Editing Menstrual cycle

{{Short description|Natural changes in the human female reproductive system}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{About|biological aspects of the reproductive cycle in humans|information specific to monthly periods|menstruation|and|menstruation (mammal)}}
{{Use dmy dates|date=March 2021}}
[[File:Menstrual cycle.svg|thumb|upright=1.8|right|Menstrual cycle]]
The '''menstrual cycle''' is a series of natural changes in [[hormone]] production and the structures of the [[uterus]] and [[ovaries]] of the [[female reproductive system]] that makes [[pregnancy]] possible. The ovarian cycle controls the production and release of [[Egg cell|eggs]] and the cyclic release of [[estrogen]] and [[progesterone]]. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an [[embryo]]. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a [[median]] length of 28 days. [[Menarche]] (the onset of the first period) usually occurs around the age of 12 years; menstrual cycles continue for about 30–45 years.

Naturally occurring hormones drive the cycles; the cyclical rise and fall of the [[follicle stimulating hormone]] prompts the production and growth of [[oocyte]]s (immature egg cells). The hormone estrogen stimulates the uterus lining ([[endometrium]]) to thicken to accommodate an embryo should [[Human fertilization|fertilization]] occur. The blood supply of the thickened lining provides [[nutrient]]s to a successfully [[Implantation (embryology)|implanted]] embryo. If implantation does not occur, the lining breaks down and blood is released. Triggered by falling progesterone levels, [[menstruation]] (commonly referred to as a "period") is the cyclical shedding of the lining, and is a sign that pregnancy has not occurred.

Each cycle occurs in phases based on events either in the ovary (ovarian cycle) or in the uterus (uterine cycle). The ovarian cycle consists of the [[follicular phase]], [[ovulation]], and the [[luteal phase]]; the uterine cycle consists of the menstrual, proliferative and secretory phases. Day one of the menstrual cycle is the first day of the period, which lasts for about five days. Around day fourteen, an egg is usually released from the ovary.

The menstrual cycle can cause some women to experience [[premenstrual syndrome]] with symptoms that may include  [[Breast tenderness|tender breasts]], and [[Fatigue|tiredness]]. More severe symptoms that affect daily living are classed as [[premenstrual dysphoric disorder]], and are experienced by 3–8% of women. During the first few days of menstruation some women experience [[Dysmenorrhea|period pain]] that can spread from the abdomen to the back and upper thighs. The menstrual cycle can be modified by [[hormonal birth control]].

== Cycles and phases ==
[[File:Figure 28 02 07.jpg|thumb|upright=1.5|right|Progression of the menstrual cycle and some of the hormones contributing to it]]

The menstrual cycle encompasses the ovarian and uterine cycles. The ovarian cycle describes changes that occur in the [[Ovarian follicle|follicles]] of the [[ovary]],<ref name="pmid29544627">{{cite journal|vauthors=Richards JS|date=2018|title=The ovarian cycle|journal=Vitamins and Hormones|volume=107|issue=|pages=1–25|doi=10.1016/bs.vh.2018.01.009|isbn=978-0-128-14359-9|pmid=29544627 |type= Review}}</ref> whereas the uterine cycle describes changes in the [[Endometrium|endometrial lining]] of the uterus.  Both cycles can be divided into phases.  The ovarian cycle consists of alternating [[follicular phase|follicular]] and [[luteal phase]]s, and the uterine cycle consists of the [[menstruation|menstrual phase]], the proliferative phase, and the secretory phase.{{sfn|Tortora|2017|p=944}} The menstrual cycle is controlled by the [[hypothalamus]] in the brain, and the [[anterior pituitary gland]] at the base of the brain. The hypothalamus releases [[gonadotropin-releasing hormone]] (GnRH), which causes the nearby anterior pituitary to release [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH). Before [[puberty]], GnRH is released in low steady quantities and at a steady rate. After puberty, GnRH is released in large pulses, and the frequency and magnitude of these determine how much FSH and LH are produced by the pituitary.{{sfn|Prior|2020|p=42}}

Measured from the first day of one menstruation to the first day of the next, the length of a menstrual cycle varies but has a [[median]] length of 28 days.<ref name="Reed2018" /> The cycle is often less regular at the beginning and end of a woman's reproductive life.<ref name="Reed2018" /> At puberty, a child's body begins to mature into an adult body capable of [[sexual reproduction]]; the first period (called [[menarche]]) occurs at around 12 years of age and continues for about 30–45 years.{{sfn|Prior|2020|p=40}}<ref name="pmid29261991">{{cite journal |vauthors=Lacroix AE, Gondal H, Langaker MD |title=Physiology, menarche |journal=StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing |year=2020 |pmid=29261991|type= Review }}</ref> Menstrual cycles end at [[menopause]], which is usually between 45 and 55 years of age.{{sfn | Rodriguez-Landa | 2017 | p=8}}<ref name="pmid26703478" />

=== Ovarian cycle ===
Between menarche and menopause the ovaries regularly alternate between luteal and follicular phases during the monthly menstrual cycle.{{sfn | Sherwood | 2016 | p=741}} Stimulated by gradually increasing amounts of [[estrogen]] in the follicular phase, discharges of blood flow stop and the uterine lining thickens. Follicles in the ovary begin developing under the influence of a complex interplay of hormones, and after several days one, or occasionally two, become dominant, while non-dominant follicles shrink and die. About mid-cycle, some 10–12 hours after the increase in luteinizing hormone, known as the LH surge,<ref name= Reed2018>{{cite journal |vauthors= Reed BF, Carr BR, Feingold KR, et al |title= The Normal Menstrual Cycle and the Control of Ovulation |journal= Endotext |date= 2018 |pmid= 25905282 |url= https://www.ncbi.nlm.nih.gov/books/NBK279054/?report=classic |type= Review |access-date= 8 January 2021 |archive-date= 28 May 2021 |archive-url=https://web.archive.org/web/20210528022539/https://www.ncbi.nlm.nih.gov/books/NBK279054/?report=classic |url-status= live }}</ref> the dominant follicle releases an [[oocyte]], in an event called [[ovulation]].{{sfn | Sherwood | 2016 | p=747}}

After ovulation, the oocyte lives for 24 hours or less without [[Human fertilization|fertilization]],{{sfn|Tortora|2017|p=957}} while the remains of the dominant follicle in the ovary become a [[corpus luteum]] –  a body with the primary function of producing large amounts of the hormone [[progesterone]].{{sfn|Tortora|2017|p=929}}{{efn|Progesterone levels exceed those of estrogen (estradiol) by a hundred-fold.{{sfn|Prior|2020|p=41}}}} Under the influence of progesterone, the uterine lining changes to prepare for potential [[Implantation (embryology)|implantation]] of an [[embryo]] to establish a pregnancy. The thickness of the endometrium continues to increase in response to mounting levels of estrogen, which is released by the [[antral follicle]] (a mature ovarian follicle) into the blood circulation. Peak levels of estrogen are reached at around day thirteen of the cycle and coincide with ovulation. If implantation does not occur within about two weeks, the corpus luteum degenerates into the [[corpus albicans]], which does not produce hormones, causing a sharp drop in levels of both progesterone and estrogen. This drop causes the uterus to lose its lining in menstruation; it is around this time that the lowest levels of estrogen are reached.{{sfn|Tortora|2017|pp=942–946}}

In an ovulatory menstrual cycle, the ovarian and uterine cycles are concurrent and coordinated and last between 21 and 35 days, with a population average of 27–29 days.{{sfn|Prior|2020|p=45}} Although the average length of the human menstrual cycle is similar to that of the [[lunar cycle]], there is [[Lunar effect|no causal relation]] between the two.{{sfn|Norris|Carr|2013|p= [https://books.google.com/books?id=F_NaW1ZcSSAC&pg=PA361 361]}}

==== Follicular phase ====
{{main|Follicular phase}}
The ovaries contain a finite number of [[Oogonium|egg stem cells]], [[granulosa cells]] and [[Theca of follicle|theca cells]], which together form primordial follicles.{{sfn|Tortora|2017|p=929}} At around 20 weeks into [[gestation]] some 7 million immature eggs have already formed in an ovary. This decreases to around 2&nbsp;million by the time a girl is born, and 300,000 by the time she has her first period. On average, one egg matures and is released during ovulation each month after menarche.{{sfn | Ugwumadu | 2014 | p=115}} Beginning at puberty, these mature to primary follicles independently of the menstrual cycle.{{sfn | Watchman | 2020 | p=8}}  The development of the egg is called [[oogenesis]] and only one cell survives the [[Prophase#Meiotic prophase|divisions]] to await fertilization. The other cells are discarded as [[polar body|polar bodies]], which cannot be fertilized.<ref name="pmid21268179">{{cite journal |vauthors=Schmerler S, Wessel GM |title=Polar bodies – more a lack of understanding than a lack of respect |journal=Molecular Reproduction and Development |volume=78 |issue=1 |pages=3–8 |date=January 2011 |pmid=21268179 |pmc=3164815 |doi=10.1002/mrd.21266 |type= Review}}</ref> The follicular phase is the first part of the ovarian cycle and it ends with the completion of the [[antral follicles]].{{sfn | Sherwood | 2016 | p=741}} [[Meiosis]] (cell division) remains incomplete in the egg cells until the antral follicle is formed. During this phase usually only one ovarian follicle fully matures and gets ready to release an egg.{{sfn | Tortora | 2017 | p=945}} The follicular phase shortens significantly with age, lasting around 14 days in women aged 18–24 compared with 10 days in women aged 40–44.{{sfn | Tortora | 2017 | pp=942–946}}

Through the influence of a rise in [[follicle stimulating hormone]] (FSH) during the first days of the cycle, a few ovarian follicles are stimulated. These follicles, which have been developing for the better part of a year in a process known as [[folliculogenesis]], compete with each other for dominance. All but one of these follicles will stop growing, while one dominant follicle – the one that has the most FSH receptors –  will continue to maturity. The remaining follicles die in a process called [[follicular atresia]].{{sfn|Johnson|2007|page=86}} [[Luteinizing hormone]] (LH) stimulates further development of the ovarian follicle. The follicle that reaches maturity is called an antral follicle, and it contains the [[ovum]] (egg cell).{{sfn|Tortora|2017|p=942}}

The theca cells develop receptors that bind LH, and in response secrete large amounts of [[androstenedione]]. At the same time the granulosa cells surrounding the maturing follicle develop receptors that bind FSH, and in response start secreting androstenedione, which is converted to estrogen by the enzyme [[aromatase]]. The estrogen inhibits further production of FSH and LH by the pituitary gland. This [[negative feedback]] regulates levels of FSH and LH. The dominant follicle continues to secrete estrogen, and the rising estrogen levels make the pituitary more responsive to GnRH from the hypothalamus. As estrogen increases this becomes a [[positive feedback]] signal, which makes the pituitary secrete more FSH and LH. This surge of FSH and LH usually occurs one to two days before ovulation and is responsible for stimulating the rupture of the antral follicle and release of the oocyte.{{sfn | Watchman | 2020 | p=8}}{{sfn | Sherwood | 2016 | p=745}}

==== Ovulation ====
{{main|Ovulation}}
[[File:ovulation.jpg|thumb|An ovary about to release an egg]]
Around day fourteen, the egg is released from the ovary.{{sfn | Tortora | 2017 | p=943}}  Called [[ovulation]], this occurs when a mature egg is released from the ovarian follicles into the pelvic cavity and enters the [[fallopian tube]], about 10–12 hours after the peak in LH surge.<ref name= Reed2018/> Typically only one of the 15–20 stimulated follicles reaches full maturity, and just one egg is released.{{sfn | Sadler | 2019 | p=48}} Ovulation only occurs in around 10% of cycles during the first two years following menarche, and by the age of 40–50, the number of ovarian follicles is depleted.{{sfn|Tortora|2017|p=953}} LH initiates ovulation at around day 14 and stimulates the formation of the corpus luteum.{{sfn|Tortora|2017|p=944}} Following further stimulation by LH, the corpus luteum produces and releases estrogen, progesterone, [[relaxin]] (which relaxes the uterus by inhibiting contractions of the [[myometrium]]), and [[inhibin]] (which inhibits further secretion of FSH).{{sfn|Tortora|2017|p=920}}

The release of LH matures the egg and weakens the follicle wall in the ovary, causing the fully developed follicle to release its oocyte.{{sfn | Sherwood | 2016 | p=746}} If it is fertilized by a sperm, the oocyte promptly matures into an [[ootid]], which blocks the other [[spermatozoa|sperm cells]] and becomes a mature egg. If it is not fertilized by a sperm, the oocyte degenerates. The mature egg has a diameter of about {{cvt|0.1|mm}},<ref>{{Cite book| vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P |date=2002|chapter=Eggs|title=Molecular Biology of the Cell|edition=4th|isbn=0-8153-3218-1|chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK26842/ |location=New York|publisher=Garland Science |access-date=25 February 2021 |archive-date=16 December 2019 |archive-url= https://web.archive.org/web/20191216042524/https://www.ncbi.nlm.nih.gov/books/NBK26842/ |url-status=live}}</ref> and is the largest human cell.<ref name="pmid30739329">{{cite journal | vauthors = Iussig B, Maggiulli R, Fabozzi G, Bertelle S, Vaiarelli A, Cimadomo D, Ubaldi FM, Rienzi L | title = A brief history of oocyte cryopreservation: Arguments and facts | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 98 | issue = 5 | pages = 550–558 | date = May 2019 | pmid = 30739329 | doi = 10.1111/aogs.13569 | type = Review | doi-access = free }}</ref>

Which of the two ovaries – left or right – ovulates appears random;{{sfn | Parker | 2019 | p=283}} no left and right coordinating process is known.{{sfn|Johnson|2007|pp=192–193}} Occasionally both ovaries release an egg; if both eggs are fertilized, the result is [[fraternal twin]]s.{{sfn|Johnson|2007|p=192}} After release from the ovary into the pelvic cavity, the egg is swept into the fallopian tube by the [[Fimbria (female reproductive system)|fimbria]] –  a fringe of tissue at the end of each fallopian tube. After about a day, an unfertilized egg disintegrates or dissolves in the fallopian tube, and a fertilized egg reaches the uterus in three to five days.{{sfn | Sadler | 2019 | p=36}}

Fertilization usually takes place in the [[Ampulla of uterine tube|ampulla]], the widest section of the fallopian tubes. A [[Zygote|fertilized egg]] immediately starts the process of [[Human embryonic development|embryonic development]]. The developing embryo takes about three days to reach the uterus, and another three days to implant into the endometrium. It has reached the [[blastocyst]] stage at the time of implantation: this is when pregnancy begins.{{sfn | Tortora | 2017 | p=959}} The loss of the corpus luteum is prevented by fertilization of the egg.  The [[syncytiotrophoblast]] (the outer layer of the resulting embryo-containing blastocyst that later becomes the outer layer of the placenta) produces [[human chorionic gonadotropin]] (hCG), which is very similar to LH and preserves the corpus luteum. During the first few months of pregnancy, the corpus luteum continues to secrete progesterone and estrogens at slightly higher levels than those at ovulation. After this and for the rest of the pregnancy, the [[placenta]] secretes high levels of these hormones – along with hCG, which stimulates the corpus luteum to secrete more progesterone and estrogens, blocking the menstrual cycle.{{sfn|Tortora|2017|page=976}} These hormones also prepare the mammary glands for milk{{efn|[[Breastfeeding]] women can experience complete suppression of follicular development, follicular development but no ovulation, or resumption of normal menstrual cycles.<ref name="pmid25869631">{{cite journal |vauthors=Carr SL, Gaffield ME, Dragoman MV, Phillips S |title=Safety of the progesterone-releasing vaginal ring (PVR) among lactating women: A systematic review |journal=Contraception |volume=94 |issue=3 |pages=253–261 |date=September 2016 |pmid=25869631 |doi=10.1016/j.contraception.2015.04.001 |doi-access=free |type= Review}}</ref>}} production.{{sfn|Tortora|2017|page=976}}

==== Luteal phase ====
{{main|Luteal phase}}
Lasting about 14 days,<ref name="Reed2018" /> the luteal phase is the final phase of the ovarian cycle and it corresponds to the secretory phase of the uterine cycle. During the luteal phase, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone.{{sfn|Johnson|2007|page=91}}{{efn|In the corpus luteum, [[cholesterol side-chain cleavage enzyme]] converts [[cholesterol]] to [[pregnenolone]], which is converted to progesterone.<ref name="pmid22201776">{{cite journal |vauthors=King SR, LaVoie HA |title=Gonadal transactivation of STARD1, CYP11A1 and HSD3B |journal=Frontiers in Bioscience (Landmark Edition) |volume=17 |issue= 3|pages=824–846 |date=January 2012 |pmid=22201776 |doi=10.2741/3959 |doi-access=free }}</ref>}} The increased progesterone starts to induce the production of estrogen. The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. The level of FSH and LH fall quickly, and the corpus luteum atrophies.{{sfn | Ugwumadu | 2014 | p=117}} Falling levels of progesterone trigger menstruation and the beginning of the next cycle. For an individual woman, the follicular phase often varies in length from cycle to cycle; by contrast, the length of her luteal phase will be fairly consistent from cycle to cycle at 10 to 16 days (average 14 days).{{sfn | Tortora | 2017 | pp=942–946}}

=== Uterine cycle ===
[[File:Illu cervix.svg|right|thumb|upright=1.6|The anatomy of the uterus]]
The uterine cycle has three phases: menses, proliferative and secretory.<ref name="pmid30521482">{{cite journal |vauthors=Salamonsen LA |title=Women in reproductive science: Understanding human endometrial function |journal=Reproduction |volume=158 |issue=6 |pages=F55–F67 |date=December 2019 |pmid=30521482 |doi=10.1530/REP-18-0518 |doi-access=free |type= Review}}</ref>

==== Menstruation ====
{{main|Menstruation}}
Menstruation (also called menstrual bleeding, menses or a period) is the first and most evident phase of the uterine cycle and first occurs at puberty. Called menarche, the first period occurs at the age of around twelve or thirteen years.<ref name="pmid26703478">{{cite journal |vauthors=Papadimitriou A |title=The evolution of the age at menarche from prehistorical to modern times |journal=Journal of Pediatric and Adolescent Gynecology |volume=29 |issue=6 |pages=527–530 |date=December 2016 |pmid=26703478 |doi=10.1016/j.jpag.2015.12.002 |type= Review}}</ref> The average age is generally later in the [[developing world]] and earlier in the [[developed world]].<ref name="pmid29778270">{{cite journal |vauthors=Alvergne A, Högqvist Tabor V |title=Is female health cyclical? Evolutionary perspectives on menstruation |journal=Trends in Ecology & Evolution |volume=33 |issue=6 |pages=399–414 |date=June 2018 |pmid=29778270 |doi=10.1016/j.tree.2018.03.006 |arxiv=1704.08590 |bibcode=2018TEcoE..33..399A |s2cid=4581833 |type= Review}}</ref>  In [[precocious puberty]], it can occur as early as age eight years,<ref name="pmid28591132">{{cite journal |vauthors=Ibitoye M, Choi C, Tai H, Lee G, Sommer M |title=Early menarche: A systematic review of its effect on sexual and reproductive health in low- and middle-income countries |journal=PLOS ONE |volume=12 |issue=6 |pages=e0178884 |date=2017 |pmid=28591132 |pmc=5462398 |doi=10.1371/journal.pone.0178884 |bibcode=2017PLoSO..1278884I |type= Review|doi-access=free }}</ref> and this can still be normal.<ref name=Women2014Men>{{cite web|title=Menstruation and the menstrual cycle fact sheet|url=http://www.womenshealth.gov/publications/our-publications/fact-sheet/menstruation.html|website=Office of Women's Health |publisher= US Department of Health and Human Services |access-date=25 June 2015|date=23 December 2014|url-status=dead|archive-url=https://web.archive.org/web/20150626134338/http://www.womenshealth.gov/publications/our-publications/fact-sheet/menstruation.html|archive-date=26 June 2015}}</ref><ref name="pmid29422239">{{cite journal |vauthors=Sultan C, Gaspari L, Maimoun L, Kalfa N, Paris F |title=Disorders of puberty |journal=Best Practice & Research. Clinical Obstetrics & Gynaecology |volume=48 |issue= |pages=62–89 |date=April 2018 |pmid=29422239 |doi=10.1016/j.bpobgyn.2017.11.004 |url=https://hal.umontpellier.fr/hal-01797379/file/2018%20Sultan%20et%20al.%2C%20Disorders%20of%20puberty.pdf |type=Review |access-date=27 February 2021 |archive-date=1 July 2020 |archive-url=https://web.archive.org/web/20200701081342/https://hal.umontpellier.fr/hal-01797379/file/2018%20Sultan%20et%20al.,%20Disorders%20of%20puberty.pdf |url-status=live }}</ref>

Menstruation is initiated each month by falling levels of estrogen and progesterone and the release of [[prostaglandin]]s,{{sfn|Tortora|2017|p=945}} which constrict the [[spiral artery|spiral arteries]]. This causes them to [[spasm]], contract and break up.{{sfn|Johnson|2007|p=152}} The blood supply to the endometrium is cut off and the cells of the top layer of the endometrium (the stratum functionalis) become deprived of oxygen and die. Later the whole layer is lost and only the bottom layer, the stratum basalis, is left in place.{{sfn|Tortora|2017|page=945}} An [[enzyme]] called [[plasmin]] breaks up the [[blood clotting|blood clots]] in the menstrual fluid, which eases the flow of blood and broken down lining from the uterus.{{sfn | Tortora | 2017 | p=600}} The flow of blood continues for 2–6 days and around 30–60 [[milliliters]] of blood is lost,{{sfn|Prior|2020|p=45}} and is a sign that pregnancy has not occurred.{{sfn|Johnson|2007|p=99}}

The flow of blood normally serves as a sign that a woman has not become pregnant, but this cannot be taken as certainty, as several factors can cause [[Vaginal bleeding#Pregnant women|bleeding during pregnancy]].<ref name="pmid27166462">{{cite journal |vauthors=Breeze C |title=Early pregnancy bleeding |journal=Australian Family Physician |volume=45 |issue=5 |pages=283–286 |date=May 2016 |pmid=27166462 |type= Review}}</ref> Menstruation occurs on average once a month from menarche to menopause, which corresponds with a woman's fertile years. The average age of menopause in women is 52 years, and it typically occurs between 45 and 55 years of age.<ref name="pmid27022074">{{cite journal |vauthors=Towner MC, Nenko I, Walton SE |title=Why do women stop reproducing before menopause? A life-history approach to age at last birth |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=371 |issue=1692 |page=20150147 |date=April 2016 |pmid=27022074 |pmc=4822427 |doi=10.1098/rstb.2015.0147 |type= Review}}</ref> Menopause is preceded by a stage of hormonal changes called [[perimenopause]].{{sfn | Rodriguez-Landa | 2017 | p=8}}

''Eumenorrhea'' denotes normal, regular menstruation that lasts for around the first 5 days of the cycle.{{sfn|Tortora|2017|p=943}} Women who experience [[menorrhagia]] (heavy menstrual bleeding) are more susceptible to [[iron deficiency (medicine)|iron deficiency]] than the average person.<ref name=iron>{{cite journal | vauthors = Harvey LJ, Armah CN, Dainty JR, Foxall RJ, John Lewis D, Langford NJ, Fairweather-Tait SJ | title = Impact of menstrual blood loss and diet on iron deficiency among women in the UK | journal = The British Journal of Nutrition | volume = 94 | issue = 4 | pages = 557–564 | date = October 2005 | pmid = 16197581 | doi = 10.1079/BJN20051493 | doi-access = free| type= Comparative study}}</ref>

==== Proliferative phase ====
[[File:Estradiol and progesterone % changes across the menstrual cycle.tif|thumb|upright=1.6|During the menstrual cycle, levels of estradiol (an estrogen) vary by 200 percent. Levels of progesterone vary by over 1200 percent.<ref>{{cite journal|vauthors=Prior JC|title=Women's reproductive system as balanced estradiol and progesterone actions—A revolutionary, paradigm-shifting concept in women's health|journal=Drug Discovery Today: Disease Models|volume=32 | issue = Part B|year=2020|pages=31–40|doi=10.1016/j.ddmod.2020.11.005|ref=none|doi-access=free}}</ref>]]

The proliferative phase is the second phase of the uterine cycle when estrogen causes the lining of the uterus to grow and proliferate.{{sfn | Ugwumadu | 2014 | p= 117}} The latter part of the follicular phase overlaps with the proliferative phase of the uterine cycle.{{sfn|Parker|2019|p=283}} As they mature, the ovarian follicles secrete increasing amounts of [[estradiol]], an estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus with the spiral arterioles.{{sfn|Tortora|2017|p=944}}

As estrogen levels increase, cells in the cervix produce a type of [[cervical mucus]]<ref>{{cite journal |vauthors=Simmons RG, Jennings V |title=Fertility awareness-based methods of family planning |journal=Best Practice & Research. Clinical Obstetrics & Gynaecology |volume=66 |pages=68–82 |date=July 2020 |pmid=32169418 |doi=10.1016/j.bpobgyn.2019.12.003 |doi-access=free |type= Review}}</ref> that has a higher [[pH]] and is less [[viscosity|viscous]] than usual, rendering it more friendly to sperm.{{sfn|Tortora|2017|pp=936–937}} This increases the chances of fertilization, which occurs around day 11 to day 14.{{sfn|Tortora|2017|p=957}} This cervical mucus can be detected as a vaginal discharge that is copious and resembles raw egg whites.<ref name= Su2017 /> For women who are practicing [[fertility awareness]], it is a sign that ovulation may be about to take place,<ref name= Su2017>{{cite journal |vauthors=Su HW, Yi YC, Wei TY, Chang TC, Cheng CM |title=Detection of ovulation, a review of currently available methods |journal=Bioeng Transl Med |volume=2 |issue=3 |pages=238–246 |date=September 2017 |pmid=29313033 |pmc=5689497 |doi=10.1002/btm2.10058 |type= Review}}</ref> but it does not mean ovulation will definitely occur.{{sfn|Prior|2020|p=45}}

==== Secretory phase ====
The secretory phase is the final phase of the uterine cycle and it corresponds to the luteal phase of the ovarian cycle. During the secretory phase, the corpus luteum produces progesterone, which plays a vital role in making the endometrium [[Implantation (embryology)#Uterus receptivity|receptive]] to the [[Implantation (embryology)|implantation]] of a [[blastocyst]] (a fertilized egg, which has begun to grow).<ref name="pmid30929718">{{cite journal |vauthors=Lessey BA, Young SL |title=What exactly is endometrial receptivity? |journal=Fertility and Sterility |volume=111 |issue=4 |pages=611–617|date=April 2019 |pmid=30929718 |doi=10.1016/j.fertnstert.2019.02.009 |type= Review|doi-access=free }}</ref> [[Glycogen]], [[lipid]]s, and [[protein]]s are secreted into the uterus<ref name="pmid26661899">{{cite journal |vauthors=Salamonsen LA, Evans J, Nguyen HP, Edgell TA |title=The microenvironment of human implantation: determinant of reproductive success |journal=American Journal of Reproductive Immunology |volume=75 |issue=3 |pages=218–225 |date=March 2016 |pmid=26661899 |doi=10.1111/aji.12450 |type= Review|doi-access=free }}</ref> and the cervical mucus thickens.<ref name="pmid28801053">{{cite journal |vauthors=Han L, Taub R, Jensen JT |title=Cervical mucus and contraception: what we know and what we don't |journal=Contraception |volume=96 |issue=5 |pages=310–321 |date=November 2017 |pmid=28801053 |doi=10.1016/j.contraception.2017.07.168 |type= Review}}</ref> In early pregnancy, progesterone also increases blood flow and reduces the [[Muscle contraction|contractility]] of the [[smooth muscle]] in the uterus{{sfn|Tortora|2017|p= 942}} and raises [[basal body temperature]].<ref name="pmid28488202">{{cite journal |vauthors=Charkoudian N, Hart EC, Barnes JN, Joyner MJ |title=Autonomic control of body temperature and blood pressure: influences of female sex hormones |journal=Clinical Autonomic Research |volume=27 |issue=3 |pages=149–155 |date=June 2017 |pmid=28488202 |doi=10.1007/s10286-017-0420-z |s2cid=3773043 |url=https://research-information.bris.ac.uk/ws/files/152610705/Charkoudian_CAR_review_final.pdf |type=Review |access-date=27 February 2021 |archive-date=10 May 2020 |archive-url=https://web.archive.org/web/20200510013255/https://research-information.bris.ac.uk/ws/files/152610705/Charkoudian_CAR_review_final.pdf |url-status=live |hdl=1983/c0c1058c-553b-4563-8dd1-b047d9b672c1 |hdl-access=free }}</ref>

If pregnancy does not occur the ovarian and uterine cycles start over again.{{sfn|Tortora|2017|page=600}}

==Anovulatory cycles and short luteal phases==
{{Main|Anovulation}}
Only two-thirds of overtly normal menstrual cycles are ovulatory, that is, cycles in which ovulation occurs.{{sfn|Prior|2020|p=45}} The other third lack ovulation or have a short luteal phase (less than ten days<ref name = Liu>{{cite book |vauthors= Liu AY, Petit MA, Prior JC|chapter= Exercise and the Hypothalamus: Ovulatory Adaptations|date=2020|doi=10.1007/978-3-030-33376-8_8|title=Endocrinology of Physical Activity and Sport|pages=124–147|veditors=Hackney AC, Constantini NW|series= Contemporary Endocrinology|publisher=Springer International Publishing|isbn=978-3-030-33376-8|s2cid= 243129220}}</ref>) in which progesterone production is insufficient for normal physiology and fertility.{{sfn|Prior|2020|p=46}} Cycles in which ovulation does not occur ([[anovulation]]) are common in girls who have just begun menstruating and in women around menopause. During the first two years following menarche, ovulation is absent in around half of cycles. Five years after menarche, ovulation occurs in around 75% of cycles and this reaches 80% in the following years.<ref name="pmid29537383">{{cite journal |vauthors=Elmaoğulları S, Aycan Z |title=Abnormal uterine bleeding in adolescents |journal=Journal of Clinical Research in Pediatric Endocrinology |volume=10 |issue=3 |pages=191–197 |date=July 2018 |pmid=29537383 |pmc=6083466 |doi=10.4274/jcrpe.0014 }}</ref> Anovulatory cycles are often overtly identical to normally ovulatory cycles.{{sfn|Prior|2020|p=44}} Any alteration to balance of hormones can lead to anovulation. Stress, anxiety and [[eating disorder]]s can cause a fall in GnRH, and a disruption of the menstrual cycle. Chronic anovulation occurs in 6–15% of women during their reproductive years. Around menopause, hormone feedback dysregulation leads to anovulatory cycles. Although anovulation is not considered a disease, it can be a sign of an underlying condition such as [[polycystic ovary syndrome]].<ref>{{cite web
 |url=https://emedicine.medscape.com/article/253190-overview
 |title=Anovulation
 |vauthors=Hernandez-Rey, AE
 |date=August 2, 2018
 |website=Medscape
 |publisher=Medscape LLC
 |access-date=March 30, 2021
 |archive-date=20 March 2021
 |archive-url=https://web.archive.org/web/20210320153521/https://emedicine.medscape.com/article/253190-overview
 |url-status=live
 }}</ref> Anovulatory cycles or short luteal phases are normal when women are under stress or athletes increasing the intensity of training. These changes are reversible as the stressors decrease or, in the case of the athlete, as she adapts to the training.<ref name = Liu/>

== Menstrual health ==

[[File:Human ovarian follicle.jpg|thumb|A human primary [[ovarian follicle]] viewed by [[microscopy]]. The round [[oocyte]] stained red in the center is surrounded by a layer of [[granulosa cell]]s, which are enveloped by the basement membrane and [[theca cell]]s. The magnification is around 1000 times. ([[H&E stain]])]]
Although a normal and natural process,{{sfn|Prior|2020|p=50}} some women experience [[premenstrual syndrome]] with symptoms that may include [[acne vulgaris|acne]], [[Breast tenderness|tender breasts]], and [[Fatigue|tiredness]].<ref name="pmid32809533">{{cite book |last1=Gudipally |first1=Pratyusha R. |last2=Sharma |first2=Gyanendra K. |chapter=Premenstrual Syndrome |title=StatPearls |date=2022 |publisher=StatPearls Publishing |id={{NCBIBook2|NBK560698}} |pmid=32809533 }}</ref> More  severe symptoms that affect daily living are classed as [[premenstrual dysphoric disorder]] and are experienced by 3 to 8% of women.<ref name="Reed2018" /><ref name="pmid29298169">{{cite journal |vauthors=Appleton SM |title=Premenstrual syndrome: evidence-based evaluation and treatment |journal=Clinical Obstetrics and Gynecology |volume=61 |issue=1 |pages=52–61 |date=March 2018 |pmid=29298169 |doi=10.1097/GRF.0000000000000339 |s2cid=28184066 |type= Review}}</ref><ref name="pmid32809533"/><ref name="pmid33030880">{{cite journal |vauthors=Ferries-Rowe E, Corey E, Archer JS |title=Primary Dysmenorrhea: Diagnosis and Therapy |journal=Obstetrics and Gynecology |volume=136 |issue=5 |pages=1047–1058 |date=November 2020 |pmid=33030880 |doi=10.1097/AOG.0000000000004096|doi-access=free }}</ref>  [[Dysmenorrhea]] (menstrual cramps or period pain) is felt as painful cramps in the abdomen that can spread to the back and upper thighs during the first few days of menstruation.<ref name="nhs1">{{cite web |title=Period pain |url=https://www.nhs.uk/conditions/period-pain/ |website=nhs.uk |access-date=12 November 2022 |language=en |date=19 October 2017}}</ref><ref name=Dysmenorrheastat>{{cite book |last1=Nagy |first1=Hassan |last2=Khan |first2=Moien AB |chapter=Dysmenorrhea |title=StatPearls |date=2022 |publisher=StatPearls Publishing |id={{NCBIBook2|NBK560834}} |pmid=32809669 }}</ref><ref name="pmid30098748">{{cite journal |vauthors=Baker FC, Lee KA |title=Menstrual cycle effects on sleep |journal=Sleep Medicine Clinics |volume=13 |issue=3 |pages=283–294 |date=September 2018 |pmid=30098748 |doi=10.1016/j.jsmc.2018.04.002 |s2cid=51968811 |type= Review}}</ref> Debilitating period pain is not normal and can be a sign of something severe such as [[endometriosis]].<ref name="pmid33132854">{{cite journal |vauthors=Maddern J, Grundy L, Castro J, Brierley SM |title=Pain in endometriosis |journal=Frontiers in Cellular Neuroscience |volume=14 |issue= |pages=590823 |date=2020 |pmid=33132854 |pmc=7573391 |doi=10.3389/fncel.2020.590823 |doi-access=free }}</ref> These issues can significantly affect a [[Women's health|woman's health]] and quality of life and timely interventions can improve the lives of these women.<ref name="pmid31378287">{{cite journal |vauthors=Matteson KA, Zaluski KM |title=Menstrual health as a part of preventive health care |journal=Obstetrics and Gynecology Clinics of North America |volume=46 |issue=3 |pages=441–453 |date=September 2019 |pmid=31378287 |doi=10.1016/j.ogc.2019.04.004 |s2cid=199437314 |type= Review}}</ref>

There are common culturally communicated misbeliefs that the menstrual cycle affects women's moods, causes depression or irritability, or that menstruation is a painful, shameful or unclean experience. Often a woman's normal mood variation is falsely attributed to the menstrual cycle. Much of the research is weak, but there appears to be a very small increase in mood fluctuations during the luteal and menstrual phases, and a corresponding decrease during the rest of the cycle.{{sfn|Else-Quest|Hyde|2021|pp= 258–261}} Changing levels of estrogen and progesterone across the menstrual cycle exert systemic effects on aspects of physiology including the brain, metabolism, and musculoskeletal system. The result can be subtle physiological and observable changes to women's athletic performance including strength, aerobic, and anaerobic performance.<ref>{{cite journal |vauthors=Carmichael MA, Thomson RL, Moran LJ, Wycherley TP |title=The impact of menstrual cycle phase on athletes' performance: a narrative review |journal=Int J Environ Res Public Health |volume=18 |issue=4 |date=February 2021 |page=1667 |pmid=33572406 |pmc=7916245 |doi=10.3390/ijerph18041667 |type=Review|doi-access=free }}</ref> 

Changes to the brain have also been observed throughout the menstrual cycle<ref>{{cite journal |vauthors=Pletzer B, Harris TA, Scheuringer A, Hidalgo-Lopez E |title=The cycling brain: menstrual cycle related fluctuations in hippocampal and fronto-striatal activation and connectivity during cognitive tasks |journal=Neuropsychopharmacology |volume=44 |issue=11 |pages=1867–1875 |date=October 2019 |pmid=31195407 |pmc=6785086 |doi=10.1038/s41386-019-0435-3 }}</ref> but do not translate into measurable changes in intellectual achievement – including academic performance, problem-solving, and memory.<ref>{{cite journal |vauthors=Le J, Thomas N, Gurvich C |title=Cognition, the menstrual cycle, and premenstrual disorders: a review |journal=Brain Sci |volume=10 |issue=4  |date=March 2020 |page=198 |pmid=32230889 |pmc=7226433 |doi=10.3390/brainsci10040198 |type=Review|doi-access=free }}</ref> Improvements in [[Spatial ability|spatial reasoning ability]] during the menstruation phase of the cycle are probably caused by decreases in levels of estrogen and progesterone.{{sfn|Else-Quest|Hyde|2021|pp= 258–261}}

In some women, ovulation features a characteristic pain{{efn|Uncharacteristic mid-cycle pain may be caused by medical conditions such as [[ectopic pregnancy]] or ruptured [[ovarian cyst]]<ref>{{cite journal |vauthors=Kruszka PS, Kruszka SJ |title=Evaluation of acute pelvic pain in women |journal=Am Fam Physician |volume=82 |issue=2 |pages=141–147 |date=July 2010 |pmid=20642266 |url=https://www.aafp.org/afp/2010/0715/p141.html |type=Review |access-date=4 March 2021 |archive-date=27 January 2021 |archive-url=https://web.archive.org/web/20210127180019/https://www.aafp.org/afp/2010/0715/p141.html |url-status=live }}</ref><ref>{{cite book|title= Acute and Emergency Care in Athletic Training |vauthors= Cleary M, Flanagan KW |publisher= Human Kinetics |date= 2019 |page= [https://books.google.com/books?id=_dWLDwAAQBAJ&pg=PA340&q=Mittelschmerz%20ectopic 340]}}</ref> or may be confused with [[appendicitis]].<ref>{{cite book |last1=Brott |first1=Nathan R. |last2=Le |first2=Jacqueline K. |chapter=Mittelschmerz |title=StatPearls |date=2022 |publisher=StatPearls Publishing |id={{NCBIBook2|NBK549822}} |pmid=31747229 }}</ref>}} called ''[[mittelschmerz]]'' (a German term meaning ''middle pain''). The cause of the pain is associated with the ruptured follicle, causing a small amount of blood loss.{{sfn|Tortora|2017|p=945}}

Even when normal, the changes in hormone levels during the menstrual cycle can increase the incidence of disorders such as [[autoimmune disease]]s,<ref name="pmid28390570">{{cite journal |vauthors=Talsania M, Scofield RH |title=Menopause and rheumatic disease |journal=Rheumatic Disease Clinics of North America |volume=43 |issue=2 |pages=287–302 |date=May 2017 |pmid=28390570 |pmc=5385852 |doi=10.1016/j.rdc.2016.12.011 |type= Review}}</ref> which might be caused by estrogen enhancement of the [[immune system]].<ref name="Reed2018" />

Around 40% of women with [[epilepsy]] find that their [[seizure]]s occur more frequently at certain phases of their menstrual cycle. This [[catamenial epilepsy]] may be due to a drop in progesterone if it occurs during the luteal phase or around menstruation, or a surge in estrogen if it occurs at ovulation. Women who have regular periods can take medication just before and during menstruation. Options include progesterone supplements, increasing the dose of their regular [[anticonvulsant]] drug, or temporarily adding an anticonvulsant such as [[clobazam]] or [[acetazolamide]]. If this is ineffective, or when a woman's menstrual cycle is irregular, then treatment is to stop the menstrual cycle occurring. This may be achieved using [[medroxyprogesterone]], [[triptorelin]] or [[goserelin]], or by sustained use of oral contraceptives.<ref name="pmid34528245">{{cite journal |vauthors=Maguire MJ, Nevitt SJ |title=Treatments for seizures in catamenial (menstrual-related) epilepsy |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue= 9|pages=CD013225 |date=September 2021 |pmid=34528245 |doi=10.1002/14651858.CD013225.pub3|pmc=8444032 }}</ref><ref name="pmid25079452">{{cite journal |vauthors=Sveinsson O, Tomson T |title=Epilepsy and menopause: potential implications for pharmacotherapy |journal=Drugs & Aging |volume=31 |issue=9 |pages=671–675 |date=September 2014 |pmid=25079452 |doi=10.1007/s40266-014-0201-5 |s2cid=21166687 }}</ref>

=== Hormonal contraception ===
{{main|Hormonal contraception}}
Hormonal contraceptives prevent pregnancy by inhibiting the secretion of the hormones, FSH, LH and GnRH. Hormonal contraception that contains estrogen, such as [[combined oral contraceptive pills]] (COCPs), stop the development of the dominant follicle and the mid-cycle LH surge and thus ovulation.{{sfn|Tortora|2017|p=948}}  Sequential dosing and discontinuation of the COCP can mimic the uterine cycle and produce bleeding that resembles a period. In some cases, this bleeding is lighter.<ref name="pmid29940996">{{cite journal |vauthors=Polis CB, Hussain R, Berry A |title=There might be blood: a scoping review on women's responses to contraceptive-induced menstrual bleeding changes |journal=Reproductive Health |volume=15 |issue=1 |pages=114 |date=June 2018 |pmid=29940996 |pmc=6020216 |doi=10.1186/s12978-018-0561-0 |doi-access=free }}</ref>

Progestin-only methods of hormonal contraception do not always prevent ovulation but instead work by stopping the cervical mucus from becoming sperm-friendly. Hormonal contraception is available in a variety of forms such as pills, [[contraceptive patch|patches]], [[Long-acting reversible contraception|skin implants]] and [[Hormonal IUDs|hormonal intrauterine devices]] (IUDs).{{sfn|Tortora|2017|pp=948–949}}

==Evolution and other species==
{{further|Menstruation (mammal)}}
Most [[female mammals]] have an [[estrous cycle]], but only ten primate species, four [[bat]] species, the [[elephant shrew]]s and the [[Cairo spiny mouse]] (''Acomys cahirinus'') have a [[Menstruation (mammal)|menstrual cycle]].<ref name = Bellofiore>{{cite journal | vauthors = Bellofiore N, Ellery SJ, Mamrot J, Walker DW, Temple-Smith P, Dickinson H | title = First evidence of a menstruating rodent: the spiny mouse&nbsp;(Acomys&nbsp;cahirinus) | journal = American Journal of Obstetrics and Gynecology | volume = 216 | issue = 1 | pages = 40.e1–40.e11 | date = January 2017 | pmid = 27503621 | doi = 10.1016/j.ajog.2016.07.041 | s2cid = 88779 |type= Journal article| url = https://www.biorxiv.org/content/biorxiv/early/2016/06/03/056895.full.pdf }}</ref><ref>{{Cite journal|last1=Bellofiore|first1=Nadia|last2=Cousins|first2=Fiona|last3=Temple-Smith|first3=Peter|last4=Evans|first4=Jemma|date=2019-02-01|title=Altered exploratory behaviour and increased food intake in the spiny mouse before menstruation: a unique pre-clinical model for examining premenstrual syndrome|url=https://academic.oup.com/humrep/article/34/2/308/5248532|journal=Human Reproduction|language=en|volume=34|issue=2|pages=308–322|doi=10.1093/humrep/dey360|pmid=30561655|issn=0268-1161|doi-access=free}}</ref> The cycles are the same as in humans apart from the length, which ranges from 9 to 37 days.<ref name="pmid32129461"/><ref name = Bellofiore/> The lack of immediate relationship between these groups suggests that four distinct evolutionary events have caused menstruation to arise.<ref name=Emera2012/> There are four theories on the evolutionary significance of menstruation:<ref name=Emera2012>{{cite journal |vauthors=Emera D, Romero R, Wagner G |title=The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness |journal=BioEssays |volume=34 |issue=1 |pages=26–35 |date=January 2012 |pmid=22057551 |pmc=3528014 |doi=10.1002/bies.201100099 |type=Journal article}} See [https://web.archive.org/web/20210801180159/http://www.bbc.com/earth/story/20150420-why-do-women-have-periods BBC Earth lay summary], 20 April 2015.</ref>

# Control of sperm-borne pathogens.<ref name="pmid18046752">{{cite journal |vauthors=Martin RD |title=The evolution of human reproduction: a primatological perspective |journal=American Journal of Physical Anthropology |volume=134 |issue=S45 |pages=59–84 |date=2007 |pmid=18046752 |doi=10.1002/ajpa.20734 |s2cid=44416632 |type= Review|doi-access=free }}</ref><ref name="pmid9618925">{{cite journal |vauthors=Finn CA |title=Menstruation: a nonadaptive consequence of uterine evolution |journal=The Quarterly Review of Biology |volume=73 |issue=2 |pages=163–173 |date=June 1998|pmid=9618925|doi=10.1086/420183 |s2cid=25135630 |type= Review}}</ref><ref name="pmid8210311">{{cite journal |vauthors=Profet M |title=Menstruation as a defense against pathogens transported by sperm |journal=The Quarterly Review of Biology |volume=68 |issue=3 |pages=335–386 |date=September 1993 |pmid=8210311 |doi=10.1086/418170 |s2cid=23738569 |type= Review}}</ref>  This hypothesis held that menstruation protected the uterus against [[pathogen]]s introduced by [[sperm]]. Hypothesis 1 does not take into account that [[Sexual intercourse|copulation]] can take place weeks before menstruation and that potentially infectious [[semen]] is not controlled by menstruation in other species.<ref name=Emera2012/>
# Energy conservation.<ref name="pmid9618925"/><ref name="pmid8693059">{{cite journal |vauthors=Strassmann BI |title=The evolution of endometrial cycles and menstruation |journal=The Quarterly Review of Biology |volume=71 |issue=2 |pages=181–220 |date=June 1996 |pmid=8693059 |doi=10.1086/419369 |s2cid=6207295 |type= Review}}</ref> This hypothesis claimed that it took less energy to rebuild a uterine lining than to maintain it if pregnancy did not occur.  Hypothesis&nbsp;2 does not explain other species that also do not maintain a uterine lining but do not menstruate.<ref name= Emera2012/>
# A theory based on spontaneous decidualization (a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy). Decidualization leads to the differentiation of the endometrial stroma, which involves cells of the immune system,<ref name="pmid32129461">{{cite journal |vauthors=Catalini L, Fedder J |title=Characteristics of the endometrium in menstruating species: lessons learned from the animal kingdom† |journal=Biology of Reproduction |volume=102 |issue=6 |pages=1160–1169 |date=May 2020 |pmid=32129461 |pmc=7253787 |doi=10.1093/biolre/ioaa029 |type= Journal article}}</ref> the formation of a new blood supply, hormones and tissue differentiation. In non-menstruating mammals, decidualization is driven by the embryo, not the mother.<ref>{{Cite journal |last1=Muter |first1=Joanne |last2=Kong |first2=Chow-Seng |last3=Brosens |first3=Jan J. |date=2021-12-23 |title=The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage |journal=Frontiers in Reproductive Health |language=English |volume=3 |doi=10.3389/frph.2021.804921 |doi-access=free |pmid=36303960 |pmc=9580781 |issn=2673-3153}}</ref> According to this theory, menstruation is an unintended consequence of the decidualization process and the body uses spontaneous decidualization to identify and reject defective embryos early on.<ref name=":0">{{Cite journal |last1=Teklenburg |first1=Gijs |last2=Salker |first2=Madhuri |last3=Molokhia |first3=Mariam |last4=Lavery |first4=Stuart |last5=Trew |first5=Geoffrey |last6=Aojanepong |first6=Tepchongchit |last7=Mardon |first7=Helen J. |last8=Lokugamage |first8=Amali U. |last9=Rai |first9=Raj |last10=Landles |first10=Christian |last11=Roelen |first11=Bernard A. J. |last12=Quenby |first12=Siobhan |last13=Kuijk |first13=Ewart W. |last14=Kavelaars |first14=Annemieke |last15=Heijnen |first15=Cobi J. |date=2010-04-21 |title=Natural Selection of Human Embryos: Decidualizing Endometrial Stromal Cells Serve as Sensors of Embryo Quality upon Implantation |journal=PLOS ONE |volume=5 |issue=4 |pages=e10258 |doi=10.1371/journal.pone.0010258 |doi-access=free |issn=1932-6203 |pmc=2858159 |pmid=20422011|bibcode=2010PLoSO...510258T }}</ref> This process happens because the decidual cells of the stroma can recognize and respond to defects in a developing embryo by stopping the secretion of [[cytokine]]s needed for the embryo to implant.<ref name=":0" />
# Uterine pre-conditioning.<ref name="pmid19136085">{{cite journal |vauthors=Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA |title=A role for menstruation in preconditioning the uterus for successful pregnancy |journal=American Journal of Obstetrics and Gynecology |volume=200 |issue=6 |pages=615.e1–6 |date=June 2009 |pmid=19136085 |doi=10.1016/j.ajog.2008.11.037 |type= Journal article}}</ref> This hypothesis claims that a monthly pre-conditioning of the uterus is needed in species, such as humans, that have deeply invasive (deep-rooted) [[placenta]]s. In the process leading to the formation of a placenta, maternal tissues are invaded. This hypothesis holds that menstruation was not evolutionary, rather the result of a coincidental pre-conditioning of the uterus to protect uterine tissue from the deeply rooting placenta, in which a thicker endometrium develops.<ref name="pmid19136085"/> Hypothesis&nbsp;4 does not explain menstruation in non-primates.<ref name=Emera2012/>

== Notes ==
{{Notelist}}

== References ==
{{Reflist}}

=== Book sources ===
{{Refbegin|30em}}
* {{cite book|title= The Psychology of Women and Gender: Half the Human Experience +|vauthors= Else-Quest N, Hyde JS |location= Los Angeles |publisher= [[SAGE Publishing]]|date= 2021 |edition = 10th |isbn= 978-1-544-39360-5 |chapter= Psychology, gender, and health: psychological aspects of the menstrual cycle }}
* {{cite book | vauthors=Johnson MH | title=Essential Reproduction | publisher=[[Wiley-Blackwell]] | publication-place=[[Malden, Massachusetts]]| year=2007 | isbn=978-1-4051-1866-8 | oclc=76074156 }}
* {{cite book| vauthors= Norris DA, Carr JA|title=Vertebrate Endocrinology|date=2013|publisher=[[Academic Press]]|isbn=978-0-123-96465-6|edition=5th}}
* {{cite book | vauthors= Parker S | title=The Concise Human Body Book: An Illustrated Guide to its Structures, Function and Disorders | publisher=[[DK (publisher)|DK]] | publication-place=London | year=2019 | isbn=978-0-241-39552-3 | oclc=1091644711}}
* {{cite book |vauthors=[[Jerilynn Prior|Prior JC]]| veditors = Ussher JM, Chrisler JC, Perz J |title=Routledge International Handbook of Women's Sexual and Reproductive Health |publisher=[[Routledge]] |edition= 1st|date=2020 |chapter=The menstrual cycle: its biology in the context of silent ovulatory disturbances |isbn= 978-1-138-49026-0 |location=[[Abingdon, Oxon]]|oclc=1121130010}}
* {{cite book | vauthors=Rodriguez-Landa J | title=A Multidisciplinary Look at Menopause | publisher=IntechOpen | publication-place= [[Rijeka, Croatia]]| year=2017 | isbn=978-953-51-3405-3 | oclc=1193045564}}
* {{cite book |vauthors=Sadler TW | title=Langman's Medical Embryology | publisher=[[Wolters Kluwer]] | location=Philadelphia | year=2019 | isbn=978-1-4963-8390-7 | oclc=1042400100}}
* {{cite book | vauthors= Sherwood L| title=Human Physiology: From Cells to Systems | publisher=[[Cengage]] Learning | publication-place=Boston, Massachusetts | year=2016 | isbn=978-1-285-86693-2 | oclc=905848832}}
* {{cite book | vauthors= Tortora G| title=Tortora's Principles of Anatomy & Physiology | publisher=[[Wiley (publisher)|John Wiley & Sons, Inc]] | publication-place=[[Hoboken, New Jersey]]| year=2017 | isbn=978-1-119-38292-8 | oclc=990424568}}
* {{cite book |vauthors=Ugwumadu A | title=Basic Sciences for Obstetrics and Gynaecology: Core Material for MRCOG | publisher=[[Oxford University Press]] | publication-place=Oxford, England | year=2014 | isbn=978-0-19-953508-8 | oclc=889303297}}
* {{cite book | vauthors=Watchman T | title=Zero to Finals : Obstetrics and Gynaecology | publisher=Zero to Finals | publication-place=Manchester | year=2020 | isbn=979-8-6037-9726-7 | oclc=1233034578}}
{{Refend}}

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