14 weeks of ges-tation [2]. At one end of the spectrum is the group of (46, XY) individuals with female external and internal genita-lia in whom the deficiency of the testicular function pre-sumably occurred before 8th week of gestation [6]. These individuals have either no gonads or streak gonads. Loss of function of fetal testis at 8 to 10 weeks of gestation would lead to ambiguous genitalia and variable develop-ment of genital ducts, from complete absence of both mullerian and wolffian ducts to partial development of either [7]. Loss of testicular function after the critical phase of male differentiation (12 to 14 weeks) results in testicular vanishing syndrome, characterized by normal male differentiation both internally and externally with absence of gonadal tissue [8]. Presence of normal male genitalia and absence of the mullerian duct derivatives implies that the testicular function was normal before 14th week of gestation [8].

The testis develops in the abdomen from the genital ridge at the 8th week of the gestational age under the influence of ‘SRY’ gene on the short arm of the ‘Y’ chromosome. If there is any mutation in ‘SRY’ gene of the ‘Y’ chromo-some, there will be ‘46, XY pure gonadal dysgenesis’ in which gonads will be seen as bilateral streak gonads and the phenotype will be feminine [9]. Testis descent in the scrotum at the end of 9th month of intrauterine life. Insulin like 3 (INSL3) and Leucine rich repeat containing G pro-tein coupled receptor 8 (LGR8) genes on the ‘Y’ chromo-some regulate the descent of testis. If the testis fails to reach in the scrotum at birth, it is called as cryptorchidism [9]. Mutation has been reported in INSL3 and LGR8 genes in a few of the patients with cryptorchidism [9]. Further the cryptorchid testis are more prone for torsion, and torsion of the testis during descent may lead to kink-ing or blockage of the vessels supplying the gonad, which might causes atrophy and degeneration of the gonads [3,9,10]. There is no known reason which explains why the testis does vanish; it could be either genetic, environ-mental or a vascular event [3,9].

As testicular function becomes impaired, testicular secre-tion of both the testosterone and estrogen decreases [8]. Lower testosterone level with intact hypothalamus causes marked rise in LH and FSH levels above the normal by stimulating the pituitary gland with negative feed back mechanism[9,11,12]. Estrogen in a male with anorchia is almost exclusively derived from extra glandular acromati-zation of adrenal androgens. At this point estrogen forma-tion although low, it is relatively high to that of testoster-one and thus reversing the androgen: estrogen ratio, which causes gynecomastia in male [8]. In this clinical report we have also observed the increased levels of FSH and LH, reversed androgen: estrogen ratio, which might have developed gynecomastia in the subject.

Inadequate leydig cell function or androgen action during embryogenesis may manifest itself by the presence of hypospadiasis, cryptorchidism or microphallus. If leydig cell failure occurs before puberty, sexual maturation will not occur. There will be poor development of skeletal muscles, failure of closure of epiphyses so that lower body segment is markedly longer than upper body seg-ment and infantile distribution of body hairs [13]. The number of hairs per unit area of skin is determined by genetic factors and is same for both sexes of a similar ethnic group [14]. In both men and women, hair follicles cover the body except for lips, palms of hand and soles of feet. In males testosterone is responsible for characteristic hair growth at puberty which involves development of the mustache and beard; regression of scalp line, appearance of truncal, extremity and perianal hairs, and extension of the pubic hair upward into a diamond shaped pattern [14]. Testosterone stimulates hair growth in males while estro-gen inhibits it in females [14]. It seems that in the vanish-ing testis syndrome, the disturbed androgen: estrogen ra-tio gives a feminine hair pattern.

In the clinical report we are presenting; as the anti mulle-rian hormone level was undetectable, it indicates that the patient does not have any testicular tissue and confirms bilateral anorchism [9]. Since the external and internal genitalia are well developed and there is no remnant of the mullerian duct derivatives, testes had secreted the AMH and were functioning in the early weeks and it had vanished after 14th weeks of gestation. It seems that van-ishing testis syndrome arises due to the disturbance in the unknown genetic pathways and vascular abnormality in post embryonic but early fetal life. Other somatic changes like abnormal body stature, female hair pattern and gyne-comastia are due to the abnormal hormonal profile be-cause of agonadal condition. The torsion of testis causing vascular occlusion and vanishing of testes itself might be due to some unknown mutation in the either INSL3 or LGR8 genes responsible for the descent of the testis. There is no known genetic reason explaining the etiology of vanishing testis syndrome but we believe it needs fur-ther study to reveal the condition.

References

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  2. Sadler TW. Urogenital system. In: Langman’s medical embryology. 11th ed. Lippincott Williams & Wilkins; 2009: 235-263.
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  4. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 4th ed. Cambridge: Cambridge University Press.1999: 1-86.
  5. Ambulkar PS, Ghosh SK, Pal AK. Genotoxic and cyto-toxic effects of antibacterial drug, ciprofloxacin, on hu-man lymphocytes in vitro. Nepal Med Coll J 2009; 11(3): 147-151.
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  7. Edwan CD, Winters A, Porter J, et.al. Embryonic tes-ticular regression: A clinical spectrum of XY agonadal individuals. Obstet Gynecol 1977; 49: 208-217.
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  9. Giovanna V, Marie-Noelle A, Christine T, et.al. An analysis of the genetic factors involved in testicular de-scent in a cohort of 14 male patients with anorchia. J Clin Endocrinol Metab 2004; 89 (12): 6282-6285.
  10. Belman AB, Rushton HG. Is the vanished testis always a scrotal event? BJU 2001; 87: 480-483.
  11. Hirsch HJ, Eldar-Geva T, Benarroch F, et.al. Primary testicular dysfunction is a major contributor to abnormal pubertal development in males with prader-willi syn-drome. J Clin Endocrinol Metab 2009; 94 (7): 2262-2268.
  12. Ramesh S, Sadhnani MD, Swarna M, et.al. Evaluation of FSH, LH and testosterone levels in different sub-groups of infertile males. Indian Journal of Clinical Bio-chemistry 2004; 19(1): 45-49.
  13. Carr BR. Disorders of the ovaries and female reproduc-tive tract. In: Wilson J, Foster D, Kronberg H, Laresn P (eds). Williams textbook of endocrinology. 9th ed. W.B.Saunders compony; 1998: 751-817.
  14. Uno H. Biology of hair growth. Semin Reprod Endocri nol 1986; 4: 131-141.

Correspondence to:
A.K. PAL

Department of Anatomy
Mahatma Gandhi Institute of Medical sciences
Sevagram 442102, Wardha (Maharashtra), India

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