View source for User:Jay9Z/Follicular atresia

It has been proposed that enhanced levels of [[Nitrogen oxide]] in rats can prevent atresia of the ovarian follicle, and depressed levels have the opposite effect.<ref>{{Cite journal |last=Najati |first=Vahid |last2=Ilkhanipour |first2=Minoo |last3=Salehi |first3=Shahpar |last4=Sadeghi-Hashjin |first4=Goudarz |date=2008 |title=Role of nitric oxide on the generation of atretic follicles in the rat ovaries |url=https://pubmed.ncbi.nlm.nih.gov/18817198/ |journal=Pakistan journal of biological sciences: PJBS |volume=11 |issue=2 |pages=250–254 |doi=10.3923/pjbs.2008.250.254 |issn=1028-8880 |pmid=18817198}}</ref><ref>{{Cite journal |last=Luo |first=Yuxin |last2=Zhu |first2=Yanbin |last3=Basang |first3=Wangdui |last4=Wang |first4=Xin |last5=Li |first5=Chunjin |last6=Zhou |first6=Xu |date=2021 |title=Roles of Nitric Oxide in the Regulation of Reproduction: A Review |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640491/ |journal=Frontiers in Endocrinology |volume=12 |pages=752410 |doi=10.3389/fendo.2021.752410 |issn=1664-2392 |pmc=8640491 |pmid=34867795}}</ref>{{Dashboard.wikiedu.org draft template/about this sandbox}}

== Article Draft ==

=== Overview ===
'''Follicular atresia''' refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg.<ref>{{Citation |last=McGee |first=Elizabeth A. |title=Follicle Atresia |date=2018 |url=https://www.sciencedirect.com/science/article/pii/B9780128012383643957 |work=Encyclopedia of Reproduction (Second Edition) |pages=87–91 |editor-last=Skinner |editor-first=Michael K. |place=Oxford |publisher=Academic Press |language=en |doi=10.1016/b978-0-12-801238-3.64395-7 |isbn=978-0-12-815145-7 |access-date=2022-07-31 |last2=Horne |first2=Jessica}}</ref> It is a normal, naturally occurring, progressive process that encompasses the breakdown of the [[ovarian follicles]] which are made in mammalian ovaries in order to secrete hormones and oocytes. Oocytes are immature eggs and are surrounded by [[granulosa cells]] and internal and external [[theca]] cells.<ref name=":0">{{Cite journal |last=Zhou |first=Jiawei |last2=Peng |first2=Xianwen |last3=Mei |first3=Shuqi |date=2019 |title=Autophagy in Ovarian Follicular Development and Atresia |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429023/ |journal=International Journal of Biological Sciences |volume=15 |issue=4 |pages=726–737 |doi=10.7150/ijbs.30369 |issn=1449-2288 |pmc=6429023 |pmid=30906205}}</ref>Oocytes are then able to mature within the follicle through meiosis. However, in female humans, this process occurs continuously, as they are born with a finite number of follicles (between 500,000-1,000,000 follicles), and about 99% of follicles undergo atresia<ref>{{Cite journal |last=Wilkosz |first=Pawel |last2=Greggains |first2=Gareth D. |last3=Tanbo |first3=Tom G. |last4=Fedorcsak |first4=Peter |date=2014 |title=Female Reproductive Decline Is Determined by Remaining Ovarian Reserve and Age |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195570/ |journal=PLoS ONE |volume=9 |issue=10 |pages=e108343 |doi=10.1371/journal.pone.0108343 |issn=1932-6203 |pmc=4195570 |pmid=25310678}}</ref>. Only one follicle will be mature enough to release an egg and may be fertilized<ref>{{Cite journal |last=Zhang |first=Jinbi |last2=Liu |first2=Yang |last3=Yao |first3=Wang |last4=Li |first4=Qifa |last5=Liu |first5=Honglin |last6=Pan |first6=Zengxiang |date=2018 |title=Initiation of follicular atresia: gene networks during early atresia in pig ovaries |url=https://rep.bioscientifica.com/view/journals/rep/156/1/REP-18-0058.xml |journal=Reproduction |language=en-US |volume=156 |issue=1 |pages=23–33 |doi=10.1530/REP-18-0058 |issn=1741-7899}}</ref>.  Typically, around 20 follicles mature each month, but only a single follicle is ovulated; the follicle from the oocyte was released becomes the corpus luteum. The corpus luteum is the last stage of the ovarian follicles' lifecycle. It has an important role in secreting estrogen and progesterone to prepare the body for conception. If conception does not occur, then it will be shed and is known as the corpus albicans<ref>{{Citation |last=Kirkendoll |first=Shelbie D. |title=Histology, Corpus Albicans |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK545270/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31424854 |access-date=2022-07-26 |last2=Bacha |first2=Dhouha}}</ref>. It has been observed that this mechanism is important in regulating and maintaining a healthy reproductive system in mammals. It is also a subject of interest in understanding and predicting fertility in female humans.  

=== Mechanism ===
Atresia is a complex, [[Hormone|hormonally]] controlled [[Apoptosis|apoptotic]] process that depends dominantly on granulosa cell apoptosis, however there have been other proposed mechanisms in which this pathway occurs. In the most known mechanism, apoptosis, follicular atresia is inhibited by [[follicle-stimulating hormone]] (FSH), which promotes follicle development. Once the follicle has developed, it secretes [[estrogen]], which in high levels decreases secretions of FSH. Granulosa cell [[apoptosis]] is considered the underlying mechanism of follicular atresia, and has been associated with five ligand-receptor systems involved in cell death: <ref name=":0" /><ref>{{Cite book |last=Torres-Ramirez |first=N |title=Endoplasmic Reticulum Stress during Mammalian Follicular Atresia |publisher=IntechOpen |year=2019 |isbn=9781838800888}}</ref>

* [[tumor necrosis factor alpha]] (TNF alpha) and [[TNF receptors|receptors]]
* [[Fas apoptosis signaling pathway|Fas]] ligand and receptors
* [[Tumor necrosis factors|TNF]]-related [[apoptosis]]-inducing ligand (TRAIL; also called APO-2) and receptors
* [[APO-3]] ligand and receptors
* [[PFG-5]] ligand and receptors

Granulosa cell apoptosis is induced by [[tumor necrosis factor-alpha]] (TNFα), although the mechanism of how it occurs is unclear.<ref>{{Cite journal |last=Yamamoto |first=Yuri |last2=Kuwahara |first2=Akira |last3=Taniguchi |first3=Yuka |last11=et |first11=al. |date=2015 |title=Tumor necrosis factor alpha inhibits ovulation and induces granulosa cell death in rat ovaries |url=http://doi.wiley.com/10.1007/s12522-014-0201-5 |journal=Reproductive Medicine and Biology |volume=14 |issue=3 |pages=107–115 |doi=10.1007/s12522-014-0201-5 |pmc=PMC4490172 |pmid=26161038}}</ref>

Fas antigen, a [[cell surface receptor]] protein, is expressed on granulosa cells and helps mediate signals that induce apoptosis by binding [[Fas ligand]] and therefore plays an important role in follicular atresia.<ref>{{Cite journal |last=Yang |first=Runjun |last2=Xu |first2=Shangzhong |last3=Zhao |first3=Zhihui |last4=Li |first4=Junya |date=2012 |title=Fas ligand expression and mediated activation of an apoptosis program in bovine follicular granulosa cells |url=https://linkinghub.elsevier.com/retrieve/pii/S0378111911007025 |journal=Gene |language=en |volume=493 |issue=1 |pages=148–154 |doi=10.1016/j.gene.2011.11.032}}</ref> Lack of a working [[Fas ligand]] / [[Fas receptor]] system has been linked to abnormal follicle development, and increased secondary follicles as a result of the inability to induce apoptosis.

TNF-related apoptosis-inducing ligand [[TRAIL|(TRAIL)]] activates [[caspase 3]] (CASP3), which interacts with [[caspases]] 6, 7, 8, 9, and 10, to induce apoptosis in granulosa cells.<ref>{{Cite journal |last=Naimi |first=Adel |last2=Movassaghpour |first2=Ali Akbar |last3=Hagh |first3=Majid Farshdousti |last6=Jadidi-Niaragh |first6=Farhad |last7=Solali |first7=Saeed |date=2018 |title=TNF-related apoptosis-inducing ligand (TRAIL) as the potential therapeutic target in hematological malignancies |url=https://www.sciencedirect.com/science/article/pii/S075333221735360X |journal=Biomedicine & Pharmacotherapy |volume=98 |pages=566–576 |doi=10.1016/j.biopha.2017.12.082 |issn=0753-3322}}</ref>

Two intracellular inhibitor proteins, cellular [[FLICE]]-like inhibitory [[protein]] short form ([[cFLIPS]]) and long form (cFLIPL), which are expressed in granulosa cells, may be anti-apoptotic factors.<ref>{{Cite journal |last=Manabe |first=Noboru |last2=Goto |first2=Yasufumi |last3=Matsuda-Minehata |first3=Fuko |last4=Inoue |first4=Naoko |date=2004 |title=Regulation Mechanism of Selective Atresia in Porcine Follicles: Regulation of Granulosa Cell Apoptosis during Atresia |url=https://www.jstage.jst.go.jp/article/jrd/50/5/50_5_493/_article |journal=Journal of Reproduction and Development |volume=50 |issue=5 |pages=493–514 |doi=10.1262/jrd.50.493 |issn=0916-8818}}</ref>

Anti-Mullerian hormone (AMH) has been studied to be a key regulator in the ovaries in humans that inhibits follicular atresia. Using indirect comparators to derive this hypothesis, exploring different patient populations such as individuals who have polycystic ovary syndrome (PCOS) help support the hypothesis that AMH may be a key regulator in inhibiting follicular atresia. <ref>{{Cite journal |last=Seifer |first=David B. |last2=Merhi |first2=Zaher |date=2014 |title=Is AMH a regulator of follicular atresia? |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389943/ |journal=Journal of Assisted Reproduction and Genetics |volume=31 |issue=11 |pages=1403–1407 |doi=10.1007/s10815-014-0328-7 |issn=1058-0468 |pmc=4389943 |pmid=25193290}}</ref>

==== Menopause ====
Follicular atresia occurs throughout all stages of follicular development, until the follicular reserve is completely exhausted.<ref>{{Cite journal |last=Banerjee |first=Sayani |last2=Banerjee |first2=Sutapa |last3=Saraswat |first3=Ghungroo |last4=Bandyopadhyay |first4=Soma Aditya |last5=Kabir |first5=Syed N. |date=2014 |title=Female Reproductive Aging Is Master-Planned at the Level of Ovary |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008600/ |journal=PLoS ONE |volume=9 |issue=5 |pages=e96210 |doi=10.1371/journal.pone.0096210 |issn=1932-6203 |pmc=4008600 |pmid=24788203}}</ref> Exhaustion of the follicular reserve occurs at [[menopause]], which is typically around the age of 51 in humans with ovaries. The dramatic decrease in [[estrogen]] and [[progesterone]] levels that is characteristic of [[menopause]], is caused by follicular atresia. Breakdown of the follicles prevent them from releasing hormones such as [[Estrogen|estrogen.]] [[Progesterone]] levels also decrease during [[menopause]] because without any follicles, there is no development of a [[corpus luteum]], which is the major source of circulating progesterone levels in humans.<ref>{{Citation |last=Gore |first=Andrea C. |title=Women's Health, Neurology of |date=2003 |url=https://www.sciencedirect.com/science/article/pii/B0122268709011369 |work=Encyclopedia of the Neurological Sciences |pages=763–766 |editor-last=Aminoff |editor-first=Michael J. |place=New York |publisher=Academic Press |language=en |doi=10.1016/b0-12-226870-9/01136-9 |isbn=978-0-12-226870-0 |access-date=2022-08-01 |editor2-last=Daroff |editor2-first=Robert B.}}</ref>   

=== Related Diseases ===
Undergoing follicular atresia is necessary in order for mammals to maintain a healthy reproductive system. However, disorders in the regulation of follicle breakdown and generation can lead to various pathologies:

==== Premature Ovarian Failure<ref>{{Citation |last=Gago |first=L. April |title=Premature Ovarian Failure |date=2004-01-01 |url=https://www.sciencedirect.com/science/article/pii/B0124755704010660 |work=Encyclopedia of Endocrine Diseases |pages=65–72 |editor-last=Martini |editor-first=Luciano |place=New York |publisher=Elsevier |language=en |isbn=978-0-12-475570-3 |access-date=2022-07-28 |last2=Ginsburg |first2=Kenneth A.}}</ref> ====
Premature ovarian failure (POF) (also called [[Primary ovarian insufficiency|premature ovarian insufficiency]]) is the loss of ovarian function before the age of 40 due to follicular dysfunction such as accelerated follicular atresia. There may be many causes of POF, ranging from genetic disorders to surgery, radiation therapy, and exposure to environmental toxicants. Accelerated follicular atresia due to chromosomal and genomic defects accounts for up to one-half of all POF cases. For example, [[Fragile X syndrome]], [[Turner syndrome]], and various autosomal diseases such as [[galactosemia]] have been linked to follicular deficiencies. Smoking has also been found to increase follicular atresia and lead to premature ovarian failure.<ref>{{Cite journal |last=Klinger |first=Francesca G. |last2=Rossi |first2=Valerio |last3=De Felici |first3=Massimo |date=2015 |title=Multifaceted programmed cell death in the mammalian fetal ovary |url=https://pubmed.ncbi.nlm.nih.gov/26374525/ |journal=The International Journal of Developmental Biology |volume=59 |issue=1-3 |pages=51–54 |doi=10.1387/ijdb.150063fk |issn=1696-3547 |pmid=26374525}}</ref>

==== Ovarian Follicular Cysts<ref>{{Citation |last=Cole |first=Laurence |title=Chapter 6.8 - Ovarian Cystic Disorders |date=2016-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780128036990000463 |work=Human Physiology, Biochemistry and Basic Medicine |pages=219–221 |editor-last=Cole |editor-first=Laurence |place=Boston |publisher=Academic Press |language=en |isbn=978-0-12-803699-0 |access-date=2022-07-28 |last2=Kramer |first2=Peter R. |editor2-last=Kramer |editor2-first=Peter R.}}</ref><ref>{{Cite web |date=2016-09-23 |title=Follicular Cyst {{!}} Definition & Patient Education |url=https://www.healthline.com/health/follicular-cyst |access-date=2022-07-28 |website=Healthline |language=en}}</ref> ====
When an ovarian follicle fails to undergo atresia and release an egg, it can grow to form a cyst. This may be due to an overproduction of FSH or an inadequate supply of LH. Most follicular cysts are harmless and resolve on their own within several months. However, rarely a cyst will grow to be very large (greater than 7 cm), cause abdominal pain or rupture, or last for longer than a few months, in which case a physician may recommend surgical removal or testing to determine if it is cancerous. Ultrasound is a common method of visualizing a cyst to determine treatment. 

==== Ovarian Cancer ====
Since FSH inhibits follicular atresia, the overproduction of FSH can lead to excessive follicle formation and increased risk of ovarian cancer. <ref>{{Cite journal |last=Zhang |first=Zhenbo |last2=Jia |first2=Lin |last3=Feng |first3=Youji |last4=Zheng |first4=Wenxin |date=2009-06-08 |title=Overexpression of follicle-stimulating hormone receptor facilitates the development of ovarian epithelial cancer |url=https://www.sciencedirect.com/science/article/pii/S0304383508009786 |journal=Cancer Letters |language=en |volume=278 |issue=1 |pages=56–64 |doi=10.1016/j.canlet.2008.12.024 |issn=0304-3835}}</ref>

The inability to regulate granulosa cell apoptosis has been linked to the development of some hormone-related cancers and chemo-resistance.[+orig. citation here]

According to the gonadotropin theory, follicular depletion associated with incessant follicular atresia has also been hypothesized as a potential etiology for ovarian cancer, due to an increase in serum gonadotropins. This leads to an inflammatory environment which promotes cellular turnover and tumor development.<ref>{{Cite journal |last=Smith |first=Elizabeth R |last2=Xu |first2=Xiang-Xi |date=2008 |title=Ovarian ageing, follicle depletion, and cancer: a hypothesis for the aetiology of epithelial ovarian cancer involving follicle depletion |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713057/ |journal=The lancet oncology |volume=9 |issue=11 |pages=1108–1111 |doi=10.1016/S1470-2045(08)70281-X |issn=1470-2045 |pmc=2713057 |pmid=19012860}}</ref>

=== Morphology ===
From studying dairy cows, two forms of follicular atresia have been identified: antral and basal. 

<u>Antral</u>

Antral follicular atresia is characterized by the [[apoptosis]] of [[Granulosa cell|granulosa cells]] within the antral layers of the granulosa membrane and sometimes within the [[Follicular antrum|antrum]] itself. During this process, the presence of [[Pyknosis|pyknotic nuclei]] in the antral layers of the membrane can be observed.<ref name=":1">{{Cite journal |last=Makarevich |first=Alexander V. |last2=Földešiová |first2=Martina |last3=Pivko |first3=Juraj |last4=Kubovičová |first4=Elena |last5=Chrenek |first5=Peter |date=2018 |title=Histological characteristics of ovarian follicle atresia in dairy cows with different milk production |url=https://onlinelibrary.wiley.com/doi/10.1111/ahe.12389 |journal=Anatomia, Histologia, Embryologia |language=en |volume=47 |issue=6 |pages=510–516 |doi=10.1111/ahe.12389}}</ref> [[Apoptosis]] ensures that the follicle gets eliminated without triggering an inflammatory response.<ref name=":2">{{Citation |last=H. |first=David |title=Ovarian Follicular Atresia |date=2012 |url=http://www.intechopen.com/books/basic-gynecology-some-related-issues/ovarian-follicular-atresia |work=Basic Gynecology - Some Related Issues |editor-last=Darwish |editor-first=Atef |publisher=InTech |language=en |doi=10.5772/32465 |isbn=978-953-51-0166-6 |access-date=2022-07-26 |last2=M.H. |first2=Catherine}}</ref> Antral follicular atresia causes no damage to basal [[Granulosa cell|granulosa cells.]] This type of follicular atresia is often considered the classic and most commonly observed form. In most species, it occurs throughout follicular development and is universally seen in large follicles (>5 mm diameter).<ref name=":2" />

<u>Basal</u>

Basal follicular atresia is characterized by the destruction of [[Granulosa cell|granulosa cells]] in the basal layer of the granulosa membrane. [[Macrophage|Macrophages]] have often been observed, penetrating the basal lamina during this type of follicular atresia. These [[Macrophage|macrophages]] [[Phagocytosis|phagocytose]] the basal [[Granulosa cell|granulosa cells.]] An increased deposition of collagen in the [[Theca of follicle|theca layer]] of the follicle can also be observed.<ref name=":1" /> Basal follicular atresia causes no damage to antral [[Granulosa cell|granulosa cells.]]This form of follicular atresia has only been observed in small follicles of dairy cows (< 5mm diameter), and has not been reported in any other species.<ref name=":2" /> 

=== References ===

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