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Cite this page: Hill, M.A. (2021, July 26) Embryology Ovary Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Ovary_Development

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)

2011

Reprod Biol Endocrinol. 2011 Feb 7;9:23. Defining ovarian reserve to better understand ovarian aging. Gleicher N, Weghofer A, Barad DH. Source Center for Human Reproduction-New York, NY, USA. ngleicher@thechr.com

Abstract

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 http://www.ncbi.nlm.nih.gov/sites/entrez/21299886

http://www.rbej.com/content/9/1/23

2010

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

Abstract

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

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008772

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

http://www.ncbi.nlm.nih.gov/pubmed/20886044

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012979


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.

Abstract

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

http://www.aihw.gov.au/publications/index.cfm/title/11158

http://www.aihw.gov.au/publications/can/48/11158.pdf

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.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636726/?tool=pubmed

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

http://www.ncbi.nlm.nih.gov/pubmed/19273500

"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

http://www.ovarianresearch.com/content/3/1/6

  • 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.

https://pathwayexplorer.genome.tugraz.at/


The ovary: basic biology and clinical implications

http://www.ncbi.nlm.nih.gov/pubmed/20364094

http://www.jci.org/articles/view/41350

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 ovarian cell survival

  • 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. PMID: 19962424

"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."


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

http://www.ncbi.nlm.nih.gov/pubmed/19809506

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007372

"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

http://www.biolreprod.org/content/80/3/449.long


endocannabinoid system

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

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004579