Germ Cell Tumours III (eBook)

Proceedings of the Third Germ Cell Tumour Conference Held in Leeds, UK, on 8th-10th September 1993

I. Appleyard, P. Harnden, W.G. Jones (Herausgeber)

eBook Download: PDF | EPUB

2013 | 1. Auflage
480 Seiten
Elsevier Science (Verlag)
978-1-4832-7838-4 (ISBN)

Infos

Advances in the Biosciences, Volume 91: Germ Cell Tumours III documents the proceedings of the Third Germ Cell Tumor Conference held in Leeds, UK on September 8-10, 1993. This book focuses on germ cell tumors, which can be cancerous or non-cancerous tumors that normally occur inside the gonads. The topics discussed include the embryological mechanisms of maldescent and tumorigenesis; epidemiology of cryptorchidism; simultaneous bilateral testicular tumors; and mediastinal germ cell tumors. The classification of germ cell tumors; role of positron emission tomography in the assessment of germ cell tumors; chemotherapy of seminoma; and prognostic factors in disseminated non-seminomatous testicular cancer are also elaborated in this text. This publication is intended for medical students and individuals interested in germ cell tumors.

Textauszug

Embryological Mechanisms of Maldescent and Tumourigenesis

John M. Hutson, Marilyn L. Baker, Masaru Terada, Baiyun Zhou and Georgia Paxton,     Surgical Research Unit, Royal Children’s Hospital, Research Foundation, Melbourne, Victoria, Australia, 3052

ABSTRACT

Testicular descent occurs in two stages with separate morphology and hormonal control. The key structure in mediating descent is the gubernaculum, which enlarges in the first phase to anchor the testes near the inguinal regions as the embryo enlarges. In the second phase, the gubernaculum migrates from the inguinal region to the scrotum. Non-androgenic hormones control the first phase, with conflicting evidence about whether Müllerian inhibiting substance (MIS) is the active agent. Testosterone controls the second phase, apparently indirectly via the nervous system. Calcitonin gene-related peptide (CGRP) has been identified recently within the gentofemoral nerve and has been postulated to act as a final common pathway for androgenic control of descent. Animal models of undescended testes, including the androgen resistant mouse, the TS rat, and the flutamide-treated rat all have an absence or deficiency of gubernacular migration and abnormality of CGRP.

These studies suggest that undescended testes may be caused by physiological or anatomical abnormalities of the gentofemoral nerve. The commonest cause of maldescent would appear to be failure of gubernacular migration, leaving the testes in the groin or so- called “superficial inguinal pouch”.

The abnormally high temperature of the undescended testes leads to deficiencies in postnatal secretion of testosterone and MIS. In addition, germ cell maturation from fetal gonocyte to type A spermatogonium is significantly inhibited. Gonocytes which fail to undergo this transformation either die off leading to infertility, or develop signs of dysplasia, eg. carcinoma-in-situ.

At present, it is not proven in humans that early surgery can prevent these hormonal and anatomical changes. However, animal experiments strongly support the view that early surgery, prior to these changes occurring, can prevent their development.

Introduction

The gubernaculum, or genitoinguinal ligament, enlarges in the male fetus between 10 and 15 weeks. The enlarged gubernaculum holds the testis near the future inguinal canal as the embryo enlarges. By contrast, failure of the homologous structure in the female to enlarge allows the ovary to ascend with the kidney, as seen in rodents, or to remain near the enlarging uterus, as seen in humans. The difference between the ovarian position in rodents and humans is probably related to the greater fusion of the Müllerian ducts in humans to form a solid uterus, thereby preventing further ovarian ascent. In either mammalian species, the long attenuated female gubernaculum is unable to anchor the ovary near the inguinal region and is preserved postnatally as two separate parts known as the ligament of the ovary and the round ligament.

The second phase, or inguinoscrotal descent, begins at 26–28 weeks of gestation, when the gubernaculum begins to migrate from the future inguinal canal towards the scrotum. A peritoneal diverticulum known as the processus vaginalis develops within the gubernaculum, allowing the testes to descend intra-peritoneally. By 35 weeks of gestation the gubernaculum has reached the scrotum and the testis arrives shortly after. Standard anatomical textbooks describe a gubernaculum attached to the bottom of the scrotum, but this is not the case until after descent is complete. Migration from the groin to the scrotum is a precarious journey of 3-5 cms for a gubernaculum which is only 1 cm in diameter. The gubernaculum after enlargement becomes gelatinous and mucoid at its distal end, and its proximal end is hollowed out by the processus vaginalis. The mucoid caudal end of the gubernaculum remains palpable until descent is complete, and then reabsorption of the extracellular matrix molecules causes it to regress. The postnatal gubernaculum is usually made up of fibrous attachments of the caudal epididyMIS and testis to the bottom of the processus vaginalis and adjacent scrotal subcutaneous tissue.

Hormonal Control

At one time it was believed that testicular descent was controlled by androgens from the fetal testis under maternal or chorionic gonadotrophin stimulation. In 1932, Engle (1) showed that the testis of immature Macaque monkeys were stimulated to descend with extracts from the anterior pituitary gland and with pregnancy urine. Since that time, cryptorchidism has been treated in many parts of the world with hCG and/or LHRH (2, 3). Although there are numerous clinical descriptions of abnormalities of the hypothalamic-pituitary-testicular axis which cause cryptorchidism, the role of androgens in controlling testicular descent has been controversial. This is because many natural mutants and experimental studies showed that the effect of androgen was absent or only partial. In particular, the second or inguinoscrotal phase of descent is absent in androgen resistant mice and humans (4). Furthermore, inguinoscrotal descent is absent in the hypogonadal mouse (5). Prenatal treatment with flutamide, which is an antiandrogen, also blocks the inguinoscrotal phase of descent (6, 7). Although the postnatal or inguinoscrotal phase of descent is blocked in the rat by flutamide, the flutamide only works when given prenatally. By contrast, no androgenic effects on descent of the testis could be observed in the fetus (8, 9). Also, androgens failed to produce the swelling reaction in the gubernaculum (8), and pituitary disconnection also failed to stop gubernacular swelling (10).

The apparent contradictions in the results of studies of androgens have been reconciled by the hypothesis that testicular descent occurs in two separate steps under independent hormonal control (11).

The first phase of testicular descent in mice can be inhibited by administering exogenous oestrogens to the pregnant dams, and this treatment also causes retention of the Müllerian ducts (5, 12). In addition, in the persistent Müllerian duct syndrome where there is a genetic defect in the synthesis of MIS or its receptor, the swelling reaction of the gubernaculum is absent in association with high intraabdominal testis and retained Müllerian ducts (13, 14). Both the oestrogen-injected mouse and the human with a mutation in the MIS gene provide evidence for an important role for this testicular hormone. However, there is some experimental evidence against a role for MIS, including the fact that immunisation of pregnant rabbits against purified MIS failed to stop testicular descent (15). Also, purified MIS did not stimulate fetal pig gubernacular fibroblasts in vitro (16).

The mechanism by which androgens control the second or inguinoscrotal phase of descent has remained obscure (17). The mechanism whereby the gubernaculum migrates from the inguinal region to the scrotum is also not understood. Although the gubernaculum was thought to be the primary target for androgens, measurement of significant numbers of androgen receptors has been controversial (18–20). A clue to an alternative site for androgen action was revealed by a study done by Lewis (21), where the gentofemoral nerve was transected in neonatal rats. This caused undescended testes which Lewis interpreted as evidence for a role by the cremaster muscle. Recently, we repeated this study and found a similar result (22). We went on to investigate the possibility that the primary action of androgen may be indirect on the gubernaculum via the central nervous system and the gentofemoral nerve. Careful study of gubernacular migration in the rodent postnatally showed that nerve transection inhibited migration (23). Looking at children with spina bifida in the high lumbar region where the gentofemoral nerve arises, we found 36% cryptorchidism (24). More importantly, when we did retrograde labelling of the gentofemoral nerve motor neurons, we found that the motor nucleus in the anterior horn is sexually dimorphic. Also, we found that the neonatal male gentofemoral nerve contains a much higher content of calcitonin gene-related peptide (CGRP) than the female equivalent (25).

In recent years we have investigated the possible role of CGRP in mediating gubernacular migration and testicular descent. CGRP receptors were identified within the cremaster muscle within the gubernaculum, (26). Also, in organ culture CGRP was found to induce rapid rhythmic contraction of the gubernacular cremaster muscle in both the rat (27) and the mouse (28) (Table 1).

Table 1

Evidence for CGRP having a role in gubernacular migration

Undescended Testis

We have looked at three rodent models of undescended testis to see if there is an abnormality of the gentofemoral nerve and/or CGRP. (Table 2). These studies show that the androgen resistant or deficient rodent has decreased CGRP in the nerve and decreased gubernacular contractions, accompanied by increased sensitivity to exogenous CGRP. By contrast, the mutant (TS) rat has excess CGRP in the gentofemoral nerve accompanied by decreased sensitivity of the...

Produkt-Details

• Erscheint lt. Verlag: 22.10.2013
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie ► Krankheiten / Heilverfahren
• Themenwelt: Medizin / Pharmazie ► Allgemeines / Lexika
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Pathologie
• Themenwelt: Studium ► Querschnittsbereiche ► Epidemiologie / Med. Biometrie
• ISBN-10: 1-4832-7838-7 / 1483278387
• ISBN-13: 978-1-4832-7838-4 / 9781483278384