Draft:Jost Model of Sexual Differentiation

The Jost Model is named after French endocrinologist Alfred Jost (1916–1991), whose pioneering experiments in the mid-20th century transformed the understanding of sexual differentiation in mammals. Before Jost’s work, sexual development was largely thought to be a passive process directed solely by genetic sex (XX or XY chromosomes). However, Jost demonstrated that the differentiation of sexual characteristics is driven by hormonal signals originating from the developing gonads.{{Cite journal |last=Josso |first=N. |date=2008-06-20 |title=Professor Alfred Jost: The Builder of Modern Sex Differentiation |url=https://karger.com/sxd/article-abstract/2/2/55/308254/Professor-Alfred-Jost-The-Builder-of-Modern-Sex?redirectedFrom=fulltext |journal=Sexual Development |volume=2 |issue=2 |pages=55–63 |doi=10.1159/000129690 |pmid=18577872 |issn=1661-5425}}{{Cite journal |last=Jost |first=Alfred |date=1968 |title=Full or Partial Maturation of Fetal Endocrine Systems under Pituitary Control |url=https://muse.jhu.edu/article/406235 |journal=Perspectives in Biology and Medicine |volume=11 |issue=3 |pages=371–375 |doi=10.1353/pbm.1968.0041 |pmid=5704208 |issn=1529-8795}}{{Citation |last=Jost |first=Alfred |title=Novartis Foundation Symposia |date=1969 |work=Ciba Foundation Symposium - Foetal Autonomy |pages=79–94 |url=https://onlinelibrary.wiley.com/doi/10.1002/9780470719688.ch5 |access-date=2025-01-26 |publisher=John Wiley & Sons, Ltd |language=en |doi=10.1002/9780470719688.ch5 |isbn=978-0-470-71968-8}}

Jost’s landmark experiments in the 1940s involved the surgical removal of gonads (gonadectomy) from rabbit embryos at different stages of development. He observed that in the absence of gonads, the embryos consistently developed female reproductive tracts, regardless of their genetic sex. These results led Jost to propose that female development occurs by default in the absence of hormonal signals, while male development requires active hormonal intervention.{{Cite journal |last=Jost |first=A. |date=1947-11-01 |title=The Age Factor in the Castration of Male Rabbit Fetuses |url=https://journals.sagepub.com/doi/abs/10.3181/00379727-66-16071 |journal=Proceedings of the Society for Experimental Biology and Medicine |language=en |volume=66 |issue=2 |pages=302–303 |doi=10.3181/00379727-66-16071 |pmid=18921738 |issn=0037-9727}}{{Citation |last=Jost |first=Alfred |title=Sexual Organogenesis |date=1985 |work=Reproduction |series=Handbook of Behavioral Neurobiology |volume=7 |pages=3–19 |editor-last=Adler |editor-first=Norman |url=https://link.springer.com/chapter/10.1007/978-1-4684-4832-0_1 |access-date=2025-01-26 |place=Boston, MA |publisher=Springer US |language=en |doi=10.1007/978-1-4684-4832-0_1 |isbn=978-1-4684-4832-0 |editor2-last=Pfaff |editor2-first=Donald |editor3-last=Goy |editor3-first=Robert W.}}

Jost identified two key hormones secreted by the testes that are essential for male differentiation:

• Testosterone: Responsible for the development of the Wolffian ducts into male internal reproductive structures, such as the epididymis, vas deferens, and seminal vesicles.{{Citation |last=Jost |first=Alfred |title=Hormonal Factors in the Development of the Male Genital System |date=1970 |work=The Human Testis: Proceedings of the Workshop Conference held at Positano, Italy, April 23–25, 1970 |series=Advances in Experimental Medicine and Biology |volume=10 |pages=11–18 |editor-last=Rosemberg |editor-first=Eugenia |url=https://link.springer.com/chapter/10.1007/978-1-4615-9008-8_2 |access-date=2025-01-26 |place=Boston, MA |publisher=Springer US |language=en |doi=10.1007/978-1-4615-9008-8_2 |isbn=978-1-4615-9008-8 |editor2-last=Paulsen |editor2-first=C. Alvin}}
• Anti-Müllerian Hormone (AMH): Produced by Sertoli cells, this hormone causes the regression of the Müllerian ducts, which would otherwise develop into female reproductive structures (e.g., uterus and fallopian tubes).{{Cite journal |last=Schoot |first=P. van der |date=1993-08-01 |title=Foetal testes control the prenatal growth and differentiation of the gubernacular cones in rabbits - a tribute to the late Professor Alfred Jost |url=https://journals.biologists.com/dev/article/118/4/1327/38118/Foetal-testes-control-the-prenatal-growth-and |journal=Development |volume=118 |issue=4 |pages=1327–1334 |doi=10.1242/dev.118.4.1327 |pmid=8269858 |issn=0950-1991}}

Jost’s work also demonstrated that external genitalia are highly sensitive to the presence of androgens. In the absence of testosterone, external genitalia develop along female pathways, while exposure to testosterone leads to masculinization.{{Cite journal |last=Jost |first=Alfred |date=1983-01-01 |title=Genetic and hormonal factors in sex differentiation of the brain |url=https://linkinghub.elsevier.com/retrieve/pii/0306453083900550 |journal=Psychoneuroendocrinology |volume=8 |issue=2 |pages=183–193 |doi=10.1016/0306-4530(83)90055-0 |pmid=6353469 |issn=0306-4530}}{{Cite journal |last=Jost |first=Alfred |date=1973 |title=Hormonal effects on fetal development: A survey |url=https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt1973144part2714 |journal=Clinical Pharmacology & Therapeutics |language=en |volume=14 |issue=4part2 |pages=714–720 |doi=10.1002/cpt1973144part2714 |pmid=4737095 |issn=1532-6535}}

Jost’s findings laid the foundation for modern endocrinology and developmental biology. His work established that gonadal hormones, rather than genetic sex alone, play a decisive role in sexual differentiation. Subsequent research has expanded on the Jost model, incorporating insights into the genetic, epigenetic, and environmental factors that also contribute to the development of sexual phenotypes.{{Cite journal |last=JOST |first=A. |date=1973 |title=A new look at the mechanisms controlling sex differentiation in mammals |url=https://cir.nii.ac.jp/crid/1573668926044482048 |journal=Johns Hopkins Med J |volume=130 |issue=1 |pages=38–53|pmid=4481103 }}

The Jost Model of sexual differentiation describes the critical role of hormones produced by the gonads in directing the development of male and female phenotypes in mammals. According to the model, sexual differentiation is governed by the interplay of genetic signals, gonadal development, and hormonal activity. The key components of the model include the following:

• The process of sexual differentiation begins with genetic sex, determined at fertilization by the combination of sex chromosomes (XX or XY).{{Cite journal |last1=Jost |first1=A. |last2=Magre |first2=S. |last3=McLaren |first3=Anne Laura Dorinthea |last4=Sharma |first4=H. |last5=McLaren |first5=Anne Laura Dorinthea |last6=Ferguson-Smith |first6=Malcolm Andrew |date=1997-01-12 |title=Control mechanisms of testicular differentiation |url=https://royalsocietypublishing.org/doi/10.1098/rstb.1988.0113 |journal=Philosophical Transactions of the Royal Society of London. B, Biological Sciences |volume=322 |issue=1208 |pages=55–61 |doi=10.1098/rstb.1988.0113|pmid=2907803 }}
• In mammals, the SRY (Sex-determining Region on the Y chromosome) gene, located on the Y chromosome, triggers the development of the undifferentiated gonads into testes.{{Cite journal |last1=Jost |first1=A. |last2=Magre |first2=S. |last3=Agelopoulou |first3=R. |date=1981-08-01 |title=Early stages of testicular differentiation in the rat |url=https://link.springer.com/article/10.1007/BF00284150 |journal=Human Genetics |language=en |volume=58 |issue=1 |pages=59–63 |doi=10.1007/BF00284150 |pmid=7286994 |issn=1432-1203}}
• In the absence of the SRY gene (e.g., in XX embryos), the gonads develop into ovaries by default.Jost, A. (1979). Fetal hormones and fetal growth. Fetal Endocrinology, Contributions to Gynecology and Obstetrics, 5, 1-20.

Male differentiation requires active hormonal signaling from the developing testes. Two key hormones are involved:

• Testosterone:
• Secreted by Leydig cells of the testes, testosterone promotes the development of the Wolffian ducts into male internal reproductive structures, including the epididymis, vas deferens, and seminal vesicles.{{Cite journal |last1=Magre |first1=S |last2=Jost |first2=A |date=1980-01-01 |title=The initial phases of testicular organogenesis in the rat. An electron microscopy study |url=https://europepmc.org/article/med/7212698 |journal=Archives d'anatomie microscopique et de morphologie experimentale |volume=69 |issue=4 |pages=297–318 |issn=0003-9594 |pmid=7212698}}{{Cite journal |last1=Jost |first1=A |last2=Perlman |first2=S |last3=Valentino |first3=O |last4=Castanier |first4=M |last5=Scholler |first5=R |last6=Magre |first6=S |date=1988-12-01 |title=Experimental control of the differentiation of Leydig cells in the rat fetal testis. |journal=Proceedings of the National Academy of Sciences |volume=85 |issue=21 |pages=8094–8097 |doi=10.1073/pnas.85.21.8094 |doi-access=free |pmc=282361 |pmid=3186712|bibcode=1988PNAS...85.8094J }}
• Testosterone is also converted into dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is critical for the masculinization of external genitalia.{{Cite journal |last1=Magre |first1=Solange |last2=Jost |first2=Alfred |date=1991 |title=Sertoli cells and testicular differentiation in the rat fetus |url=https://onlinelibrary.wiley.com/doi/10.1002/jemt.1060190205 |journal=Journal of Electron Microscopy Technique |language=en |volume=19 |issue=2 |pages=172–188 |doi=10.1002/jemt.1060190205 |pmid=1748901 |issn=1553-0817}}
• Anti-Müllerian Hormone (AMH):
• Produced by Sertoli cells of the testes, AMH induces the regression of the Müllerian ducts, preventing the development of female internal reproductive structures such as the uterus and fallopian tubes.{{Cite journal |last1=Magre |first1=S |last2=Jost |first2=A |date=1984-12-15 |title=Dissociation between testicular organogenesis and endocrine cytodifferentiation of Sertoli cells. |journal=Proceedings of the National Academy of Sciences |volume=81 |issue=24 |pages=7831–7834 |doi=10.1073/pnas.81.24.7831 |doi-access=free |pmc=392246 |pmid=6595663|bibcode=1984PNAS...81.7831M }}{{Cite journal |last=Jost |first=A. |date=1973 |title=Becoming a male |url=https://pubmed.ncbi.nlm.nih.gov/4805859/ |journal=Advances in the Biosciences |volume=10 |pages=3–13 |issn=0065-3446 |pmid=4805859}}

• In the absence of testes and their associated hormones (e.g., in XX embryos), the Müllerian ducts develop into female internal reproductive structures, including the uterus, fallopian tubes, and upper vagina.{{Cite journal |last=Jost |first=A. |date=2010-03-19 |title=Use of Androgen Antagonists and Antiandrogens in Studies on Sex Differentiation |url=https://karger.com/goi/article-abstract/2/1-6/180/388474/Use-of-Androgen-Antagonists-and-Antiandrogens-in?redirectedFrom=fulltext |journal=Gynecologic Investigation |volume=2 |issue=1–6 |pages=180–201 |doi=10.1159/000301861 |pmid=4949979 |issn=0017-5986}}
• The Wolffian ducts, which require testosterone for maintenance, degenerate in the absence of this hormone.
• External genitalia follow the "default" female developmental pathway in the absence of androgenic signaling.{{Cite book |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9780470720448 |title=Ciba Foundation Symposium 62 - Sex, Hormones and Behaviour |date=1979-01-01 |publisher=Wiley |isbn=978-0-470-66352-3 |editor-last=Porter |editor-first=Ruth |edition=1 |series=Novartis Foundation Symposia |language=en |doi=10.1002/9780470720448 |editor-last2=Whelan |editor-first2=Julie }}

• The process of sexual differentiation occurs during critical windows of embryonic development, known as sensitive periods.{{Cite journal |last1=Chartrain |first1=Isabelle |last2=Magre |first2=Solange |last3=Maingourd |first3=Michèle |last4=Jost |first4=Alfred |date=1984-12-01 |title=Effect of serum on organogenesis of the rat testis in vitro |url=https://link.springer.com/article/10.1007/BF02619664 |journal=In Vitro |language=en |volume=20 |issue=12 |pages=912–922 |doi=10.1007/BF02619664 |pmid=6530227 |issn=1475-2689}}Jost, A. (1970). Critical Periods in Endocrine Effects During Fetal Development. Environmental Influences on Genetic Expression: Biological and Behavioral Aspects of Sexual Differentiation, 16(2), 19.
• Hormones must be present at specific concentrations and times to induce male differentiation. If these signals are disrupted, development may follow the female pathway, regardless of genetic sex.{{Cite journal |last=Jost |first=Alfred |date=1954-01-01 |title=Hormonal Factors in the Development of the Fetus |url=https://symposium.cshlp.org/content/19/167.extract |journal=Cold Spring Harbor Symposia on Quantitative Biology |language=en |volume=19 |pages=167–181 |doi=10.1101/SQB.1954.019.01.023 |issn=0091-7451 |pmid=13291201}}

• The Jost model emphasizes the dominance of hormonal signals over genetic sex in determining the development of secondary sexual characteristics.{{Citation |last=Jost |first=Alfred |title=9 Anterior Pituitary Function in Foetal Life |date=2023-12-22 |work=Volume 2 The Pituitary Gland, Volume 2 |pages=299–323 |url=https://www.degruyter.com/document/doi/10.1525/9780520340046-013/html |access-date=2025-01-26 |publisher=University of California Press |language=en |doi=10.1525/9780520340046-013 |isbn=978-0-520-34004-6}}{{Cite journal |last1=Margolis |first1=Frank L. |last2=Roffi |first2=Jacques |last3=Jost |first3=Alfred |date=1966-10-14 |title=Norepinephrine Methylation in Fetal Rat Adrenals |url=https://www.science.org/doi/10.1126/science.154.3746.275 |journal=Science |volume=154 |issue=3746 |pages=275–276 |doi=10.1126/science.154.3746.275|pmid=4288079 |bibcode=1966Sci...154..275M }}
• While genetic sex initiates gonadal differentiation, the hormones produced by the gonads direct the subsequent development of internal and external reproductive structures.{{Citation |last1=Jost |first1=ALFRED |title=Hormonal Control of Fetal Development and Metabolism |date=1970-01-01 |volume=4 |pages=123–184 |editor-last=Levine |editor-first=Rachmiel |url=https://linkinghub.elsevier.com/retrieve/pii/B9780120273041500107 |access-date=2025-01-26 |publisher=Elsevier |doi=10.1016/b978-0-12-027304-1.50010-7 |last2=Picon |first2=LUC |series=Advances in Metabolic Disorders |pmid=4922838 |isbn=978-0-12-027304-1 |editor2-last=Luft |editor2-first=Rolf}}{{Cite journal |last1=Jost |first1=A |last2=Prépin |first2=J |last3=Vigier |first3=B |date=1977-01-01 |title=Hormones in the morphogenesis of the genital system |url=https://europepmc.org/article/med/568495 |journal=Birth Defects Original Article Series |volume=13 |issue=2 |pages=85–97 |issn=0547-6844 |pmid=568495}}

The Jost model highlights the critical role of gonadal hormones in shaping sexual differentiation while also demonstrating that female development occurs in the absence of these signals. This framework has since been expanded to incorporate genetic and epigenetic factors, but its foundational principles remain central to the study of developmental biology.

The Jost Model has been instrumental in shaping modern understanding of sexual differentiation. However, as research has advanced, the model has been expanded, refined, and challenged to account for complexities beyond its original scope. This section highlights key extensions and criticisms of the model.

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While the Jost model provided a foundation for understanding sexual differentiation, later research has revealed additional layers of complexity:

Jost’s model focused primarily on the hormonal influence of the gonads, but subsequent discoveries have highlighted the importance of other genes in sexual development. For example, SOX9, FOXL2, and DAX1 play crucial roles in maintaining gonadal identity and initiating downstream pathways of sexual differentiation.{{Cite journal |last=Koopman |first=Peter |date=2005-07-01 |title=Sex determination: a tale of two Sox genes |url=https://linkinghub.elsevier.com/retrieve/pii/S0168952505001368 |journal=Trends in Genetics |language=English |volume=21 |issue=7 |pages=367–370 |doi=10.1016/j.tig.2005.05.006 |issn=0168-9525 |pmid=15949865}}{{Cite journal |last1=Wilson |first1=C. A. |last2=Davies |first2=D. C. |date=2007-02-01 |title=The control of sexual differentiation of the reproductive system and brain |url=https://rep.bioscientifica.com/view/journals/rep/133/2/1330331.xml |journal=Reproduction |language=en-US |volume=133 |issue=2 |pages=331–359 |doi=10.1530/REP-06-0078 |pmid=17307903 |issn=1741-7899}}

Research has also uncovered how epigenetic modifications influence gene expression during sexual development, adding another dimension to the genetic control of differentiation.{{Cite journal |last1=Uhlenhaut |first1=N. Henriette |last2=Jakob |first2=Susanne |last3=Anlag |first3=Katrin |last4=Eisenberger |first4=Tobias |last5=Sekido |first5=Ryohei |last6=Kress |first6=Jana |last7=Treier |first7=Anna-Corina |last8=Klugmann |first8=Claudia |last9=Klasen |first9=Christian |last10=Holter |first10=Nadine I. |last11=Riethmacher |first11=Dieter |last12=Schütz |first12=Günther |last13=Cooney |first13=Austin J. |last14=Lovell-Badge |first14=Robin |last15=Treier |first15=Mathias |date=2009-12-11 |title=Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation |url=https://linkinghub.elsevier.com/retrieve/pii/S0092867409014330 |journal=Cell |language=English |volume=139 |issue=6 |pages=1130–1142 |doi=10.1016/j.cell.2009.11.021 |issn=0092-8674 |pmid=20005806}}

The Jost model emphasized the development of gonads and external genitalia, but further research has shown that the brain also undergoes sexual differentiation. This process is influenced by prenatal androgens and estrogens, affecting reproductive behavior and sex-specific traits.{{Cite journal |last1=McCarthy |first1=Margaret M. |last2=Arnold |first2=Arthur P. |date=2011-06-01 |title=Reframing sexual differentiation of the brain |journal=Nature Neuroscience |language=en |volume=14 |issue=6 |pages=677–683 |doi=10.1038/nn.2834 |issn=1546-1726 |pmc=3165173 |pmid=21613996}}

Studies on rodents and primates have demonstrated that the organizational and activational effects of hormones extend to neural development, shaping sex-specific behaviors later in life.{{Citation |last1=Bocklandt |first1=Sven |title=Sex Differences in Brain and Behavior: Hormones Versus Genes |date=2007-01-01 |journal=Advances in Genetics |volume=59 |pages=245–266 |url=https://linkinghub.elsevier.com/retrieve/pii/S0065266007590097 |access-date=2025-01-26 |series=Genetics of Sexual Differentiation and Sexually Dimorphic Behaviors |publisher=Academic Press |doi=10.1016/s0065-2660(07)59009-7 |last2=Vilain |first2=Eric|pmid=17888801 |isbn=978-0-12-017660-1 }}

Extensions to the model incorporate environmental factors, such as endocrine disruptors, which can mimic or block hormone action during critical windows of development. For example, exposure to chemicals like bisphenol A (BPA) or phthalates has been shown to affect sexual differentiation in both humans and animals.{{Cite journal |last1=Gore |first1=A. C. |last2=Chappell |first2=V. A. |last3=Fenton |first3=S. E. |last4=Flaws |first4=J. A. |last5=Nadal |first5=A. |last6=Prins |first6=G. S. |last7=Toppari |first7=J. |last8=Zoeller |first8=R. T. |date=2015-12-01 |title=EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals |journal=Endocrine Reviews |volume=36 |issue=6 |pages=E1–E150 |doi=10.1210/er.2015-1010 |issn=0163-769X |pmc=4702494 |pmid=26544531}}

The Jost model has been adapted to study sexual differentiation in non-mammalian species, such as reptiles with temperature-dependent sex determination and fish that undergo sequential hermaphroditism. These cases illustrate how sexual differentiation pathways vary across taxa, offering insights into their evolutionary diversity.{{Cite journal |last=Pieau |first=Claude |date=1996 |title=Temperature variation and sex determination in reptiles |url=https://onlinelibrary.wiley.com/doi/10.1002/bies.950180107 |journal=BioEssays |language=en |volume=18 |issue=1 |pages=19–26 |doi=10.1002/bies.950180107 |issn=1521-1878}}{{Cite journal |last1=Devlin |first1=Robert H. |last2=Nagahama |first2=Yoshitaka |date=2002-06-21 |title=Sex determination and sex differentiation in fish: an overview of genetic, physiological, and environmental influences |url=https://linkinghub.elsevier.com/retrieve/pii/S0044848602000571 |journal=Aquaculture |series=Sex determination and sex differentation in fish |volume=208 |issue=3 |pages=191–364 |doi=10.1016/S0044-8486(02)00057-1 |bibcode=2002Aquac.208..191D |issn=0044-8486}}{{Cite journal |last1=Pfennig |first1=Frank |last2=Standke |first2=Andrea |last3=Gutzeit |first3=Herwig O. |date=2015-11-01 |title=The role of Amh signaling in teleost fish – Multiple functions not restricted to the gonads |url=https://linkinghub.elsevier.com/retrieve/pii/S0016648015002695 |journal=General and Comparative Endocrinology |volume=223 |pages=87–107 |doi=10.1016/j.ygcen.2015.09.025 |pmid=26428616 |issn=0016-6480}}

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While groundbreaking, the Jost model has faced criticism for its oversimplified assumptions and incomplete coverage of the factors influencing sexual differentiation:

The model posits that female development occurs by default in the absence of gonadal hormones, but more recent studies suggest that ovarian differentiation and female pathways are actively regulated by specific genetic factors, such as RSPO1, WNT4, and FOXL2. Female differentiation is not merely a passive process but an equally active one.{{Cite journal |last1=Parma |first1=Pietro |last2=Radi |first2=Orietta |last3=Vidal |first3=Valerie |last4=Chaboissier |first4=Marie Christine |last5=Dellambra |first5=Elena |last6=Valentini |first6=Stella |last7=Guerra |first7=Liliana |last8=Schedl |first8=Andreas |last9=Camerino |first9=Giovanna |date=2006-11-01 |title=R-spondin1 is essential in sex determination, skin differentiation and malignancy |url=https://www.nature.com/articles/ng1907 |journal=Nature Genetics |language=en |volume=38 |issue=11 |pages=1304–1309 |doi=10.1038/ng1907 |pmid=17041600 |issn=1546-1718}}{{Cite journal |last1=Liu |first1=Chia-Feng |last2=Bingham |first2=Nathan |last3=Parker |first3=Keith |last4=Yao |first4=Humphrey H.-C. |date=2009-02-01 |title=Sex-specific roles of β-catenin in mouse gonadal development |url=https://academic.oup.com/hmg/article/18/3/405/2527108 |journal=Human Molecular Genetics |volume=18 |issue=3 |pages=405–417 |doi=10.1093/hmg/ddn362 |issn=0964-6906 |pmc=2638797 |pmid=18981061}}{{Cite journal |last1=Corada |first1=Monica |last2=Orsenigo |first2=Fabrizio |last3=Bhat |first3=Ganesh Parameshwar |last4=Conze |first4=Lei Liu |last5=Breviario |first5=Ferruccio |last6=Cunha |first6=Sara Isabel |last7=Claesson-Welsh |first7=Lena |last8=Beznoussenko |first8=Galina V. |last9=Mironov |first9=Alexander A. |last10=Bacigaluppi |first10=Marco |last11=Martino |first11=Gianvito |last12=Pitulescu |first12=Mara E. |last13=Adams |first13=Ralf H. |last14=Magnusson |first14=Peetra |last15=Dejana |first15=Elisabetta |date=2019-02-15 |title=Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier |journal=Circulation Research |volume=124 |issue=4 |pages=511–525 |doi=10.1161/CIRCRESAHA.118.313316 |pmc=6407809 |pmid=30591003}}

By focusing primarily on hormonal signals, the Jost model downplays the interactions between chromosomal sex and molecular signaling pathways. These genetic networks are crucial in coordinating the development of gonads and secondary sexual characteristics.{{Cite journal |last1=Knoedler |first1=Joseph R |last2=Shah |first2=Nirao M |date=2018-12-01 |title=Molecular mechanisms underlying sexual differentiation of the nervous system |journal=Current Opinion in Neurobiology |series=Developmental Neuroscience |volume=53 |pages=192–197 |doi=10.1016/j.conb.2018.09.005 |issn=0959-4388 |pmc=6347421 |pmid=30316066}}{{Cite journal |last1=Blencowe |first1=Montgomery |last2=Chen |first2=Xuqi |last3=Zhao |first3=Yutian |last4=Itoh |first4=Yuichiro |last5=McQuillen |first5=Caden N. |last6=Han |first6=Yanjie |last7=Shou |first7=Benjamin L. |last8=McClusky |first8=Rebecca |last9=Reue |first9=Karen |last10=Arnold |first10=Arthur P. |last11=Yang |first11=Xia |date=2022-05-01 |title=Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation |url=https://genome.cshlp.org/content/32/5/807 |journal=Genome Research |language=en |volume=32 |issue=5 |pages=807–824 |doi=10.1101/gr.275965.121 |issn=1088-9051 |pmc=9104702 |pmid=35396276}}

The model assumes a binary pathway of development (male or female) and does not fully address the diversity of sex development observed in nature, including intersex conditions and variations in DSDs.{{Cite book |last=Fausto-Sterling |first=Anne |url=https://archive.org/details/sexingbodygender0000faus |title=Sexing the body : gender politics and the construction of sexuality |date=2000 |publisher=New York, NY : Basic Books |others=Internet Archive |isbn=978-0-465-07713-7}}

It also fails to account for sex determination systems beyond the XX/XY framework, such as the ZW system in birds or haplodiploidy in insects.{{Cite journal |last1=Trukhina |first1=Antonina V. |last2=Lukina |first2=Natalia A. |last3=Wackerow-Kouzova |first3=Natalia D. |last4=Smirnov |first4=Alexander F. |date=2013 |title=The Variety of Vertebrate Mechanisms of Sex Determination |journal=BioMed Research International |language=en |volume=2013 |issue=1 |pages=587460 |doi=10.1155/2013/587460 |doi-access=free |issn=2314-6141 |pmc=3867867 |pmid=24369014}}{{Cite journal |last1=Bertho |first1=Sylvain |last2=Herpin |first2=Amaury |last3=Schartl |first3=Manfred |last4=Guiguen |first4=Yann |date=2021-07-12 |title=Lessons from an unusual vertebrate sex-determining gene |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=376 |issue=1832 |pages=20200092 |doi=10.1098/rstb.2020.0092 |pmc=8273500 |pmid=34247499}}

Although the model explains physical differentiation, it does not address the influence of hormones and genes on behavioral traits or their interaction with environmental and social factors. These aspects are critical for understanding the full spectrum of sexual development in humans and animals.{{Citation |last1=Robakis |first1=T. K. |title=Hormonal Influences on Behavior |date=2014-01-01 |work=Reference Module in Biomedical Sciences |url=https://linkinghub.elsevier.com/retrieve/pii/B978012801238300221X |access-date=2025-01-26 |publisher=Elsevier |doi=10.1016/b978-0-12-801238-3.00221-x |isbn=978-0-12-801238-3 |last2=Rasgon |first2=N. L.}}{{Cite journal |last1=Garland |first1=Theodore, Jr. |last2=Zhao |first2=Meng |last3=Saltzman |first3=Wendy |date=2016-08-01 |title=Hormones and the Evolution of Complex Traits: Insights from Artificial Selection on Behavior |url=https://academic.oup.com/icb/article/56/2/207/2240669 |journal=Integrative and Comparative Biology |volume=56 |issue=2 |pages=207–224 |doi=10.1093/icb/icw040 |issn=1540-7063 |pmc=5964798 |pmid=27252193}}{{Cite journal |last=Rubenstein |first=Dustin R |date=2007-01-17 |title=Stress hormones and sociality: integrating social and environmental stressors |journal=Proceedings of the Royal Society B: Biological Sciences |volume=274 |issue=1612 |pages=967–975 |doi=10.1098/rspb.2006.0051 |pmc=2141667 |pmid=17251100}}

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The limitations of the Jost model have led to the development of more comprehensive frameworks, such as the biopsychosocial model of sex development, which integrates genetics, hormones, environment, and cultural factors. Additionally, ongoing research continues to expand the understanding of sexual differentiation by exploring:

• The role of non-coding RNAs in gonadal development.{{Cite journal |last1=Li |first1=Ziming |last2=Liu |first2=Xinghai |last3=Tang |first3=Xinyue |last4=Yang |first4=Yujia |date=2025-06-01 |title=Analysis of gonadal transcriptome reveals core long non-coding RNA-mRNA regulatory network in sea cucumber Apostichopus japonicus |url=https://linkinghub.elsevier.com/retrieve/pii/S1744117X24002090 |journal=Comparative Biochemistry and Physiology Part D: Genomics and Proteomics |volume=54 |pages=101396 |doi=10.1016/j.cbd.2024.101396 |pmid=39667089 |issn=1744-117X}}{{Cite journal |last1=Huang |first1=Tianqing |last2=Gu |first2=Wei |last3=Liu |first3=Enhui |last4=Shi |first4=Xiulan |last5=Wang |first5=Bingqian |last6=Wu |first6=Wenhua |last7=Dong |first7=Fulin |last8=Xu |first8=Gefeng |date=2021-11-01 |title=Comprehensive analysis of miRNA-mRNA/lncRNA during gonadal development of triploid female rainbow trout (Oncorhynchus mykiss) |url=https://linkinghub.elsevier.com/retrieve/pii/S0888754321003347 |journal=Genomics |volume=113 |issue=6 |pages=3533–3543 |doi=10.1016/j.ygeno.2021.08.018 |pmid=34450291 |issn=0888-7543}}
• The interplay between maternal hormones and embryonic development.{{Citation |last1=Abruzzese |first1=Giselle Adriana |title=Role of Hormones During Gestation and Early Development: Pathways Involved in Developmental Programming |date=2023 |work=Advances in Maternal-Fetal Biomedicine: Cellular and Molecular Mechanisms of Pregnancy Pathologies |pages=31–70 |editor-last=Gonzalez-Ortiz |editor-first=Marcelo |url=https://link.springer.com/chapter/10.1007/978-3-031-32554-0_2 |access-date=2025-01-26 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-031-32554-0_2 |isbn=978-3-031-32554-0 |last2=Arbocco |first2=Fiorella Campo Verde |last3=Ferrer |first3=María José |last4=Silva |first4=Aimé Florencia |last5=Motta |first5=Alicia Beatriz|volume=1428 |pmid=37466768 }}{{Cite journal |last1=Eising |first1=Corine M |last2=Müller |first2=Wendt |last3=Groothuis |first3=Ton G.G |date=2005-10-05 |title=Avian mothers create different phenotypes by hormone deposition in their eggs |journal=Biology Letters |volume=2 |issue=1 |pages=20–22 |doi=10.1098/rsbl.2005.0391 |pmc=1617191 |pmid=17148315}}
• The long-term effects of prenatal hormone exposure on health and behavior.{{Cite journal |last1=Mouton |first1=James C. |last2=Duckworth |first2=Renée A. |date=2021-01-27 |title=Maternally derived hormones, neurosteroids and the development of behaviour |journal=Proceedings of the Royal Society B: Biological Sciences |volume=288 |issue=1943 |pages=20202467 |doi=10.1098/rspb.2020.2467 |pmc=7893274 |pmid=33499795}}{{Cite journal |last1=Welberg |first1=L. a. M. |last2=Seckl |first2=J. R. |date=2001 |title=Prenatal Stress, Glucocorticoids and the Programming of the Brain |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2826.2001.00601.x |journal=Journal of Neuroendocrinology |language=en |volume=13 |issue=2 |pages=113–128 |doi=10.1111/j.1365-2826.2001.00601.x |pmid=11168837 |issn=1365-2826}}

These modern extensions acknowledge the complexity and diversity of sexual differentiation processes, building on Jost’s foundational insights while addressing its shortcomings.{{Cite journal |last1=Houk |first1=Christopher P. |last2=Hughes |first2=Ieuan A. |last3=Ahmed |first3=S. Faisal |last4=Lee |first4=Peter A. |last5=Writing Committee for the International Intersex Consensus Conference Participants |date=2006-08-01 |title=Summary of Consensus Statement on Intersex Disorders and Their Management |url=https://publications.aap.org/pediatrics/article-abstract/118/2/753/69039/Summary-of-Consensus-Statement-on-Intersex?redirectedFrom=fulltext |journal=Pediatrics |volume=118 |issue=2 |pages=753–757 |doi=10.1542/peds.2006-0737 |pmid=16882833 |issn=0031-4005}}{{Citation |last=Zarkower |first=David |title=Gametogenesis |chapter=DMRT Genes in Vertebrate Gametogenesis |date=2013-01-01 |series=Current Topics in Developmental Biology |volume=102 |pages=327–356 |editor-last=Wassarman |editor-first=Paul M. |chapter-url=https://linkinghub.elsevier.com/retrieve/pii/B978012416024800012X |access-date=2025-01-26 |publisher=Academic Press |doi=10.1016/b978-0-12-416024-8.00012-x|pmid=23287039 |isbn=978-0-12-416024-8 }}{{Cite journal |last=Schoot |first=P. van der |date=1996-01-01 |title=Autonomous testicular hormonal control of fetal gubernaculum development in rabbits: a re-examination of histological slides in the legacy of the late Professor Alfred Jost |url=https://rep.bioscientifica.com/view/journals/rep/106/1/jrf_106_1_022.xml |journal=Reproduction |language=en-US |volume=106 |issue=1 |pages=153–159 |doi=10.1530/jrf.0.1060153 |pmid=8667340 |issn=0022-4251}}{{Cite journal |last1=Blecher |first1=Stan R. |last2=Erickson |first2=Robert P. |date=2007 |title=Genetics of sexual development: A new paradigm |url=https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32037 |journal=American Journal of Medical Genetics Part A |language=en |volume=143A |issue=24 |pages=3054–3068 |doi=10.1002/ajmg.a.32037 |pmid=18000910 |issn=1552-4833}}

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