206:
181:
198:
189:
of testosterone can result in incomplete masculinisation, whilst reduced expression of insulin-like factor 3 can lead to incomplete testes descent. The downstream disorders of such abnormalities can include both genital malformations (e.g. hypospadias and cryptorchidism) and delayed reproductive disorders (e.g. testicular cancer and poor semen quality) which comprise TDS.
146:(male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like
252:
108:. The concept was first introduced by N.E. Skakkebæk in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.
22:
129:(GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a 'risk factor network' that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in
291:
The diagnosis is confirmed in different ways. An ultrasound scan can be used to diagnose to a 90-95% accuracy. Bloods can also be taken to look for elevated tumour markers which is also used to analyse the patient's response to treatment. 80% of testicular cancer cases are from the 20-34 year old age
231:
a diagnosis is made from a physical examination which is performed when the baby is lacking one or both testes in the dependant portion of the scrotal sac. 70% of cryptorchid testes can be felt and are unable to be pulled into the scrotum or retreats quickly after being pulled into a higher position.
188:
The TDS hypothesis proposes that testicular dysgenesis, which has various primary causes, can lead to abnormalities in
Sertoli and/or Leydig cell function. This leads to both impaired germ cell development and hormonal changes during male sexual differentiation. For instance, insufficient production
158:
differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be
263:
is measured not only by the number of sperm a man produces but also by how effective the sperm is at fertilising an egg. The motility and shape of the sperm are important for this role. A man with poor semen quality will often present with fertility problems which is defined as a couple trying to
218:
Hypospadias presents as an abnormal location for the end of the urethra which is typically found on the distal end of the penis. It is generally diagnosed at birth from visual confirmation of the hallmark features. As well as an unusual location of the urethra, the prepuce (foreskin) is typically
171:
Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders
116:
Central to the cause of irreversible TDS are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with TDS in the last decades indicates that it is under a powerful
133:
genes are highly implicated, as these are involved in penile development, testes descent, and testes development. Testicular germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function.
159:
present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via
276:
The most common presentation of testicular cancer is a hard, painless lump which can be felt on one of the testis. It is either noticed by a clinician during a routine examination, or the patient themselves. Risk factors for TC include:
654:
Gill, W. B.; Schumacher, G. F.; Bibbo, M.; Straus, F. H.; Schoenberg, H. W. (1979-07-01). "Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities".
117:
environmental influence. The fetal origins of TDS are reinforced by the high incidence of TDS disorders found occurring together in one individual. Associated with mutation of
Insulin like Factor 3 (INSL3)
548:
Skakkebaek, Niels E.; Meyts, Ewa
Rajpert-De; Louis, Germaine M. Buck; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H. (2016-01-01).
150:(DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects
747:
Skakkebæk, Niels E.; Meyts, Ewa
Rajpert-De; Louis, Germaine M. Buck; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H. (2016-01-01).
358:
VIRTANEN, H; RAJPERTDEMEYTS, E; MAIN, K; SKAKKEBÆK, N; TOPPARI, J (1 September 2005). "Testicular dysgenesis syndrome and the development and occurrence of male reproductive disorders".
40:
172:
encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons.
894:
Bay, Katrine; Asklund, Camilla; Skakkebæk, Niels E.; Andersson, Anna-Maria (2006-03-01). "Testicular dysgenesis syndrome: possible role of endocrine disrupters".
205:
219:
incomplete as well. The abnormal 'hooded' prepuce is what often draws attention to the condition but can occur separately to hypospadias.
393:
Toppari, J; Larsen, J C; Christiansen, P; Giwercman, A; Grandjean, P; Guillette, L J; Jégou, B; Jensen, T K; Jouannet, P (1996-08-01).
58:
929:
943:
232:
In 30% of cases the testes cannot be felt indicating an intra-abdominal location. The risk factors for cryptorchidism are:
163:
mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS.
126:
142:
Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of
1032:
806:"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion"
700:"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion"
501:"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion"
311:"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion"
452:"Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization"
450:
Ferlin, A.; Bogatcheva, N. V.; Gianesello, L.; Pepe, A.; Vinanzi, C.; Agoulnik, A. I.; Foresta, C. (June 2006).
607:"Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects"
268:, taking a sample of the man's semen and running tests to count numbers and quality of the individual sperm.
184:
Schematic diagram illustrating the pathogenic links that lead to TDS. CIS = carcinoma in situ; GC = Germ Cell
96:
is a male reproduction-related condition characterized by the presence of symptoms and disorders such as
749:"Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility"
550:"Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility"
1037:
147:
957:
971:
1008:
911:
876:
835:
827:
786:
768:
729:
721:
680:
672:
636:
628:
587:
569:
530:
522:
481:
473:
432:
414:
375:
340:
332:
130:
105:
82:
998:
903:
866:
817:
776:
760:
711:
664:
618:
577:
561:
512:
463:
422:
406:
367:
322:
855:"Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects"
781:
748:
582:
549:
427:
394:
265:
228:
101:
668:
180:
1026:
871:
854:
260:
805:
699:
606:
500:
310:
151:
160:
155:
97:
907:
764:
565:
371:
822:
716:
517:
327:
1003:
986:
831:
772:
725:
676:
632:
573:
526:
477:
418:
336:
623:
468:
451:
197:
1012:
915:
880:
839:
790:
733:
640:
591:
534:
485:
410:
379:
344:
251:
436:
143:
684:
264:
conceive for over 1 year with no success. Diagnosis can be made from
896:
Best
Practice & Research Clinical Endocrinology & Metabolism
804:
Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01).
698:
Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01).
499:
Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01).
309:
Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01).
179:
985:
Jemal, A; Siegel, R; Ward, E; Murray, T; Xu, J; Thun, MJ (2007).
125:
Many genes have been implicated in the disorders of TDS, with
15:
395:"Male reproductive health and environmental xenoestrogens"
36:
930:"BMJ Best Practice: Anatomical Penile Abnormalities"
81:
76:
31:
may be too technical for most readers to understand
853:Sharpe, Richard M.; Skakkebæk, Niels E. (2008).
209:Cryptorchidism - Can see one missing testicle
8:
73:
1002:
870:
821:
780:
715:
622:
581:
516:
467:
426:
326:
59:Learn how and when to remove this message
43:, without removing the technical details.
250:
204:
196:
301:
972:"BMJ Best Practice: Testicular Cancer"
958:"NHS Choices: Infertility - Diagnosis"
255:Human sperm stained for semen analysis
41:make it understandable to non-experts
7:
605:Meyts, Ewa Rajpert-De (2006-05-01).
991:CA: A Cancer Journal for Clinicians
944:"BMJ Best Practice: Cryptorchidism"
360:Toxicology and Applied Pharmacology
14:
399:Environmental Health Perspectives
236:A family history of the condition
872:10.1016/j.fertnstert.2007.12.026
20:
127:genome wide association studies
94:Testicular dysgenesis syndrome
77:Testicular dysgenesis syndrome
1:
669:10.1016/s0022-5347(17)56240-0
456:Molecular Human Reproduction
1054:
908:10.1016/j.beem.2005.09.004
765:10.1152/physrev.00017.2015
566:10.1152/physrev.00017.2015
372:10.1016/j.taap.2005.01.058
287:Previous testicular cancer
104:, poor semen quality, and
987:"Cancer Statistics, 2007"
611:Human Reproduction Update
1004:10.3322/canjclin.57.1.43
898:. Endocrine Disrupters.
859:Fertility and Sterility
823:10.1093/humrep/16.5.972
717:10.1093/humrep/16.5.972
518:10.1093/humrep/16.5.972
328:10.1093/humrep/16.5.972
657:The Journal of Urology
411:10.1289/ehp.96104s4741
256:
210:
202:
185:
753:Physiological Reviews
624:10.1093/humupd/dmk006
554:Physiological Reviews
469:10.1093/molehr/gal043
254:
208:
200:
183:
405:(Suppl 4): 741–803.
1033:Testicle disorders
810:Human Reproduction
704:Human Reproduction
505:Human Reproduction
315:Human Reproduction
257:
247:Poor semen quality
211:
203:
186:
148:diethylstilbestrol
272:Testicular cancer
131:androgen receptor
106:testicular cancer
91:
90:
71:Medical condition
69:
68:
61:
1045:
1017:
1016:
1006:
982:
976:
975:
968:
962:
961:
954:
948:
947:
940:
934:
933:
926:
920:
919:
891:
885:
884:
874:
850:
844:
843:
825:
801:
795:
794:
784:
744:
738:
737:
719:
695:
689:
688:
651:
645:
644:
626:
602:
596:
595:
585:
545:
539:
538:
520:
496:
490:
489:
471:
447:
441:
440:
430:
390:
384:
383:
355:
349:
348:
330:
306:
239:Low birth weight
74:
64:
57:
53:
50:
44:
24:
23:
16:
1053:
1052:
1048:
1047:
1046:
1044:
1043:
1042:
1023:
1022:
1021:
1020:
984:
983:
979:
970:
969:
965:
956:
955:
951:
942:
941:
937:
928:
927:
923:
893:
892:
888:
852:
851:
847:
803:
802:
798:
746:
745:
741:
697:
696:
692:
653:
652:
648:
604:
603:
599:
547:
546:
542:
498:
497:
493:
449:
448:
444:
392:
391:
387:
357:
356:
352:
308:
307:
303:
298:
274:
249:
225:
216:
195:
178:
169:
140:
123:
114:
72:
65:
54:
48:
45:
37:help improve it
34:
25:
21:
12:
11:
5:
1051:
1049:
1041:
1040:
1035:
1025:
1024:
1019:
1018:
977:
963:
949:
935:
921:
886:
865:(2): e33–e38.
845:
816:(5): 972–978.
796:
739:
710:(5): 972–978.
690:
646:
617:(3): 303–323.
597:
540:
511:(5): 972–978.
491:
462:(6): 401–406.
442:
385:
366:(2): 501–505.
350:
321:(5): 972–978.
300:
299:
297:
294:
289:
288:
285:
284:Family history
282:
281:Cryptorchidism
273:
270:
266:semen analysis
248:
245:
244:
243:
240:
237:
229:cryptorchidism
224:
223:Cryptorchidism
221:
215:
212:
194:
191:
177:
174:
168:
165:
139:
136:
122:
119:
113:
110:
102:cryptorchidism
89:
88:
85:
79:
78:
70:
67:
66:
28:
26:
19:
13:
10:
9:
6:
4:
3:
2:
1050:
1039:
1036:
1034:
1031:
1030:
1028:
1014:
1010:
1005:
1000:
996:
992:
988:
981:
978:
973:
967:
964:
960:. 2017-10-23.
959:
953:
950:
945:
939:
936:
931:
925:
922:
917:
913:
909:
905:
901:
897:
890:
887:
882:
878:
873:
868:
864:
860:
856:
849:
846:
841:
837:
833:
829:
824:
819:
815:
811:
807:
800:
797:
792:
788:
783:
778:
774:
770:
766:
762:
758:
754:
750:
743:
740:
735:
731:
727:
723:
718:
713:
709:
705:
701:
694:
691:
686:
682:
678:
674:
670:
666:
662:
658:
650:
647:
642:
638:
634:
630:
625:
620:
616:
612:
608:
601:
598:
593:
589:
584:
579:
575:
571:
567:
563:
559:
555:
551:
544:
541:
536:
532:
528:
524:
519:
514:
510:
506:
502:
495:
492:
487:
483:
479:
475:
470:
465:
461:
457:
453:
446:
443:
438:
434:
429:
424:
420:
416:
412:
408:
404:
400:
396:
389:
386:
381:
377:
373:
369:
365:
361:
354:
351:
346:
342:
338:
334:
329:
324:
320:
316:
312:
305:
302:
295:
293:
286:
283:
280:
279:
278:
271:
269:
267:
262:
261:semen quality
253:
246:
241:
238:
235:
234:
233:
230:
222:
220:
213:
207:
199:
192:
190:
182:
175:
173:
166:
164:
162:
157:
153:
149:
145:
138:Environmental
137:
135:
132:
128:
120:
118:
111:
109:
107:
103:
99:
95:
86:
84:
80:
75:
63:
60:
52:
42:
38:
32:
29:This article
27:
18:
17:
997:(1): 43–66.
994:
990:
980:
966:
952:
938:
924:
902:(1): 77–90.
899:
895:
889:
862:
858:
848:
813:
809:
799:
759:(1): 55–97.
756:
752:
742:
707:
703:
693:
663:(1): 36–39.
660:
656:
649:
614:
610:
600:
560:(1): 55–97.
557:
553:
543:
508:
504:
494:
459:
455:
445:
402:
398:
388:
363:
359:
353:
318:
314:
304:
290:
275:
258:
226:
217:
187:
176:Pathogenesis
170:
141:
124:
115:
93:
92:
55:
49:January 2017
46:
30:
242:Prematurity
214:Hypospadias
201:Hypospadias
156:Leydig cell
98:hypospadias
1027:Categories
296:References
161:epigenetic
1038:Syndromes
832:0268-1161
773:0031-9333
726:0268-1161
677:0022-5347
633:1355-4786
574:0031-9333
527:0268-1161
478:1360-9947
419:0091-6765
337:0268-1161
193:Diagnosis
167:Lifestyle
144:androgens
83:Specialty
1013:17237035
916:16522521
881:18308057
840:11331648
791:26582516
734:11331648
641:16540528
592:26582516
535:11331648
486:16687567
380:16005920
345:11331648
782:4698396
583:4698396
437:8880001
428:1469672
152:Sertoli
121:Genetic
87:Urology
35:Please
1011:
914:
879:
838:
830:
789:
779:
771:
732:
724:
683:
675:
639:
631:
590:
580:
572:
533:
525:
484:
476:
435:
425:
417:
378:
343:
335:
292:range
112:Causes
685:37351
259:Poor
1009:PMID
912:PMID
877:PMID
836:PMID
828:ISSN
787:PMID
769:ISSN
730:PMID
722:ISSN
681:PMID
673:ISSN
637:PMID
629:ISSN
588:PMID
570:ISSN
531:PMID
523:ISSN
482:PMID
474:ISSN
433:PMID
415:ISSN
376:PMID
341:PMID
333:ISSN
154:and
999:doi
904:doi
867:doi
818:doi
777:PMC
761:doi
712:doi
665:doi
661:122
619:doi
578:PMC
562:doi
513:doi
464:doi
423:PMC
407:doi
403:104
368:doi
364:207
323:doi
227:In
39:to
1029::
1007:.
995:57
993:.
989:.
910:.
900:20
875:.
863:89
861:.
857:.
834:.
826:.
814:16
812:.
808:.
785:.
775:.
767:.
757:96
755:.
751:.
728:.
720:.
708:16
706:.
702:.
679:.
671:.
659:.
635:.
627:.
615:12
613:.
609:.
586:.
576:.
568:.
558:96
556:.
552:.
529:.
521:.
509:16
507:.
503:.
480:.
472:.
460:12
458:.
454:.
431:.
421:.
413:.
401:.
397:.
374:.
362:.
339:.
331:.
319:16
317:.
313:.
100:,
1015:.
1001::
974:.
946:.
932:.
918:.
906::
883:.
869::
842:.
820::
793:.
763::
736:.
714::
687:.
667::
643:.
621::
594:.
564::
537:.
515::
488:.
466::
439:.
409::
382:.
370::
347:.
325::
62:)
56:(
51:)
47:(
33:.
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
