Talk:Genital System Development
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Cite this page: Hill, M.A. (2019, March 24) Embryology Genital System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Genital_System_Development
Differences of sex development: the road to diagnosis
Lancet Diabetes Endocrinol. 2019 Feb 22. pii: S2213-8587(18)30339-5. doi: 10.1016/S2213-8587(18)30339-5. [Epub ahead of print]
León NY1, Reyes AP2, Harley VR3. Author information Abstract The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies. Copyright © 2019 Elsevier Ltd. All rights reserved. PMID: 30803928 DOI: 10.1016/S2213-8587(18)30339-5
Bmp4 is an essential growth factor for the initiation of genital tubercle (GT) outgrowth
Congenit Anom (Kyoto). 2019 Feb 3. doi: 10.1111/cga.12326. [Epub ahead of print]
Kajioka D1, Suzuki K1, Nakada S1, Matsushita S1, Miyagawa S1, Takeo T2, Nakagata N2, Yamada G1.
Abstract The external genitalia are appendage organs outgrowing from the posterior body trunk. Murine genital tubercle (GT), anlage of external genitalia, initiates its outgrowth from embryonic day (E) 10.5 as a bud structure. Several growth factors such as fibroblast growth factor (FGF), Wnt and Sonic hedgehog (Shh) are essential for the GT outgrowth. However, the mechanisms of initiation of GT outgrowth are poorly understood. We previously identified bone morphogenetic protein (Bmp) signaling as a negative regulator for GT outgrowth. We show here novel aspects of Bmp4 functions for GT outgrowth. We identified the Bmp4 was already expressed in cloaca region at E9.5, before GT outgrowth. To analyze the function of Bmp4 at early stage for the initiation of GT outgrowth, we utilized the Hoxa3-Cre driver and Bmp4 flox/flox mouse lines. Hoxa3 Cre/+ ; Bmp4 flox/flox mutant mice showed the hypoplasia of GT with reduced expression of outgrowth promoting genes such as Wnt5a, Hoxd13 and p63, whereas Shh expression was not affected. Formation of distal urethral epithelium (DUE) marked by the Fgf8 expression is essential for controlling mesenchymal genes expression in GT and subsequent its outgrowth. Furthermore, Fgf8 expression was dramatically reduced in such mutant mice indicating the defective DUE formation. Hence, current results indicate that Bmp4 is an essential growth factor for the initiation of GT outgrowth independent of Shh signaling. Thus, Bmp4 positively regulates for the formation of DUE. The current study provides new insights into the function of Bmp signaling at early stage for the initiation of GT outgrowth. © 2019 Japanese Teratology Society. KEYWORDS: Bmp4; DUE (distal urethral epithelium); Fgf8; cloaca; genital tubercle (GT) PMID: 30714224 DOI: 10.1111/cga.12326
Development of the human female reproductive tract
Differentiation. 2018 Sep - Oct;103:46-65. doi: 10.1016/j.diff.2018.09.001. Epub 2018 Sep 6.
Cunha GR1, Robboy SJ2, Kurita T3, Isaacson D4, Shen J4, Cao M4, Baskin LS4. Author information Abstract Development of the human female reproductive tract is reviewed from the ambisexual stage to advanced development of the uterine tube, uterine corpus, uterine cervix and vagina at 22 weeks. Historically this topic has been under-represented in the literature, and for the most part is based upon hematoxylin and eosin stained sections. Recent immunohistochemical studies for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium and its known pelvic derivatives) shed light on an age-old debate on the derivation of vaginal epithelium supporting the idea that human vaginal epithelium derives solely from urogenital sinus epithelium. Aside for the vagina, most of the female reproductive tract is derived from the Müllerian ducts, which fuse in the midline to form the uterovaginal canal, the precursor of uterine corpus and uterine cervix an important player in vaginal development as well. Epithelial and mesenchymal differentiation markers are described during human female reproductive tract development (keratins, homeobox proteins (HOXA11 and ISL1), steroid receptors (estrogen receptor alpha and progesterone receptor), transcription factors and signaling molecules (TP63 and RUNX1), which are expressed in a temporally and spatially dynamic fashion. The utility of xenografts and epithelial-mesenchymal tissue recombination studies are reviewed.
Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Cervix; Human Müllerian duct; Urogenital sinus; Uterovaginal canal; Uterus; Vagina; Wolffian duct PMID: 30236463 PMCID: PMC6234064 [Available on 2019-09-06] DOI: 10.1016/j.diff.2018.09.001
Reproductive Medicine Seminar 2018
Dr Rachael Rodgers Male and female reproductive/urogenital systems, breast, thyroid, adrenals, kidneys, hypothalamus and pituitary, it would be perfect.
It’s Rachael Rodgers here. I’m one of the fertility fellow / gynaecologists at the Royal Hospital for Women. I’m writing to ask if it would be possible for you to give a presentation on embryology at one of the teaching sessions we hold in the Reproductive Medicine department. Every second Tuesday morning, we have a teaching session in the Reproductive Medicine department that runs from 8-9am. The specialists, fellows, registrars, junior doctors and nurses from the Royal Hospital for Women attend, as well as some scientists from UNSW.
We would be very grateful if you would be able to give a lecture, Professor Ledger indicated to me that he thought you would be excellent. Specifically we were hoping that you could give a presentation on the embryonic development of the male and female reproductive structures (urogenital system primarily, also a brief mention of related structures such as the breast, urinary system, thyroid and adrenals if time permits). Our teaching restarts on 13th Feb, and then is held every second week after this.
Dr Rachael Rodgers
BA, BSc, MBBS (Hons), MScMed (RHHG), FRANZCOG CREI Fellow / Gynaecology Senior Registrar Royal Hospital for Women Department of Reproductive Medicine Barker St, Randwick 2031 Phone: +61 402 136 657
Sex determination and maintenance: the role of DMRT1 and FOXL2
Huang S1, Ye L2, Chen H2.
Asian J Androl. 2017 Nov-Dec;19(6):619-624. doi: 10.4103/1008-682X.194420.
In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 (Dmrt1) and forkhead box L2 (Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility. PMID: 28091399 PMCID: PMC5676419 DOI: 10.4103/1008-682X.194420
- Initial activation of SRY (Mouse - Wilms tumor 1 (Wt1), GATA binding protein 4 (Gata4), zinc fnger protein, fog family member 2 (Zfpm2), chromobox homolog 2 (Cbx2), mitogen-activated protein kinase 4 (Map3k4), and the insulin receptors.
- SRY activates SOX9
- SOX9 expression requires positive regulatory loop with fibroblast growth factor 9 (Fgf9) and lipocalin-type prostaglandin D2 synthase (Ptgds) PTGDS is an enzyme that catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2).
- feed-forward regulatory loop between Sox9 and Fgf9 results in upregulation of Fgf9 expression and repression of a female promoting gene, wingless-related MMTV integration site 4 (Wnt4)
expressions of SOX9, FGF9, and PTGDS in bipotential embryonic genital ridges determine the fate of Sertoli cells.
- mesonephric cell migration, testis cord formation, testis-speci c vascularization, and myoid and Leydig cell di erentiation.
- late stages of testicular development, including WT1, steroidogenic factor 1 (SF1), GATA4, DMRT1, desert hedgehog (DHH), and platelet-derived growth factor (PDGF).
- DMRT proteins are transcription factors that share a DNA-binding domain that is similar to a zinc nger, called the DM domain.
- DMRT1 is predominantly expressed in Sertoli cells, whereas at later gestation (GW 22-40), childhood, and postpuberty, DMRT1 is most abundant in spermatogonia.
Retinoic acid (RA) signaling between Sertoli and germ cells is essential for adult mammalian spermatogenesis.
Male, the positive feedback regulatory loops (Sox9-Fgf9 and Sox9-Ptgds) not only reinforce the activation of the male signaling network but also inhibit the key members of the female network members (Wnt4, Rspo1, and Foxl2).
activation of female signaling molecules has negative e ects on the expression of male genes.
DMRT1 and FOXL2 maintain male and female gonadal sex phenotypes
- essential ovary-specific factors exist (β-catenin, follistatin [Fst], FOXL2, R-spondin [RSPO1], and WNT4)
- germ cells, which enter meiosis and become primary oocytes in the developing ovary; the granulosa cells, which support germ cell development (analogous to Sertoli cells); and the theca cells, which produce steroid hormones (analogous to Leydig cells)
- duplications of the WNT4 gene in males or loss of functional mutations in females resulted in diverse sexual anomalies including cryptorchidism
- Wnt4 in the XX gonad is to inhibit important testis-specific processes, including migration of endothelial cells from the mesonephros39 and steroidogenesis, either by repressing Sf140 or precluding the recruitment of steroidogenic cell precursors.
- mutations in RSPO1, a ligand for canonical WNT signaling,41,42 resulted in female-to-male sex reversal
- RSPO1 suppresses the male pathway in the absence of SRY by activating WNT4 signaling.
- β-catenin is the common e ector of both RSPO1 and WNT4 signaling
- FOXL2 (mice) not be involved in early XX female-to-male sex reversal but is necessary for correct follicle development and female fertility maintenance in postnatal animals.
- FOXL2 directly repress the testis-specific enhancer of Sox9 through synergistic interaction with estrogen receptors-α and -β (ER-α-β)
- Foxl2 expression is necessary to actively suppress Sox9 expression in the ovary throughout life.
- sustained Foxl2 expression is necessary for repressing genetic reprogramming of the postnatal ovarian somatic cells to testicular cell types, and thus for the maintenance of the adult female phenotype
- Mutations in the FOXL2 gene in humans are associated with Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES), a condition that a ects development of the eyelids and premature ovarian failure in females
- mice Foxl2 was found to play a role in maintaining ovarian functions postnatally, FOXL2 is a bona fide female sex-determining gene in goat.
Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development
Clin Genet. 2017 Feb;91(2):143-156. doi: 10.1111/cge.12932.
Bashamboo A1, Eozenou C1, Rojo S1, McElreavey K1.
Human sex determination (SD) involves complex mutually antagonistic genetic interactions of testis- and ovary-determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro-male and pro-female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double-repressive pathway. Here, we review genetic data generated through large-scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent NR5A1 p.R92W mutation associated with testis development in 46,XX children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of SD across species. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
KEYWORDS: NR5A1; cell-fate choice decisions; cellular models of human disease; disorders of sex development; gonadal dysgenesis; infertility; sex determination; testicular DSD PMID 27893151 DOI: 10.1111/cge.12932
Why boys will be boys and girls will be girls: Human sex development and its defects
Birth Defects Res C Embryo Today. 2016 Dec;108(4):365-379. doi: 10.1002/bdrc.21143.
Eid W1,2, Biason-Lauber A1. Author information Abstract Among the most defining events of an individual's life, is the development of a human embryo into male or a female. The phenotypic sex of an individual depends on the type of gonad that develops in the embryo, a process which itself is determined by the genetic setting of the individual. The development of the gonads is different from any other organ, as they possess the potential to differentiate into two functionally distinct organs, testes, or ovaries. Sex development can be divided into two distinctive processes, "sex determination," which is the commitment of the undifferentiated gonad into either a testis or an ovary, a process that is genetically programmed in a critically timed manner and "sex differentiation," which takes place through hormones produced by the gonads, once the developmental sex determination decision has been made. Disruption of any of the genes involved in either the testicular or ovarian development pathway could lead to disorders of sex development. In this review, we provide an insight into the factors important for sex determination, their antagonistic actions and whenever possible, references on the "prismatic" clinical cases are given. Birth Defects Research (Part C) 108:365-379, 2016. © 2016 Wiley Periodicals, Inc. KEYWORDS: bipotential state; disorders of sex development (DSD); ovary; sex determination; sex development; sex differentiation; testis PMID: 28033664 DOI: 10.1002/bdrc.21143
On the development of extragonadal and gonadal human germ cells
Biol Open. 2016 Feb 1;5(2):185-94. doi: 10.1242/bio.013847.
Heeren AM1, He N1, de Souza AF2, Goercharn-Ramlal A1, van Iperen L1, Roost MS1, Gomes Fernandes MM1, van der Westerlaken LA3, Chuva de Sousa Lopes SM4.
Human germ cells originate in an extragonadal location and have to migrate to colonize the gonadal primordia at around seven weeks of gestation (W7, or five weeks post conception). Many germ cells are lost along the way and should enter apoptosis, but some escape and can give rise to extragonadal germ cell tumors. Due to the common somatic origin of gonads and adrenal cortex, we investigated whether ectopic germ cells were present in the human adrenals. Germ cells expressing DDX4 and/or POU5F1 were present in male and female human adrenals in the first and second trimester. However, in contrast to what has been described in mice, where 'adrenal' and 'ovarian' germ cells seem to enter meiosis in synchrony, we were unable to observe meiotic entry in human 'adrenal' germ cells until W22. By contrast, 'ovarian' germ cells at W22 showed a pronounced asynchronous meiotic entry. Interestingly, we observed that immature POU5F1+ germ cells in both first and second trimester ovaries still expressed the neural crest marker TUBB3, reminiscent of their migratory phase. Our findings highlight species-specific differences in early gametogenesis between mice and humans. We report the presence of a population of ectopic germ cells in the human adrenals during development. © 2016. Published by The Company of Biologists Ltd. KEYWORDS: Adrenals; Development; Ectopic; Fetal; Germ cells; Human; Meiosis; Ovaries
Fine time course expression analysis identifies cascades of activation and repression and maps a putative regulator of mammalian sex determination
PLoS Genet. 2013 Jul;9(7):e1003630. doi: 10.1371/journal.pgen.1003630. Epub 2013 Jul 11.
Munger SC, Natarajan A, Looger LL, Ohler U, Capel B. Source Department of Cell Biology, Duke University, Durham, North Carolina, USA.
In vertebrates, primary sex determination refers to the decision within a bipotential organ precursor to differentiate as a testis or ovary. Bifurcation of organ fate begins between embryonic day (E) 11.0-E12.0 in mice and likely involves a dynamic transcription network that is poorly understood. To elucidate the first steps of sexual fate specification, we profiled the XX and XY gonad transcriptomes at fine granularity during this period and resolved cascades of gene activation and repression. C57BL/6J (B6) XY gonads showed a consistent ~5-hour delay in the activation of most male pathway genes and repression of female pathway genes relative to 129S1/SvImJ, which likely explains the sensitivity of the B6 strain to male-to-female sex reversal. Using this fine time course data, we predicted novel regulatory genes underlying expression QTLs (eQTLs) mapped in a previous study. To test predictions, we developed an in vitro gonad primary cell assay and optimized a lentivirus-based shRNA delivery method to silence candidate genes and quantify effects on putative targets. We provide strong evidence that Lmo4 (Lim-domain only 4) is a novel regulator of sex determination upstream of SF1 (Nr5a1), Sox9, Fgf9, and Col9a3. This approach can be readily applied to identify regulatory interactions in other systems.
Mammalian sex determination—insights from humans and mice
Chromosome Res. 2012 Jan;20(1):215-38. doi: 10.1007/s10577-012-9274-3.
Eggers S, Sinclair A. Source Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.
Sex determination strategies in 2012: towards a common regulatory model?
Reprod Biol Endocrinol. 2012 Feb 22;10:13.
Angelopoulou R, Lavranos G, Manolakou P. Source Experimental Embryology Unit, Department of Histology and Embryology, Medical School, Athens University, Athens, Greece. email@example.com
Sex determination is a complicated process involving large-scale modifications in gene expression affecting virtually every tissue in the body. Although the evolutionary origin of sex remains controversial, there is little doubt that it has developed as a process of optimizing metabolic control, as well as developmental and reproductive functions within a given setting of limited resources and environmental pressure. Evidence from various model organisms supports the view that sex determination may occur as a result of direct environmental induction or genetic regulation. The first process has been well documented in reptiles and fish, while the second is the classic case for avian species and mammals. Both of the latter have developed a variety of sex-specific/sex-related genes, which ultimately form a complete chromosome pair (sex chromosomes/gonosomes). Interestingly, combinations of environmental and genetic mechanisms have been described among different classes of animals, thus rendering the possibility of a unidirectional continuous evolutionary process from the one type of mechanism to the other unlikely. On the other hand, common elements appear throughout the animal kingdom, with regard to a) conserved key genes and b) a central role of sex steroid control as a prerequisite for ultimately normal sex differentiation. Studies in invertebrates also indicate a role of epigenetic chromatin modification, particularly with regard to alternative splicing options. This review summarizes current evidence from research in this hot field and signifies the need for further study of both normal hormonal regulators of sexual phenotype and patterns of environmental disruption. © 2012 Angelopoulou et al; licensee BioMed Central Ltd.
Table 1 - Regulatory elements in sex determination/dosage compensation
Development of the human Müllerian duct in the sexually undifferentiated stage
An embryological explanation for the development of the Müllerian duct still poses a major challenge. The development of this duct was investigated systematically in human embryos. Seven embryos (Carnegie stages 18-23) were serially sectioned in the frontal, sagittal, and transversal planes at a thickness of 10 microm and stained with hematoxylin and eosin (H&E) for histological analysis. In all observed embryos, the caudal end of the Müllerian duct was found to be intimately connected to the Wolffian duct. The opening of the Müllerian duct to the coelomic cavity was formed as the result of an invagination of the coelomic epithelium at Carnegie stage 18. The duct grew independently from the invagination during stages 19-23. The fused duct (uterovaginal canal) bifurcated at the caudal portion at Carnegie stages 22 and 23. This is the first description of the caudal portion of the fused Müllerian ducts separating again and returning to each of the Wolffian ducts in human embryos. Copyright 2003 Wiley-Liss, Inc.
MicroRNA in the ovary and female reproductive tract
Carletti MZ, Christenson LK. J Anim Sci. 2009 Apr;87(14 Suppl):E29-38. Epub 2008 Sep 12. Review. PMID: 18791135
Meeting report: measuring endocrine-sensitive endpoints within the first years of life. Arbuckle TE, Hauser R, Swan SH, Mao CS, Longnecker MP, Main KM, Whyatt RM, Mendola P, Legrand M, Rovet J, Till C, Wade M, Jarrell J, Matthews S, Van Vliet G, Bornehag CG, Mieusset R. Environ Health Perspect. 2008 Jul;116(7):948-51. PMID: 18629319 | PMC: 2453165] | Supplementary PDF
Anogenital distance from birth to 2 years: a population study
Environ Health Perspect. 2009 Nov;117(11):1786-90. Epub 2009 Jul 13.
Thankamony A, Ong KK, Dunger DB, Acerini CL, Hughes IA.
Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom. Abstract BACKGROUND: Anogenital distance (AGD) is sexually dimorphic in rodents and humans, being 2- to 2.5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy.
OBJECTIVE: This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures.
MATERIALS AND METHODS: Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age.
RESULTS: Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (+/- SD) at birth was 19.8 +/- 6.1 mm in males and 9.1 +/- 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex-dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r = 0.20, p = 0.001).
CONCLUSION: We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.
The Timing and Sequence of Events in the Development of the Human Reproductive System During the Embryonic Period Proper
Anat Embryol (c) 166:247—261 Anatomy and Embryology
Carnegie Laboratories of Embryology, California Primate Research Center and Departments of Human Anatomy and Neurology, University of California, Davis, California 95616, U.S.A.
Summary. A documented scheme of the early development of the human reproductive system is presented. It is based on (1) reports of workers who personally studied staged embryos, and (2) personal observations and conﬁrmations. The necessity of using staged embryos in order to determine the precise sequence of developmental events is stressed.
The urinary and reproductive organs are closely related embryologically and teratologically, to such an extent that they “form an inseparable whole in the adult organism” (Felix 1912). Hence the development of the urinary system, which has been described in a previous publication (O’Rahilly and Muecke 1972), is extremely important for the present account of the reproductive system.
Although many articles and even some books have been written on the development of various reproductive organs, no comprehensive account based on staged embryos seems to be available, such as have been published in regard to other systems of the body (O’Rahilly 1979).
Material and Methods
The scheme presented here is based on ﬁrst—hand reports of workers who personally studied staged human embryos, supplemented by personal observations and conﬁrmations of the pres— ent writer. Only staged embryos have been considered, that is, those speciﬁcally assigned to one of the recognized Carnegie stages (O’Rahi Ly 1973). Certain early embryos, the stages of which were not specified, have here been assigned to stages on the basis of their somitic count. Moreover, Carnegie embryos that were described prior to the establishment of the staging system have since been staged. The following list indicates the stages described and illustrated by several authors.
Pohlman (1911) on the cloaca: stage 11 (No. 164), 13 (186), 14 (80), 15 (2), 16 (221), and 19 (43).
Wilson (1926a) on the rete: stage 16 (No. 1836), 17 (544), 18 (423; 511; 841), 19 (432), 20 (368; 460), 21 (22; 455; 2937), and 23 (75; 782; 1945)
Wilson (1926b) on external genitalia: stage 20 (No. 2393) and stage 23 (No. 950).
Koff (1933) on the vagina: stage 17 (No. 353), 20 (966), 22 (584A; 4304; 4339; 4638), and 23 (4205; 4289; 5725).
Pillett (1971, 1968, 1969, and 1967) prepared reconstructions of the pelvis at stages 15, 16, 17, and 18 and 23, respectively.
Sequence of Events
Stage 1 (ca 1-2 days)
Pronuclei. It has been claimed that pronuclei can be distinguished as male and female (Khvatov 1959).
P.G.C. Alarge cell in the inner cell mass has been thought to be “ presumably a germ cell” (Hertig 1968).
Sex Chromatin. It has been claimed that, “ based on current studies concerning sex chromatin,” a 100-cell blastocyst was female and a 107—cell blastocyst
was male (Khvatov 1967).
Stage 6 (ca 0.2 mm; ca 13 days)
P.G.C. Possible primordial germ cells may be seen in the wall of the yolk sac (Politzer 1933).
Sex Chromatin. Sex chromatin may be found in the trophoblast (Park 1957).
Cloacal Membrane. Possibly the cloacal membrane (Fetzer embryo: Florian 1933), or at least its site (No. 7801: Heuser et al. 1945), becomes detectable.
Stage 7 (ca 0.4 mm; ca 16 days)
P.G.C. Primordial germ cells have been identiﬁed at stages 7, 8, and 9 (Jirasek 1971; 1977).
Sex Chromatin. Sex chromatin may be found in the wall of the yolk sac (Park 1957).
Stage 8 (ca 1.0-1.5 mm; ca 18 days)
Sex Chromatin. Sex chromatin may be seen in the future notochordal region (Park 1957). Development of Human Reproductive System 249
Cioacal Membrane. A cloacal membrane has been described (Heuser 1932) and has been plotted in reconstructions (O’Rahilly and Muller 1981).
Stage 9 (ca 1.5-2.5 mm; 1-3 pairs of somites; ca 20 days)
Mesoderm. The paraxial mesoderm and the lateral plate become distinguishable (Ludwig 1928).
Cioacal Membrane. The cloaca] membrane has been unequivocally observed (de Vries and Friedland 1974).
Stage 10 (ca 2-3.5 mm; 4-12 pairs of somites; ca 22 days) Mesoderm. The intermediate mesoderm becomes visible (Payne 1925).
Stage 11 (ca 2.5-4.5 mm; 13-20 pairs of somites; ca 24 days)
P.G.C. The primordial germ cells are migrating from the yolk sac to the hindgut (Witschi 1948).
Mesonephric Duct. The mesonephric duct develops as a solid rod in situ from the nephrogenic cord (Torrey 1954) or from ectodermal buds lateral to somites 8 to 13 (Jirasek 1971).
Stage 12 (ca 3-5 mm; 21-29 somites; ca 26 days)
P.G.C. The primordial germ cells are in the wall of the hindgut (Witschi 1948). The primordial germ cells, characterized by glycogen and pseudopo— dia, are escaping into the mesenchyme through breaks in the basal lamina (Fujimoto et al. 1977). An embryo of 26-27 pairs of somites, reconstructed by Politzer (1928), showed 586 germ cells (330 in the mesoderm and 256 in the endoderm of the hindgut). Some of the germ cells were in mitosis.
Mesonephric Duct. The mesonephric duct at first ends immediately short of the cloaca (Torrey 1954) but soon (at 27 pairs of somites) becomes at— tached to the cloaca (Vogl 1925), i.e., the terminal part of the hindgut. The mesonephric duct develops a lumen (Torrey 1954).
Stage 13 (ca 4-6 mm; 30 or more pairs of somites; ca 28 days)
P.G.C. The primordial germ cells migrate from the hindgut to the meson ephric ridges, and several hundred of them are present in the embryo (Witschi 1948).
Mesonep/zric Duct. The mesonephric duct opens into the cloaca (Streeter 1945)
Mammary Gland. The ectodermal ring, which includes the so—called Mz'Zeh— szrezfen, is present (Blechschmidt 1951). 250 R. O’Rahilly
Stage 14 (ca 5-7 mm; ca 32 days)
Gonad. The primordial germ cells migrate from the mesentery to the gonadal ridges (Witschi 1948). Each gonadal ridge appears as a rnesodermal proliferation along the medial surface of the mesonephros (Witschi 1948; Jirasek 1971)
Stage 15 (ca 7-9 mm; ca 33 days)
Gonaal. The gonadal ridges contain numerous germ cells rich in glycogen (J irasek 1971). A basement membrane is lacking (J irasek 1976). The primordial germ cells (studied by electron microscopy at stages 12—15) frequently display pseudopodia and numerous glycogen particles (Fukuda 1976).
Urogenital Sinus. The primary urogenital sinus is distinguishable (Personal observations).
Cloacal Membrane. The cloacal membrane appears to be rotating so that its external surface may no longer face the allantoic diverticulum (Personal observations).
Stage 16 (ca 8411 mm; ca 37 days)
Gonad. The primordial germ cells in the gonadal ridge may show long, glycogen-rich processes (J irasek 1971). The gonadal primordium is indicated by proliferation of the coelomic epithelium and the invasion of the underlying mesonephric stroma (Wilson 1926a). The coelomic epithelium of the gonadal ridge was thought by Gillman (1948) to form short cords.
Paramesonepltric Ducts. The primordium of the paramesonephric duct appears as an invagination of thickened coelomic epithelium over the mesonephros at the level of thoracic segments 3 and 4 (Faulconer 1951).
External Genitalia. The genital tubercle includes slight urethral folds, a urethral groove, and an anal pit (Spaulding 1921, Plate 1, Fig. 2). The apex of the genital eminence indicates the future glans (ibid).
Mammary Gland. The ectodermal ring, including the mammary crest (M ilclt— leiste) and the apical ectodermal ridge (A.E.R.) of the limbs, has been plotted carefully (Strube 1950).
Stage 17 (ca 11-14 mm; ca 41 days)
Gonad. Invasion of the mesonephric stroma by coelomic epithelium is beginning to show a cord—like arrangement (Wilson 1926 a)
Pararnesoneplzric Ducts. The paramesonephric ducts are still seen as invagi— nations of the coelomic epithelium at stage 17 (Koff 1933) and 18 (Streeter
External Genitalia. The genital eminence forms the phallus at stage 17 or stage 18 (Spaulding 1921).
Mammary Giana’. The nipples appear as buds on the mammary crest (Bossy 1980)
Stage 18 (ca 13»——17 mm; ca 44 days)
P.G.C. Extragonadal germ cells were identified (e.g., in gut epithelium at stage 18) up to 30 mm (Jirasek 1971).
G0;/tad. The gonad forms a pronounced elevation and extends to the rostral pole of the mesonephros. The rete is beginning (Wilson 1926a). The sex ratio from stage 18 to stage 23 has been found to vary from 125 to 385 (preponderance of male embryos) (Lee and Takano 1970).
Testis. The gonadal blastema differentiates into testicular cords (Jirasek 1971). Primordial germ cells were identified in the testis from stage 18 to stage 23, and in the fetal period (Narbaitz 1962).
Ovary. Gonadal cords are identifiable in the ovary (Gillman 1948).
Stage 19 (ca 16«18 mm; ca 48 days)
Gorzad. True hermaphroditism has been recorded at stages 19 to 23 (Lee 1971)
Testis. The rete testis develops from the siminiferous cords at stages 19 to 23 (Jirasek 1971). The tunica albuginea forms at stages 19 to 23 (Jirasek 1971)
Ovary. Cords representing the rete ovarii (or rete testis) are developing from cells of the gonad (Wilson 1926 a).
Mammary Gland. The nipple forms a marked elevation (Bossy 1980).
Stage 20 (ca 18-22 mm; ca 51 days)
Ovary. The ovary consists of “a mass of undifferentiated oogonia” (which may begin to show a cord-like arrangement) covered by the surface epithelium. The rete is invading the mesonephros (Wilson 1926a).
Paramesonephric Ducts. The paramesonephric ducts are approaching the caudal limit of the mesonephros (Koff 1933).
Mammary Giand. The mammary crest disappears (Bossy 1980).
Stage 21 (ca 22=24 mm; ca 52 days)
Testis. The testis shows a ﬂattened surface epithelium, an underlying tunica albuginea, and branching and anastomosing cords: “the forerunners of the seminiferous tubules.” The rete is invading the mesonephros (Wilson 1926a)
Stage 22 (ca 23-28 mm; ca 54 days)
Ovary. Although the rete ovarii is present, Gillman (1948) did not identify cords in the ovarian cortex.
Peremesonepltric Ducts. The paramesonephric ducts lie side-by~side caudally (Koff 1933) and show rostral vertical, middle transverse, and caudal vertical portions, although they do not yet reach the urogenital sinus.
Stage 23 (ca 27-31 mm; ca 57 days)
Testis. Testicular tubules are identiﬁable (Gillman 1948) The rete testis makes contact but no actual union with the mesonephric elements (Wilson 1926a). The urogenital union occurs in the fetal period (ibid). Clusters of cells “have started their differentiation into the interstitial cells” by 29 mm (Pelliniemi and Niemi 1969)
Ovary. The rete ovarii is closely related to but not united with the mesonephric elements (Wilson 1926a). A urogenital union may or may not occur during the fetal period (ibid).
Paramesonepltric Ducts. The paramesonephric ducts meet the urogenital sinus and fuse with each other in the median plane (Koff 1933; Pillet 1967). The sinusal (Miillerian) tubercle has appeared by stage 23 (Koff 1933).
External Genitalia. The external genitalia are Well developed but do not suffice for sex detection. In particular, some males tend to be diagnosed as females (Wilson 1926 b).
Only staged embryos have been considered in this study and hence it has not been possible to include much otherwise valuable information, e.g., ultrastructural observations of the testis (V ossmeyer 1971; Wartenberg et al. 1971; Holstein et al. 1971).
In order to appreciate better the various features that appear already during the embryonic period and those that wait for the onset of fetal life, a brief account of fetal development will be included in this discussion.
Early Development of Gonad
The gonad appears at stage 14 as a mesodermal proliferation on the medial side of the rnesonephros. The early development of the gonads may be Development of Human Reproductive System 253
considered in two morphological phases: the “indifferent phase”, in which no morphological sex differentiation is evident, and the phase of differentiation into testes or ovaries.
Indzﬂerenz Phase. “Every vertebrate embryo forms at first an indifferent reproductive gland from which, by the emphasis of certain characters, the sexually differentiated organ is formed” (Felix 1912). In the human, this phase lasts about 12 days, from stage 14 to stage 18. The gonad includes coelomic epithelium, primordial germ cells, and mesoderm, at least some of which is believed to be derived from the mesonephros. However, “the genital ridge tissue is so primitive that it can be classiﬁed as neither epithelium nor mesenchyme” (Jirasek 1976). Various theories of gonadal histogene sis from the different constituents have been proposed (See Carlon and Stahl 1973, for a review).
Phase of Diﬂeremiation. The differentiation “consists in the characters of the male gland being developed in embryos of 13 mm greatest length, at
9 the earliest,” i.e., at stage 18 (13~17 mrn C.R.). The gonadal blastema shows
testicular cords, and (at stage 19) a tunica albuginea begins to form beneath the coelomic epithelium.
The presence of an ovary is first determined per exclusionem. If absence of retarded differentiation in the male be assumed, then “one may say that the embryo has reached the age when testis cords should be present; they are not present and therefore the embryo must be a female” (Felix 1912). By taking other features also into account (such as the formation of the uterovesical pouch, according to Felix), “the beginning of the sexual differentiation may be determined in female embryos at... 18 to 20 mm in length,” i.e., probably by stage 20 (18~22 mm C.-R.).
The early part of the phase of sexual differentiation in the female is “essentially an extension of the indifferent gonad” phase (Zuckerman and Baker 1977). Ovarian histogenesis begins during the first half of prenatal life (approximately 85w200 mm).
The distinction between the two phases, however, does not appear to be clear—cut, because “the germ cells become preferentially associated with the dominant component,” i.e., cortex in the female, medulla in the male (Zuckerman and Baker 1977), in accordance with Witschi’s theory of corticomedullary antagonism.
Germ Cell Line
The term Keimba//m is used for the totality of the germ cells from embryonic life to adulthood, and also for the path taken by the germ cells during embryonic life (Politzer 1954: “Unter Eisenbahn verstehen wir je gleichfalls die Lokomotiven und Waggons, wie auch die Schienen”).
The primordial germ cells (P.G.C.) arise extragonadally (Eddy et al. 1981). The concept of a continuous, single germ line originating in early embryonic development is “likely for mammals” (Nieuwkoop and Sutasurya 1979). Moreover, “the resulting PGC population gives rise to all 254 R. O’Rahilly
the deﬁnitive gametes of the adult” (ibid.). In mammals the P.G.C. are probably first detectable in the wall of the yolk sacl, from which they migrate to the gonads. Four modes of migration have been postulated (Zuckerman and Baker 1977): active, by amoeboid movements; passive, by differential growth of surrounding tissues; passive, via the blood stream; and chemotactic, under the inﬂuence of inductors diffusing from the presumptive gonadal area. In the human, the migration of the P.G.C. has been followed particularly in Carnegie embryos by Witschi (1948), who found them moving first from the yolk sac to the hindgut (stage 11), then from the hindgut to the mesonephric ridges (stages 13), and finally reaching the gonadal ridges (stage 14). The presence of P.G.C. is not necessary for otherwise normal gonadal development.
The development of the testis, including biochemical differentiation and functional considerations, has been reviewed recently and an extensive bibliography has been provided (Gondos 1977).
The gonadal blastema (under the influence of the Y chromosome) becomes differentiated into testicular cords, beginning at stage 18. In the human, “there is no ingrowth of cords from the surface epithelium ” (J irasek 1976; see also Gruenwald 1942). Moreover, what are generally referred to as testicular cords are at first (13-25 mm) sheets, which later (30—35 mm) begin to break up into cords that (110 mm onwards) develop lumina and so form seminiferous tubules (Elias 1971).
By about stage 21, the portions of the testicular cords near the future mediastinum are in contact with the mesonephric tubules and glomerular capsules. This is the basis of the connexion between the testis and the future epididymis. Germ cells in cords “can for the first time properly be termed spermatogonia” (Jirasek 1976).
The possible origins of the somatic cells of the gonad are the coelomic epithelium, the subjacent mesenchyme, and the mesonephros (Wartenberg 1981). The mesonephros is now believed to play an essential role in the morphogenesis of both male and female gonads (Zamboni et al. 1981).
It has been proposed that two types of sustentacular cells appear: light (MP) cells, which become incorporated into the testicular cords at 21-28 mm, and dark (MI) cells, which appear at 40 mm and separate the light cells from the germ cells (W artenberg 1978). Furthermore, it has been suggested that the two types of sustentacular cells are derived from the coelomic epithelium and the mesonephros, respectively (ibid).
The interstitial cells are generally described as differentiating from mesenchymal cells of the stroma (Niemi et al. 1967) but it has been suggested that they (together with the dark sustentacular cells and the peritubular cells) are derived from the “central gonadal blastema”, which develops under the influence of, or originates from the mesonephros (Vi/artenberg
1 Various workers have proposed that the P.G.C. of the mouse originate from the ectoderm, or the rnesoderm, or the endoderrn (Nieuwkoop and Sutasurya 1979) Development of Human Reproductive System 255
1978). The onset of the capacity of the testis to form testosterone occurs at 31-50 mm (Siiteri and Wilson 1974).
The following features of the human testis have been illustrated in photomicrographs by van Wagenen and Simpson (1965) at the end of the embryonic period and during the fetal period: sustentacular cells (23 mm), [pro]sp— ermatogonia (23-31 mm), testicular cords containing germ cells and sustentacular cells, and surrounded by a basement membrane (31 mm), mesor— chium (31—32 mm), interstitial cells (32~37 mm), closed straight and rete tubules but patent efferent ductules and duct of epididymis (117 mm), external ﬁbrous and internal vascular layers in tunica albuginea (110 mm), convoluted tubules and maximal development of interstitial tissue (120-~140 mm), connective tissue septa (133—205 mm), lumina in straight and rete tubules (170 mm), and deﬁnite lobulation (270 mm).
The testis is at first in the iliac fossa (29.5—42.5 mm C.~R.), is abdominal during the first half of fetal life (to 210 mm), then enters the inguinal region (210—~250 mm) and ﬁnally reaches the scrotum (250 mm onwards) (Youssef and Raslan 1971). Intra—abdominal descent of the testis is denied (ibid.).
T he Ovary
The development of the ovary and the process of oogenesis have been reviewed recently and an extensive bibliography has been provided (Zuckerman and Baker 1977).
During stages 20 to 22, the gonadal blastema becomes differentiated into irregular groups of cells termed medullary cordsz. These contain germ cells, incorporated as oogonia (Jirasek 1976). There is no evidence that the embryonic ovary possesses endocrine activity (ibid.).
The ovary is covered by a “superficial epithelium” (Epithelium superficiale, Nomimz hiszologica and Nomina embryologica), continuous with the coelomic epithelium and still sometimes called the germinal epithelium, although “it is now clear that the epithelial cells which cover the ovary lack any ability to give rise to germ cells either during development or after birth” (Zuckerman and Baker 1977).
Particularly from 26 to 46 mm (van Wagenen and Simpson 1965), the ovary appears to be composed of central and peripheral zones (ibid., Plate 4, Fig. C), commonly but incautiously referred to as the “ﬁrst ingrowth” and the “second ingrowth,” better termed central and peripheral epithelial proliferations.
Gillman (1948) believed that “the theca cell is a modiﬁed stroma cell, of mesenchymal origin; the granulosa cells of the primordial follicle... arise from the coelomic epithelium”. However, the precursors of the granulosa cells may be derived from the mesonephros (Zamboni et al. 1981) and it has been suggested that two types exist. MP (meiosis—preventing) and MI (meiosis-inducing) (Wartenberg 1978).
3 Gillman (1948, Figs. 20 and 21) illustrated a gonad at stage 18, which he believed to be an ovary and to show genital cords and four types of cells: primordial germ cells, pregranulosa cells, cells of coelomic epithelium, and mesenchymal cells. Pﬂiiger’s tubes in the ovary “are nothing more than the much thickened sex cords of the indifferent stage” (ibid.) 256 R. O’Rahilly
The following germ cells are present in the human fetal ovary (Baker 1972; Jirasek 1976): oogonia (days 5055 until birth), leptotene oocytes (day 60 until birth), zygotene and paehytene oocytes (day 80 until after birth) and diplotene oocytes (approximately day 90 until shortly after birth). In the fetal ovary “primitive granulosa cells, present in the epithelial cords of the ovary, organize around leptotene, zygotene, and paehytene oocytes to form a single layer of ﬂattened follicular cells” (Jirasek 1976). These complexes of oocyte and granulosa cells are the primordial follicles. Later in fetal life, primary follicles (completely surrounded by connective tissue and containing diplotene oocytes) appear. Secondary (multilayered stratum granulosum) and vesicular (with an antrum) follicles3 may be found in the perinatal ovary. Thecal cells (after 245 mm) surrounded the stratum granulosum (Gillman 1948). Although almost mature follicles (Dontchev 1971, Fig. 6) may be present in the newborn, they undergo atresia. Indeed, it is believed that 4.8 million of the original 6.8 million germinal cells degenerate prior to birth (Baker 1963).
The following features of the human ovary have been illustrated in photomicrographs by van Wagenen and Simpson (1965) during the fetal period: cortex established and small medulla present (53-57 mm), large cells presumed to be oogonia (77 mm), primary oocytes and prophase of meiosis (86~140 mm), lobulation in cortex (86~150 mm), pregranulosa cells (94 mm), primordial follicles (196«200 mm), atresia (210 mm), and tunica albuginea (250—430 mm).
Medullary cords, which do not normally develop lumina, begin to regress at about 150 mm and disappear between aprroximately 280 and 357 mm
(Forbes 1942). T he Mammary Gland
The developing mammary and salivary glands are well-known examples of epitheliomesenchymal interactions.
The ectodermal ring of Schmitt (discussed by Graumann 1950, and Blechschmidt 1951) includes the so—called Milchstreﬂen, frequently but wrongly referred to as the “ mammary band ” (Hughes 1950). The ring comes to include other features, such as the apical ectodermal ridge (A.E.R.) of the limbs and the Schwcmzleisre. In the rostral half of the intermembral portion of the ring, the mammary crest appears (Hughes 1950, Fig. 1B). The nipples form as buds in the crest (Bossy 1980). After the appearance of the nipples, a latent period occurs until outgrowths (Sprossen), which begin at 170 mm (Hughes 1950) or 180 mm (Thiilen 1949), indicate the future glandular system. Hence the nipples appear during the embryonic period whereas the mammary glands proper begin to develop during the fetal period. The development in the male and female is similar.
3 In the N omina histologica (1977), a primordial follicle has ﬂattened follicular cells, a primary follicle has one or more layers of cuboidal cells, a secondary or vesicular follicle has an antrum, and a mature follicle is ready for ovulation
Fig. 1. Graphic representation of the migration of primordial germ cells (P.G.C.) and the development of the gonads in relation to Carnegie stages (rectangles). Embryonic length (ordinate) has been plotted against postovulatory age (abscissa). Y.S., yolk sac
Of the Various components of sexual differentiation, some appear during the embryonic period, others during the fetal period, and still others postnatally. Thus, chromosomal sex and gonadal sex appear during the embryonic period, whereas ductal sex and external genital sex become manifest during the fetal period. Hormonal status, certainly established early during fetal life, may begin at the very end of the embryonic period.
Sex chromatin, the detection of which (“nuclear sex”) is used as an indication of chromosomal sex, was first observed in young human embryos by Glenister (1956). In a study of Carnegie embryos (Park 1957), sex chromatin was found extra-embryonically in early stages (6 and 7), and shortly thereafter (at stage 8) within the embryonic disc.
Gonadal sex, as has been mentioned already, begins at stages 18 to 20.
The sexual differentiation of the ductal system is characteristic of the fetal period, although some indications have been claimed during embryonic life. (For example, Candreviotis 1973, believed that the mesenchyme surrounding the paramesonephric ducts shows differentiation from its earliest appearance at 18.5 mm in the female but not in the 16 mm male embryo.) In general, however, no noticeable difference in the form and degree of development of the urogenital duct system in the male and female is found 258 R. O’Rahilly
until 35 mm (Glenister 1962). Sexual differentiation of the reproductive pathway begins early in fetal life and is attributed to the inﬂuence of gonadal hormones.
The persistence of the paramesonephric ducts in the female fetus leads to the formation of the uterus, which may be said to be present as an organ as early as 36 or 37 mm. The development of the uterus has been reviewed recently (O’Rahilly 1977) and will not be discussed here. The development of the vagina, which remains in dispute, has also been considered (O"'Rahilly 1977). An appropriate bibliography can be found in these two publications.
The paramesonephric ducts begin to regress in the male at 30 mm (Jirasek 1971). The regression “is related to development of testicular connective tissue” (J irasek 1976) and is attributed to a discrete, fetal testicular, anti-paramesonephric hormone (J osso et al. 1977). The further development of mesonephric structures and external genitalia in the male fetus is accomplished by androgens produced by fetal interstitial cells (J irasek 1976).
The external genitalia first become evident at about stages 16 to 18 but remain in an indifferent phase for the next four weeks. Contrary to some previous viewpoints, 40 mm (Broman 1946) or 50 mm (Glenister 1954) fetuses are the earliest at which sex can be assessed from the appearance of the external genitalia.
Some features of the development of the reproductive system are summarized in Fig. 1.
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Accepted November 9, 1982
- Wilson KM. Origin and development of the rete ovarii and the rete testis in the human embryo. (1926) Carnegie Instn. Wash. Publ. 362, Contrib. Embryol., Carnegie Inst. Wash., 17:69-88.