Definition and research guide
This page combines a MeSH definition, publication statistics and selected research abstracts. It is a starting point for reading the literature, not a medical textbook or a systematic evidence review.
Content available: 4 complete abstracts (676 words), 10 references. Full article text is not stored or reproduced here; follow the PMID, DOI or PMC links to read the original sources and their access terms.
Definition
The process in developing sex- or gender-specific tissue, organ, or function after sex determination processes have set the sex of the gonads. Major areas of sex differentiation occur in the reproductive tract (genitalia) and the brain.
Definition: NLM Medical Subject Headings (MeSH) scope note (Public domain (U.S. National Library of Medicine); attribution requested). View the MeSH record.
Also known as: Sexual Differentiation; Differentiation, Sexual; Differentiation, Sex.
Where it fits in the MeSH classification
- Broader topics
- Organogenesis; Sexual Development
- See also
- Sex Determination Processes
Related concepts
- Sex Determination Processes
- Gonads
- Genitalia
Research landscape
PubMed indexes 5,636 records tagged with the MeSH heading “Sex Differentiation” (counts retrieved 2026-10-31). 709 of them (12.6%) were published from 2020 onward, and the busiest period so far is through 1999 with 2,329 records.
Reviews account for 1,260 records (22.4%) and meta-analyses for 1. Randomized controlled trials number 1 (0.0%) as a share of all records on the topic. Randomized trials make up only a small share of this literature, so much of what is known comes from laboratory, observational or descriptive work.
Show the data
| Period | Records |
|---|---|
| through 1999 | 2,329 |
| 2000-2009 | 1,366 |
| 2010-2019 | 1,232 |
| 2020 onward | 709 |
Publication-type chart data
| Type | Records | Share |
|---|---|---|
| Reviews | 1,260 | 22.4% |
| Meta-analyses | 1 | 0.0% |
| Randomized controlled trials | 1 | 0.0% |
Method: PubMed query "Sex Differentiation"[MeSH Terms] with publication-type and date filters, retrieved 2026-10-31.
Reading the evidence in anatomy and physiology
Anatomy describes how body structures are built and physiology describes how they normally work, so most findings here are descriptive or mechanistic rather than evidence about treatment. Much of what is known comes from dissection, imaging, tissue studies and experiments in animals, and measurements in healthy volunteers can differ from those in people with disease or at different ages. Normal ranges vary between individuals and populations. Check whether a result was measured in people or in another species, the age and health of the participants, and the method used.
Evidence from open-access studies
These open-access studies come from PubMed’s best-match results for this heading (papers whose main topic it is), ranked here by citation count, with one recent addition. Each abstract is reproduced in full under its recorded open licence so that you can read the authors’ own words. They illustrate the literature; they are not a systematic summary of it. Citation counts measure attention, not reliability or clinical benefit.
| Study / authors | Year | Source label / design | Europe PMC citations | Licence / source |
|---|---|---|---|---|
| Single-cell roadmap of human gonadal development | 2022 | Research article Design not recorded in structured metadata | 417 | cc by PMID 35794482 · DOI · PMC9300467 |
| Sex and the single cell. II. There is a time and place for sex | 2010 | Research article Design not recorded in structured metadata | 223 | cc by PMID 20454565 · DOI · PMC2864297 |
| Function and evolution of sex determination mechanisms, genes and pathways in insects | 2011 | Review article Design not recorded in structured metadata | 151 | cc by PMID 21110346 · DOI · PMC3040292 |
| Single-nucleus multiomics of murine gonads reveals transcriptional regulatory network underlying supporting lineage differentiation | 2026 | Research article Design not recorded in structured metadata | 6 | cc by PMID 41481707 · DOI · PMC12758517 |
Single-cell roadmap of human gonadal development [1]
Abstract reading summary — source excerpts
- Opening excerpt
- Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries1.
- Closing excerpt
- This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (214 words)
Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries1. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal-mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15+ and TREM2+ fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 35794482 · DOI · PMC9300467
Sex and the single cell. II. There is a time and place for sex [2]
Abstract reading summary — source excerpts
- Opening excerpt
- The Drosophila melanogaster sex hierarchy controls sexual differentiation of somatic cells via the activities of the terminal genes in the hierarchy, doublesex (dsx) and fruitless (fru).
- Closing excerpt
- Thus tissue-specific aspects of sexual development are jointly specified by post-transcriptional control by Sxl and by the transcriptional controls of dsx and fru expression.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (208 words)
The Drosophila melanogaster sex hierarchy controls sexual differentiation of somatic cells via the activities of the terminal genes in the hierarchy, doublesex (dsx) and fruitless (fru). We have targeted an insertion of GAL4 into the dsx gene, allowing us to visualize dsx-expressing cells in both sexes. Developmentally and as adults, we find that both XX and XY individuals are fine mosaics of cells and tissues that express dsx and/or fruitless (fru(M)), and hence have the potential to sexually differentiate, and those that don't. Evolutionary considerations suggest such a mosaic expression of sexuality is likely to be a property of other animal species having two sexes. These results have also led to a major revision of our view of how sex-specific functions are regulated by the sex hierarchy in flies. Rather than there being a single regulatory event that governs the activities of all downstream sex determination regulatory genes-turning on Sex lethal (Sxl) RNA splicing activity in females while leaving it turned off in males-there are, in addition, elaborate temporal and spatial transcriptional controls on the expression of the terminal regulatory genes, dsx and fru. Thus tissue-specific aspects of sexual development are jointly specified by post-transcriptional control by Sxl and by the transcriptional controls of dsx and fru expression.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 20454565 · DOI · PMC2864297
Function and evolution of sex determination mechanisms, genes and pathways in insects [3]
Abstract reading summary — source excerpts
- Opening excerpt
- Animals have evolved a bewildering diversity of mechanisms to determine the two sexes.
- Closing excerpt
- This review summarises recent findings in insects, surveys evidence of how and why sex determination mechanisms can change rapidly and suggests fruitful areas of future research.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (111 words)
Animals have evolved a bewildering diversity of mechanisms to determine the two sexes. Studies of sex determination genes--their history and function--in non-model insects and Drosophila have allowed us to begin to understand the generation of sex determination diversity. One common theme from these studies is that evolved mechanisms produce activities in either males or females to control a shared gene switch that regulates sexual development. Only a few small-scale changes in existing and duplicated genes are sufficient to generate large differences in sex determination systems. This review summarises recent findings in insects, surveys evidence of how and why sex determination mechanisms can change rapidly and suggests fruitful areas of future research.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 21110346 · DOI · PMC3040292
Single-nucleus multiomics of murine gonads reveals transcriptional regulatory network underlying supporting lineage differentiation [4]
Abstract reading summary — source excerpts
- Opening excerpt
- Sex determination of mammalian gonads hinges upon sex-specific differentiation of gonadal supporting cells: Sertoli cells in the testis and granulosa cells in the ovary.
- Closing excerpt
- Our results not only identify the gene regulatory framework underlying supporting cell sex differentiation but also provide invaluable resources for the field.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (143 words)
Sex determination of mammalian gonads hinges upon sex-specific differentiation of gonadal supporting cells: Sertoli cells in the testis and granulosa cells in the ovary. To gain insights into how supporting cells acquire their identities, we performed joint single-nucleus transcriptomics and chromatin accessibility assays on murine gonadal cells during sex determination. By contrasting sex-specific gene expression and corresponding chromatin accessibility among progenitor and differentiated cells, we found that sex-specific chromatin regions in supporting cells are established shortly after sex determination, accompanied by the acquisition of active histone marks. The presence of potential transcription factor-binding motifs in the open chromatin regions revealed regulatory networks underlying ovary-enriched factors LEF1 and MSX1, which promote granulosa fate by inducing granulosa-specific genes such as Foxl2 and Fst. Our results not only identify the gene regulatory framework underlying supporting cell sex differentiation but also provide invaluable resources for the field.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 41481707 · DOI · PMC12758517
Key reviews and meta-analyses
The most cited review-type papers among PubMed’s best-match results for this heading, listed with bibliographic details only. Follow the links for the full text and access terms.
- Research article Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence [5]
- Research article Human behavioral sex differences: a role for gonadal hormones during early development? [6]
- Research article A review on sex differences in processing emotional signals [7]
- Research article A starring role for microglia in brain sex differences [8]
- Research article Dmrt genes in the development and evolution of sexual dimorphism [9]
- Research article Sex determination, gonadal sex differentiation, and plasticity in vertebrate species [10]
References
- Garcia-Alonso L, Lorenzi V, Mazzeo CI, Alves-Lopes JP, Roberts K, Sancho-Serra C, et al.. Single-cell roadmap of human gonadal development. . 2022. PMID 35794482 · DOI · PMC9300467
- Robinett CC, Vaughan AG, Knapp JM, Baker BS. Sex and the single cell. II. There is a time and place for sex. . 2010. PMID 20454565 · DOI · PMC2864297
- Gempe T, Beye M. Function and evolution of sex determination mechanisms, genes and pathways in insects. . 2011. PMID 21110346 · DOI · PMC3040292
- Chen YY, Rodriguez K, Alexander AK, Xu X, Papas B, Estermann MA, et al.. Single-nucleus multiomics of murine gonads reveals transcriptional regulatory network underlying supporting lineage differentiation. . 2026. PMID 41481707 · DOI · PMC12758517
- Schulz KM, Molenda-Figueira HA, Sisk CL. Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence. Horm Behav. 2009. PMID 19446076 · DOI · PMC2720102
- Collaer ML, Hines M. Human behavioral sex differences: a role for gonadal hormones during early development?. Psychol Bull. 1995. PMID 7644606 · DOI
- Kret ME, De Gelder B. A review on sex differences in processing emotional signals. Neuropsychologia. 2012. PMID 22245006 · DOI
- Lenz KM, McCarthy MM. A starring role for microglia in brain sex differences. Neuroscientist. 2015. PMID 24871624 · DOI · PMC5742269
- Kopp A. Dmrt genes in the development and evolution of sexual dimorphism. Trends Genet. 2012. PMID 22425532 · DOI · PMC3350790
- Nagahama Y, Chakraborty T, Paul-Prasanth B, Ohta K, Nakamura M. Sex determination, gonadal sex differentiation, and plasticity in vertebrate species. Physiol Rev. 2021. PMID 33180655 · DOI
About this article
- Sources
- NLM Medical Subject Headings (definition, synonyms); NCBI PubMed (counts, identifiers); Europe PMC (open-access abstracts and citation counts).
- Verification
- Every reference was resolved against PubMed on 2026-10-31; title, year and DOI matched.
- Review state
- automated source verified; no human expert review has been recorded yet.
- Version
- 1, last updated 2026-10-31.
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Evidence strength
EvidenceHelix's computed view of the study designs behind this topic: how common meta-analyses, randomized trials and reviews are, how recent the literature is, and a plain-language reading. It describes the design mix of the literature. It is not a quality appraisal of any study, and it is not medical advice.