Difference between revisions of "Talk:Ovary Development"

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'''Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells'''
The human ovary orchestrates sex hormone production and undergoes monthly structural changes to release mature oocytes. The outer lining of the ovary (cortex) has a key role in defining fertility in women as it harbors the ovarian reserve. It has been postulated that putative oogonial stem cells exist in the ovarian cortex and that these can be captured by DDX4 antibody isolation. Here, we report single-cell transcriptomes and cell surface antigen profiles of over 24,000 cells from high quality ovarian cortex samples from 21 patients. Our data identify transcriptional profiles of six main cell types; oocytes, granulosa cells, immune cells, endothelial cells, perivascular cells, and stromal cells. Cells captured by DDX4 antibody are perivascular cells, not oogonial stem cells. Our data do not support the existence of germline stem cells in adult human ovaries, thereby reinforcing the dogma of a limited ovarian reserve.
PMID: 32123174 DOI: 10.1038/s41467-020-14936-3

Revision as of 11:41, 5 March 2020

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Cite this page: Hill, M.A. (2021, November 29) Embryology Ovary Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Ovary_Development


Wagner M, Yoshihara M, Douagi I, Damdimopoulos A, Panula S, Petropoulos S, Lu H, Pettersson K, Palm K, Katayama S, Hovatta O, Kere J, Lanner F & Damdimopoulou P. (2020). Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nat Commun , 11, 1147. PMID: 32123174 DOI.

Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells

Abstract The human ovary orchestrates sex hormone production and undergoes monthly structural changes to release mature oocytes. The outer lining of the ovary (cortex) has a key role in defining fertility in women as it harbors the ovarian reserve. It has been postulated that putative oogonial stem cells exist in the ovarian cortex and that these can be captured by DDX4 antibody isolation. Here, we report single-cell transcriptomes and cell surface antigen profiles of over 24,000 cells from high quality ovarian cortex samples from 21 patients. Our data identify transcriptional profiles of six main cell types; oocytes, granulosa cells, immune cells, endothelial cells, perivascular cells, and stromal cells. Cells captured by DDX4 antibody are perivascular cells, not oogonial stem cells. Our data do not support the existence of germline stem cells in adult human ovaries, thereby reinforcing the dogma of a limited ovarian reserve. PMID: 32123174 DOI: 10.1038/s41467-020-14936-3


Neural crest-derived neurons invade the ovary but not the testis during mouse gonad development

Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5570-5575. doi: 10.1073/pnas.1814930116. Epub 2019 Feb 28.

McKey J1, Bunce C1, Batchvarov IS1, Ornitz DM2, Capel B3.

Testes and ovaries undergo sex-specific morphogenetic changes and adopt strikingly different morphologies, despite the fact that both arise from a common precursor, the bipotential gonad. Previous studies showed that recruitment of vasculature is critical for testis patterning. However, vasculature is not recruited into the early ovary. Peripheral innervation is involved in patterning development of many organs but has been given little attention in gonad development. In this study, we show that while innervation in the male reproductive complex is restricted to the epididymis and vas deferens and never invades the interior of the testis, neural crest-derived innervation invades the interior of the ovary around E16.5. Individual neural crest cells colonize the ovary, differentiate into neurons and glia, and form a dense neural network within the ovarian medulla. Using a sex-reversing mutant mouse line, we show that innervation is specific to ovary development, is not dependent on the genetic sex of gonadal or neural crest cells, and may be blocked by repressive guidance signals elevated in the male pathway. This study reveals another aspect of sexually dimorphic gonad development, establishes a precise timeline and structure of ovarian innervation, and raises many questions for future research. KEYWORDS: innervation; neural crest; organogenesis; ovary; testis PMID: 30819894 PMCID: PMC6431225 [Available on 2019-09-19] DOI: 10.1073/pnas.1814930116 [Indexed for MEDLINE]

  • XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage[1] "The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry- mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry- females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry- PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry- oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as "Swyer syndrome," in which patients with an XY karyotype present as typical females and are infertile."

5A80 Ovarian dysfunction

  • 5A80.0 Clinical hyperandrogenism - Presence of hirsutism, acne or androgenic alopecia (scalp hair loss in women)
  • 5A80.1 Polycystic ovary syndrome
  • 5A80.2 Polycystic ovary - Ovary with increased size (> 7 mL) and stromal volume, and with increased number of follicles (12 or more measuring 2-0 mm in diameter), that may be present in women with PCOS, but also in women with normal ovulatory function and normal fertility (unilaterally or bilaterally).
  • 5A80.3 Anovulation
  • 5A80.4 Oligo-ovulation - Oligo-ovulation (less than 4 ovulations in the last 12 months) not related to described categories of endocrine dysfunction. Excludes anovulation related to PCOS, hyperprolactinemia or amenorrhea.
  • 5A80.5 Diminished ovarian reserve - Ovaries with lower number of oocytes than expected for female chronologic age, marked by biochemical abnormalities (increased serum FSH levels, decreased serum AMH levels) and/or ultrasound findings (low antral follicle count) associated with ovarian ageing, reduced response to ovarian stimulation, and female infertility.

Removed old ICD-10 codings

E28 Ovarian dysfunction

  • Excl.: isolated gonadotropin deficiency (E23.0); postprocedural ovarian failure (E89.4)

E28.0 Estrogen excess

  • Use additional external cause code (Chapter XX), if desired, to identify drug, if drug-induced.

E28.1 Androgen excess

  • Hypersecretion of ovarian androgens
  • Use additional external cause code (Chapter XX), if desired, to identify drug, if drug-induced.

E28.2 Polycystic ovarian syndrome

  • Sclerocystic ovary syndrome
  • Stein-Leventhal syndrome

E28.3 Primary ovarian failure

  • Decreased oestrogen
  • Premature menopause NOS
  • Resistant ovary syndrome
  • Excl.: menopausal and female climacteric states (N95.1); pure gonadal dysgenesis (Q99.1); Turner syndrome (Q96.-)

E28.8 Other ovarian dysfunction

  • Ovarian hyperfunction NOS

E28.9 Ovarian dysfunction, unspecified

Human fetal ovarian germ cell development

  • 8–9 weeks gestation (mitotic PGC proliferation only)
  • 14–16 weeks gestation (formation of syncitial clusters of oogonia and onset of meiotic germ cell differentiation)
  • 17–20 weeks gestation (breakdown of syncitial clusters and assembly of primordial follicles)
Human Follicle Classification
Follicle Alternate nomenclature Type Number of Cells Size (diameter µm)
Primordial small 1, 2, 3 25 less than 50
Primary preantral 4
26 - 100
101 - 300
up to 200
Secondary small antral
large antral
3001 - 500
501 - 1000
Preovulatory Graafian 8 greater than1000 greater than 6000
Links: Ovary Development | Oocyte Development
Human Ovarian Follicle Classification
Class Alternate nomenclature Type Number of Cells Size (diameter µm) Size ultrasound (mm)
primordial follicle small 1, 2, 3 25 less than 50
primary follicle preantral 4
26 - 100
101 - 300
up to 200
secondary follicle antral
small antral
large antral


3001 - 500
501 - 1000
1000 - 6000
less than 18
preovulatory follicle Graafian 8 greater than 1000 greater than 6000 18 – 28
  Links: ovary | oocyte | menstrual cycle
Human Ovarian Follicle Classification  
Class Alternate nomenclature Type Number of Cells Size (diameter µm) Size ultrasound (mm)
primordial follicle small 1, 2, 3 25 less than 50
primary follicle preantral 4
26 - 100
101 - 300
up to 200
secondary follicle antral
small antral
large antral


3001 - 500
501 - 1000
1000 - 6000
less than 18
preovulatory follicle Graafian 8 greater than 1000 greater than 6000 18 – 28
  Links: ovary | oocyte | menstrual cycle
Follicle Classification
Primordial Follicle Preantral Follicle Antral Follicle Preovulatory Follicle
Alternative nomenclature: small follicle or type 1, 2, 3 (25 cells) less than 50 micron diameter Alternative nomenclature: preantral follicle or type 4 (26-100 cells), type 5 (101-300 cells) up to 200 micron diameter Alternative nomenclature: small antral type 6 (301-500 cells), large antral type 7 (501-1000 cells) small antral 500 micron diameter, large antral 1000-6000 micron diameter Alternative nomenclature: largest antral follicle or Graafian follicle or type 8 (>1000 cells) greater than 6000 micron diameter


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Reelin and aromatase cooperate in ovarian follicle development

Sci Rep. 2018 Jun 7;8(1):8722. doi: 10.1038/s41598-018-26928-x.

Meseke M1,2, Pröls F1,3, Schmahl C1, Seebo K1, Kruse C1, Brandt N1,4, Fester L1, Zhou L1, Bender R1, Rune GM5.


Reelin plays an important role in cerebral cortex development and synaptogenesis. In the hippocampus, the neurosteroid estrogen affects reelin expression. In this study we tested a potential crosstalk between estradiol and reelin, thus the possibility of a reelin-induced activation of the estradiol synthesizing enzyme aromatase. As a model system, we used ovaries, which express reelin and are a major source of estradiol. We found that in wild-type mice, reelin and aromatase are expressed in granulosa cells of growing follicles. The expression of reelin varies with the estrus cycle and is highest shortly before ovulation, when estradiol serum levels are at their maximum. In ovaries of reelin-deficient reeler mice, aromatase mRNA and protein are significantly reduced, as evidenced by real-time PCR, western blot analysis, and quantitative immunohistochemistry in granulosa cells of preovulatory follicles. In line with reduced estradiol synthesis, ovarian estrus cycle length is prolonged in reeler mice. Most importantly, treating cultured granulosa cells with recombinant reelin results in significant upregulation of aromatase mRNA and protein and increased secretion of estradiol into the supernatant. Our data provide evidence of a local increase of aromatase expression by reelin. Regarding reproduction, this crosstalk may contribute to follicular stability and counteract luteinization in ovaries. PMID: 29880879 PMCID: PMC5992190 DOI: 10.1038/s41598-018-26928-x

Effect of lysophosphatidic acid on the follicular development and the expression of lysophosphatidic acid receptor genes during in vitro culture of mouse ovary

Vet Res Forum. 2018 Winter;9(1):59-66. Epub 2018 Mar 15.

Abedpour N1, Salehnia M1, Ghorbanmehr N2.


Lysophosphatidic acid (LPA) known as a serum-derived growth factor, is involved in several cell physiological functions in the female reproductive system including: oocyte maturation, in vitro fertilization and embryo implantation by its transmembrane G protein-coupled receptors. The aim of the present study was to examine the effect of LPA on in vitro follicular development of mouse ovarian tissue. Neonatal mouse ovarian tissues were cultured in five different concentrations of LPA (0, 5, 10, 20 and 40 µM). The developmental competence and the function of cultured ovarian tissue were assessed by morphological study using hematoxylin and eosin staining and hormonal analysis. The expression of LPA receptor (LPAR 1-4) genes were analyzed by real-time RT-PCR. The proportion of preantral follicles and the level of E2 hormone were significantly higher in the 20 µM LPA-treated group than those in the other treatment groups. There was a significant difference in the expression of LPAR 1-4 genes in 20 µM LPA treated group in comparison with 0 µM LPA (control group) treated and non-cultured groups. In addition, the expression of LPAR1 gene was higher than other receptor genes in all studied groups. In conclusion supplementation of the media with 20 µM LPA, could improve the survival and developmental potential of follicles and it had positive effects on cell function and stimulation of E2 synthesis in mouse whole ovarian tissues. KEYWORDS: In vitro culture; Lysophosphatidic acid; Lysophosphatidic acid receptor; Mouse; Ovary PMID: 29719665

Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment

Nat Rev Endocrinol. 2018 May;14(5):270-284. doi: 10.1038/nrendo.2018.24. Epub 2018 Mar 23.

Escobar-Morreale HF1,2,3,4.


Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in premenopausal women. Heterogeneous by nature, PCOS is defined by a combination of signs and symptoms of androgen excess and ovarian dysfunction in the absence of other specific diagnoses. The aetiology of this syndrome remains largely unknown, but mounting evidence suggests that PCOS might be a complex multigenic disorder with strong epigenetic and environmental influences, including diet and lifestyle factors. PCOS is frequently associated with abdominal adiposity, insulin resistance, obesity, metabolic disorders and cardiovascular risk factors. The diagnosis and treatment of PCOS are not complicated, requiring only the judicious application of a few well-standardized diagnostic methods and appropriate therapeutic approaches addressing hyperandrogenism, the consequences of ovarian dysfunction and the associated metabolic disorders. This article aims to provide a balanced review of the latest advances and current limitations in our knowledge about PCOS while also providing a few clear and simple principles, based on current evidence-based clinical guidelines, for the proper diagnosis and long-term clinical management of women with PCOS. PMID: 29569621 DOI: 10.1038/nrendo.2018.24

Quantitative proteomic profiling of the human ovary from early to mid-gestation reveals protein expression dynamics of oogenesis and folliculogenesis

Stem Cells Dev. 2018 Apr 10. doi: 10.1089/scd.2018.0002. [Epub ahead of print]

Bothun A1, Gao Y2, Takai Y3, Ishihara O4, Seki H5, Karger B6, Tilly J7, Woods DC8. Author information Abstract The in-vivo gene networks involved in coordinating human fetal ovarian development remain obscure. Here, quantitative mass spectrometry was conducted on ovarian tissue collected at key stages during the first two trimesters of human gestational development, confirming the expression profiling data using immunofluorescence as well as in-vitro modeling with human oogonial stem cells (OSCs) and human embryonic stem cells (ESCs). A total of 3,837 proteins were identified in samples spanning developmental days 47-137. Bioinformatics clustering and Ingenuity Pathway Analysis identified DNA mismatch repair and base excision repair as major pathways upregulated during this time. Additionally, MAEL and TEX11, two key meiosis-related proteins, were identified as highly expressed during the developmental window associated with fetal oogenesis. These findings were confirmed and extended using in-vitro differentiation of OSCs into in-vitro-derived oocytes, and of ESCs into primordial germ cell-like cells and oocyte-like cells, as models. In conclusion, the global protein expression profiling data generated by this study have provided novel insights into human fetal ovarian development in-vivo and will serve as a valuable new resource for future studies of the signaling pathways used to orchestrate human oogenesis and folliculogenesis. PMID: 29631484 DOI: 10.1089/scd.2018.0002


Role of androgens in the ovary

Mol Cell Endocrinol. 2017 Jul 4. pii: S0303-7207(17)30353-2. doi: 10.1016/j.mce.2017.06.026. [Epub ahead of print]

Walters KA1, Handelsman DJ2.


It has been well established for decades that androgens, namely testosterone (T) plays an important role in female reproductive physiology as the precursor for oestradiol (E2). However, in the last decade a direct role for androgens, acting via the androgen receptor (AR), in female reproductive function has been confirmed. Deciphering the specific roles of androgens in ovarian function has been hindered as complete androgen resistant females cannot be generated by natural breeding. In addition, androgens can be converted into estrogens which has caused confusion when interpreting findings from pharmacological studies, as observed effects could have been mediated via the AR or estrogen receptor. The creation and analysis of genetic mouse models with global and cell-specific disruption of the Ar gene, the sole mediator of pure androgenic action, has now allowed the elucidation of a role for AR-mediated androgen actions in the regulation of normal and pathological ovarian function. This review aims to summarize findings from clinical, animal, pharmacological and novel genetic AR mouse models to provide an understanding of the important roles androgens play in the ovary, as well as providing insights into the human implications of these roles. KEYWORDS: Androgen receptor; Androgens; Ovary; PCOS PMID: 28687450 DOI: 10.1016/j.mce.2017.06.026


Anti-Mullerian Hormone: Above and Beyond Conventional Ovarian Reserve Markers

Dis Markers. 2016;2016:5246217. doi: 10.1155/2016/5246217. Epub 2016 Feb 10. Jamil Z1, Fatima SS1, Ahmed K1, Malik R1.


Management of ovarian dysfunctions requires accurate estimation of ovarian reserve (OR). Therefore, reproductive hormones and antral follicle count (AFC) are assessed to indicate OR. Serum anti-Mullerian hormone (AMH) is a unique biomarker that has a critical role in folliculogenesis as well as steroidogenesis within ovaries. Secretion from preantral and early antral follicles renders AMH as the earliest marker to show OR decline. In this review we discuss the dynamics of circulating AMH that remarkably vary with sex and age. As it emerges as a marker of gonadal development and reproductive disorders, here we summarize the role of AMH in female reproductive physiology and provide evidence of higher accuracy in predicting ovarian response to stimulation. Further, we attempt to compile potential clinical applications in children and adults. We propose that AMH evaluation has a potential role in effectively monitoring chemotherapy and pelvic radiation induced ovarian toxicity. Furthermore, AMH guided ovarian stimulation can lead to individualization of therapeutic strategies for infertility treatment. However future research on AMH levels within follicular fluid may pave the way to establish it as a marker of "quality" besides "quantity" of the growing follicles.

PMID 26977116


Transcriptome profiling of the theca interna from bovine ovarian follicles during atresia

PLoS One. 2014 Jun 23;9(6):e99706. doi: 10.1371/journal.pone.0099706. eCollection 2014.

Hatzirodos N1, Irving-Rodgers HF1, Hummitzsch K1, Rodgers RJ1.


The theca interna is a specialized stromal layer that envelops each growing ovarian follicle. It contains capillaries, fibroblasts, immune cells and the steroidogenic cells that synthesize androgens for conversion to estradiol by the neighboring granulosa cells. During reproductive life only a small number of follicles will grow to a sufficient size to ovulate, whereas the majority of follicles will undergo regression/atresia and phagocytosis by macrophages. To identify genes which are differentially regulated in the theca interna during follicular atresia, we undertook transcriptome profiling of the theca interna from healthy (n = 10) and antral atretic (n = 5) bovine follicles at early antral stages (<5 mm). Principal Component Analyses and hierarchical classification of the signal intensity plots for the arrays showed primary clustering into two groups, healthy and atretic. A total of 543 probe sets were differentially expressed between the atretic and healthy theca interna. Further analyses of these genes by Ingenuity Pathway Analysis and Gene Ontology Enrichment Analysis Toolkit software found most of the genes being expressed were related to cytokines, hormones and receptors as well as the cell cycle and DNA replication. Cell cycle genes which encode components of the replicating chromosome complex and mitotic spindle were down-regulated in atretic theca interna, whereas stress response and inflammation-related genes such as TP53, IKBKB and TGFB1 were up-regulated. In addition to cell cycle regulators, upstream regulators that were predicted to be inhibited included Retinoblastoma 1, E2 transcription factor 1, and hepatocyte growth factor. Our study suggests that during antral atresia of small follicles in the theca interna, arrest of cell cycle and DNA replication occurs rather than up- regulation of apoptosis-associated genes as occurs in granulosa cells. PMID 24956388

Development of mammalian ovary

J Endocrinol. 2014 Jun;221(3):R145-61. doi: 10.1530/JOE-14-0062. Epub 2014 Apr 16.

Smith P1, Wilhelm D2, Rodgers RJ2.


Pre-natal and early post-natal ovarian development has become a field of increasing importance over recent years. The full effects of perturbations of ovarian development on adult fertility, through environmental changes or genetic anomalies, are only now being truly appreciated. Mitigation of these perturbations requires an understanding of the processes involved in the development of the ovary. Herein, we review some recent findings from mice, sheep, and cattle on the key events involved in ovarian development. We discuss the key process of germ cell migration, ovigerous cord formation, meiosis, and follicle formation and activation. We also review the key contributions of mesonephric cells to ovarian development and propose roles for these cells. Finally, we discuss polycystic ovary syndrome, premature ovarian failure, and pre-natal undernutrition; three key areas in which perturbations to ovarian development appear to have major effects on post-natal fertility. © 2014 Society for Endocrinology. KEYWORDS: development; fetus; ovary; polycystic ovary syndrome; premature ovary failure

PMID 24741072



A new model of development of the mammalian ovary and follicles

PLoS One. 2013;8(2):e55578. doi: 10.1371/journal.pone.0055578. Epub 2013 Feb 7.

Hummitzsch K1, Irving-Rodgers HF, Hatzirodos N, Bonner W, Sabatier L, Reinhardt DP, Sado Y, Ninomiya Y, Wilhelm D, Rodgers RJ.


Ovarian follicular granulosa cells surround and nurture oocytes, and produce sex steroid hormones. It is believed that during development the ovarian surface epithelial cells penetrate into the ovary and develop into granulosa cells when associating with oogonia to form follicles. Using bovine fetal ovaries (n = 80) we identified a novel cell type, termed GREL for Gonadal Ridge Epithelial-Like. Using 26 markers for GREL and other cells and extracellular matrix we conducted immunohistochemistry and electron microscopy and chronologically tracked all somatic cell types during development. Before 70 days of gestation the gonadal ridge/ovarian primordium is formed by proliferation of GREL cells at the surface epithelium of the mesonephros. Primordial germ cells (PGCs) migrate into the ovarian primordium. After 70 days, stroma from the underlying mesonephros begins to penetrate the primordium, partitioning the developing ovary into irregularly-shaped ovigerous cords composed of GREL cells and PGCs/oogonia. Importantly we identified that the cords are always separated from the stroma by a basal lamina. Around 130 days of gestation the stroma expands laterally below the outermost layers of GREL cells forming a sub-epithelial basal lamina and establishing an epithelial-stromal interface. It is at this stage that a mature surface epithelium develops from the GREL cells on the surface of the ovary primordium. Expansion of the stroma continues to partition the ovigerous cords into smaller groups of cells eventually forming follicles containing an oogonium/oocyte surrounded by GREL cells, which become granulosa cells, all enclosed by a basal lamina. Thus in contrast to the prevailing theory, the ovarian surface epithelial cells do not penetrate into the ovary to form the granulosa cells of follicles, instead ovarian surface epithelial cells and granulosa cells have a common precursor, the GREL cell.

PMID 23409002


Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche

Nature. 2013 Mar 14;495(7440):241-5. doi: 10.1038/nature11979. Epub 2013 Mar 6.

Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, Nikitin AY. Author information


Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood. Some epithelial cancers are known to occur in transitional zones between two types of epithelium, whereas others have been shown to originate in epithelial tissue stem cells. The stem cell niche of the ovarian surface epithelium (OSE), which is ruptured and regenerates during ovulation, has not yet been defined unequivocally. Here we identify the hilum region of the mouse ovary, the transitional (or junction) area between the OSE, mesothelium and tubal (oviductal) epithelium, as a previously unrecognized stem cell niche of the OSE. We find that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1, LGR5, LEF1, CD133 and CK6B. These cells display long-term stem cell properties ex vivo and in vivo, as shown by our serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells show increased transformation potential after inactivation of tumour suppressor genes Trp53 and Rb1, whose pathways are altered frequently in the most aggressive and common type of human EOC, high-grade serous adenocarcinoma. Our study supports experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in those areas. Identification of a stem cell niche for the OSE may have important implications for understanding EOC pathogenesis. Comment in Ovarian cancer: At the starting line. [Nat Rev Cancer. 2013] Stem cells: Anatomy of an ovarian cancer. [Nature. 2013]

PMID 23467088

Genome-wide methylated DNA immunoprecipitation analysis of patients with polycystic ovary syndrome

PLoS One. 2013 May 21;8(5):e64801. doi: 10.1371/journal.pone.0064801. Print 2013.

Shen HR, Qiu LH, Zhang ZQ, Qin YY, Cao C, Di W. Source Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.


Polycystic ovary syndrome (PCOS) is a complex, heterogeneous disorder of uncertain etiology. Recent studies suggested that insulin resistance (IR) plays an important role in the development of PCOS. In the current study, we aimed to investigate the molecular mechanism of IR in PCOS. We employed genome-wide methylated DNA immunoprecipitation (MeDIP) analysis to characterize genes that are differentially methylated in PCOS patients vs. healthy controls. Besides, we also identified the differentially methylated genes between patients with PCOS-non-insulin resistance (PCOS-NIR) and PCOS-insulin resistance (PCOS-IR). A total of 79 genes were differentially methylated between PCOS-NIR vs. PCOS-IR patients, and 40 genes were differentially methylated in PCOS patients vs. healthy controls. We analyzed these differentially methylated genes by constructing regulatory networks and protein-protein interaction (PPI) networks. Further, Gene Ontology (GO) and pathway enrichment analysis were also performed to investigate the biological functions of networks. We identified multiple categories of genes that were differentially methylated between PCOS-NIR and PCOS-IR patients, or between PCOS patients and healthy controls. Significantly, GO categories of immune response were differentially methylated in PCOS-IR vs. PCOS-NIR. Further, genes in cancer pathways were also differentially methylated in PCOS-NIR vs. PCOS-IR patients or in PCOS patients vs. healthy controls. The results of this current study will help to further understand the mechanism of PCOS.

PMID 23705014


Variation in ovarian follicle density during human fetal development

J Assist Reprod Genet. 2012 Sep;29(9):969-72. doi: 10.1007/s10815-012-9810-2. Epub 2012 Jun 19.

Geber S1, Megale R, Vale F, Lanna AM, Cabral AC.

Abstract PURPOSE: To obtain a precise estimate of ovarian follicle density and variation in the number of follicles at several gestational ages during human fetal development. METHODS: Twelve necropsied ovaries from 9 fetuses (gestational age: 24 to 36 weeks) and 3 neonates (who died within the first hours of life) were studied. Ovaries were fixed with 4 % formaldehyde and embedded in paraffin. Serial, 7 mm thick sections of the ovaries were cut and evaluated at every 50 cuts. Follicles were counted in 10 regions (each measuring 625 μm(2)) of the ovarian cortex and the number of follicles per mm³ was calculated. RESULTS: The number of follicles per 0.25 mm² ranged from 10.9 (± 4.8) in a neonate to 34.7 (± 10.6) also in a neonate. Among fetuses, follicle density was lowest at 36 weeks of gestation (11.1 ± 6.2) and highest at 26 weeks (32 ± 8.9). The total number of follicles ranged from 500,000 at the age of 22 weeks to > 1,000,000 at the age of 39 weeks. CONCLUSION: Our results show a peak in the number of follicles during intrauterine life at approximately 26 weeks, followed by a rapid reduction in this number before birth, providing a step forward towards the understanding of primordial follicular assembly in humans and, ultimately, the identification of the determinants of reproductive capacity.

PMID 22710858


The complete control of murine pregnancy from embryo implantation to parturition

Reproduction. 2011 Dec 23. [Epub ahead of print]

Terakawa J, Watanabe T, Obara R, Sugiyama M, Inoue N, Ohmori Y, Hosaka YZ, Hondo E. Source J Terakawa, Laboratory of Animal Morphology, Division of Biofunctional Development, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.


The ovary is the main secretory source of progestin and estrogen and is indispensable to the maintenance of all events of pregnancy in mice. The purpose of this study was to control all processes of pregnancy in mice, from embryo implantation to parturition, without ovaries. The ovaries were removed before embryo implantation, and a single injection of medroxyprogesterone acetate (MPA) was given. Embryo implantation was induced by leukemia inhibitory factor, which can substitute 17β-estradiol. Continuous exposure to 17β-estradiol was necessary at mid-pregnancy, when placentation was completed. All mice sustained pregnancy without ovaries before parturition, which was initiated by the removal of 17β-estradiol and MPA. Murine pregnancy is a complicated process involving embryo implantation, placentation, and parturition. Complete control of pregnancy was achieved with the simple treatment of MPA and 17β-estradiol after induction of embryo implantation. Here, time-dependent events in the uterus during pregnancy could be realized without the ovaries, because the initiation of each event could be stringently controlled by hormonal treatments.

PMID 22198945

Human RSPO1/R-spondin1 is expressed during early ovary development and augments β-catenin signaling

PLoS One. 2011 Jan 28;6(1):e16366.

Tomaselli S, Megiorni F, Lin L, Mazzilli MC, Gerrelli D, Majore S, Grammatico P, Achermann JC. Source Medical Genetics, Molecular Medicine Department, S. Camillo-Forlanini Hospital, Sapienza-University of Rome, Rome, Italy.


Human testis development starts from around 42 days post conception with a transient wave of SRY expression followed by up-regulation of testis specific genes and a distinct set of morphological, paracrine and endocrine events. Although anatomical changes in the ovary are less marked, a distinct sub-set of ovary specific genes are also expressed during this time. The furin-domain containing peptide R-spondin1 (RSPO1) has recently emerged as an important regulator of ovary development through up-regulation of the WNT/β-catenin pathway to oppose testis formation. Here, we show that RSPO1 is upregulated in the ovary but not in the testis during critical early stages of gonad development in humans (between 6-9 weeks post conception), whereas the expression of the related genes WNT4 and CTNNB1 (encoding β catenin) is not significantly different between these tissues. Furthermore, reduced R-spondin1 function in the ovotestis of an individual (46,XX) with a RSPO1 mutation leads to reduced β-catenin protein and WNT4 mRNA levels, consistent with down regulation of ovarian pathways. Transfection of wild-type RSPO1 cDNA resulted in weak dose-dependent activation of a β-catenin responsive TOPFLASH reporter (1.8 fold maximum), whereas co-transfection of CTNNB1 (encoding β-catenin) with RSPO1 resulted in dose-dependent synergistic augmentation of this reporter (approximately 10 fold). Furthermore, R-spondin1 showed strong nuclear localization in several different cell lines. Taken together, these data show that R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of β-catenin signaling to oppose testis determination.

PMID 21297984

Mammalian ovary differentiation - A focus on female meiosis

Mol Cell Endocrinol. 2011 Sep 21. [Epub ahead of print]

Baillet A, Mandon-Pepin B. Source Laboratoire de Génétique et Biologie Cellulaire, EA 4589 Université de Versailles Saint-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, F-78035 Versailles cedex, France. Abstract Over the past 50 years, the ovary development has been subject of fewer studies as compare to the male pathway. Nevertheless due to the advancement of genetics, mouse ES cells and the development of genetic models, studies of ovarian differentiation was boosted. This review emphasizes some of new progresses in the research field of the mammalian ovary differentiation that have occurred in recent years with focuses of the period around prophase I of meiosis and of recent roles of small non-RNAs in the ovarian gene expression.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID 21964319

Defining ovarian reserve to better understand ovarian aging

Reprod Biol Endocrinol. 2011 Feb 7;9:23.

Gleicher N, Weghofer A, Barad DH. Source Center for Human Reproduction-New York, NY, USA. ngleicher@thechr.com


Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes.

  • primordial follicles are activated to enter maturation is not well understood yet but reflects complex processes of bi-directional signaling between oocytes and surrounding somatic cells
  • Cohorts of resting primordial, also called non-growing follicles (NGFs), are consistently recruited though, ultimately, only one single oocyte usually reaches ovulation
  • Over more than four months of follicle maturation randomly recruited follicles are progressively aligned into generational cohorts of maturing follicles.
  • Ovarian reserve (OR) is a widely used term that has largely remained undefined. What is generally referred to as OR, really represents only small components of total ovarian reserve (TOR). A woman's cumulative hypothetical pregnancy chance is mathematically reflected in her complete follicle pool, her TOR.
  • TOR mostly consists of NGFs (largely primordial follicles) and to a lesser degree of maturing growing follicles (GFs) after recruitment. But only the latter reflect the so-called functional OR (FOR)
  • premature ovarian aging (POA), also called occult primary ovarian insufficiency (OPOI)
  • Wallace and Kelsey, suggest between 35,000 and 2.5 million follicles (average 295,000) per ovary at birth (http://www.ncbi.nlm.nih.gov/pubmed/20111701)

PMID 21299886



Building pathways for ovary organogenesis in the mouse embryo

Curr Top Dev Biol. 2010;90:263-90.

Liu CF, Liu C, Yao HH. Source Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Illinois, USA.


Despite its significant role in oocyte generation and hormone production in adulthood, the ovary, with regard to its formation, has received little attention compared to its male counterpart, the testis. With the exception of germ cells, which undergo a female-specific pattern of meiosis, morphological changes in the fetal ovary are subtle. Over the past 40 years, a number of hypotheses have been proposed for the organogenesis of the mammalian ovary. It was not until the turn of the millennium, thanks to the advancement of genetic and genomic approaches, that pathways for ovary organogenesis that consist of positive and negative regulators have started to emerge. Through the action of secreted factors (R-spondin1, WNT4, and follistatin) and transcription regulators (beta-catenin and FOXL2), the developmental fate of the somatic cells is directed toward ovarian, while testicular components are suppressed. In this chapter, we review the history of studying ovary organogenesis in mammals and present the most recent discoveries using the mouse as the model organism.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID 20691852

Human ovarian reserve from conception to the menopause

PLoS One. 2010 Jan 27;5(1):e8772.

Wallace WH, Kelsey TW. Source Department of Reproductive and Developmental Sciences, Division of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom. hamish.wallace@nhs.net


The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.

PMID: 20111701 http://www.ncbi.nlm.nih.gov/pubmed/20111701


Induction of ovarian primordial follicle assembly by connective tissue growth factor CTGF

PLoS One. 2010 Sep 24;5(9):e12979.

Schindler R, Nilsson E, Skinner MK. Source Center for Reproductive Biology, School Biological Sciences, Washington State University, Pullman, Washington, United States of America.

Abstract Primordial follicle assembly is a process that occurs when oocyte nests break down to form individual primordial follicles. The size of this initial pool of primordial follicles in part determines the reproductive lifespan of the female. Connective tissue growth factor (CTGF) was identified as a potential regulatory candidate for this process in a previous microarray analysis of follicle development. The current study examines the effects of CTGF and associated transforming growth factor beta 1 (TGFβ-1) on follicle assembly. Ovaries were removed from newborn rat pups and placed in an organ culture system. The ovaries treated with CTGF for two days were found to have an increased proportion of assembled follicles. CTGF was found to regulate the ovarian transcriptome during primordial follicle assembly and an integrative network of genes was identified. TGFβ-1 had no effect on primordial follicle assembly and in combination with CTGF decreased oocyte number in the ovary after two days of culture. Over ten days of treatment only the combined treatment of CTGF and TGFβ-1 was found to cause an increase in the proportion of assembled follicles. Interestingly, treatment with TGFβ-1 alone resulted in fewer total oocytes in the ovary and decreased the primordial follicle pool size after ten days of culture. Observations indicate that CTGF alone or in combination with TGFβ-1 stimulates primordial follicle assembly and TGFβ-1 can decrease the primordial follicle pool size. These observations suggest the possibility of manipulating primordial follicle pool size and influencing female reproductive lifespan.

PMID: 20886044 [PubMed - indexed for MEDLINE] PMCID: PMC2945314



The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue

Hum Reprod. 2010 May;25(5):1280-1. Epub 2010 Feb 19.

Ernst E, Bergholdt S, Jørgensen JS, Andersen CY. Source Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark.


Worldwide eight children have been born as a result of transplanting frozen/thawed ovarian tissue. Two of these children were born in Denmark following transport of the ovarian tissue for a period of 5 h prior to cryopreservation. One of these women, who was originally transplanted with six pieces of ovarian cortex, after having experienced a period of menopause has now conceived again following natural conception. She gave birth to a healthy girl on 23 September 2008 and is therefore the first woman in the world to have had two children, from separate pregnancies, born as a result of transplanting frozen/thawed ovarian tissue. This result encourages further development of cryopreservation of ovarian tissue for fertility preservation as a clinical procedure for girls and young women facing gonadotoxic treatment.

PMID: 20172869

Ovarian cancer in Australia An overview, 2010



In 2006, ovarian cancer was the ninth most commonly diagnosed cancer among Australian women (excluding non-reportable skin cancers) and the second most commonly diagnosed gynaecological cancer, with a total of 1,226 ovarian cancer cases diagnosed. Ovarian cancer is mainly a disease of postmenopausal women, with six in ten (60%) cases diagnosed in women aged 60 years and over.

A total of 795 women died from ovarian cancer in 2006, making it the sixth most common cause of cancer-related death for Australian women, and the most common cause of gynaecological cancer death, representing over half (55%) of such deaths.

The prognosis for women with ovarian cancer is relatively poor. Women who were diagnosed with ovarian cancer between 2000 and 2006 were 40% as likely to live five years after diagnosis as their counterparts in the general population. Significantly poorer survival was seen for older women, with 5-year relative survival estimates ranging from a high of 86% for those aged less than 30 years when diagnosed with ovarian cancer to a low of 15% for those aged 80 years or older at diagnosis.


The molecular control of corpus luteum formation, function, and regression

Endocr Rev. 2007 Feb;28(1):117-49. Epub 2006 Oct 31.

Stocco C, Telleria C, Gibori G. Source Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine, New Haven, CT 06510, USA.


The corpus luteum (CL) is one of the few endocrine glands that forms from the remains of another organ and whose function and survival are limited in scope and time. The CL is the site of rapid remodeling, growth, differentiation, and death of cells originating from granulosa, theca, capillaries, and fibroblasts. The apparent raison d'etre of the CL is the production of progesterone, and all the structural and functional features of this gland are geared toward this end. Because of its unique importance for successful pregnancies, the mammals have evolved a complex series of checks and balances that maintains progesterone at appropriate levels throughout gestation. The formation, maintenance, regression, and steroidogenesis of the CL are among the most significant and closely regulated events in mammalian reproduction. During pregnancy, the fate of the CL depends on the interplay of ovarian, pituitary, and placental regulators. At the end of its life span, the CL undergoes a process of regression leading to its disappearance from the ovary and allowing the initiation of a new cycle. The generation of transgenic, knockout and knockin mice and the development of innovative technologies have revealed a novel role of several molecules in the reprogramming of granulosa cells into luteal cells and in the hormonal and molecular control of the function and demise of the CL. The current review highlights our knowledge on these key molecular events in rodents.

PMID 17077191


zona pellucida” domain, a stretch of 260 amino acids containing eight conserved cysteine residues (5), plays a role in polymerization of the zona pellucida glycoproteins

Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Su YQ, Sugiura K, Eppig JJ. Semin Reprod Med. 2009 Jan;27(1):32-42. Epub 2009 Feb 5. Review. PMID: 19197803 | PMC2742468

extracellular matrix in ovarian follicle development

The role of the extracellular matrix in ovarian follicle development. Woodruff TK, Shea LD. Reprod Sci. 2007 Dec;14(8 Suppl):6-10. Review. PMID: 18089604

oocyte control of granulosa cell development

Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Su YQ, Sugiura K, Eppig JJ. Semin Reprod Med. 2009 Jan;27(1):32-42. Epub 2009 Feb 5. Review. PMID: 19197803 | PMC2742468

The biology of activin


"Activin was discovered in the 1980s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades, many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly and by extracellular antagonists. Over the past 5 years, a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3, as well as identification of activin's roles in gonadal sex development, follicle development, luteolysis, beta-cell proliferation and function in the islet, stem cell pluripotency and differentiation into different cell types and in immune cells. These advances are reviewed to provide perspective for future studies."

Germ cell sex determination

Germ cell sex determination in mammals. Kocer A, Reichmann J, Best D, Adams IR. Mol Hum Reprod. 2009 Apr;15(4):205-13. Epub 2009 Feb 13. Review. PMID: 19218284

Molecular Factors


  • Lox was expressed 2.8-fold higher in mural granulosa cells in follicles producing normal oocyte than poor oocyte developmental competence.
  • Pdia5 is also up-regulated at less extent in the normal oocyte developmental competence group.


The ovary: basic biology and clinical implications



Aging of the human ovary and testis

  • Aging of the human ovary and testis. Perheentupa A, Huhtaniemi I. Mol Cell Endocrinol. 2009 Feb 5;299(1):2-13. Epub 2008 Nov 18. Review. PMID: 19059459 |
  • Increases in norepinephrine release and ovarian cyst formation during ageing in the rat. Acuña E, Fornes R, Fernandois D, Garrido MP, Greiner M, Lara HE, Paredes AH. Reprod Biol Endocrinol. 2009 Jun 16;7:64. PMID: 19531218

Compare these 2 different findings on new adult follicles

oocyte population is not renewed in transplanted or irradiated adult ovaries

The oocyte population is not renewed in transplanted or irradiated adult ovaries. Begum S, Papaioannou VE, Gosden RG. Hum Reprod. 2008 Oct;23(10):2326-30. Epub 2008 Jul 1. PMID: 18596027

BACKGROUND: According to conventional theory, the oocyte population is not renewed in mammalian ovaries after birth. A new hypothesis proposes that oocytes are generated continuously from haematopoietic progenitor cells. There is, however, no evidence that they can ovulate, although they may partially restore fertility by organizing 'helper follicles'. The hypothesis that follicles can form de novo in adult ovaries has been tested in a transplant model. METHODS: Ovaries from adult mice were transplanted under the kidney capsule or into the ovarian bursa of histocompatible, transgenic CAG::H2B-EGFP host animals. Some donors were sterilized before transplantation by X-irradiation to ensure 'empty niches' were available for repopulation. The phenotype of follicular oocytes at 2, 4 and 8 weeks post-transplantation was scored by epifluorescence. RESULTS: A total of 819 oocytes were examined in 30 ovarian grafts. None expressed green fluorescence, as would be predicted if they had formed de novo from germ cell progenitors in the systemic circulation of the host. Furthermore, small follicles eliminated by irradiation were not replaced in transplanted ovaries, and the few growing follicles present were apparently survivors of the original population. CONCLUSIONS: No evidence was found to support the hypothesis that progenitor cells from extra-ovarian sources can repopulate the adult ovary. The findings are consistent with the conventional view that a limited number of oocytes are formed before birth and declines with age. The study did not, however, rule out the possibility that germline stem cells may reside in the adult ovary.

new primary follicles in adult human and rat ovaries

  • Origin of germ cells and formation of new primary follicles in adult human ovaries. Bukovsky A, Caudle MR, Svetlikova M, Upadhyaya NB. Reprod Biol Endocrinol. 2004 Apr 28;2:20. PMID: 15115550 | Reprod Biol Endocrinol.
" During follicle formation, extensions of granulosa cells enter the oocyte cytoplasm, forming a single paranuclear CK+ Balbiani body supplying all the mitochondria of the oocyte. In the ovarian medulla, occasional vessels show an accumulation of ZP+ oocytes (25-30 microns) or their remnants, suggesting that some oocytes degenerate. In contrast to males, adult human female gonads do not preserve germline type stem cells. This study expands our previous observations on the formation of germ cells in adult human ovaries. Differentiation of primitive granulosa and germ cells from the bipotent mesenchymal cell precursors of TA in adult human ovaries represents a most sophisticated adaptive mechanism created during the evolution of female reproduction. Our data indicate that the pool of primary follicles in adult human ovaries does not represent a static but a dynamic population of differentiating and regressing structures. An essential mission of such follicular turnover might be elimination of spontaneous or environmentally induced genetic alterations of oocytes in resting primary follicles."
"Follicular atresia - Atresia of primary follicles is common during the reproductive period of human females [51]. Our observations suggest that it is a rapid process, assisted by the massive influx of macrophages. The process resembles immune-system mediated corpus luteum regression [94]. Gougeon suggested that depletion of the primary follicle pool is caused mainly by atresia in younger women and by entrance into the growing pool in older women, with the change-over at 38 ± 2.4 years [54]. Since cyclic ovarian function continues in "early premenopausal" women, we speculate that ~10000 primary follicles detected during the age period 40–44 years (Fig. 15B) is a sufficient depot for continuation of ovulatory ovarian function. A 50000 difference compared to younger females fits well with the observation that 70–95% of oocytes in primary follicles show various stages of degeneration [51,52]. It appears that Gougeon was right, and it is possible to conclude that the pool of healthy primary follicles is at least 10000 during the reproductive years."
"In adult mammalian ovaries, 70–95% of oocytes are in various stages of degeneration [51,52].

51. Ingram DL: Atresia. In The Ovary (Edited by: Zuckerman S). London: Academic Press 1962, 247-273.

52. Erickson BH: Development and senescence of the postnatal bovine ovary. J Anim Sci 1966, 25:800-805. PubMed Abstract

  • Study origin of germ cells and formation of new primary follicles in adult human and rat ovaries. Bukovsky A, Gupta SK, Virant-Klun I, Upadhyaya NB, Copas P, Van Meter SE, Svetlikova M, Ayala ME, Dominguez R. Methods Mol Biol. 2008;450:233-65. PMID: 18370063
"The central thesis regarding the human ovaries is that, although primordial germ cells in embryonal ovaries are of extraovarian origin, those generated during the fetal period and in postnatal life are derived from the ovarian surface epithelium (OSE) bipotent cells. With the assistance of immune system-related cells, secondary germ cells and primitive granulosa cells originate from OSE stem cells in the fetal and adult human gonads. Fetal primary follicles are formed during the second trimester of intrauterine life, prior to the end of immune adaptation, possibly to be recognized as self-structures and renewed later. With the onset of menarche, a periodical oocyte and follicular renewal emerges to replace aging primary follicles and ensure that fresh eggs for healthy babies are always available during the prime reproductive period. The periodical follicular renewal ceases between 35 and 40 yr of age, and the remaining primary follicles are utilized during the premenopausal period until exhausted. However, the persisting oocytes accumulate genetic alterations and may become unsuitable for ovulation and fertilization. The human OSE stem cells preserve the character of embryonic stem cells, and they may produce distinct cell types, including new eggs in vitro, particularly when derived from patients with premature ovarian failure or aging and postmenopausal ovaries. Our observations also indicate that there are substantial differences in follicular renewal between adult human and rat ovaries. As part of this chapter, we present in detail protocols utilized to analyze oogenesis in humans and to study interspecies differences when compared to the ovaries of rat females."

WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival

Jääskeläinen M, Prunskaite-Hyyryläinen R, Naillat F, Parviainen H, Anttonen M, Heikinheimo M, Liakka A, Ola R, Vainio S, Vaskivuo TE, Tapanainen JS. Mol Cell Endocrinol. 2010 Apr 12;317(1-2):106-11. Epub 2009 Dec 3.

"WNT4 plays an important role in female sexual development and ovarian function. WNT4-deficiency leads disturbed development of the internal genitalia in mouse and human, and to a dramatic reduction of mouse oocytes. However, the expression and role of WNT4 in human ovaries is yet unknown. The expression of WNT4 mRNA and protein was studied in human adult and fetal ovaries (gestational ages 12-41 weeks), and the role of WNT4 in oocyte apoptosis was investigated in WNT4-deficient mice. WNT4 mRNA and protein were present in human ovaries throughout fetal development and in different follicular stages in adult ovaries. Compared with wild-type mice, WNT4-deficient mice had a markedly enhanced rate of oocyte apoptosis, with the highest values at gestational ages of 14.5 and 16.5 days post-coitum. The current results support a view that WNT4 may have a role in oocyte selection and follicle formation and maturation in human ovaries."

PMID 19962424

Stem cell support of oogenesis

Stem cell support of oogenesis in the human. Abban G, Johnson J. Hum Reprod. 2009 Dec;24(12):2974-8. Epub 2009 Aug 17. PMID: 19687054

Stem cells in aged mammalian ovaries. Virant-Klun I, Skutella T. Aging (Albany NY). 2010 Jan 26;2(1):3-6.PMID: 20228938 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837201/?tool=pubmed

"Ovarian surface epithelium (OSE) is an important structure of the human ovary and is involved in both reproductive function and ovarian tumor formation. Primordial germ cells (PGCs) in embryonic ovaries are of extraovarian origin, but those developing during the fetal period are derived from the OSE.

primordial pool of follicles

The primordial pool of follicles and nest breakdown in mammalian ovaries. Tingen C, Kim A, Woodruff TK. Mol Hum Reprod. 2009 Dec;15(12):795-803. Epub 2009 Aug 26. Review. PMID: 19710243 | Mol Hum Reprod.

"The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number and outline how the ovary quality-controls the germ cells produced."

PAR6, A Potential Marker for the Germ Cells Selected to Form Primordial Follicles in Mouse Ovary

PAR6, a potential marker for the germ cells selected to form primordial follicles in mouse ovary. Wen J, Zhang H, Li G, Mao G, Chen X, Wang J, Guo M, Mu X, Ouyang H, Zhang M, Xia G. PLoS One. 2009 Oct 7;4(10):e7372. PMID: 19809506



"Partitioning-defective proteins (PAR) are detected to express mainly in the cytoplast, and play an important role in cell polarity. However, we showed here that PAR6, one kind of PAR protein, was localized in the nuclei of mouse oocytes that formed primordial follicles during the perinatal period, suggesting a new role of PAR protein. It is the first time we found that, in mouse fetal ovaries, PAR6 appeared in somatic cell cytoplasm and fell weak when somatic cells invaded germ cell cysts at 17.5 days post coitus (dpc). Meanwhile, the expression of PAR6 was observed in cysts, and became strong in the nuclei of some germ cells at 19.5 dpc and all primordial follicular oocytes at 3 day post parturition (dpp), and then obviously declined when the primordial follicles entered the folliculogenic growth phase. "

Mouse TEX14 is required for embryonic germ cell intercellular bridges but not female fertility


Localisation and function of the endocannabinoid system in the human ovary

El-Talatini MR, Taylor AH, Elson JC, Brown L, Davidson AC, Konje JC. PLoS One. 2009;4(2):e4579. Epub 2009 Feb 24.

PMID 19238202



Comparative analysis of follicle morphology and oocyte diameter in four mammalian species (mouse, hamster, pig, and human)

J Exp Clin Assist Reprod. 2006 Mar 1;3:2.

Griffin J1, Emery BR, Huang I, Peterson CM, Carrell DT.


BACKGROUND: Laboratory animals are commonly used for evaluating the physiological properties of the mammalian ovarian follicle and the enclosed oocyte. The use of different species to determine the morphological relationship between the follicle and oocyte has led to a recognizable pattern of follicular stages, but differences in follicle size, oocyte diameter and granulosa cell proliferation are not consistent across the different species. In an effort to better understand how these differences are expressed across multiple species, this investigation evaluates oocyte and follicle diameters and granulosa cell proliferation in the mouse, hamster, pig, and human. METHODS: Histological sections of ovaries from the mouse, hamster, pig, and human were used to calculate the diameter of the oocyte and follicle and the number of granulosa cells present at pre-determined stages of follicular development. A statistical analysis of these data was performed to determine the relationship of follicular growth and development within and between the species tested. RESULTS: These data have revealed that the relationships of the features listed are tightly regulated within each species, but they vary between the species studied. CONCLUSION: This information may be useful for comparative studies conducted in different animal models and the human. PMID 16509981



Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles

Theriogenology. 2005 Apr 1;63(6):1717-51.

van den Hurk R1, Zhao J.

Abstract The limited knowledge on the regulation of oocyte formation, the different steps of folliculogenesis and the required conditions for oocytes to undergo proper growth, differentiation and maturation are major causes of the failure in obtaining viable offspring from in vitro cultured early oocytes from domestic animals and humans. This review highlights the factors that at present are known to be involved in the formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. PMID 15763114


  • The Oestrous Cycle and the Formation of the Corpus Luteum in the Sheep. Marshall, F Proceedings of the Royal Society of London (1854-1905). 1902-01-01. 71:354–355


  1. Sakashita A, Wakai T, Kawabata Y, Nishimura C, Sotomaru Y, Alavattam KG, Namekawa SH & Kono T. (2019). XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage†. Biol. Reprod. , 100, 697-710. PMID: 30289439 DOI.